The Supported vs Unsupported Ross in Pediatric Patients: Neoaortic Root and Ventricular Function.

BACKGROUND: The supported Ross is used to mitigate the neoaortic root dilation that has been described with the unsupported Ross. There is limited literature assessing the efficacy of the supported Ross in young patients. In this study, the fate of the neoaortic root was compared in the supported and unsupported Ross procedure in adolescent patients. METHODS: A retrospective review was performed of patients who underwent the Ross procedure between 1996 and 2019. An analysis was conducted of patients aged 10 to 18 years who underwent the supported and unsupported Ross operation, without a Konno enlargement, to assess for longitudinal echocardiographic changes. Given differences in follow-up time, both regression analysis and Mann-Whitney nonparametric tests were used to correct for time from discharge to most recent follow-up. RESULTS: The median follow-up time for supported and unsupported Ross patients without a Konno enlargement was 2.90 years (0.21-13.03 years) and 12.13 years (2.63-19.47 years), respectively. Unsupported Ross patients experienced a higher rate of change per year in the aortic annulus (P = .003 and P = .014) and aortic sinus (P = .002 and P = .002) diameters, respectively. There was no significant difference in the rate of change of end-diastolic left ventricular internal diameter (P = .703 and P = .92) and aortic insufficiency (P = .687 and P = .215) between the supported and unsupported Ross patients. CONCLUSIONS: Progressive dilation of the neoaortic root in unsupported Ross patients is significantly mitigated with the supported Ross with excellent stability. The supported Ross is safe and effective and may play an increasing role in the management of children with aortic disease.

Phase II trial of vorinostat in advanced melanoma.

INTRODUCTION: Vorinostat is a small molecule inhibitor of class I and II histone deacetylases with preclinical activity in melanoma. METHODS: We evaluated 32 patients with advanced primary cutaneous or ocular melanoma in a multi-institutional setting (PMH Phase II Consortium) with continuous daily oral vorinostat 400 mg. The primary endpoint was response rate by RECIST, with time to progression as a secondary endpoint. The study was designed to distinguish a response rate of 20 % from a RR of 5 % and to distinguish a 2 month median progression-free survival (PFS), from one of 3.1 months. The study proceeded to stage 2 following 2 of 16 responses.. We also assessed VEGF, FGF levels, P52 polymorphisms and chromatin-associated proteins as potential biomarkers. RESULTS: Therapy was associated with significant side effects, including fatigue, nausea, lymphopenia, and hyperglycemia. Eleven patients experienced at least one grade 3 or higher adverse event. There were two confirmed PRs in patients with cutaneous melanoma. Sixteen patients had stable disease and 14 patients had progressive disease for best response. In addition, two patients with cutaneous melanoma scored as stable disease had early unconfirmed partial responses with subsequent progression. Patients with stable disease or partial response (n = 18) had a median progression free survival of 5 months. (range 2-12 months). CONCLUSIONS: Vorinostat demonstrated some early responses and a high proportion of patients with stable disease, but did not meet its primary endpoint of response. Different schedules of this agent with BRAF mutation status and markers of histone acetylation could be explored in melanoma.

Aurora kinase A mediates epithelial ovarian cancer cell migration and adhesion.

Aurora kinase A (AURKA) localizes to centrosomes and mitotic spindles where it mediates mitotic progression and chromosomal stability. Overexpression of AURKA is common in cancer, resulting in acquisition of alternate non-mitotic functions. In the current study, we identified a novel role for AURKA in regulating ovarian cancer cell dissemination and evaluated the efficacy of an AURKA-selective small molecule inhibitor, alisertib (MLN8237), as a single agent and combined with paclitaxel using an orthotopic xenograft model of epithelial ovarian cancer (EOC). Ovarian carcinoma cell lines were used to evaluate the effects of AURKA inhibition and overexpression on migration and adhesion. Pharmacological or RNA interference-mediated inhibition of AURKA significantly reduced ovarian carcinoma cell migration and adhesion and the activation-associated phosphorylation of the cytoskeletal regulatory protein SRC at tyrosine 416 (pSRC(Y416)). Conversely, enforced expression of AURKA resulted in increased migration, adhesion and activation of SRC in cultured cells. In vivo tumor growth and dissemination were inhibited by alisertib treatment as a single agent. Moreover, combination of alisertib with paclitaxel, an agent commonly used in treatment of EOC, resulted in more potent inhibition of tumor growth and dissemination compared with either drug alone. Taken together, these findings support a role for AURKA in EOC dissemination by regulating migration and adhesion. They also point to the potential utility of combining AURKA inhibitors with taxanes as a therapeutic strategy for the treatment of EOC patients.

Aortic aneurysms remain a significant source of morbidity and mortality after use of Dacron(®) patch aortoplasty to repair coarctation of the aorta: results from a single center.

Aortic aneurysm formation after coarctation repair is a serious and life-threatening complication. Repairs using synthetic materials such as Dacron(®) may carry the highest risk of aneurysm formation and rupture. The authors sought to determine the prevalence of aneurysm formation in patients who previously underwent coarctation repair using Dacron(®) patch aortoplasty at their institution. Between 1977 and 1994, 63 patients underwent isolated coarctation repair using Dacron(®) patch aortoplasty. Aneurysms were defined as an aortic dimension 1.5 times that of the aorta at the level of the diaphragm as shown by angiography, computed tomography (CT) scan, or magnetic resonance imaging (MRI). Of 61 early survivors, 29 (47 %) experienced an aneurysm in the area of previous repair. Nine patients (31 %) had spontaneous rupture of the aneurysm, which caused death in seven cases. Elective or emergent aneurysm repair was performed for 20 patients without complication, and 2 patients are being monitored at this writing. The mean interval from patch placement to aneurysm repair was 15 years (range, 4-27 years). Overall freedom from the development of an aortic aneurysm was 97 % at 5 years, 90 % at 10 years, 69 % at 20 years, and 42 % at 25 years. After repair of coarctation using Dacron(®) patch aortoplasty, the risk for aneurysm formation in the area of repair and death from rupture is extremely high. Therefore, in accordance with the 2008 American Heart Association/American College of Cardiology (AHA/ACC) guidelines, all patients with repaired aortic coarctation should undergo either CT or MRI imaging at least every 5 years to assess for aortic aneurysm formation. More frequent imaging should be obtained for patients previously repaired with Dacron(®) patch aortoplasty.

Dual inhibition of SRC and Aurora kinases induces postmitotic attachment defects and cell death.

Increased activity of SRC family kinases promotes tumor invasion and metastasis, and overexpression of the mitotic regulator Aurora kinase A (AURKA) drives tumor aneuploidy and chromosomal instability. These functions nominate SRC and AURKA as valuable therapeutic targets for cancer, and inhibitors for SRC and Aurora kinases are now being used in the clinic. In this study, we demonstrate potent synergy between multiple inhibitors of Aurora and SRC kinases in ovarian and colorectal cancer cell lines, but not in normal ovarian epithelial cell lines. Combination of Aurora and SRC inhibitors selectively killed cells that have undergone a preceding aberrant mitosis, and was associated with a postmitotic reattachment defect, and selective removal of aneuploid cell populations. Combined inhibition of Aurora kinase and SRC potentiated dasatinib-dependent loss of activated (Y(416)-phosphorylated) SRC. SRC and AURKA share a common interaction partner, NEDD9, which serves as a scaffolding protein with activities in cell attachment and mitotic control, suggesting SRC and AURKA might interact directly. In vitro, we observed physical interaction and mutual cross-phosphorylation between SRC and AURKA that enhanced SRC kinase activity. Together, these findings suggest that combination of SRC and Aurora-targeting inhibitors in the clinic may be a productive strategy.

Evaluation of nilotinib in advanced GIST previously treated with imatinib and sunitinib.

PURPOSE: Patients with advanced GIST following standard imatinib and sunitinib often have good performance status and need additional therapy. This study tested nilotinib, a second-generation tyrosine kinase inhibitor, in patients with advanced GIST refractory to standard therapies. METHODS: This single-center open-label phase II study has a primary objective to determine progression-free survival at 6 months. Using a novel statistical design, 17 patients were to be enrolled; if ≥ 10 were progression free (PF) at 2 months, 19 additional patients would be enrolled. The therapy was considered of benefit if ≥ 13 of 36 patients were PF at 6 months. All patients signed informed consent and entry criteria included normal cardiac function. Exploratory analyses correlating genotype with response were also performed. RESULTS: Thirteen patients were treated; 2 had received agents after imatinib and sunitinib. Treatment was well tolerated with one grade 4 anemia attributed to nilotinib. No measurable responses were observed; median time to progression was 2 months. One patient remained on study with stable disease for 12 months. Mutation testing is available from 10 primary tumors with 7 exon 11 mutations, 1 exon 9 mutation, and 2 without KIT/PDGFR mutations. Two samples from recurrent disease had 2 mutations, both primary exon 11 mutations with an additional exon 17 mutation, including the patient with prolonged stable disease. CONCLUSIONS: Nilotinib was well tolerated in these patients with advanced GIST. Accrual was halted due to insufficient clinical benefit. However, nilotinib may provide benefit to specific subsets of advanced GIST with exon 17 mutations.

Noninvasive diagnosis of cardiac allograft rejection using echocardiography indices of systolic and diastolic function.

BACKGROUND: Limited and conflicting data exist on the diagnosis of cardiac allograft rejection with the use of echocardiography. The purpose of our study was to evaluate various systolic and diastolic indices, including newer tissue Doppler imaging techniques, in diagnosing cardiac allograft rejection. METHODS: We prospectively performed 426 echocardiography studies at the time of endomyocardial biopsy in 54 cardiac transplant patients. We measured left ventricular (LV) systolic and diastolic dimensions, mitral inflow pattern and annular velocities, and the myocardial performance index. Biopsies were assessed for cellular rejection and antibody-mediated rejection (AMR). RESULTS: Mild cellular rejection was diagnosed in 74 biopsy specimens and significant cellular rejection in 10 biopsy specimens. AMR was diagnosed in 30 biopsy specimens. In patients with mild or significant cellular rejection, no significant differences in echocardiographic parameters were observed. In patients with AMR, LV fractional shortening was significantly reduced compared with those with no AMR (mean±SD 31.8±8.9% vs 36.0±7.1%; P=.02). CONCLUSIONS: Although 1 echocardiographic parameter was statistically different in the setting of rejection, lack of consistency and overlap between nonrejection and rejection groups does not permit definitive noninvasive diagnosis of cardiac allograft rejection using this imaging modality.

Unobstructive total anomalous pulmonary venous return: impact of early elective repair on the need for prolonged mechanical ventilatory support.

Optimal timing for elective repair of total anomalous pulmonary venous return (TAPVR) in the case of an unobstructed anomalous pathway is unclear. All infants with a diagnosis of TAPVR as an isolated lesion who underwent surgical repair at Children's Hospital of Wisconsin from 1991 to 2007 were reviewed to assess location of drainage, presence of obstruction, age at presentation, age at surgery, death, need for extracorporeal membrane oxygenation (ECMO), length of hospital stay, length of mechanical ventilation (MV), and late pulmonary venous obstruction. A total of 65 patients were identified: 38 (59%) with supracardiac drainage, 10 (15%) with cardiac drainage, 11 (17%) with infracardiac drainage, and 6 (9%) with mixed drainage. For 39 (60%) of the 65 patients, obstruction was identified preoperatively. Three early and five late deaths occurred after surgery (12%), all involving patients with preoperative obstruction. Most of the late deaths (80%) involved patients who experienced recurrent obstruction. Of the 65 patients, 26 (40%) had no obstruction preoperatively, and none died, required ECMO support, or experienced late obstruction. For the 26 patients without obstruction, the timing of surgery was elective at the discretion of the supervising cardiologist. Among these 26 patients, 15 had surgery less than 10 days after presentation (median age, 18 days), and 53% of these 15 patients (8/15) had MV less than 5 days. In contrast, all 11 patients who had elective surgery more than 10 days after presentation (median age, 56 days) required MV for more than 5 days (p = 0.007). Isolated TAPVR appears to be at the highest risk for death and late postoperative obstruction when obstruction is present preoperatively. Patients with unobstructive TAPVR do very well, but potential morbidity related to prolonged MV appears to be significantly reduced by early elective surgery.

Esophageal motion during radiotherapy: quantification and margin implications.

The purpose was to evaluate interfraction and intrafraction esophageal motion in the right-left (RL) and anterior-posterior (AP) directions using computed tomography (CT) in esophageal cancer patients. Eight patients underwent CT simulation and CT-on-rails imaging before and after radiotherapy. Interfraction displacement was defined as differences between pretreatment and simulation images. Intrafraction displacement was defined as differences between pretreatment and posttreatment images. Images were fused using bone registries, adjusted to the carina. The mean, average of the absolute, and range of esophageal motion were calculated in the RL and AP directions, above and below the carina. Thirty-one CT image sets were obtained. The incidence of esophageal interfraction motion > or =5 mm was 24% and > or =10 mm was 3%; intrafraction motion > or =5 mm was 13% and > or =10 mm was 4%. The average RL motion was 1.8 +/- 5.1 mm, favoring leftward movement, and the average AP motion was 0.6 +/- 4.8 mm, favoring posterior movement. Average absolute motion was 4.2 mm or less in the RL and AP directions. Motion was greatest in the RL direction above the carina. Coverage of 95% of esophageal mobility requires 12 mm left, 8 mm right, 10 mm posterior, and 9 mm anterior margins. In all directions, the average of the absolute interfraction and intrafraction displacement was 4.2 mm or less. These results support a 12 mm left, 8 mm right, 10 mm posterior, and 9 mm anterior margin for internal target volume (ITV) and can guide margins for future intensity modulated radiation therapy (IMRT) trials to account for organ motion and set up error in three-dimensional planning.

Hepatocyte turnover in transient and chronic hepadnavirus infections.

Hepatocyte turnover appears to be an important feature in the resolution of transient and progression of chronic hepadnavirus infections. Hepatocyte death, initiated through attack by antiviral cytotoxic T-lymphocytes (CTL), and compensatory hepatocyte proliferation, are both believed to be major contributing factors in the loss of virus DNA during immune resolution of transient infections. Noncytopathic curing of hepatocytes is also suggested to occur, though this mechanism does not prevent the death of large numbers of hepatocytes. Hepatocyte death, proliferation and curing are also important features of chronic infections, though the outcomes are different. In particular, immune selection due to persistent attack by antiviral CTL is thought to play a role in the emergence of hepatocytes infected with mutant strains of hepatitis B virus (HBV) (e.g. HBV e antigen-negative strains) and in the emergence of hepatocytes that appear refractory to HBV infection. In both instances, clonal expansion of subpopulations of hepatocytes may be inferred to have taken place. Interestingly, foci of altered hepatocytes and hepatocellular carcinomas (HCC) typically do no support virus replication. Thus, immune selection of hepatocytes by antiviral CTL, by inducing clonal expansion, may also play an important role in the progression to HCC. In this review, we discuss the evidence in support of roles for hepatocyte turnover in the resolution of transient and progression of chronic HBV infections.

Mixed venous oxygen saturation monitoring after stage 1 palliation for hypoplastic left heart syndrome.

BACKGROUND: Staged palliation for hypoplastic left heart syndrome has been marked by high early mortality due to the limited cardiac output of the postischemic single right ventricle combined with the inefficiency and volatility of parallel circulation. METHODS: Since July 1996, we have performed stage 1 palliation (S1P) in 178 patients. Within this group is a consecutive cohort of 116 patients with true hypoplastic left heart syndrome that underwent S1P with a modified Blalock-Taussig shunt. A prospective database containing postoperative hemodynamic data was maintained on all patients. Studied were the incidence of organ failure, extracorporeal membrane oxygenation (ECMO), and mortality, as well as the relationship between these outcomes and postoperative hemodynamics. RESULTS: Hospital survival for this cohort was 93% (108/116). Patients who died after S1P had a lower superior vena cava oxygen saturation (SVO2) level compared with survivors (53.1% +/-10.6% versus 59.3% +/-9.2%, p = 0.034). Renal failure developed in 2 (1.7%) of the 116 patients, necrotizing enterocolitis developed in 1 (0.9%), and 5 (4.3%) had clinical seizures. ECMO support was instituted in 12 patients (10.3%). The SVO2 level was lower in patients requiring ECMO (54.0% +/- 9.7% versus 59.9% +/- 9.2%, p = 0.031). CONCLUSIONS: Goal-directed therapy with SVO2 as an indicator of systemic oxygen delivery is associated with excellent early survival and a low incidence of organ failure after S1P. Inability to optimize SVO2 in the early postoperative period is associated with an increased risk of organ failure, ECMO, and death.

The double patch repair for complete atrioventricularis communis.

This article is a review of our experience with the two-patch repair of complete atrioventricularis communis. From October 1988 through December 2005, 222 infants and children underwent surgery. There were six early (2.7%) and six late (2.7%) deaths. Reoperation was required in 22 patients (10%) for residual or recurrent mitral regurgitation or stenosis, subaortic stenosis, repair of a ventricular septal defect with or without pulmonary stenosis, placement of a right heart valved conduit, and/or placement of a permanent cardiac pacemaker. All patients survived second operations and no child required early or late mitral valve replacement. The two-patch repair is a reliable surgical technique resulting in low mortality and a low need for reoperation.

Complex atrioventricular canal.

Complex forms of atrioventricular (AV) canal (C) such as; AVC with left ventricular outflow tract obstruction, tetralogy of Fallot with complete AVC, double orifice left AV valve, unbalanced complete AVC, and single ventricle patients with common AVC valve require careful preoperative planning and special techniques. This review will explore these technical modifications and outcomes for repair of complex variants of AVC. Optimal results will be achieved using an individually tailored approach that is guided by careful evaluation of the preoperative studies, precise operative technique, and intraoperative assessment of the reconstructed AV valve, as well as a willingness to re-intervene should the postoperative course not proceed as anticipated.

Aortic valve repair.

Aortic valve replacement options are limited in children, and all of them have disadvantages. Aortic valve repair techniques have evolved slowly and have not gained wide acceptance; however, large series using a variety of techniques demonstrate that valve repair is possible with excellent early hemodynamics and satisfactory intermediate durability. The results of aortic valve repair at the Children's Hospital of Wisconsin are presented. Simple repairs (blunt valvotomy, commissurotomy, or commissurotomy with leaflet thinning) directed at congenital aortic stenosis resulted in 86% +/- 5% freedom from reintervention at 10 years. Repair of aortic insufficiency with ventricular septal defect (VSD) resulted in 93.3% +/- 6% freedom from reoperation at 10 years. Complex repairs included a combination of techniques and yielded 5-year freedom from reintervention of 83% +/- 7% compared with 73% +/- 11% for patients undergoing aortic valve replacement (P = .62). Aortic valve repair provides an alternative to aortic valve replacement in selected patients. The utility of aortic valve repair and aortic valve replacement must be measured not only in freedom from reintervention but also in regression of left ventricular mass and exercise testing. Improvement in outcome depends on better patient selection and suitable bioprosthetic materials.

Complex aortic valve repair as a durable and effective alternative to valve replacement in children with aortic valve disease.

OBJECTIVE: This study was undertaken to determine the utility of aortic valve repair in children. METHODS: A retrospective analysis was conducted on aortic valve surgery from 1973 to 2004 at Children's Hospital of Wisconsin. RESULTS: Procedures were classified as simple repairs (blunt valvotomy, commissurotomy with or without thinning, n = 147), repair of aortic insufficiency with ventricular septal defect (n = 22), complex repairs (any combination of additional procedures including suspension of prolapsed leaflets, leaflet extensions, repair of torn or perforated leaflets, annuloplasty, reduction of sinus of Valsalva plasty, and concomitant repair of supravalvular or subvalvular stenosis, n = 57), and replacements (n = 57, 20 mechanical, 2 porcine, and 35 human valves). Freedoms from reintervention for simple repairs and repair of aortic insufficiency with ventricular septal defect at 10 years were 86% +/- 5% and 93.3% +/- 6%, respectively. For complex valve repair, freedoms from reintervention at 1, 5, and 10 years were 94% +/- 3%, 85% +/- 6%, and 44% +/- 15%, versus 96% +/- 3%, 77% +/- 9%, and 77% +/- 9% for valve replacement ( P = .3). At intermediate follow-up, patients with complex valve repair had a residual gradient of 20 +/- 21 mm Hg, and 94% were free of severe aortic insufficiency. Residual aortic stenosis ( P < .05) but not the preoperative diagnosis of combined aortic stenosis and insufficiency predicted the need for reintervention. CONCLUSION: Freedom from reintervention after complex valve repairs was not different from that after valve replacement, with acceptable residual aortic stenosis and insufficiency. Simple repairs and repair of aortic insufficiency with ventricular septal defect yielded excellent long-term freedom from reintervention.

Surgical therapy for sudden cardiac death in children.

Sudden cardiac death (SCD) in children is the result of multiple etiologies and treatment (prophylaxis) must be tailored accordingly. In children who do not have congenital heart disease, surgical therapy of SCD typically consists of implantation of an internal defibrillator, with specific attention to the small size of the patient. In children who have unrepaired congenital heart disease, therapy of SCD is primarily repair of the congenital anomaly. In children or young adults who have previously undergone surgery for congenital heart disease, SCD therapy consists of repair of any residual or acquired structural defect, often in combination with antiarrhythmia surgery or defibrillator implantation.

Home surveillance program prevents interstage mortality after the Norwood procedure.

OBJECTIVE: To determine whether early identification of physiologic variances associated with interstage death would reduce mortality, we developed a home surveillance program. METHODS: Patients discharged before initiation of home surveillance (group A, n = 63) were compared with patients discharged with an infant scale and pulse oximeter (group B, n = 24). Parents maintained a daily log of weight and arterial oxygen saturation according to pulse oximetry and were instructed to contact their physician in case of an arterial oxygen saturation less than 70% according to pulse oximetry, an acute weight loss of more than 30 g in 24 hours, or failure to gain at least 20 g during a 3-day period. RESULTS: Interstage mortality among infants surviving to discharge was 15.8% (n = 9/57) in group A and 0% (n = 0/24) in group B (P =.039). Surveillance criteria were breached for 13 of 24 group B patients: 12 patients with decreased arterial oxygen saturation according to pulse oximetry with or without poor weight gain and 1 patient with poor weight gain alone. These 13 patients underwent bidirectional superior cavopulmonary connection (stage 2 palliation) at an earlier age, 3.7 +/- 1.1 months of age versus 5.2 +/- 2.0 months for patients with an uncomplicated interstage course (P =.028). A growth curve was generated and showed reduced growth velocity between 4 and 5 months of age, with a plateau in growth beyond 5 months of age. CONCLUSION: Daily home surveillance of arterial oxygen saturation according to pulse oximetry and weight selected patients at increased risk of interstage death, permitting timely intervention, primarily with early stage 2 palliation, and was associated with improved interstage survival. Diminished growth identified 4 to 5 months after the Norwood procedure brings into question the value of delaying stage 2 palliation beyond 5 months of age.

Cellular redistribution of inducible Hsp70 protein in the human and rabbit heart in response to the stress of chronic hypoxia: role of protein kinases,.

Many infants who undergo cardiac surgery have a congenital cyanotic defect where the heart is chronically perfused with hypoxemic blood. Infant hearts adapt to chronic hypoxemia by activation of intracellular protein kinase signal transduction pathways. However, the involvement of heat shock protein 70 in adaptation to chronic hypoxemia and its role in protein kinase signaling pathways is unknown. We determined expression of message and subcellular protein distribution for inducible (Hsp70i) and constitutive heat shock protein 70 (Hsc70) in chronically hypoxic and normoxic infant human and rabbit hearts and their relationship to protein kinases. In chronically hypoxic human and rabbit hearts message levels for Hsp70i were elevated 4- to 5-fold compared with normoxic hearts, Hsp70i protein was redistributed from the particulate to the cytosolic fraction. In normoxic infants Hsp70i protein was distributed almost equally between the cytosolic and particulate fractions. Hsc70 message and subcellular distribution of Hsc70 protein were unaffected by chronic hypoxia. We then determined if protein kinases influence Hsp70i protein subcellular distribution. In rabbit hearts SB203580 and chelerythrine reduced Hsp70i message levels, whereas SB203580, chelerythrine, and curcumin reversed the subcellular redistribution of Hsp70i protein caused by chronic hypoxia, with no effect in normoxic hearts, indicating regulation of Hsp70i message and subcellular distribution of Hsp70i protein in chronically hypoxic rabbit hearts is influenced by protein kinase C and mitogen-activated protein kinases, specifically p38 MAPK and JNK. We conclude the Hsp70 signal transduction pathway plays an important role in adaptation of infant human and rabbit hearts to chronic hypoxemia.

Improved survival of patients undergoing palliation of hypoplastic left heart syndrome: lessons learned from 115 consecutive patients.

BACKGROUND: Outcome of stage 1 palliation (S1P) for hypoplastic left heart syndrome (HLHS) has improved coincident with application of treatment strategies including continuous superior vena cava oximetry (SvO2), phenoxybenzamine (POB), strategies to minimize the duration of deep hypothermic circulatory arrest (DHCA) and efforts to ameliorate the inflammatory response to cardiopulmonary bypass (CPB) using aprotinin and modified ultrafiltration. METHODS AND RESULTS: Analysis of a consecutive series of 115 patients undergoing S1P was done to identify the risk factors for mortality and the impact of new treatment strategies. For the current era, July 1996 to October 2001, hospital survival was 93% (75/81) compared with 53% (18/34) for the time period, January 1992 to June 1996, P<0.001. Survival to stage 2 palliation (S2P) was also significantly improved in the current era, 81% (66/81) versus 44% (15/34), P<0.01. Anti-inflammatory treatment strategies demonstrated improved survival by univariate analysis (P<0.001). Multivariate analysis identified continuous SvO2 monitoring as a factor favoring S1P survival (P=0.02) and use of POB as a factor favoring survival to S2P (P=0.003). In the current era shorter duration of DHCA was associated with improved survival to S2P (P=0.02). CONCLUSIONS: Improved survival following S1P can be achieved with strategies that allow for early identification of decreased systemic output and the use of afterload reduction to stabilize systemic vascular resistance and therefore the pulmonary to systemic flow ratio. Strategies to ameliorate the inflammatory response to CPB may decrease the degree and duration of postoperative support. Strategies to minimize duration of DHCA may improve intermediate survival and merit additional studies.