Aberrantly low STAT3 and STAT5 responses are associated with poor outcome and an inflammatory gene expression signature in pediatric acute myeloid leukemia.

The relapse rate for children with acute myeloid leukemia is nearly 40% despite aggressive chemotherapy and often stem cell transplant. We sought to understand how environment-induced signaling responses are associated with clinical response to treatment. We previously reported that patients whose AML cells showed low G-CSF-induced STAT3 activation had inferior event-free survival compared to patients with stronger STAT3 responses. Here, we expanded the paradigm to evaluate multiple signaling parameters induced by a more physiological stimulus. We measured STAT3, STAT5 and ERK1/2 responses to G-CSF and to stromal cell-conditioned medium for 113 patients enrolled on COG trials AAML03P1 and AAML0531. Low inducible STAT3 activity was independently associated with inferior event-free survival in multivariate analyses. For inducible STAT5 activity, those with the lowest and highest responses had inferior event-free survival, compared to patients with intermediate STAT5 responses. Using existing RNA-sequencing data, we compared gene expression profiles for patients with low inducible STAT3/5 activation with those for patients with higher inducible STAT3/5 signaling. Genes encoding hematopoietic factors and mitochondrial respiratory chain subunits were overexpressed in the low STAT3/5 response groups, implicating inflammatory and metabolic pathways as potential mechanisms of chemotherapy resistance. We validated the prognostic relevance of individual genes from the low STAT3/5 response signature in a large independent cohort of pediatric AML patients. These findings provide novel insights into interactions between AML cells and the microenvironment that are associated with treatment failure and could be targeted for therapeutic interventions.

In vitro effect of dexmedetomidine on the respiratory burst of neutrophils.

The immunosuppressive effects of dexmedetomidine, a highly selective and widely used a2-adrenoceptor agonist for sedation, analgesia, and stress management, are investigated in vitro. In the present study, the respiratory burst of human neutrophils separated from venous blood was evaluated with dexmedetomidine treatment after Escherichia coli stimulation. The effects of five concentrations of dexmedetomidine (1, 5, 10, 50, 100 µg/mL) were evaluated by rhodamine in a flow cytometer. The nitric oxide (NO) production and nitric oxide synthase (iNOS) activity were also determined by using commercial kits. The results were compared to the positive control responses (respiratory burst without drug). We found that dexmedetomidine significantly suppressed respiratory burst, NO production, and iNOS activity after stimulation with E. coli, in a dose-dependent manner. The suppressive effects of dexmedetomidine on phagocytic activity of human neutrophils were associated with respiratory burst coupled with NO production.

Histidine-tryptophan-ketoglutarate solution decreases mortality and morbidity in high-risk patients with severe pulmonary arterial hypertension associated with complex congenital heart disease: an 11-year experience from a single institution.

Cardioplegic reperfusion during a long term ischemic period interrupts cardiac surgery and also increases cellular edema due to repeated solution administration. We reviewed the clinical experiences on myocardial protection of a single perfusion with histidine-tryptophan-ketoglutarate (HTK) for high-risk patients with severe pulmonary arterial hypertension associated with complex congenital heart disease. This retrospective study included 101 high-risk patients undergoing arterial switch operation between March 2001 and July 2012. We divided the cohort into two groups: HTK group, myocardial protection was carried out with one single perfusion with HTK solution; and St group, myocardial protection with conventional St. Thomas' crystalloid cardioplegic solution. The duration of cardiopulmonary bypass did not differ between the two groups. The mortality, morbidity, ICU stay, post-operative hospitalization time, and number of transfusions in HTK group were lower than those in St group (P<0.05). Univariate and multivariate analysis showed that HTK is a statistically significant independent predictor of decreased early mortality and morbidity (P<0.05). In conclusion, HTK solution seems to be an effective and safe alternative to St. Thomas' solution for cardioplegic reperfusion in high-risk patients with complex congenital heart disease.

Histidine-tryptophan-ketoglutarate solution decreases mortality and morbidity in high-risk patients with severe pulmonary arterial hypertension associated with complex congenital heart disease: an 11-year experience from a single institution

Cardioplegic reperfusion during a long term ischemic period interrupts cardiac surgery and also increases cellular edema due to repeated solution administration. We reviewed the clinical experiences on myocardial protection of a single perfusion with histidine-tryptophan-ketoglutarate (HTK) for high-risk patients with severe pulmonary arterial hypertension associated with complex congenital heart disease. This retrospective study included 101 high-risk patients undergoing arterial switch operation between March 2001 and July 2012. We divided the cohort into two groups: HTK group, myocardial protection was carried out with one single perfusion with HTK solution; and St group, myocardial protection with conventional St. Thomas' crystalloid cardioplegic solution. The duration of cardiopulmonary bypass did not differ between the two groups. The mortality, morbidity, ICU stay, post-operative hospitalization time, and number of transfusions in HTK group were lower than those in St group (P<0.05). Univariate and multivariate analysis showed that HTK is a statistically significant independent predictor of decreased early mortality and morbidity (P<0.05). In conclusion, HTK solution seems to be an effective and safe alternative to St. Thomas' solution for cardioplegic reperfusion in high-risk patients with complex congenital heart disease.

Unsuspected gallbladder carcinoma discovered during or after cholecystectomy: focus on appropriate radical re-resection according to the T-stage.

BACKGROUND: The long-term survival of patients with unsuspected gallbladder carcinoma (UGC) and the role of radical re-resection for this disease remain unclear. METHODS: A retrospective study was carried out on 38 UGC patients. The time-to-event data were demonstrated by Kaplan-Meier curves. Comparing survival curves of two groups using the log-rank test. RESULTS: The overall incidence of UGC in patients underwent cholecystectomy in our hospital was 0.18 % (25 of 14,073). Distribution according to actual pT-stage (the UICC) was: pT1a: n = 3; pT1b: n = 11; pT2: n = 4; pT3: n = 12; pT4: n = 8. The preoperative diagnosis included a high rate of acute biliary tract inflammation (24 of 38, 63.2 %). Compared with other gallbladder carcinoma patients, UGC group had significantly higher proportion of early stages (pT1) (36.8 %, 14 of 38 cases) (p < 0.01), and better prognosis. The comparison of radical re-resection versus simple cholecystectomy showed a significant benefit in overall survival for the pT3 group (22.0 ± 5.48 vs. 5.0 ± 0.9 months; p = 0.02). There are median survival differences between the two subgroups of patients with pT1b tumors whether received re-resection or not. Median survival was 62.0 months and 24.0 ± 8.5 months, respectively, though the differences are not statistically significant (p = 0.131). CONCLUSION: Radical re-resection is strongly recommended for patients with pT1b-stage cancer. The reoperation should be performed as soon as possible, preferably within 10 days after the initial operation.