Multiple antibodies targeting tumor-specific mutations redirect immune cells to inhibit tumor growth and increase survival in experimental animal models.

BACKGROUND: T cell therapy for cancer involves genetic introduction of a target-binding feature into autologous T cells, ex vivo expansion and single large bolus administration back to the patient. These reprogrammed T cells can be highly effective in killing cells, but tumor heterogeneity results in regrowth of cells that do not sufficiently express the single antigen being targeted. We describe a cell-based therapy that simultaneously targets multiple tumor-specific antigens. METHODS: High-affinity polyclonal rabbit antibodies were generated against nine different surface-related tumor-specific mutations on B16F10 cells. Unsorted splenic effector cells from syngeneic mice were incubated with a cocktail of the nine anti-B16F10 antibodies. These 'armed' effector cells were used to treat mice previously inoculated with B16F10 melanoma cells. RESULTS: The cocktail of nine antibodies resulted in dense homogeneous binding to histological sections of B16F10 cells. Five treatments with the armed effector cells and PD1 inhibition inhibited tumor growth and improved survival. Shortening the interval of the five treatments from every three days to every day increased survival. Arming effector cells with the four antibodies showing best binding to B16F10 cells even further increased survival. CONCLUSIONS: This study demonstrates that ex vivo arming a mixed population of immune effector cells with antibodies targeting multiple tumor-specific mutated proteins in conjunction with PD1 inhibition delayed tumor growth and prolonged survival in mice inoculated with an aggressive melanoma. A remarkably low total antibody dose of less than 5 µg was sufficient to accomplish tumor inhibition. Scaling up to clinical level may be feasible.

Identification and management of fetal isolated right-sided aortic arch in an unselected population.

OBJECTIVE: Inclusion of the three vessels and trachea view in the routine assessment of the fetal heart at the 18-20-week morphology scan improves recognition of a right-sided aortic arch (RAA). We report our experience of RAA diagnosed in an unselected population of pregnant women attending for a routine morphology scan. METHODS: The obstetric imaging databases of two ultrasound centers were reviewed retrospectively to identify all routine fetal morphology scans performed at 18-22 weeks' gestation between January 2011 and December 2014. A review of postnatal charts was conducted to ascertain findings at birth, neonatal complications and the anatomical findings at any neonatal echocardiographic or surgical procedure. Parents of older infants were contacted by phone to assess their wellbeing and identify any respiratory or feeding difficulties. RESULTS: In the 48-month study period, 43 083 routine anomaly scans were performed. Twenty-three cases of isolated RAA were identified, a prevalence of 0.05%. Nineteen (83%) cases of isolated RAA had a left-sided arterial duct and four (17%) had a right-sided duct. Postnatal follow-up data were obtained in all cases. The prevalence of a symptomatic vascular ring due to a double aortic arch was 13% (3/23). One (4%) case was diagnosed with DiGeorge syndrome. CONCLUSIONS: RAA can be identified easily on a routine fetal anomaly scan, however the prevalence of RAA is low in an unselected population. Antenatally diagnosed cases should be referred for detailed fetal echocardiography and the patient should be made aware of the association with DiGeorge syndrome and the symptoms associated with a vascular ring. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Pulmonary hypertension--a new manifestation of mitochondrial disease.

Mitochondrial respiratory chain (RC) abnormalities in children can present as multiorgan disease, including liver failure, usually within the first year of life. Cardiorespiratory complications have previously been described in association with RC defects; however, to our knowledge no cases of pulmonary hypertension have been described. We discuss two patients with proven mitochondrial RC liver disease who developed severe pulmonary hypertension, one subsequent to cadaveric orthotopic liver transplantation, the second in the neonatal period. It is our contention that pulmonary hypertension should now be included as another potential manifestation of paediatric mitochondrial disease.

Balloon dilatation of aortic stenosis in infants younger than 6 months of age: intermediate outcome.

The objectives of this study were to review the outcome of balloon dilatation of critical/severe aortic valve stenosis in patients younger than 6 months of age, with particular emphasis on subdivisions of age at intervention, and to identify factors that might influence outcome. From 1988 to 1998, 42 patients underwent dilatation. Patients were divided into three groups (group 1: 1-7 days, n = 16; group 2: 8-30 days; n = 10; group 3: 1-6 months, n = 16). Medical records and echocardiograms were reviewed retrospectively for presentation, clinical course, and left ventricular, aortic valve, and Doppler flow parameters. Median follow-up was 53 months (range, 6 months to 10 years). Of 16 group 1 patients, 11 (70%) had, respiratory distress requiring ventilator support, 12 (80%) received prostaglandin, and 5 (30%) received inotropic support. Nine (56.2%) patients died and 7 (44%) required reintervention. Of 10 group 2 patients, 4 (40%) were ventilated, 2 (20%) received prostaglandin, and 3 (30%) received inotropic support. Three (30%) patients died and 5 (50%) required reintervention. Of 16 group 3 patients, only 1 had symptoms (respiratory distress) at presentation. One (6%) patient died and 4 (15%) required reintervention. The overall actuarial survival rate at 10 years was 72% (88% at 10 years for indexed aortic annulus > 25 mm/m2. Freedom from reintervention was 70% and 21% at 5 and 10 years, respectively (80 and 33% at 5 and 10 years, respectively, for indexed aortic annulus > 25 mm/m2). The actuarial survival rates at 10 years for groups 1, 2, and 3 were 42%, 65%, and 93%, respectively. Predictors of death included young age at presentation, and multivariate analysis of left heart measures yielded an 83% positive prediction of outcome. An improved chance of survival was associated with indexed aortic valve annulus > 25 mm/m2. Patients with critical aortic stenosis who require balloon dilatation within the first month of life, but especially within the first week, have a poorer outcome than those requiring the procedure later, and this can be accounted for by a tendency toward less favorable anatomical features. Many will require repeat intervention.

Three-dimensional (3D) echocardiographic analysis of congenital heart disease in the fetus: comparison with cross-sectional (2D) fetal echocardiography.

OBJECTIVE: We attempted to assess the ability of Doppler-gated three-dimensional (3D) fetal echocardiography to reconstruct and display specific cardiac structures in fetuses with cardiac anomalies and to determine whether any advantage is offered by 3D sonographic cardiac examination over conventional fetal echocardiography. DESIGN: After 2D fetal echocardiographic examination, 3D cardiac data were collected prospectively in 22 fetuses with various congenital heart defects. Their ages ranged from 19 to 35 weeks' gestation. Basic echocardiographic key views of the venoatrial, atrioventricular and ventriculoarterial connections were derived from volume data sets and selected for 3D reconstruction and analysis. Comparisons were made with 2D echocardiographic imaging of the fetal hearts and the diagnostic image quality of visualized structural details was evaluated. RESULTS: The underlying cardiac malformation was well or satisfactorily visualized in 20 fetuses using 2D imaging. Gated 3D volume data sets enabled diagnostically acceptable visualization of all affected cardiac structures in 7 of 22 fetuses. High-quality 3D reconstruction of the site and spatial orientation of ventricular septal defects was obtained in 9 of 13 patients. Two-dimensional imaging remained the principal diagnostic modality in all cases with additional structural detail being obtained by 3D imaging in only two fetuses. CONCLUSIONS: Three-dimensional imaging of fetal heart disease is feasible for a wide range of lesions, and may provide additional information of clinical value in a small number of cases when compared with 2D imaging.

Comparative analysis of pattern, management and outcome of pre- versus postnatally diagnosed major congenital heart disease: a population-based study.

OBJECTIVES: Most pregnant women in New South Wales undergo obstetric ultrasound examination, including some assessment of fetal cardiac anatomy. We aimed to review the spectrum of cardiac defects, management and outcome data of all fetuses with diagnosis of major congenital heart disease between 1994 and 1996 and compare them to major congenital heart disease in infants born during the same 3-year study period. METHODS: Descriptive comprehensive study of the New South Wales population. Study centers included the single fetal echocardiographic referral service and the two pediatric cardiac centers of New South Wales. RESULTS: Ninety-seven fetuses and 562 infants with major congenital heart disease were identified (240,000 livebirths), resulting in a prenatal detection rate of 15%. Anomalies detectable by cardiac four-chamber views were diagnosed at an average rate of 30% (68/229) in utero. By contrast, lesions associated with abnormal ventricular outflow and great artery views were detected in only 6.7% (29/430; P < 0.0001) of cases prior to birth. Of the 97 fetuses, 29 were aborted, 16 died in utero, and 9 died early postnatally without treatment. Within 2 weeks of age, 23% with fetal and 40% (P < 0.05) with infant major congenital heart disease diagnosis required an intervention, mainly for patent ductus arteriosus dependent lesions. Postnatal survival was similar for the fetal and infant series up to 2 years of age: 77% (95% confidence interval 64-90%) vs. 85% (95% confidence interval 82-88%). CONCLUSIONS: Prenatal diagnosis has important implications for pregnancy outcome, in particular for univentricular lesions. However, the present mode of obstetric routine ultrasound scanning fails to identify most ductus arteriosus dependent cardiac lesions with a predictable need for early postnatal intervention.

Correlation between fetal cardiac diagnosis by obstetric and pediatric cardiologist sonographers and comparison with postnatal findings.

OBJECTIVE: To assess the level of agreement between obstetric and pediatric cardiologist sonographers' diagnosis of fetuses with suspected congenital heart disease and to compare this with the final postnatal diagnosis. DESIGN: We retrospectively reviewed the notes of 1037 patients undergoing fetal echocardiography over a 5-year period (1995-99) at the principal tertiary referral center for fetal cardiology in New South Wales, Australia. The median gestational age at presentation was 21 weeks (range 17-38) with 49% of the scans performed at < 21 weeks and a further 17% performed at 21-24 weeks. The accuracy of the fetal cardiac diagnosis was validated by neonatal cardiac investigation or autopsy. RESULTS: A total of 249 cases of congenital heart disease were identified antenatally during this 5-year period with the majority (84%) referred because of suspicion of a cardiac malformation during an obstetric scan. Of the 268 fetuses with congenital heart disease suspected by obstetric sonographers, 209 had confirmed cardiac defects. Complete correlation between obstetric sonographers' and pediatric cardiologists' prenatal cardiac findings was achieved in 62% of cases. There were major differences involving the atrioventricular morphology in 18% of cases and the outflow tract anatomy in 20%. Complete agreement between prenatal and postnatal diagnosis in fetuses with complex congenital heart disease was achieved in 59% of cases for obstetric sonography (17% false positive; 41% false negative) and 95% for fetal echocardiography by pediatric cardiologists (2% false positive; 5% false negative). CONCLUSIONS: Improved accuracy in diagnosis can be achieved through a pediatric cardiologist with special skills in fetal echocardiography working collaboratively with obstetric sonographers to optimize the details of diagnosis. This may influence management and counseling.

Three-dimensional quantitative echocardiographic assessment of ventricular volume in healthy human fetuses and in fetuses with congenital heart disease.

The purpose of this study was to evaluate the feasibility of three-dimensional freehand echocardiographic assessment of ventricular volumetry in healthy fetuses and in fetuses with congenital heart disease. The study was approved by the hospital institutional review board. After echocardiographic examination by conventional ultrasonographic equipment interfaced with a magnetic tracking system, three-dimensional cardiac data were collected prospectively in 57 fetuses. Ventricular volumes were determined from three-dimensional data sets, and 22 fetuses with congenital heart disease were compared with 29 healthy fetuses. A multiple regression analysis of covariance was performed to assess between-group differences. Gated three-dimensional volume data sets enabled assessment of ventricular volumes in 51 of the 57 fetuses. Both fetuses with and without congenital heart disease had exponential increases in cardiac volumes during gestation. In fetuses with congenital heart disease and a marked inequality of ventricular size but no heart failure, the combined end-diastolic and stroke volumes of both ventricles were found to be significantly reduced compared with controls with no disease and fetuses with other types of congenital heart disease. Three-dimensional imaging can provide estimates of ventricular volume changes in fetal hearts with abnormal ventricular morphology that cannot easily be performed by two-dimensional echocardiography, and it may provide insight into evolving congenital heart disease.

Communicating hydrocephalus secondary to a cardiac tumour compressing the superior vena cava.

An infant developing communicating hydrocephalus as a result of a rare cardiac tumour compressing the superior vena cava is reported. The development and regression of the hydrocephalus parallels the degree of obstruction to venous outflow. This finding is reviewed in the light of previous studies and case reports, and it is argued that the hydrocephalus is secondary to a reversible defect in cerebrospinal fluid absorption caused by the reversal of the normal cerebrospinal fluid to sagittal sinus pressure gradient.

Transesophageal echocardiographic guidance of blade atrial septostomy in children.

Transesophageal echocardiography (TEE) was used to guide blade atrial septostomy in children requiring decompression of right or left atrium. In conjunction with biplane fluoroscopy, TEE was used to position the blade septostomy catheter and to monitor the pullback from left atrium to right atrium. Subsequent balloon dilatation of atrial septum was also carried out under TEE control. The use of TEE monitoring facilitated the procedure by providing optimal views of intracardiac structures while also limiting the total radiation exposure.

Supraventricular electrical interaction in conjoined twins with common coronary sinus.

Conjoined twins with echocardiographic evidence of continuity of the coronary sinuses had identical heart rates on ECG. Both had broad, polyphasic QRS complexes, and various imaging modalities were unable to determine whether there was ventricular myocardial continuity. Administration of adenosine demonstrated that the broad polyphasic complexes were a "fusion" of the twins' individual QRS complexes, which could be clearly distinguished after administration of the drug. Ventricular pacing resulted in dissociation of the individual QRS complexes, thus demonstrating an absence of ventricular myocardial continuity. This was confirmed when the twins were successfully separated at the age of 10 months.

Simplified single patch technique for the repair of atrioventricular septal defect.

OBJECTIVE: Because of the complexity of traditional 1- and 2-patch techniques for the repair of complete atrioventricular septal defect, we modified our repair technique to avoid the use of any ventricular septal patch material. We report our prospective experience with this simplified 1-patch technique. METHOD: Forty-seven consecutive patients between May 1995 and August 1998 underwent repair with the use of this technique without modification. Repair was done in all patients by direct suturing of the common atrioventricular valve leaflets to the crest of the ventricular septum. No division of valve leaflets was necessary. A single pericardial patch was used to close the defect in the atrial septal component. Follow-up included electrocardiography and echocardiographic assessment of ventricular function, atrioventricular valve function, and adequacy of the left ventricular outflow tract. RESULTS: There were 2 deaths (4%), only 1 cardiac related, in the series. There were 17 male patients and 30 female patients. Mean age at repair was 5.6 months (median, 3.4 months). Associated lesions were repaired in 19 patients (40%). Mean follow-up was 1.85 years (median, 1.9 years). There was no heart block. There were no significant residual ventricular septal defects detected and no left ventricular outflow tract obstruction seen on echocardiography in any patient to date. Mitral valve status after operation was assessed as no incompetence in 13 patients (28%), minimal in 19 patients (40%), mild in 12 patients (26%), and moderate in 3 patients (6%). CONCLUSION: The repair of complete atrioventricular septal defect by direct suturing of the atrioventricular valve leaflets to the crest of the ventricular septum with a single-patch technique greatly simplifies the repair and does not lead to left ventricular outflow tract obstruction nor interfere with valve function.

Branch pulmonary artery growth after blalock-taussig shunts in tetralogy of fallot and pulmonary atresia with ventricular septal defect: a retrospective, echocardiographic study.

We performed a retrospective echocardiographic study in tetralogy of Fallot (TOF) or pulmonay atresia with ventricular septal defect (PA&VSD) to evaluate the effects of Blalock-Taussig shunt on branch pulmonary artery growth. There were 35 patients with TOF and 11 with PA&VSD. We measured the right and left pulmonary artery area index and also the combined pulmonary artery area index, both before and after shunt operation. The mean +/- SD of these three variables before the shunt operation in the TOF group were 63.5 +/- 22.5, 57.8 +/- 24.9, and 121.4 +/- 42.8 mm(2)/m(2); after shunt operation they were 98.5 +/- 33.6, 85.9 +/- 31.9, and 184.0 +/- 59.8 mm(2)/m(2), respectively (p values <0.0001, <0.0002, and <0.0001, respectively). In the PA&VSD group the comparable values before shunt operation were 66.5 +/- 16.0, 55.4 +/- 10.6, and 120.9 +/- 26.9 mm(2)/m(2) and after shunt operation were 90.5 +/- 22.9, 77.2 +/- 24.1, and 166.6 +/- 44.4 mm(2)/m(2), respectively (p values <0.0006, <0.014, and <0. 002, respectively). We also examined the effect of distensibility of pulmonary arteries by comparing the percentage change in size of the combined pulmonary artery area index in the first 4 months after shunt with those after this time (p < 0.023). There were no significant differences between left- and right-sided shunts, origin and distal pulmonary artery growth, and the TOF and PA&VSD groups.

Myocardial infarction complicating neonatal enterovirus myocarditis.

A 10-week-old, 31-week gestation preterm boy re-presented with heart failure after an initial episode of neonatal aseptic meningitis with positive CSF enterovirus polymerase chain reaction. Investigation demonstrated global myocardial dysfunction with left ventricle posterolateral myocardial infarction. The boy's heart failure was controlled with medical treatment but his myocardial dysfunction persisted 9 months after presentation.

Prolonged QT interval in Rett syndrome.

Rett syndrome is a severe neurodevelopmental disorder of unknown aetiology. A prolonged QT interval has been described previously in patients with Rett syndrome. To investigate QT prolongation and the presence of cardiac tachyarrhythmias in Rett syndrome electrocardiography and 24 hour Holter monitoring were performed prospectively in a cohort of 34 girls with Rett syndrome. The corrected QT value was prolonged in nine patients. Compared with a group of healthy controls of a similar age range, the patients with Rett syndrome had significantly longer corrected QT values. Clinical severity was not a predictor for prolonged QT intervals in the Rett syndrome cohort. The prolonged QT syndrome is a serious and potentially lethal cardiac disorder and should be considered in all girls with Rett syndrome.

Adenosine in the management of supraventricular tachycardia in children.

OBJECTIVE: To assess the efficacy and safety of adenosine in the management of supraventricular tachycardia in children. METHODOLOGY: A review of 43 children with supraventricular tachycardia who received intravenous adenosine between June 1992 and July 1995. RESULTS: Thirty-five patients had re-entrant supraventricular tachycardia and eight patients had atrial tachydysrhythmias. Reversion to sinus rhythm occurred in 75% of episodes in all patients treated for supraventricular tachycardia, and in 96% of episodes in patients with re-entrant supraventricular tachycardia. Early re-initiation of supraventricular tachycardia after reversion to sinus rhythm occurred in 25% of episodes. Sixteen percent of patients reverted with the recommended 0.05 mg/kg starting dose, and 35% reverted with a dose of 0.1 mg/kg. Four patients were given adenosine as a diagnostic procedure to elicit occult pre-excitation. The most common side effects were brief feelings of discomfort. No serious side effects occurred. CONCLUSION: Adenosine is safe and effective in the management of supraventricular tachycardia in children. A commencing dose of 0.1 mg/kg is appropriate.

Kawasaki disease in Australia, 1993-95.

AIM: To describe the epidemiology, management, and rate of cardiac sequelae of Kawasaki disease in Australia. DESIGN: Cases were notified to the Australian Paediatric Surveillance Unit, an active national surveillance scheme, from May 1993 to June 1995. RESULTS: 139 cases of Kawasaki disease were confirmed. In 1994, the annual incidence was 3.7/100,000 children < 5 years old. Sixteen children were not admitted to hospital. Coronary artery abnormalities were reported in 35 (25%) children. Two patients were diagnosed at postmortem examination. Sixty six per cent of patients were diagnosed within 10 days of onset and 81% of these received intravenous gammaglobulin within 10 days. Forty five of the notified children did not fulfil the study criteria because of streptococcal infection or insufficient clinical criteria. One child with streptococcal infection had coronary artery dilatation. CONCLUSION: Diagnosis of Kawasaki disease was delayed beyond 10 days in one third of patients, and almost 20% of children who could have received gammaglobulin within 10 days did not. The distinction between Kawasaki disease, streptococcal infection, and other possible diagnoses is problematic in some children.

Internal mammary artery grafting in a neonate for coronary hypoperfusion after arterial switch.

Coronary hypoperfusion may occur after the arterial switch operation, especially when coronary anatomy is complicated. We report successful use of the left internal mammary artery graft for a neonate with coronary hypoperfusion after the arterial switch operation for transposition of great arteries with intramural left coronary artery. Internal mammary arteriography showed a patent graft 19 months after operation.

Evaluation of a staged treatment protocol for rapid automatic junctional tachycardia after operation for congenital heart disease.

OBJECTIVES: This study sought to 1) develop an efficient treatment protocol for postoperative automatic junctional tachycardia (JT) using conventional drugs and techniques, and 2) identify clinical features associated with this disorder by analyzing a large study group. BACKGROUND: Postoperative JT is a transient arrhythmia that may be fatal after operation for congenital cardiac defects. Its precise cause is unknown. A variety of palliative treatments have evolved, but because of a low incidence of JT, large studies of the most efficient therapeutic sequence are lacking. METHODS: A protocol for rapid JT (>170 beats/min) was adopted in 1986, and was tested in 71 children between 1986 and 1994. Staged therapy involved 1) a reduction of catecholamines; 2) correction of fever; 3) atrial pacing to restore synchrony; 4) digoxin; 5) phenytoin or propranolol or verapamil; 6) procainamide or hypothermia; and 7) combined procainamide and hypothermia. Effective therapy was defined as a sustained reduction of JT rate <170 beats/min within 2 h. Clinical profiles of the study group were contrasted with all patients without JT from this same era to identify features associated with JT. RESULTS: Of the multiple treatment stages, only correction of fever and combined procainamide and hypothermia appeared to be efficacious. By refining the protocol to eliminate nonproductive stages, the time to JT control was significantly shortened for the last 30 patients. Treatment was ultimately successful in 70 of 71 children. Postoperative JT was strongly associated with young age, transient atrioventricular block and operations involving ventricular septal defect closure. CONCLUSIONS: A staged approach to therapy, with emphasis on combined hypothermia and procainamide in difficult cases, appears to be an effective management strategy for postoperative JT. These results may also serve as comparison data for evaluation of newer and promising JT options, such as intravenous amiodarone. Trauma to conduction tissue may play a central role in the etiology of this disorder.