Multi-slice computed tomography assessment of bronchial compression with absent pulmonary valve.

BACKGROUND: Absent pulmonary valve is a rare cardiovascular anomaly that can result in profound tracheobronchial compression. OBJECTIVE: To demonstrate the advantage of multi-slice CT in diagnosing tracheobronchial compression, its severity as related to the adjacent dilated pulmonary arteries, and associated lung and cardiac lesions. MATERIALS AND METHODS: We included children with absent pulmonary valve who were reviewed by multi-slice CT during a 17-year period. The number and locations of stenoses and lung lesions were noted and the severity of stenosis was categorized. The diameter of the pulmonary artery was measured and associated cardiac defects were demonstrated. RESULTS: Thirty-one children (14 girls and 17 boys) were included. Of these, 29 had ventricular septal defect and 2 had an intact ventricular septum. Twenty-nine children (94%) had tracheobronchial compression, judged to be mild in nine children (31%), moderate in 10 (34%) and severe in 10 (34%). The different locations of the stenosis (carina, main bronchi, lobar and segmental bronchi) were observed. And the number and location of lung lesions demonstrated that the right middle and left upper and lower lobes were often affected. The diameter of the pulmonary artery in these children was well above normal published values, and Spearman rank correlation analysis showed a correlation between the size of the pulmonary artery and the severity of the tracheobronchial stenosis. Nineteen children (61%) underwent surgery and 4 of these children had a multi-slice CT post-operative follow-up study. CONCLUSION: Absent pulmonary valve can cause significant morbidity and mortality in children. Multi-slice CT can accurately depict areas of tracheobronchial compression, associated lung lesions and cardiac defects, helping to direct the surgeon.

[Surgical repair of truncus arteriosus in children: early results and long-term outcomes].

OBJECTIVE: To recite early results and long-term outcomes after surgical repair of persistent truncus arteriosus (PTA). METHODS: The clinic data of 54 patients underwent surgical repair for PTA from January 1999 to December 2009 was analyzed retrospectively. There were 36 male and 18 female patients, with a mean age of (9 ± 10) months (range, 1 to 38 months; median, 5 months). Preoperative mechanical ventilation was required in 5 patients. The surgical procedures were closure of ventricular septal defect and re-establishment of continuity between right ventricle and pulmonary artery. The right ventricular outflow tract (RVOT) was reconstructed by direct anastomosis pulmonary artery to right ventriculotomy with anterior wall patch enlargement (28 cases), or by inserting conduits (26 cases). Valvuloplasty were performed in 4 patients with truncal valves moderate to severe insufficiency and aortoplasty in 3 patients with interrupted aortic arch (IAA). RESULTS: There were 3 patients (5.6%) died of pulmonary hypertensive crisis in hospital. The mean duration of ventilation was 6.8 days in 5 patients who were intubated before operation, while the others were 3.6 days. Forty-seven (92.2%) patients were followed-up for mean (6.8 ± 2.5) years (from 2.5 to 11.0 years). There were 2 patients with mild to moderate aortic regurgitation. One patient with aortic arch obstruction underwent balloon dilatation 2 years postoperatively. Among those patients who underwent direct anastomoses, 8 (32.0%) patients had pulmonary branch stenosis at 7 months to 1.5 years postoperatively, 12 (48.0%) patients were freedom from surgical reintervention 5.0 to 11.0 years postoperatively. Among those inserting conduits, 7 patients (31.8%) had conduit stenosis at 2.8 to 7.0 years after operation. Reoperations were performed for RVOT in 15 patients and there was no mortality. CONCLUSIONS: It is difficult to treat the PTA patients with IAA, intra-mural coronary artery or mechanical ventilation support before operation. The technique of direct anastomosis between pulmonary artery and right ventricle offers the potential growth for RVOT, but bilateral pulmonary branch stenosis may be occurred at earlier period of postoperation in some patients.

[Treatment strategies for pediatric patients with primary cardiac tumors].

OBJECTIVE: To analyze the experience of treatment strategies for pediatric patients with primary cardiac tumors. METHODS: The clinical data of 27 patients with primary cardiac tumors which detected by echocardiography from May 1999 to May 2009 was analyzed retrospectively. There were 20 male and 7 female patients, aged from 24 d to 12.6 years. There were 59.2% less than 1 year old at the time of diagnosis. A single tumor were present in 22 cases and multiple in 5 cases. Surgery was performed for 22 patients due to the varied significant symptoms such as arrhythmia, pericardial effusion, swoon and congestive heart failure with dyspnoea. Five patients were discharged hospital without surgical treatment. The surgical approaches were adopted according to tumor location. Complete surgical resection was performed in 14 patients and partial resection in 8 patients. Seven patients were underwent valve reconstruction, 5 involving the mitral valve and 2 involving the tricuspid valve. RESULTS: Histologic examination of the surgically resected tumors showed rhabdomyomas in 8 cases, fibromas in 5 cases, hemangiomas 3 cases, myxomas in 4 cases, fibrosarcoma in 1 case and yolk sac sarcoma in 1 case. Sixteen cases revealed stable haemodynamic status postoperative. Two cases occurred apparent symptoms of low cardiac output and significant arrhythmias, finally recovery after comprehensive treatment of restoration the heart function. There was a total of 4 patients in-hospital death following surgery due to multiorgan system failure. Of the 18 patients who survived after the surgery were followed up from 1 to 10 years, echocardiography showed the residual mass of the tumor with partial resection, rhabdomyoma diminishing in 2 patients and almost vanishing in 1 patient. The residual mass of one fibrosarcoma patient and one hemangioma patient were not increased. Patients with myxomas had no recur or systemic embolisation after the initial surgery. Five nonsurgical patients were followed up from 1 to 3 years, 2 patients without haemodynamic alterations, 1 patients with giant tumor of left ventricular free wall was died of arrhythmia, the other one was alive; the patient of multiple cardiac tumor with low cardiac output was died of heart failure. CONCLUSIONS: Despite the benign histology of most paediatric primary cardiac tumours, there may be significant associated with morbidity and occasional mortality. Therapy strategies should be individualised: surgery is indicated in cases with significant clinical symptoms and close follow-up is necessary for asymptomatic patients. Total resection is not the only therapeutic aim. Most important is the restoration of the normal haemodynamic heart function.

[Judgement of the left ventricle retraining in the rapid two stage-switch operation].

OBJECTIVES: To Summarize the results of left ventricle retraining in rapid two-stage switch operation and to determine the estimating index of left ventricle retraining and the best time of the second stage operation. METHODS: From September 2002 to September 2007, 21 patients underwent rapid two stage switch operation. There were 13 male and 8 female patients, ageing from 29 to 250 d [mean (103 ± 69) d, median 75 d], weighting from 3.5 to 7.0 kg [mean (5.0 ± 1.2) kg, median 5.0 kg]. After pulmonary band, bedside echocardiography was regularly done every other day. Paired t-test was used to analyze the changes of left ventricular end-diastolic dimension (LVDd), left ventricular posterior wall dimensions (LVPWd), diastolic intra-ventricular septal dimensions (IVSd), left ventricular (LV) mass and LV mass indexed for body surface area. RESULTS: The mean interval was (9 ± 5) d. After the left ventricle preparative operation, the left ventricular to right ventricular pressure ratio (pLV/RV) raised from 0.47 ± 0.15 to 0.91 ± 0.20 (P < 0.01). LV mass indexed for body surface area raised from (30 ± 11) g/m(2) to (60 ± 20) g/m(2) (P < 0.01). Extremely significant difference of LV mass existed between pre-arterial switch operation and pre-left ventricle preparative operation, and significant difference existed in LVDd, LVDd(3), LVPWd and IVSd between the two operative timing points. CONCLUSIONS: The left ventricular function of the transposition of the great arteries can be retraining by the left ventricle preparative operation. The interval of left ventricle retraining should be controlled in 7 to 10 d, and the pLV/RV reach 0.65 and the LV mass index over 50 g/m(2) are two important indicators of the second stage operation of arterial switch operation.

[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.

[Effect of prone or spine position on mechanically ventilated neonates after cardiac surgery with acute lung injury].

OBJECTIVE: To compare the efficacy and safety ventilated with pressure support ventilation (PSV) or neurally adjusted ventilatory assist (NAVA) in neonates undergoing open-heart surgery with acute lung injury (ALI) in spine and prone positions. METHODS: Fifteen neonates with a mean age of (15 +/- 9) days and a mean weight of (3.5 +/- 0.6) kg underwent open-heart surgery with ALI from July to December in 2009 were enrolled in this study. After hemodynamic stabilization ventilated with pressure regulated volume control (PRVC-base), all cases were ventilated with PSV and NAVA both in spine (SP) and prone (PP) positions for 60 minutes in a randomized crossover trial respectively. The hemodynamics, blood gas analysis, airway pressure, electrical activity of diaphragm (EAdi) and asynchrony index (AI) during every mode were recorded. RESULTS: The heart rate, systolic blood pressure and central venous pressure were stable in every mode. The peak inspiratory pressure and mean airway pressure in every mode had no significant difference but were significantly lower than in PRVC-base either in spine or prone position. The respiratory rate in PSV and NAVA with prone position was more rapid than in spine position and in PRVC-base (P < 0.05). But there was no significant difference in minute ventilation (MV) for each mode. The oxygenation index was higher in NAVA or PSV in both positions versus PRVC-base [(200 +/- 60) mm Hg in PRVC-base, (272 +/- 76) mm Hg in PSV-SP, (308 +/- 90) mm Hg in PSV-PP, (347 +/- 84) mm Hg in NAVA-SP and (365 +/- 87) mm Hg in NAVA-PP respectively, P < 0.01]. The oxygenation index was significantly higher in NAVA-PP than in PSV-SP (P < 0.05) while PaCO(2) was in normal range and had no significant difference for any mode. The minimal EAdi in NAVA-PP was significant lower than that in PSV-SP [(0.2 +/- 0.1) microV vs (0.5 +/- 0.2) microV, P < 0.05]. The AI of NAVA either in spine or in prone position was 0. It was significantly lower than that in PSV-SP [(21.5 +/- 4.8)%, P < 0.01] and PSV-PP [(22.4 +/- 3.4)%, P < 0.01]. CONCLUSION: Especially in a prone position, NAVA demonstrates a better synchrony in ALI neonates after cardiac surgery. It helps to provide a better oxygenation for the patients.

Neonatal surgical outcomes after prenatal diagnosis of complex congenital heart disease: experiences of a perinatal integrated diagnosis and treatment program.

BACKGROUND: This study aimed to evaluate neonatal surgical outcomes of patients diagnosed with complex congenital heart disease (CHD) during pregnancy and treated by the newly initiated "perinatal integrated diagnosis and treatment program (PIDTP)". METHODS: We reviewed clinical data of 207 neonates (surgical age ≤ 28 days) who underwent cardiac surgeries in a single center from January 2017 to December 2018, including 31 patients with referrals from the "PIDTP" (integration group) and 176 patients with routine referral treatment (non-integrated group). RESULTS: In the integration group, median admission age was 0 days and median age at surgery was 4 days. In the non-integrated group, median admission age was 8 days (P = 0.001) and median age at surgery was 13 days (P = 0.001). The emergency surgery rate in patients with duct-dependent defects was 36% in the integration group and 59% (P = 0.042) in the non-integrated group, respectively. The in-hospital mortality was 16% in the integration group and 14% (P = 0.78) in the non-integrated group. The 2-year cumulative survival rate after surgery was 83.9% ± 6.6% in the integration group and 80.3% ± 3.1% (P = 0.744) in the non-integrated group. According to multivariable regression analysis, independent risk factors for early mortality of overall neonatal cardiac surgery were low body weight, high serum lactate level, postoperative extracorporeal membrane oxygenation (ECMO) support and prolonged cardiopulmonary bypass (CPB) time. CONCLUSIONS: PIDTP shortens the postnatal transit interval, reduces the emergency operation rate of neonatal critical CHD, and provides better preoperative status for surgery. Patients treated by the PIDTP tend to have more complicated anatomical deformity and a greater requirement for the operation and postoperative management, but early outcome and follow-up prognosis are satisfactory.

[Outcome of oral bosentan in children with congenital heart disease associated pulmonary arterial hypertension].

OBJECTIVE: To investigate the outcome of dual endothelin receptor antagonist bosentan in children with congenital heart disease (CHD) associated pulmonary arterial hypertension (PAH). METHODS: A total of 32 children were recruited into this prospective and observational study. Among them, there were 18 cases with left-to-right shunt and 14 cases with elevated pulmonary vascular resistance (PVR) in functional single ventricle (FSV). All the cases were treated with oral bosentan, initiated from 90 days before or 8 years after operation, and were followed up periodically to analyze the clinical outcome and monitor its side effects. RESULTS: In the left-to-right shunt group, pulmonary arterial pressure (PAP) was measured at (57 +/- 26), (52 +/- 31) and (46 +/- 22) mm Hg after oral bosentan therapy at 1, 2 and 3 months respectively. The measurements significantly decreased as compared with the pre-dosing level of (74 +/- 15) mm Hg (P < 0.05). After a 3-months therapy of bosentan, World Health Organization functional class (WHO FC) improved significantly (P < 0.01). In the elder cases, the 6-minute walking distance after a 3-month bosentan therapy significantly increased as compared with the pre-dosing level, i. e. (497 +/- 56) vs (424 +/- 31) m (P < 0.05). In the FSV group, as compared with the pre-dosing level, the transcutaneous oxygen saturation increased significantly in the last follow-up during bosentan exposure, i. e. (86 +/- 5)% vs (78 +/- 6)% (P < 0.01). WHO FC improved significantly (P < 0.01) and the incidence of facial edema and pleural effusion was significant lower (P < 0.05) in the last follow-up for the treatment group. Patients tolerated bosentan well and no significant rise in hepatic transaminases was observed. CONCLUSIONS: Bosentan is safe in treating CHD associated PAH in children. In left-to-right shunt cases, oral bosentan can reduce PAP and improve both WHO FC and exercise capacity. And it can also improve WHO FC and transcutaneous oxygen saturation in FSV and reduces the occurrence of elevated PVR-related complications.

[Application of neurally adjusted ventilatory assist in infants who underwent cardiac surgery for congenital heart disease].

OBJECTIVE: Neurally adjusted ventilatory assist (NAVA) is a new mode of mechanical ventilation that delivers ventilatory assist in proportion to neural effort. This study aimed to compare the hemodynamic safety, oxygenation and gas exchange effects ventilated with NAVA and with pressure support ventilation (PSV) in infants who underwent open-heart surgery. METHODS: Twenty-one infants who underwent open-heart surgery for congenital heart disease (mean age 2.9+/- 2.1 months and mean weight 4.2+/- 1.4 kg) were enrolled. They were ventilated with PSV and NAVA for 60 minutes respectively in a randomized order. The hemodynamic, oxygenation and gas exchange effects produced by the two ventilation modes were compared. RESULTS: Three cases failed to shift to NAVA because of the bilateral diaphragmatic paralysis after operation. In the other 18 cases, there were no significant differences in the heart rate (HR), systolic blood pressure (BPs) and central venous pressure (CVP) in the two ventilation modes. The PaO2/FiO2 (P/F) ratio in NAVA was slightly higher than in PSV, but there was no statistical difference. PaCO2 did not show significant differences in the two modes. The peak inspiratory pressure (PIP) and electrical activity of the diaphragm (EAdi) in NAVA were significantly lower than in PSV. The EAdi signal after extubation was higher in infants who needed reintubation or intervention of noninvasive mechanical ventilation than in those who were extubated successfully (30.0+/- 8.4 microV vs 11.1+/- 3.6 microV; P<0.01). CONCLUSIONS: As the first study of application of NAVA in infants in China, this study shows that NAVA has the same homodynamic effects as PSV. However the PIP for maintaining the same level of PaCO2 in NAVA is significantly lower than that in the traditional PSV. Monitoring the EAdi signal after extubation may show the risks of reintubation or intervention of noninvasive mechanical ventilation.

Transcriptional repression of O6-methylguanine DNA methyltransferase gene rendering cells hypersensitive to N,N'-bis(2-chloroethyl)-N-nitrosurea in camptothecin-resistant cells.

O(6)-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that removes alkyl-adducts from the O(6)-guanine in DNA and is a crucial defense against O(6)-alkylating agent-induced cytotoxicity. We demonstrated here that two camptothecin (CPT)-resistant cell lines (CPT30 and KB100) were more sensitive to N,N'-bis(2-chloroethyl)-N-nitrosurea (BCNU) than their parental cells. Enhanced sensitivity to BCNU in these two CPT-resistant cells involved transcriptional repression of the MGMT gene. The mechanism of MGMT gene down-regulation in CPT-resistant cells was not through gene abnormality, mRNA stability, and CpG island hypermethylation. However, the high level of methyl-CpG-binding protein 2 (MeCP2) and dimethylation of H3K9 in the promoter region were found in CPT30 and KB100 cells. Furthermore, increased MeCP2 binding on MGMT promoter was also found to be correlated with MGMT gene-silencing in short-term CPT treatment; thus, enhanced BCNU sensitivity was found in CPT-treated cells. Taken together, we suggest that CPT is able to suppress the transcription of the MGMT gene through recruiting of MeCP2 and H3K9 dimethylation, thus causing a synergistic interaction with BCNU. These findings provide a possible explanation regarding why the combination of CPT and BCNU results in a better objective response than single-use alone. In addition, this study supports a new indication for treating patients who are receiving refractory CPT derivatives with BCNU.

Arterial switch operation with coronary arteries from a single sinus in infants.

BACKGROUND: The implantation of a coronary artery (CA) is critical for the arterial switch operation (ASO) done to treat complete transposition of the great arteries (TGA). Coronary artery abnormalities are risk factors for both early and late mortality after surgery. In this study, the methodology and effects of ASO surgery with coronary arteries from a single sinus were evaluated. METHODS AND RESULTS: From March 1999 to June 2006, 31 patients were treated with ASO with coronary arteries from a single sinus in our hospital. They aged 11 hours 16 months (2.8 +/- 3.9 months) and weighted 2.3 7.8 Kg (3.1 +/- 2.5 Kg). 27 cases had TGA and a ventricular septal defect (VSD), and 4 had TGA and an intact ventricular septum (IVS). During surgery, a CA button was implanted in the new proximal aorta with "trapdoor" technique or by inverting 90 degrees dorsally; pericardium or arterial augmentation was implanted at the base of the new major artery. The mortality rate after surgery was 25.8%. After 2-5 years of follow-up, 2 cases with residual shunting recovered spontaneously, 2 cases had residual pulmonary artery obstruction (30-56 mmHg), and none of the patients had any significant changes in myocardial ischemia. CONCLUSION: The implantation of an abnormal coronary artery is practical and feasible; it can reduce both the occurrence of twisting and deforming in the coronary artery after implantation, as well as myocardial ischemia after surgery. Thus, this could improve the surgical success and cure rates.

Use of the lecompte procedure for ventriculoarterial connection abnormalities in infants and children with congenital heart diseases.

BACKGROUND: The Lecompte (REV) procedure is used to correct abnormal ventriculoarterial connections in patients with congenital heart diseases; it avoids the need for an extracardiac conduit for pulmonary outflow tract reconstruction. The present study aimed to investigate effectiveness and criteria of the REV procedure in children with abnormal ventriculoarterial connections. METHODS: Thirty-eight children (mean age, (2.2 +/- 1.7) years; mean weight, (11.5 +/- 3.8) kg) with abnormal ventriculoarterial connections who had an REV procedure in our hospital from January 1998 to May 2006 were studied. Only 10 patients had the usual anteroposterior relationship of the two great arteries. The infundibular septum between the two semilunar valves was aggressively resected to enlarge it and construct a straighter left ventricular outflow tract and a wide tunnel between the ventricular septal defect (VSD) and the aorta. Eighteen cases had the original REV procedure; 20 had a modified REV procedure. RESULTS: All patients are alive; none developed severe complications. The postoperative right ventricular (RV) to left ventricular (LV) pressure ratio was 0.20-0.45. Five patients had RV dysfunction; 2 patients had a pressure gradient in the RV ventricular outlet of 30.0-34.5 mmHg; 3 cases had a 37.5-47.3 mmHg pressure difference in the RPA. All patients had an RV pressure less than half the systemic pressure. These gradients' magnitudes in all patients were consistent with the post-operative RV to LV pressure ratio (P < 0.05). During the follow-up (mean, (4.2 +/- 0.6) years), 2 patients had an RPA pressure gradient of 24.0-29.3 mmHg which abated to less than 10 mmHg after two years. CONCLUSIONS: The REV procedure provides satisfactory short- to medium-term results. It may be superior to the Rastelli procedure for treating ventriculoarterial connection abnormalities; it allows early, complete anatomic repair and reduces the need for late re-operation, since no extracardiac conduit is needed. Longer follow-up is needed to determine long-term outcomes.

[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

Tamoxifen accelerates proteasomal degradation of O6-methylguanine DNA methyltransferase in human cancer cells.

Tamoxifen, a synthetic triphenyl-ethylene compound, is a member of a class of anticancer drugs known as selective estrogen receptor modulators. It may block tumor growth by mimicking estrogen and binding to the estrogen receptors, preventing cancerous growth. Clinical studies have demonstrated that a combination chemo/hormonal therapy regimen with tamoxifen and O(6)-alkylating drugs increased the tumor response rate in cancer patients. The mechanism of action of this combined regimen remains undefined. In this study, we demonstrated that treatment of human colorectal HT-29 carcinoma cells with tamoxifen decreased the repair activity and expression level of O(6)-methylguanine DNA methyltransferase (MGMT) protein in a concentration- and time-dependent manner. This inhibition was also shown in other malignant human cells, regardless of their estrogen receptor status. Furthermore, MGMT inactivation by tamoxifen was associated with a significantly increased susceptibility of cells to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). No alteration in MGMT mRNA levels was observed in tamoxifen-treated cells. The half-life of MGMT protein was markedly decreased in the presence of tamoxifen. Tamoxifen-induced MGMT degradation could be blocked by MG-132, a proteasome inhibitor. An increased level of ubiquitinated MGMT protein was found after tamoxifen treatment. We conclude that tamoxifen decreased the MGMT protein level by accelerating protein degradation through the ubiquitin-dependent proteasomal pathway. These findings provide a strong rationale for combined chemo/hormonal therapy with tamoxifen and BCNU in the treatment of human cancers.

[Analysis surgical results of 113 patients with complete transposition of the great arteries].

OBJECTIVE: To review and analysis the surgical results of 113 arteries Switch operations. METHODS: One hundred and thirteen patients had been repaired by arterial Switch operation from January 2001 to December 2005. There were 60 patients with transposition of the great arteries and intact ventricular septum (TGA/IVS), 53 patients with transposition of great arteries and ventricular septal defect (TGA/VSD). The lowest body weight was 2.3 kg, and the youngest operative age was 6 h. The arteries Switch operation was performed underwent deep hypothermic circulation arrest and low-flow perfusion. RESULTS: The total mortality was 9.7%. There were 5 deaths among TGA/IVS (8.3%), 6 deaths among TGA/VSD (11.3%). Following improvement of surgical technique, post-operative management and cardiopulmonary bypass, the operative mortality was decreased from 16.6% to 5.5%. CONCLUSIONS: The main reason for operative mortality was abnormal coronary arteries. The incidence of abnormal coronary arteries was high at TGA/VSD. The surgical results was not infected by the position of great arteries. The low cardiac output was appeared if the ratio of left ventricular pressure and right ventricular pressure less than 0.6.

Seven years' experience of pediatric cardiopulmonary bypass: 8685 cases in Shanghai Children's Medical Center.

Herein we report our 7-year-experience of cardiopulmonary bypass. Between April 1, 1999, and December 31, 2005, 8685 children with congenital heart disease underwent cardiopulmonary bypass in Shanghai Children's Medical Center. The number of cases increased every year, and the number of patients younger than 1 year or weighing <10 kg also increased. Different bypass technology was adapted according to the operation. Roller pumps were used for most of the patients. Crystal cardioplegia (St. Thomas II) was used until blood cardioplegia was introduced in 2003. Ultrafiltrators were set up for infants weighing <10 kg. Mortality rates per year ranged from 1.81% to 3.70%. The most frequent complication was low cardiac output, about 12% in recent years. Arrhythmia, infection, and lung complications were the next three most frequent problems after surgery.

Novel mutation of topoisomerase I in rendering cells resistant to camptothecin.

To identify mechanisms of camptothecin (CPT) resistance and the relationship between CPT-resistant cells and other anticancer agents, a CPT-resistant cell line (CPT30) and its partial revertant cell line (CPT30R) were established from a human nasopharyngeal carcinoma cell line (HONE-1). CPT30 and CPT30R cells displayed a 14- and 3.5-fold resistance to CPT compared with HONE-1 cells, respectively. The resistant and partial revertant cell lines showed cross-resistance to topotecan and increased sensitivity to cisplatin, carboplatin, and 1,3-bis(chloroethyl)-1-nitrosurea. The topoisomerase (Top) I catalytic activity of CPT30 and CPT30R cells was 30% and 200%, respectively, compared with that of HONE-1 cells. The expression of Top I protein and mRNA levels in CPT30 cells was 40% and 30% less than that in HONE-1 cells, respectively, whereas in CPT30R cells, the levels of Top I protein and mRNA were 50% and 20% higher, respectively, than that in HONE-1 cells. Both the resistant and revertant cell line whole-cell lysates demonstrated different levels of sensitivity to CPT in in vitro assays in comparison with that of HONE-1 cells. Furthermore, CPT exhibited 15- and 7-fold better binding affinity in stabilizing protein-linked DNA breaks in HONE-1 cells than in CPT30 and CPT30R cells, respectively. Direct DNA sequencing of the reverse transcription-PCR product and genomic DNA revealed a point mutation resulting in E418K mutation in the Top I of both CPT30 and CPT30R cells. Wild-type Top I RNA and genomic DNA were also detected in these two cell lines. A yeast system was used to examine whether this mutation could be responsible for CPT resistance. Our results showed that a single amino acid change (E418K) resulted in CPT resistance. Therefore, quantitative and qualitative changes in Top I were responsible for CPT resistance in CPT30 cells. CPT resistance in CPT30R cells was caused by mutation of Top I.

Dual inhibition of topoisomerase I and tubulin polymerization by BPR0Y007, a novel cytotoxic agent.

Through the screening of DNA topoisomerase I (Top I) inhibitors, a new cytotoxic agent, BPR0Y007 [2,5-bis(4-hydroxy-3-methoxybenzylidene)cyclopentanone], was identified. BPR0Y007 was less potent than camptothecin (CPT) in the inhibition of Top I in vitro. Also, in vitro data showed that BPR0Y007 induces DNA cleavage in the presence of Top I at micromolar concentrations, with a cleavage specificity similar to that of CPT. High concentrations of BPR0Y007 did not produce detectable DNA unwinding, suggesting that BPR0Y007 is not a DNA intercalator. However, BPR0Y007 displaced Hoechst 33342 dye, suggesting that BPR0Y007 binds to DNA at the Hoechst 33342 binding site. Furthermore, BPR0Y007 generated protein-linked DNA breaks in a cell-based study. Cell cycle analysis demonstrated that the cell cycle effect of BPR0Y007 differs from that of CPT. Cells accumulated in the S-phase when treated with high concentrations of CPT, whereas cells accumulated gradually in the G(2)/M phase when treated with increasing concentrations of BPR0Y007. Further studies showed that BPR0Y007 inhibits tubulin polymerization in vivo and in vitro, and induces apoptosis in a concentration-dependent manner. No cross-resistance with BPR0Y007 was observed in CPT-, VP-16-, or vincristine-resistant cell lines. The IC(50) of BPR0Y007 for various human cancer cell lines ranged from 1 to 8 microM. Taken together, these results suggest that BPR0Y007 acts on both Top I and tubulin. Given its unique biochemical mechanisms of action, BPR0Y007 warrants exploration as an antitumor compound.

Azaindolylsulfonamides, with a more selective inhibitory effect on histone deacetylase 6 activity, exhibit antitumor activity in colorectal cancer HCT116 cells.

A series of indolylsulfonylcinnamic hydroxamates has been synthesized. Compound 12, (E)-3-(3-((1H-pyrrolo[2,3-b]pyridin-1-yl)sulfonyl)phenyl)-N-hydroxyacrylamide, which has a 7-azaindole core cap, was shown to have antiproliferative activity against KB, H460, PC3, HSC-3, HONE-1, A549, MCF-7, TSGH, MKN45, HT29, and HCT116 human cancer cell lines. Pharmacological studies indicated that 12 functions as a potent HDAC inhibitor with an IC50 value of 0.1 µM. It is highly selective for histone deacetylase 6 (HDAC6) and is 60-fold more active than against HDAC1 and 223-fold more active than against HDAC2. It has a good pharmacokinetic profile with oral bioavailability of 33%. In in vivo efficacy evaluations in colorectal HCT116 xenografts, compound 12 suppresses tumor growth more effectively than SAHA (1, N-hydroxy-N'-phenyloctanediamide) and is therefore seen as a suitable candidate for further investigation.