Effect of radiochemotherapy on peripheral immune response in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is a primary brain tumor with a dismal prognosis, often resistant to immunotherapy and associated with immune suppression. This study aimed to assess the impact of steroids and Stupp-regimen treatment on peripheral blood immune parameters in GBM patients and their association with outcomes. METHODS: Using cytometry panels and bioplex assays, we analyzed the immune phenotype and serum cytokines of 54 GBM patients and 21 healthy volunteers. RESULTS: GBM patients exhibited decreased lymphoid cell numbers (CD4, CD8 T cells, NKT cells) with heightened immune checkpoint expression and increased myeloid cell numbers (especially neutrophils), along with elevated pro-inflammatory cytokine levels. Steroid use decreased T and NK cell numbers, while radio-chemotherapy led to decreased lymphoid cell numbers, increased myeloid cell numbers, and heightened immune checkpoint expression. Certain immune cell subsets were identified as potential outcome predictors. CONCLUSION: Overall, these findings shed light on the peripheral immune landscape in GBM, emphasizing the immunosuppressive effects of treatment. Baseline immune parameters may serve as prognostic indicators for treatment response.

Stat3 and Gfi-1 transcription factors control Th17 cell immunosuppressive activity via the regulation of ectonucleotidase expression.

Although Th17 cells are known to promote tissue inflammation and autoimmunity, their role during cancer progression remains elusive. Here, we showed that in vitro Th17 cells generated with the cytokines IL-6 and TGF-ß expressed CD39 and CD73 ectonucleotidases, leading to adenosine release and the subsequent suppression of CD4(+) and CD8(+) T cell effector functions. The IL-6-mediated activation of the transcription factor Stat3 and the TGF-ß-driven downregulation of Gfi-1 transcription factor were both essential for the expression of ectonucleotidases during Th17 cell differentiation. Stat3 supported whereas Gfi-1 repressed CD39 and CD73 expression by binding to their promoters. Accordingly, Th17 cells differentiated with IL-1ß, IL-6, and IL-23 but without TGF-ß did not express ectonucleotidases and were not immunosuppressive. Finally, adoptive transfer of Th17 cells induced by TGF-ß and IL-6 promoted tumor growth in a CD39-dependent manner. Thus, ectonucleotidase expression supports the immunosuppressive fate of Th17 cells in cancer.

Comparison of the investigational device exemption and post-approval trials of the Melody transcatheter pulmonary valve.

OBJECTIVE: We compared 5-year outcomes of transcatheter pulmonary valve (TPV) replacement with the Melody TPV in the post-approval study (PAS) and the investigational device exemption (IDE) trial. BACKGROUND: As a condition of approval of the Melody TPV after the IDE trial, the Food and Drug Administration required that a PAS be conducted to evaluate outcomes of TPV replacement in a "real-world" environment. The 5-year outcomes of the PAS have not been published, and the IDE and PAS trials have not been compared. METHODS: The cohorts comprised all patients catheterized and implanted at 5 IDE sites and 10 PAS sites. Differences in trial protocols were detailed. Time-related outcomes and valve-related adverse events were compared between the two trials with Kaplan-Meier curves and log-rank testing. RESULTS: 167 patients (median age, 19 years) were catheterized and 150 underwent TPV replacement in the IDE trial; 121 were catheterized (median age, 17 years) and 100 implanted in the PAS. Freedom from hemodynamic dysfunction (p = .61) or any reintervention (p = .74) over time did not differ between trials. Freedom from stent fracture (p = .003) and transcatheter reintervention (p = .010) were longer in PAS, whereas freedom from explant (p = .020) and TPV endocarditis (p = .007) were shorter. Clinically important adverse events (AEs) were reported in 14% of PAS and 7.2% of IDE patients (p = .056); the incidence of any particular event was low in both. CONCLUSIONS: Hemodynamic and time-related outcomes in the PAS and IDE trials were generally similar, confirming the effectiveness of the Melody TPV with real-world providers. There were few significant complications and limited power to identify important differences in AEs. The lack of major differences in outcomes between the two studies questions the usefulness of mandated costly post-approval studies as part of the regulatory process for Class III medical devices.

Impact of granulocyte colony-stimulating factor on FOLFIRINOX-induced neutropenia prevention: A population pharmacokinetic/pharmacodynamic approach.

AIMS: Granulocyte colony-stimulating factor (G-CSF) is frequently prescribed to prevent chemotherapy-induced neutropenia, but the administration schedule remains empirical in case of bimonthly chemotherapy such as FOLFIRINOX regimen. This pharmacokinetic/pharmacodynamic (PK/PD) study was performed to determine the effect of different G-CSF regimens on the incidence and duration of neutropenia following FOLFIRINOX administration in order to propose an optimal G-CSF dosing schedule. METHODS: A population PK/PD model was developed to describe individual neutrophil time course from absolute neutrophil counts (ANC) obtained in 40 advanced cancer patients receiving FOLFIRINOX regimen. The structural model considered ANC dynamics, neutropenic effect of cytotoxics and the stimulating effect of G-CSF on neutrophils. Final model estimates were used to simulate different G-CSF dosing schedules for 1000 virtual subjects. The incidence and duration of neutropenia were then calculated for different G-CSF dosing schedules. RESULTS: The final model successfully described the myelosuppressive effect induced by the 3 cytotoxics for all patients. Simulations showed that pegfilgrastim administration reduced the risk of severe neutropenia by 22.9% for subjects with low ANC at the start of chemotherapy. Median duration in this group was also shortened by 3.1 days when compared to absence of G-CSF. Delayed G-CSF administration was responsible for higher incidence and longer duration of neutropenia compared to absence of administration. CONCLUSION: The PK/PD model well described our population's ANC data. Simulations showed that pegylated-G-CSF administration 24 hours after the end of chemotherapy seems to be the optimal schedule to reduce FOLFIRINOX-induced neutropenia. We also underline the potential negative effect of G-CSF maladministration.

Cell lines and immune classification of glioblastoma define patient's prognosis.

BACKGROUND: Prognostic markers for glioblastoma are lacking. Both intrinsic tumour characteristics and microenvironment could influence cancer prognostic. The aim of our study was to generate a pure glioblastoma cell lines and immune classification in order to decipher the respective role of glioblastoma cell and microenvironment on prognosis. METHODS: We worked on two large cohorts of patients suffering from glioblastoma (TCGA, n = 481 and Rembrandt, n = 180) for which clinical data, transcriptomic profiles and outcome were recorded. Transcriptomic profiles of 129 pure glioblastoma cell lines were clustered to generate a glioblastoma cell lines classification. Presence of subtypes of glioblastoma cell lines and immune cells was determined using deconvolution. RESULTS: Glioblastoma cell lines classification defined three new molecular groups called oncogenic, metabolic and neuronal communication enriched. Neuronal communication-enriched tumours were associated with poor prognosis in both cohorts. Immune cell infiltrate was more frequent in mesenchymal classical classification subgroup and metabolic-enriched tumours. A combination of age, glioblastoma cell lines classification and immune classification could be used to determine patient's outcome in both cohorts. CONCLUSIONS: Our study shows that glioblastoma-bearing patients can be classified based on their age, glioblastoma cell lines classification and immune classification. The combination of these information improves the capacity to address prognosis.

Association between patient age at implant and outcomes after transcatheter pulmonary valve replacement in the multicenter Melody valve trials.

OBJECTIVES: To investigate whether age and valve size at implant contribute to outcomes after Melody transcatheter pulmonary valve replacement (TPVR). BACKGROUND: Patient age and valve size at implant contribute to longevity of surgical pulmonary valves. METHODS: All patients discharged with a Melody valve in the pulmonary position, as part of three prospective Melody valve multicenter studies, comprised the study cohort. Acute and time-related outcomes were analyzed according to age: children (≤12 years), adolescents (13-18 years), young adults (19-29 years), and older adults (≥30 years). RESULTS: Successful Melody valve implantation occurred in 49 children, 107 adolescents, 96 young adults, and 57 older adults. Pediatric patients (≤18 years) were more likely to have TPVR for conduit stenosis than adults (62% vs. 44%); children had the smallest conduits. After TPVR, pediatric and adult patients had similar decreases in right ventricular (RV) size by MRI, but adults had improved percentage predicted peak VO2 (58% preimplant to 64% postimplant, p = .02) and FEV1 (69% pre to 71% post, p = .005). Younger age was associated with shorter freedom from RVOT dysfunction, reintervention, and explant. Children had the shortest freedom from endocarditis (p = .041), but all other groups had 5-year freedom from endocarditis of ≥90%. CONCLUSIONS: Younger age was associated with shorter time to RVOT dysfunction, reintervention, and explant after Melody TPVR. Patients ≥13 years of age were at low risk for endocarditis and explant to 5 years. A better understanding of time-related outcomes by age will aid in the comparison of therapeutic options for TPVR candidates. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT00740870 (NCT00740870), https://clinicaltrials.gov/ct2/show/NCT01186692 (NCT01186692), and https://clinicaltrials.gov/ct2/show/NCT00688571 (NCT00688571).

Does the age of evaluation change the long-term follow-up of untreated pre-excitation syndrome?

BACKGROUND: Due to high rates of ablation at the time of diagnostic EP study, follow-up of the natural history of untreated pre-excitation syndrome has become difficult. We present patients in which such data is available and study the effect of initial age on the evolution. METHODS: In this retrospective review, 126 patients, 47 aged ≤19 years, 79 aged more than>19 underwent 2 similar electrophysiological studies (EPS) within 1 to 25 years of one another (8.8 ±â€¯6.8) for occurrence of symptoms or new evaluation. First EPS was indicated for syncope (10), atrioventricular re-entrant tachycardias (AVRT) (58), atrial fibrillation (AF) (5), spontaneous PS-related adverse event (7) or asymptomatic PS (46). RESULTS: Clinical data remained unchanged in 76 patients (60.3%). AVRT symptom was more frequently unchanged than other symptoms. Electrophysiological data remained unchanged in 105 patients (82%), but signs of initial malignant signs were variable with a disappearance in 53.5% of patients. At EPS1, AF induction was rarer in patients ≤19 years. Syncope had a low predictive value of malignant form. AVRT induction at EPS1 was not predictive of AVRT occurrence. Maximal rate over accessory pathway increased, but unexpected changes could occur. After multivariate analysis, data of first EPS were limited for the prediction of AVRT or adverse event; effect of age was not significant. CONCLUSIONS: Clinical data remained unchanged in 60.3% of patients and electrophysiological data in 82%. Initial age of evaluation did not change the modifications. Electrophysiological signs associated with sudden death varied over time. Clinical AVRT was inconstantly related to inducible AVRT (78.5%).

Cardiac Catheterization in Pediatric Patients Supported by Extracorporeal Membrane Oxygenation: A 15-Year Experience.

Cardiac catheterization is commonly performed in patients being supported by extracorporeal membrane oxygenation (ECMO). We aimed to evaluate the safety, benefit, and outcomes of catheterization in pediatric patients supported by ECMO. Retrospective review of cardiac catheterizations performed in patients ≤18 years of age while on ECMO at a large tertiary care center between January 2000 and May 2015. A total of 55 catheterizations were performed on 51 patients during 53 unique ECMO courses. Indications for ECMO include ventricular dysfunction (22), cardiac arrest (20), inability to wean from cardiopulmonary bypass (7), and persistent cyanosis (4). Catheterizations included purely diagnostic studies (11), atrial septostomies (34), stenting of vessels or surgical shunts (6), adjustment of a stent (1), coil embolization (1), and endomyocardial biopsy (1). Septostomy was elective in 58.8% of cases (20) and emergent in 41.2% (14). Forty-six catheterizations had either surgical or catheter intervention during the same or subsequent study (83.6%). High severity complications occurred in three patients (5.6%), including one death due to hemothorax after pulmonary artery stent placement. There were no complications during patient transport. In total, 38 out of 53 (71.7%) ECMO courses resulted in decannulation, 29 (54.7%) patients survived to discharge from the hospital, and 25 (47.2%) were alive at follow-up. Cardiac catheterization can be safely performed on patients supported by ECMO. Cardiac catheterization is a critical tool in the early recognition, diagnosis, and direct treatment of hemodynamic/anatomic abnormalities in patients supported by ECMO.

Clinical and hemodynamic outcomes up to 7 years after transcatheter pulmonary valve replacement in the US melody valve investigational device exemption trial.

BACKGROUND: Studies of transcatheter pulmonary valve (TPV) replacement with the Melody valve have demonstrated good short-term outcomes, but there are no published long-term follow-up data. METHODS AND RESULTS: The US Investigational Device Exemption trial prospectively enrolled 171 pediatric and adult patients (median age, 19 years) with right ventricular outflow tract conduit obstruction or regurgitation. The 148 patients who received and were discharged with a TPV were followed up annually according to a standardized protocol. During a median follow-up of 4.5 years (range, 0.4-7 years), 32 patients underwent right ventricular outflow tract reintervention for obstruction (n=27, with stent fracture in 22), endocarditis (n=3, 2 with stenosis and 1 with pulmonary regurgitation), or right ventricular dysfunction (n=2). Eleven patients had the TPV explanted as an initial or second reintervention. Five-year freedom from reintervention and explantation was 76±4% and 92±3%, respectively. A conduit prestent and lower discharge right ventricular outflow tract gradient were associated with longer freedom from reintervention. In the 113 patients who were alive and reintervention free, the follow-up gradient (median, 4.5 years after implantation) was unchanged from early post-TPV replacement, and all but 1 patient had mild or less pulmonary regurgitation. Almost all patients were in New York Heart Association class I or II. More severely impaired baseline spirometry was associated with a lower likelihood of improvement in exercise function after TPV replacement. CONCLUSIONS: TPV replacement with the Melody valve provided good hemodynamic and clinical outcomes up to 7 years after implantation. Primary valve failure was rare. The main cause of TPV dysfunction was stenosis related to stent fracture, which was uncommon once prestenting became more widely adopted. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00740870.

Percutaneous coronary artery revascularization procedures in pediatric heart transplant recipients: A large single center experience.

OBJECTIVES: To describe our experience, at a large pediatric heart transplant center, with percutaneous coronary interventions (PCI) for cardiac allograft vasculopathy (CAV). BACKGROUND: CAV is a leading cause of late graft failure, mortality, and re-transplantation in pediatric heart transplant (HTx) recipients. Studies of PCI in adult patients have shown some short-term improvements, but no significant change in long-term outcomes. There are limited data on PCI for CAV in pediatric patients. We describe the largest single-center experience to date. METHODS: We performed a retrospective chart review of all pediatric HTx recipients who underwent PCI for a diagnosis of CAV from 2005 to 2014. RESULTS: Twenty-three procedures were performed in 13 patients, at a median age of 16.4 years (range 5.6-21.2) and median time from HTx to first PCI of 8.3 years (range 2.9-20.3). Three cases consisted of angioplasty alone, two cases had bare metal stents implanted, and the remaining 18 had drug-eluting stents implanted. There was acute procedural success in all but one case, and there was only one procedure-related complication (rebleeding from access site). During the follow-up interval (median 10.4 months, range 0.2-111.8), 7/13 patients had repeat PCI performed, two patients died (at 1.8 and 5.8 months post-PCI), and five were re-transplanted (range 0.2-18 months post-PCI). Freedom from death or retransplant by Kaplan-Meier analysis was 54% at 1 year. CONCLUSIONS: PCI can be performed safely and effectively in pediatric HTx recipients with CAV. Similar to the adult experience, there remains a high rate of disease progression and graft failure. © 2016 Wiley Periodicals, Inc.

Aortic Root Distortion and Aortic Insufficiency During Balloon Angioplasty of the Right Ventricular Outflow Tract Prior to Transcatheter Pulmonary Valve Replacement.

OBJECTIVE: To describe the significance of aortic root distortion (AD) and/or aortic valve insufficiency (AI) during balloon angioplasty of the right ventricular outflow tract (RVOT) performed to rule out coronary artery compression prior to transcatheter pulmonary valve (TPV) implantation. METHODS: AD/AI was assessed by retrospective review of all procedural aortographies performed to evaluate coronary anatomy prior to TPV implantation. AD/AI was also reviewed in all pre-post MPV implant echocardiograms to assess for progression. RESULTS: From 04/2007 to 3/2015, 118 pts underwent catheterization with intent for TPV implant. Mean age and weight were 24.5 ± 12 years and 64.3 ± 20 kg, respectively. Diagnoses were: TOF (53%), D-TGA/DORV (18%), s/p Ross (15%), and Truncus (9%). Types of RV-PA connections were: conduits (96), bioprosthetic valves (14), and other (7). Successful TPV implant occurred in 91 pts (77%). RVOT balloon angioplasty was performed in 43/118 pts (36%). Aortography was performed in 18/43 pts with AD/AI noted in 6/18 (33%); 2 with D-TGA (1 s/p Lecompte, 1 s/p Rastelli), 2 with TOF, 1 Truncus and 1 s/p Ross. Procedure was aborted in the 2 who developed severe AD/AI. TPV was implanted in 3/4 patients with mild AD/AI. Review of pre-post TPV implantation echocardiograms in 83/91 pts (91%) revealed no new/worsened AI in any patient. CONCLUSION: AD/AI is relatively common on aortography during simultaneous RVOT balloon angioplasty. Lack of AI progression by echocardiography post-TPV implant suggests these may be benign findings in most cases. However, AD/AI should be carefully evaluated in certain anatomic subtypes with close RVOT/aortic alignments.

Evolution of Clinical and Electrophysiological Data in Children with a Preexcitation Syndrome.

BACKGROUND: With ablation, the follow-up of preexcitation syndrome now is difficult to assess. The purpose was to collect data of children with a preexcitation syndrome studied on two separate occasions within a minimal interval of 1 year. METHODS: This is a retrospective chart review of 47 children initially aged 12 ± 4 years, who underwent two or more invasive electrophysiological studies (EPS) within 1-25 years of one another (6.3 ± 4.8) for occurrence of symptoms or new evaluation. RESULTS: Among initially symptomatic children (n = 25), four (19%) became asymptomatic and one presented life-threatening arrhythmia. Among asymptomatic children (n = 22), five became symptomatic (22.7%). Anterograde conduction disappeared in seven of 23 children with initially long accessory pathway-effective refractory period, but four of six had still induced atrioventricular reentrant tachycardia (AVRT). AVRT was induced at second EPS in three of 13 asymptomatic preexcitation syndrome with negative initial EPS. There were no spontaneous adverse events in the five children with criteria of malignancy at initial EPS; signs of malignancy disappeared in two. At multivariate analysis, AVRT at initial EPS was the only independent factor of symptomatic AVRT during follow-up. Absence of induced AVRT at initial EPS was the only factor of absence of symptoms and a negative study at the second EPS. CONCLUSIONS: There were no significant changes of data in children after 6.3 ± 4.8 years of follow-up. Most children with spontaneous/inducible AVRTs at initial EPS had still inducible AVRT at second EPS. Induced AF conducted with high rate has a relatively low prognostic value for the prediction of adverse events.

Is Endomyocardial Biopsy a Safe and Useful Procedure in Children with Suspected Cardiomyopathy?

Endomyocardial biopsy (EMB) is a common procedure used to aid in the diagnosis, prognosis and treatment of suspected pediatric cardiomyopathy. In suspected cardiomyopathy, no multicenter experience has previously reported on the safety and utility of EMBs. Retrospectively, adverse event (AE) and patient and procedural characteristics were obtained at seven institutions participating in the Congenital Cardiac Catheterization Outcomes Project for both a cardiomyopathy (n = 158) and a post-transplant surveillance (n = 2665) cohort. Descriptive information regarding biopsy indication, pathology and clinical management based on EMB findings were retrospectively obtained. High-severity AEs were more common in the cardiomyopathy cohort when compared to the post-transplant surveillance cohort. The cardiomyopathy cohort was younger, more hemodynamically vulnerable and required more cardiorespiratory support during the procedure. The eight high-severity AEs in the cardiomyopathy group included one myocardial perforation, two ECMO cannulations and three deaths following the EMB. Factors associated with high-severity AEs included performing another catheter-based intervention during the EMB and longer fluoroscopy time. Notably, an increased number of biopsy attempts did not increase the risk of an AE. Suspected myocarditis was the most common indication. Diagnostic EMB pathology and thus alteration to clinical management based on pathology occurred more frequently in patients with suspected myocarditis. In conclusion, there is an increased incidence of high-severity AEs in patients undergoing EMB for suspected cardiomyopathy. EMB may be more clinically useful in the management of suspected myocarditis. The increased risk of high-severity AEs when additional interventions are performed highlights the hemodynamic vulnerability in patients with suspected cardiomyopathy.

Fluorouracil, leucovorin and irinotecan associated with aflibercept can induce microscopic colitis in metastatic colorectal cancer patients.

Aflibercept is a recombinant fusion protein that acts as a soluble decoy receptor for vascular endothelial growth factor (VEGF). This molecule binds to all isoforms of VEGF-A as well as VEGF-B and placental growth factor, preventing them from activating their respective receptors. Aflibercept is used for the treatment of metastatic colorectal cancer (mCRC) in association with irinotecan. For reasons that remain to be elucidated, the addition of aflibercept to irinotecan-based chemotherapy increases the incidence of grade 3-4 diarrhea. We performed systematic colonic biopsies in three patients with grade 3 diarrhea after introduction of fluorouracil, leucovorin, irinotecan and aflibercept treatment for mCRC. For each patient, the diarrhea necessitated treatment discontinuation. Colonoscopy showed normal colonic mucosa. However, histopathological examination of the biopsies performed in these three patients revealed typical features of microscopic colitis. All three patients were treated with budesonide and mesalazine, leading to rapid regression of clinical symptoms. Chemotherapy was reintroduced in all patients, with only mild, grade 1 diarrhea under mesalazine and budesonide treatment. These are the first observations of aflibercept-induced microscopic colitis, and support the use of specific treatment on top of anti-diarrheal treatment in case of important digestive adverse events.

The wedding cake solution: A percutaneous correction of a form fruste superior sinus venosus atrial septal defect.

We present the case of a patient with a superior sinus venosus defect (SSVD), with the atypical finding of an intact atrial septum and posterior atrial wall, which underwent percutaneous closure in the cardiac catheterization laboratory for repair. SSVDs are rare congenital cardiac anomalies, but when the anatomy is amenable to percutaneous strategies, a collaborative and creative approach can result in a safe and effective result.

Iatrogenic aortopulmonary communications after transcatheter interventions on the right ventricular outflow tract or pulmonary artery: Pathophysiologic, diagnostic, and management considerations.

OBJECTIVES: To investigate the spectrum, etiology, and management of traumatic aortopulmonary (AP) communications after transcatheter interventions on the pulmonary circulation. BACKGROUND: An iatrogenic AP communication is an unusual complication after balloon pulmonary artery (PA) angioplasty or stenting, or transcatheter pulmonary valve replacement (TPVR). However, with the increasing application of transcatheter therapies for postoperative PA stenosis and right ventricular outflow tract (RVOT) dysfunction, including percutaneous pulmonary valve replacement, consideration of the etiology, diagnosis, and management of this problem is important for interventional cardiologists performing such procedures. METHODS AND RESULTS: We present three new cases, as well as gross anatomy and histopathology data, related to AP communications after PA interventions. We also review the literature relevant to this topic. Including these new cases, there have been 18 reported cases of iatrogenic AP communication after transcatheter interventions on the PAs or RVOT, primarily patients with transposition of the great arteries who underwent PA angioplasty after an arterial switch operation, or after TPVR in patients who had undergone a Ross procedure. The likely cause of such defects is PA trauma plus distortion of the neo-aortic anastomosis resulting from angioplasty or stenting of the RVOT or central PAs, with subsequent dissection through the extravascular connective tissue and into the closely adjacent vessel through the devitalized tissue at the anastomosis. CONCLUSIONS: Cardiologists performing PA or RVOT interventions should be aware of the possibility of a traumatic AP communication and consider this diagnosis when confronted with suggestive signs and symptoms.

Balloon valvuloplasty for congenital aortic stenosis: Multi-center safety and efficacy outcome assessment.

OBJECTIVE: To describe contemporary outcomes of balloon aortic valvuloplasty (BAVP) performed in 22 US centers. BACKGROUND: BAVP constitutes first-line therapy for congenital aortic stenosis (cAS) in many centers. METHODS: We used prospectively-collected data from two active, multi-institutional, pediatric cardiac catheterization registries. Acute procedural success was defined, for purposes of this review, as a residual peak systolic gradient≤35 mm Hg and no more than mild aortic regurgitation (AR) for patients with isolated cAS. For patients with mixed aortic valve disease, a residual peak systolic gradient≤35 mm Hg without worsening of AR was considered successful outcome. RESULTS: In 373 patients with a median age of 8 months (1 day to 40 years of age) peak systolic gradient had a median of 59 [50, 71] mm Hg pre-BAVP and 22 [15, 30] mm Hg post-BAVP (P<0.001). Procedural success was achieved in 160 patients (71%). The factors independently associated with procedural success were: first time intervention (OR=2.0 (1.0, 4.0) P=0.04), not-prostaglandin dependent, (OR=3.5 (1.5, 8.1); P=0.003), and isolated cAS (absence of AR) (OR=2.1 (1.1-3.9); P=0.03). Twenty percent of patients experienced adverse events, half of which were of high severity. There was no procedural mortality. Neonatal status was the only factor associated with increased risk of high severity adverse events (OR 3.7; 95% CI 1.5-9.0). CONCLUSION: In the current era, BAVP results in procedural success (gradient reduction with minimal increase in AR) in 71% of patients treated at US centers where BAVP is considered first-line therapy relative to surgery.

Sedation and Anesthesia in Pediatric and Congenital Cardiac Catheterization: A Prospective Multicenter Experience.

Sedation/anesthesia is critical to cardiac catheterization in the pediatric/congenital heart patient. We sought to identify current sedation/anesthesia practices, the serious adverse event rate related to airway, sedation, or anesthesia, and the rate of intra-procedural conversion from procedural sedation to the use of assisted ventilation or an artificial airway. Data from 13,611 patients who underwent catheterization at eight institutions were prospectively collected from 2007 to 2010. Ninety-four (0.69 %) serious sedation/airway-related adverse events occurred; events were more likely to occur in smaller patients (<4 kg, OR 4.4, 95 % CI 2.3-8.2, p < 0.001), patients with non-cardiac comorbidities (OR 1.7, 95 % CI 1.1-26, p < 0.01), and patients with low mixed venous oxygen saturation (OR 2.3, 95 % CI 1.4-3.6, p < 0.001). Nine thousand three hundred and seventy-nine (69 %) patients were initially managed with general endotracheal anesthesia, LMA, or tracheostomy, whereas 4232 (31 %) were managed with procedural sedation without an artificial airway, of which 75 (1.77 %) patients were converted to assisted ventilation/general anesthesia. Young age (<12 months, OR 5.2, 95 % CI 2.3-11.4, p < 0.001), higher-risk procedure (category 4, OR 10.1, 95 % CI 6.5-15.6, p < 0.001), and continuous pressor/inotrope requirement (OR 11.0, 95 % CI 8.6-14.0, p < 0.001) were independently associated with conversion. Cardiac catheterization in pediatric/congenital patients was associated with a low rate of serious sedation/airway-related adverse events. Smaller patients with non-cardiac comorbidities or low mixed venous oxygen saturation may be at higher risk. Patients under 1 year of age, undergoing high-risk procedures, or requiring continuous pressor/inotrope support may be at higher risk of requiring conversion from procedural sedation to assisted ventilation/general anesthesia.

Intervention for recoarctation in the single ventricle reconstruction trial: incidence, risk, and outcomes.

BACKGROUND: Recoarctation after the Norwood procedure increases risk for mortality. The Single Ventricle Reconstruction (SVR) trial randomized subjects with a single right ventricle undergoing a Norwood procedure to a modified Blalock-Taussig shunt or a right ventricle-pulmonary artery shunt. We sought to determine the incidence of recoarctation, risk factors, and outcomes in the SVR trial. METHODS AND RESULTS: Recoarctation was defined by intervention, either catheter based or surgical. Univariate analysis and multivariable Cox proportional hazard models were performed with adjustment for center. Of the 549 SVR subjects, 97 (18%) underwent 131 interventions (92 balloon aortoplasty, 39 surgical) for recoarctation at a median age of 4.9 months (range, 1.1-10.5 months). Intervention typically occurred at pre-stage II catheterization (n=71, 54%) or at stage II surgery (n=38, 29%). In multivariable analysis, recoarctation was associated with the shunt type in place at the end of the Norwood procedure (hazard ratio, 2.0 for right ventricle-pulmonary artery shunt versus modified Blalock-Taussig shunt; P=0.02), and Norwood discharge peak echo-Doppler arch gradient (hazard ratio, 1.07 per 1 mm Hg; P<0.01). Subjects with recoarctation demonstrated comorbidities at pre-stage II evaluation, including higher pulmonary arterial pressures (15.4±3.0 versus 14.5±3.5 mm Hg; P=0.05), higher pulmonary vascular resistance (2.6±1.6 versus 2.0±1.0 Wood units·m(2); P=0.04), and increased echocardiographic volumes (end-diastolic volume, 126±39 versus 112±33 mL/BSA(1.3), where BSA is body surface area; P=0.02). There was no difference in 12-month postrandomization transplantation-free survival between those with and without recoarctation (P=0.14). CONCLUSIONS: Recoarctation is common after Norwood and contributes to pre-stage II comorbidities. Although with intervention there is no associated increase in 1-year transplantation/mortality, further evaluation is warranted to evaluate the effects of associated morbidities.

Bevacizumab efficacy in metastatic colorectal cancer is dependent on primary tumor resection.

PURPOSE: Bevacizumab plus fluoropyrimidine-based chemotherapy is standard treatment for first-line and second-line metastatic colorectal cancer (mCRC). However, to date, there is no current biomarker predictive for the benefit of bevacizumab use for these patients. Preclinical data suggest that the presence of the primary tumor could be involved in less efficient antitumor activity of antiangiogenic agents, but no clinical data currently support this hypothesis. METHODS: We performed a retrospective analysis of factors associated with overall survival (OS) in a study cohort of 409 mCRC patients. Univariate and multivariate Cox proportional hazard regression models were used to assess the influence of primary tumor resection and bevacizumab use on OS. We evaluated associations linking bevacizumab use and OS among patients who previously underwent or did not undergo primary tumor resection. Results were externally validated in a second independent cohort of 328 mCRC patients. RESULTS: In the study cohort, bevacizumab use and resection of the primary tumor were associated with improved OS. However, subgroup analyses indicate that bevacizumab did not influence survival of patients bearing a primary colorectal tumor (hazard ratio (HR) 0.98, 95 % confidence interval (CI) 0.60-1.61, log-rank test P = 0.6). By contrast, the survival benefit of bevacizumab was restricted to patients who previously underwent primary tumor resection (HR 0.71, 95 % CI 0.55-0.92, P = 0.009). Similar results were observed in the validation cohort. CONCLUSIONS: Addition of bevacizumab to chemotherapy is associated with improvement of OS only in patients with primary tumor resection. These data support the rationale to validate prospectively the influence of primary tumor resection on bevacizumab antitumor effect in synchronous mCRC.