Blocking ATM-dependent NF-κB pathway overcomes niche protection and improves chemotherapy response in acute lymphoblastic leukemia.

Bone marrow (BM) niche responds to chemotherapy-induced cytokines secreted from acute lymphoblastic leukemia (ALL) cells and protects the residual cells from chemotherapeutics in vivo. However, the underlying molecular mechanisms for the induction of cytokines by chemotherapy remain unknown. Here, we found that chemotherapeutic drugs (e.g., Ara-C, DNR, 6-MP) induced the expression of niche-protecting cytokines (GDF15, CCL3 and CCL4) in both ALL cell lines and primary cells in vitro. The ATM and NF-κB pathways were activated after chemotherapy treatment, and the pharmacological or genetic inhibition of these pathways significantly reversed the cytokine upregulation. Besides, chemotherapy-induced NF-κB activation was dependent on ATM-TRAF6 signaling, and NF-κB transcription factor p65 directly regulated the cytokines expression. Furthermore, we found that both pharmacological and genetic perturbation of ATM and p65 significantly decreased the residual ALL cells after Ara-C treatment in ALL xenograft mouse models. Together, these results demonstrated that ATM-dependent NF-κB activation mediated the cytokines induction by chemotherapy and ALL resistance to chemotherapeutics. Inhibition of ATM-dependent NF-κB pathway can sensitize ALL to chemotherapeutics, providing a new strategy to eradicate residual chemo-resistant ALL cells.

Intraatrial conduit Fontan procedure: indications, operative techniques, and clinical outcomes.

BACKGROUND: The intraatrial conduit (IAC) Fontan procedure is one of the Fontan modifications and is usually not considered the first choice. In this large series, we report our experience of the IAC Fontan procedure for the treatment of a functional single ventricle and review its indications, techniques, and clinical outcomes. METHODS: Between 2009 and 2013, 101 patients with a functional single ventricle underwent an IAC Fontan procedure. The median surgical age was 44 months and weight was 15 kg. The cardiac malformations included tricuspid atresia in 10, double-inlet left ventricle in 8, double-inlet right ventricle in 15, double-outlet right ventricle in 18, congenitally corrected transposition of the great arteries in 11, complete atrioventricular septal defect in 8; criss-cross in 1, pulmonary atresia with intact ventricular septum in 3, Ebstein anomaly in 3, and others in 3. Heterotaxy syndrome was found in 21 patients. An intraatrial polytetrafluoroethylene conduit was implanted to construct the Fontan pathway. In 75 patients, a 2.7-mm to 4.5-mm fenestration was made to reduce the intraconduit pressure. Eighty-three patients had previously undergone a Glenn operation. Median follow-up was 29 months (range, 2 to 60 months). Doppler echocardiography, electrocardiography, and Holter monitoring were used to evaluate hemodynamic performance and arrhythmias. RESULTS: There were 2 hospital deaths, 1 Fontan takedown, and 3 midterm deaths. Conduit thrombosis developed in 1 patient. Atrial flutter developed in 2 patients, who underwent electrical cardioversion. Junctional bradycardia developed in 2 patients, but they did not require permanent pacemakers. Overall survival was 97.0% at 1 year and 94.1% at 5 years. CONCLUSIONS: The IAC modification provides excellent operative and midterm outcomes in most patients with a functional single ventricle. However, a longer follow-up time is required to demonstrate its real advantages.

Usefulness of Deep Hypothermic Circulatory Arrest and Regional Cerebral Perfusion in Children.

To compare the safety and usefulness of deep hypothermic circulatory arrest (DHCA) and regional cerebral perfusion (RCP) during pediatric open heart surgery. Between January 1, 2004 and September 30, 2012, 1250 children with congenital cardiac defect underwent corrective operation with the DHCA or RCP technique in the Shanghai Children's Medical Center. Of them, 947 cases underwent the operation with the aid of DHCA (DHCA group), and 303 cases with RCP (RCP group). The mean DHCA time was 30.64±15.81 (7-63) minutes and mean RCP time was 36.18±12.86 (10-82) minutes. The mortality rate was 7.18% (68/947) and 6.60% (20/30) in two groups, respectively. The postoperative incidences of temporary and permanent neurological dysfunction were 6.23% (59/947) in the DHCA group and 2.64% (8/303) in the RCP group (p<0.01). The incidence of other complications such as low cardiac output, renal dysfunction, and lung issues are similar in both groups. RCP is a reliable technique for cerebral protection and it facilitates time-consuming corrected procedures for complex congenital cardiac defect repair procedures.

[Staged surgical treatment of pulmonary atresia with ventricular septal defect].

OBJECTIVE: To determine the choice of palliative procedures, timing and techniques of second-stage operations. METHODS: Between April 2004 to July 2008, 50 consecutive patients with pulmonary atresia with ventricular septal defect (PA/VSD) underwent two-stage operation. Palliative procedures included modified Blalock-Taussig shunt (n = 5), central shunt (n = 2), pericardial patch enlargement (n = 10), pericardial tube (n = 4) and Gore-Tex conduit (n = 29). The interval period was 7 - 49 months (20.0 +/- 10.0 months). In the second stage, a surgical shunt was interrupted in 7 cases. Ventricular septal defect was closed in all patients, but fenestrated ventricular septal defect patch was used in 6 cases. Right ventricular outlet tract (RVOT) was widened with pericardial patch in 42 cases and conduit exchange in 8 cases. Aortopulmonary collateral arteries (MAPCASs) unifocalization (n = 1), ligation or transcatheter occlusion with embolization coils (n = 4) and maintaining open or untreated (n = 4). RESULTS: Death occurred in 2 and the mortality rate was 4%. Postoperative complications included residual shunt (n = 3), residual obstruction (n = 3), complete AV block (n = 1), athetosis (n = 1) and acute renal failure (n = 3). Neither death nor complication was reported during a follow-up period of 3 months to 4 years. CONCLUSION: A palliative procedure should be individualized to the patient's morphology of central pulmonary artery and clinical status of a patient. Right ventricular outlet tract reconstruction, pulmonary arterioplasty, fenestration of VSD patch in baby with suprasystemic right ventricular pressure and appropriate interventions with MAPCASs are key to decrease the mortality and morbidity of staged operations for PA/VSD.

[Individualized surgical management of pulmonary atresia with intact ventricular septum].

OBJECTIVE: To delineate individualized surgical management strategy for the optimal management of pulmonary atresia with intact ventricular septum (PA/IVS). METHODS: Between 1997 to 2005, 52 consecutive patients with PA/IVS, 31 male and 21 female, aged 2-9, divided into 2 groups according if right ventricle-dependent coronary circulation (RVDCC) existed, underwent individualized surgical treatment. The patients in Group I (with: RVDCC, n = 6) underwent single ventricle repair. Forty-six patients were in Group II (without RVDCC), 13 of which with severe right ventricular hypoplasia (tricuspid valve Z value < -4)underwent single ventricle repair and 33 of which were with mild to moderate right ventricular hypoplasia (Z value > -4). One critical neonate underwent systemic- pulmonary artery shunt. The other 32 of the 33 patients received right ventricular decompression procedures firstly, and 6 of them presented optimal hemodynamics and oxygenation and achieved biventricular repair. If the patients presented unstable hemodynamics or hypoxemia after right ventricular decompression procedure, an additional shunt was added. 13 young infants (0-2 months) underwent additional systemic-pulmonary artery shunt, and 13 patients (> 3 months-old) underwent additional bidirectional cavopulmonary shunt (1.5 ventricular repair)The patients were followed up for 1-10 years. RESULTS: There were 1 early death in Group I and 7 early deaths in Group II. The total early mortality was 15%. A successful definitive repair was achieved in 26 cases (50%). Follow-up reported 3 late deaths. CONCLUSION: Individualized surgical management based on the presence of RVDCC, right ventricular hypoplasia grading, right ventricular growth potential, hemodynamic situation, and oxygen saturation after the decompression procedure is helpful to improve the surgical results of PA/IVS

[The role of graded reoxygenation with cardiopulmonary bypass in prevention of reoxygenation injury and its safety].

OBJECTIVE: To investigate the role of graded reoxygenation with cardiopulmonary bypass (CPB) in prevention of reoxygenation injury in children with cyanotic congenital heart defects, and to evaluate its safety. METHODS: Twenty pediatric patients with cyanotic congenital heart defect were randomly divided into 2 equal groups according to CPB methodology: group 1, undergoing routine hyperoxic CPB with CPB primed and initiated at FiO(2) of 1.0, and group 2 undergoing modified CPB with graded reoxygenation (CPB was primed and initiated at FiO(2) of 0.21 and the FiO(2) was increased slowly to 30% to 60% over the next 5 to 10 minutes). Serum troponin 1 (TnI), S100beta protein, and malondialdehyde (MDA) were measured before CPB, and 1 minute, 5 minutes, and 10 minutes after CPB. Near infrared spectroscopy (NIRS) was applied to evaluate the cerebral oxygenated hemoglobin (HbO(2)) and oxidized cytochrome aa3 (CytOx) and jugular venous lactate was measured during the reoxygenation period. Clinical indexes were observed. RESULTS: Before CPB the TnI, S100beta, and MDA levels in these 2 groups were all normal without significant differences between them. After initiation of CPB the TnI, S100beta, and MDA levels in the two groups began to increase. The serum Tn1 levels 1 minute and 5 minutes after the initiation of CPB of the group 1 were significant lower than those of the group 2 (both P < 0.01). The serum S100beta levels 1, 5, and 10 minutes after the initiation of CPB in the group 2 were all lower than those of the group 1 and there were significant differences between these 2 group 5 and 10 minutes after (both P < 0.05). The serum MDA levels 1, 5, and 10 minutes of the group 1 were significantly higher than those of the group 2 (all P < 0.05). NIRS showed that HbO(2) decreased slightly because of hemodilution when CPB was begun, and then increased rapidly 2 minutes after the initiation of CPB; and CytOx decreased progressively during the reoxygenation period, however, without significant difference between these 2 groups. The serum lactate level was markedly increased 1 minute after the initiation of CPB and then gradually decreased through the reoxygenation period, however, without significant differences between these 2 groups. There was no significant difference between the two groups in clinical observation. CONCLUSION: Not damaging the cerebral aerobic metabolism, graded reoxygenation with CPB can reduce the extent of reoxygenation injury of routine hyperoxic CPB and is an easy, effective, and safe CPB strategy.