Dynamic changes in the clonal structure of MDS and AML in response to epigenetic therapy.

Traditional response criteria in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are based on bone marrow morphology and may not accurately reflect clonal tumor burden in patients treated with non-cytotoxic chemotherapy. We used next-generation sequencing of serial bone marrow samples to monitor MDS and AML tumor burden during treatment with epigenetic therapy (decitabine and panobinostat). Serial bone marrow samples (and skin as a source of normal DNA) from 25 MDS and AML patients were sequenced (exome or 285 gene panel). We observed that responders, including those in complete remission (CR), can have persistent measurable tumor burden (that is, mutations) for at least 1 year without disease progression. Using an ultrasensitive sequencing approach, we detected extremely rare mutations (equivalent to 1 heterozygous mutant cell in 2000 non-mutant cells) months to years before their expansion at disease relapse. While patients can live with persistent clonal hematopoiesis in a CR or stable disease, ultimately we find evidence that expansion of a rare subclone occurs at relapse or progression. Here we demonstrate that sequencing of serial samples provides an alternative measure of tumor burden in MDS or AML patients and augments traditional response criteria that rely on bone marrow blast percentage.

Prevalence of additional cardiovascular anomalies in patients referred for transcatheter closure of patent ductus arteriosus.

Catheter closure of the patent ductus arteriosus is now a reality. The purpose of this study was to establish the prevalence of associated cardiovascular defects and the accuracy of echocardiography in patients referred for transvenous ductal closure. This study reviewed 146 patients seen from 1981 to 1988: 126 with only a patent ductus arteriosus (Group I) and 20 with additional cardiovascular anomalies (Group II). Groups I and II did not differ significantly in age, gender or physical examination except for the presence of a continuous murmur (Group I 100% versus Group II 80%, p less than 0.001). A left patent ductus arteriosus was visualized by two-dimensional echocardiography in 96% of patients and was evident by Doppler study in 100%. A patent ductus arteriosus was not seen in six patients including a patient who was found to have only a collateral network from the aorta to the main pulmonary artery. The 12 patients with noncardiovascular abnormalities such as Down's syndrome were more likely than the overall group to have additional cardiovascular anomalies (6 of 12, p = 0.001). The cardiovascular anomalies encountered were varied. Eight of the 20 patients with such anomalies had only a restrictive ventricular septal defect in addition to the patent ductus arteriosus. Significant anomalies found at catheterization included two thoracic arteriovenous malformations and an isolated right carotid artery draining into the right pulmonary artery by way of a right ductus arteriosus. This study indicates that echocardiography is an effective diagnostic technique in this patient group. A thorough cardiac catheterization with angiography should be performed before implantation of a ductal device.

Balloon angioplasty of native coarctation of the aorta: midterm follow-up and prognostic factors.

UNLABELLED: OBJECTIVES, This retrospective analysis was designed to examine the intermediate and long-term effects of balloon angioplasty for native coarctation of the aorta and to determine whether any factors are predictive of outcome. BACKGROUND: Balloon angioplasty for native coarctation of the aorta is controversial. Concerns exist over lack of long-term follow-up and possible formation of aneurysms. The role of transverse arch and isthmus hypoplasia after balloon dilation is unknown. METHODS: Included in the study were all patients 3 days to 29 years old (mean age 4.6 years) referred for possible balloon dilation to the pediatric cardiac catheterization laboratory with evidence of a discrete coarctation of the aorta. The hemodynamic data, angiograms and clinical records of 102 patients were examined, with follow-up data from 2 to 117 months (median 36.2) available in 92 patients. RESULTS: Immediate success with balloon angioplasty was achieved in 93 (91.2%) of the 102 patients. Seventy-one patients (77.2%) with intermediate follow-up data (range 12 to 117 months) available are asymptomatic and normotensive, with insignificant arm to leg blood pressure gradients (< or = 20 mm Hg). Twenty-one patients (22.8%) with an initial successful result developed an increase in gradient 2 at 86 months after angioplasty, requiring reintervention in 18. Follow-up > 72 months is available in 17 patients, 16 of whom are normotensive and have not required additional intervention. No additional intervention was needed in 88.4% of older children and infants > 7 months old. Ten of the 13 surviving neonates who initially had a successful dilation required reangioplasty or operation 14 days to 10 months (median 4.6 months) after angioplasty. Transverse arch hypoplasia had minimal effect on follow-up blood pressure gradient, whereas isthmic hypoplasia was associated with reintervention in 50%. A small aneurysm was noted in 2 (1.9%) of 102 patients. CONCLUSIONS: Balloon angioplasty of native aortic coarctation is effective in infants and older children. In neonates, balloon angioplasty provides effective palliation only. Aneurysm formation is rare; however, lifetime follow-up is warranted.

Intravascular stents in congenital heart disease: short- and long-term results from a large single-center experience.

OBJECTIVES: This report describes the results of the Food and Drug Administration's phase 1 and 2 clinical trials of intravascular stents at Texas Children's Hospital. BACKGROUND: Since the late 1980s, intravascular stent implantation for the treatment of arterial and venous stenoses in congenital heart disease has been highly successful. METHODS: Stents were placed in postoperative pulmonary artery (PA) stenoses, congenital PA stenoses or stenoses of systemic veins/venous anastomoses. Prospective collection of data according to protocol was done before intervention, after stent implantation and at follow-up catheterization. RESULTS: At stent implantation, pressure gradients decreased significantly in all three groups (mean +/- SD): from 46 +/- 25 to 10 +/- 13 mm Hg in postoperative PA stenoses (p < 0.001); from 71 +/- 45 to 15 +/- 21 mm Hg in congenital PA stenoses (p < 0.001); and from 7 +/- 6 to 1 +/- 2 mm Hg in stenoses of systemic veins/venous anastomoses stenoses (p < 0.001). Vessel diameters markedly increased: from 6 +/- 3 to 12 +/- 3 mm in postoperative PA stenoses (p < 0.001); from 3 + 1 to 9 + 1 mm in congenital PA stenoses (p < 0.001); and from 3 +/- 4 to 12 +/- 4 mm in stenoses of systemic veins/venous anastomoses (p < 0.001). In the postoperative and congenital PA stenoses groups, right ventricular pressure decreased (right ventricular pressure indexed to femoral artery pressure ratio): from 0.63 +/- 0.2 to 0.41 +/- 0.02 (p < 0.001) and from 0.71 +/- 0.3 to 0.55 +/- 0.35 (p = 0.04), respectively. Perfusion to a single affected lung increased from 31 +/- 17% to 46 +/- 14% (p < 0.001). On recatheterization (mean 14 months), results varied minimally. Repeat angioplasty of residual stent stenoses was safe and effective. Complications included four early patients with stent migration, three with stent thrombosis and two deaths. There were no late complications. Significant restenosis occurred in only three patients. CONCLUSIONS: Intravascular stents for the treatment of vascular stenoses in congenital heart disease provide excellent immediate and long-term results.

Double balloon technique for dilation of valvular or vessel stenosis in congenital and acquired heart disease.

Despite the generally excellent success with balloon dilation for the stenotic lesions of congenital and acquired heart disease, technical difficulties sometimes prevent satisfactory results. Such technical difficulties include: a large diameter of the anulus of the stenotic lesion relative to available balloon diameter, difficulty in the insertion or removal of the larger balloon catheters, and permanent damage to or obstruction of the femoral vessels by the redundant deflated balloon material of the large balloons. A double balloon technique was initiated to resolve these difficulties. With this method, percutaneous balloon angioplasty catheters were inserted in right and left femoral vessels, placed side by side across the stenotic lesion and inflated simultaneously. Dilation procedures using the two balloon technique were performed in 41 patients: 18 with pulmonary valve stenosis, 14 with aortic valve stenosis, 5 with mitral valve stenosis, 3 with vena caval obstruction following the Mustard or Senning procedure and 1 with tricuspid valve stenosis. Patient ages ranged from 1 to 75 years (mean 17.8) and patient weights ranged from 8.9 to 89 kg (mean 42.3). Balloon catheter sizes ranged from 10 to 20 mm in diameter. Average maximal pressure gradient in mm Hg before dilation was 61 in pulmonary stenosis, 68 in aortic stenosis, 21 in mitral stenosis, 12 in tricuspid stenosis and 25 in vena caval stenosis. Average maximal valvular pressure gradient after dilation was 13 in pulmonary stenosis, 24 in aortic stenosis, 4 in mitral stenosis, 0 in tricuspid stenosis, and 1 in vena caval stenosis. No major complications were encountered with the procedures.(ABSTRACT TRUNCATED AT 250 WORDS)

Epigenomic analysis of the HOX gene loci reveals mechanisms that may control canonical expression patterns in AML and normal hematopoietic cells.

HOX genes are highly expressed in many acute myeloid leukemia (AML) samples, but the patterns of expression and associated regulatory mechanisms are not clearly understood. We analyzed RNA sequencing data from 179 primary AML samples and normal hematopoietic cells to understand the range of expression patterns in normal versus leukemic cells. HOX expression in AML was restricted to specific genes in the HOXA or HOXB loci, and was highly correlated with recurrent cytogenetic abnormalities. However, the majority of samples expressed a canonical set of HOXA and HOXB genes that was nearly identical to the expression signature of normal hematopoietic stem/progenitor cells. Transcriptional profiles at the HOX loci were similar between normal cells and AML samples, and involved bidirectional transcription at the center of each gene cluster. Epigenetic analysis of a subset of AML samples also identified common regions of chromatin accessibility in AML samples and normal CD34(+) cells that displayed differences in methylation depending on HOX expression patterns. These data provide an integrated epigenetic view of the HOX gene loci in primary AML samples, and suggest that HOX expression in most AML samples represents a normal stem cell program that is controlled by epigenetic mechanisms at specific regulatory elements.

Percutaneous stenting of superior vena cava syndrome: a case report and review of the literature.

Superior vena cava syndrome (SVCS) is a distressing manifestation of benign or malignant disease obstructing return of blood flow through the superior vena cava (SVC). Treatment, often centering around management of the underlying illness, may be slow in relieving symptoms, relying on the recruitment of collateral veins to reestablish blood flow. Percutaneous delivery of metallic stents into the vena cava has been used with success to relieve obstruction to blood flow quickly and completely. We present the case of a patient with complete occlusion of the SVC who underwent successful vena caval revascularization with placement of balloon expandable metallic stents. We also review published reports on the use of stents for SVCS. Results from several series demonstrate that stents can be used with excellent results. Response rates in these series reviewed range from 68% to 100%. Recurrence of symptoms occurred in 4% to 45% of patients but could often be treated with anticoagulation, angioplasty of the stented area, or repeat stenting. Stenting has been used successfully in patients with malignant diseases and in the less common cases of SVCS from a benign etiology. Complications are uncommon and usually of minor consequence. Anticoagulation, thrombolytics, and thrombectomy or atherectomy catheters have also been used during or following stent implantation although their use remains primarily empiric. Percutaneous treatment of SVC obstruction offers patients hope for prompt and dramatic relief from the symptoms of SVCS.

Transcatheter occlusion of patent ductus arteriosus in adults.

This study examines whether transcatheter closure of a patent ductus arteriosus (PDA) using a Rashkind PDA occluder device is safe and effective in adults, or if adults have complications not sited in children owing to prolonged aorticopulmonary communication, high surgical risks or calcified PDAs. Fifteen patients aged 22 to 76 years (mean 42 +/- 14) were referred for transcatheter PDA occlusion. Exercise intolerance was the most frequent clinical manifestation. Eleven of 15 patients had surgical risk factors that included left ventricular failure (n = 10), biventricular failure (n = 1), elevated pulmonary pressures (n = 1), and a calcified PDA (n = 5). Twelve millimeter devices were placed in 4 PDAs < or = 3 mm in diameter; 17 mm devices were placed in 11 PDAs 3 to 6 mm in diameter. Seven (47%) were occluded angiographically shortly after device placement; another 5 PDAs (33%) were occluded echocardiographically within 24 hours of the procedure. Completed occlusion in this time interval was more likely to occur in PDAs < 5 mm in diameter (p = 0.0009). Of the 3 remaining PDAs with follow-up ranging from 9 to 38 months, 2 have demonstrated gradual diminution of shunting and have trivial leaks by color/Doppler flow. The other patient with a residual PDA has no ductal flow after placement of a second device. No complications related to device implantation or closure of the PDA occurred in any patient. No complications were reported in the follow-up patients who received evaluation (14 of 15 patients; range 1 to 38 months).(ABSTRACT TRUNCATED AT 250 WORDS)

Relief of superior vena cava syndrome due to fibrosing mediastinitis using the Palmaz stent.

Relief of superior vena cava (SVC) syndrome due to non-neoplastic mediastinal disease presents a formidable challenge. Long-term patency of surgically created bypass grafts has been poor, and the morbidity associated with these procedures is substantial. We report a case of SVC syndrome, caused by fibrosing mediastinitis, treated with Palmaz balloon expandable intravascular stents. Intravascular stents are a promising alternative for relief of non-neoplastic SVC obstruction.

Total pulmonary artery occlusion immediately after lung transplantation: successful revascularization with intravascular stents.

Occlusion of the pulmonary artery anastomosis is an uncommon early complication of lung transplantation which necessitates emergency surgical revision. Percutaneous correction of such a complication has not been previously reported. We report a patient who had total pulmonary artery occlusion less than 24 hours after right single lung transplantation with successful revascularization achieved by means of percutaneously delivered endovascular stents.

Intraoperative stents to rehabilitate severely stenotic pulmonary vessels.

BACKGROUND: Patch enlargement of severe branch pulmonary artery stenosis (PAS) or pulmonary vein ostial stenosis (PVS) can be technically challenging. Recurrences are common and exposure may require long periods of cardiopulmonary bypass (CPB). METHODS: Since 1993, we performed 31 procedures on 27 patients with endovascular stents placed intraoperatively under direct surgical vision: 22 patients with tight PAS and 5 patients with PVS. Selection for intraoperative (vs catheterization laboratory) stent placement was prompted by: (1) the need for a concomitant cardiac surgical procedure (16 cases); (2) limited vascular access for catheterization laboratory stent placement (11 cases); or (3) "rescue" of patients with complications after attempted placement of stents (4 cases). RESULTS: In this group of very complex and challenging patients there were 5 hospital deaths (hospital survival, 81%). Follow-up of survivors has ranged from 1 month to 7 years (mean 2.8 +/- 1.7 years). There have been 3 late deaths (late "series" survival, 70%). No complication or death was related to stent placement. Surviving patients have had significant clinical improvement. Mean pulmonary gradient (postoperative vs preoperative echo) has fallen in all survivors and has decreased from a mean of 66 mm Hg preoperatively to 28 mm Hg postoperatively (p = 0.01). All pulmonary arteries are appreciably enlarged and will be easier to deal with at a later date if necessary. One patient (DORV, HLHS ) with pulmonary vein stents has gone on to a successful Glenn procedure. The other two surviving patients with PV stents have occlusion of their proximal PVs on follow-up catheterization; thus only 1 of 5 patients with stents for PVS has had a successful outcome. Four patients have had repeat surgery. Stents have produced no impediment to subsequent surgical procedures, and the pulmonary arteries were easy to work with. CONCLUSIONS: Intraoperative stenting provides an attractive option for "rehabilitation" of pulmonary vessels. Direct vision insertion on CPB is extremely quick and immediately effective, limiting the CPB exposure required to treat this problem. Once stented, vessels remain open and are amenable to future surgical intervention as necessary. Outcome is better for patients with PAS versus those with PVS.

Late conduit occlusion after modified Fontan procedure with classic Glenn shunt.

A number of patients with complex congenital heart disease who were initially palliated with a classic Glenn shunt subsequently underwent modified Fontan procedures. This report discusses the operative management of complete occlusion of right atrial-to-right ventricular conduits in patients with patent classic Glenn shunts. The literature is reviewed regarding similar patients, and alternative treatment strategies are discussed.

Conceptual structure and social functions of behavior explanations: beyond person--situation attributions.

The traditional approach to studying behavior explanations involves treating them as either person causes or situation causes and assessing them by using rating scales. An analysis of people's free-response behavior explanations reveals, however, that the conceptual distinctions people use in their explanations are more complex and sophisticated than the person-situation dichotomy suggests. The authors, therefore, introduce a model of the conceptual structure of folk behavior explanations (the network of concepts and assumptions on which explanations are based) and test it in 4 studies. The modes and features of behavior explanations within this conceptual structure also have specific social functions. In 2 additional studies, the authors demonstrate that people alter distinct features of their explanations when pursuing particular impression-management goals and that listeners make inferences about explainers' goals on the basis of these features.

Congestive heart failure in children.

Although revitalizing dead or severely injured myocardial cells is still beyond the reach of modern treatment, the ability to change the loading conditions and the contractile state of the heart has enabled practitioners to reverse deleterious compensatory mechanisms in patients with CHF. Several new and improved medicines have made this strategy possible. Early and determined surgical treatment of patients with CHF has enabled cure of some previously debilitating or fatal defects. The combined use of surgery and interventional catheterization has allowed many patients to profit from the benefits not available from either modality alone. In the future, cellular, subcellular, and gene therapy may make the treatment of patients with CHF simple and even prevent CHD.

Airway compression secondary to left atrial enlargement and increased pulmonary artery pressure.

Although congenital cardiac defects are infrequently considered a cause of major airway compression in neonates and infants, patients with left-sided cardiac enlargement can develop compression of the left mainstem bronchus. This is a consequence of the intimate relationship of the trachea and left mainstem bronchus to the left atrium, left pulmonary veins and left pulmonary artery. If the mean pulmonary arterial pressure, mean left atrial pressure and carinal angle are increased, the likelihood of major airway compression is high.

Catheter closure of secundum atrial septal defects.

Catheter occlusion of atrial septal defects has its roots in the 1950s, with early devices being implanted during closed-heart surgery without cardiopulmonary bypass. For the past 20 years, various catheter-delivered devices have undergone testing and refinement. Designs have included single- and double-disk prostheses, with a variety of materials, delivery systems, and techniques. In this monograph, the history of atrial septal defect occluders and their evaluation, results, and prognoses will be outlined. The early work of King and Mills has been advanced in the forms of the Rashkind and Lock-USCI Clamshell occluders (USCI; Billerica, Mass), the "buttoned" device (custom made by E.B. Sideris), the Babic atrial septal defect occlusion system (Osypka, GmbH; Grenzach-Wyhlen, Germany), the Das-Angel Wings atrial septal defect occlusion device (Microvena Corporation; White Bear Lake, Minn), and others. The future holds promise for approved devices in the treatment of selected secundum atrial septal defects.

Successful closure of a previously unsuspected atrial septal defect by an implantable Clamshell device and subsequent transvenous pacemaker implantation.

Implantation of transvenous leads for a permanent cardiac pacing system usually requires the absence of intracardiac shunts. We report the case of an asymptomatic atrial septal defect in an 11-year-old boy who required permanent pacing. We implanted an atrial septal defect closure (Clamshell) device prior to implantation of transvenous leads. This new device makes transvenous implantation possible and may reduce the risk of stroke in patients with these anomalies.

Adult patients with congenital heart disease.

Adult patients with congenital heart disease present complex problems that require individualized management. Unfortunately, few physicians who care for adults with congenital heart disease have received adequate specific training to deal with their problems. Pediatric cardiologists who are familiar with congenital heart disease often refer patients to adult cardiologists after adolescence. And adult cardiologists have not traditionally had much training or experience in dealing with congenital heart disease. The cardiac needs of these patients are often best managed through the collaborative efforts of adult and pediatric cardiologists, cardiac surgeons, specialized nurse clinicians, and social workers. Of course, it is crucial to their optimal care that there be involvement of a primary care physician who can help with their many medical, surgical, and psychosocial problems.

Recurrent DNMT3A mutations in patients with myelodysplastic syndromes.

Alterations in DNA methylation have been implicated in the pathogenesis of myelodysplastic syndromes (MDS), although the underlying mechanism remains largely unknown. Methylation of CpG dinucleotides is mediated by DNA methyltransferases, including DNMT1, DNMT3A and DNMT3B. DNMT3A mutations have recently been reported in patients with de novo acute myeloid leukemia (AML), providing a rationale for examining the status of DNMT3A in MDS samples. In this study, we report the frequency of DNMT3A mutations in patients with de novo MDS, and their association with secondary AML. We sequenced all coding exons of DNMT3A using DNA from bone marrow and paired normal cells from 150 patients with MDS and identified 13 heterozygous mutations with predicted translational consequences in 12/150 patients (8.0%). Amino acid R882, located in the methyltransferase domain of DNMT3A, was the most common mutation site, accounting for 4/13 mutations. DNMT3A mutations were expressed in the majority of cells in all tested mutant samples regardless of myeloblast counts, suggesting that DNMT3A mutations occur early in the course of MDS. Patients with DNMT3A mutations had worse overall survival compared with patients without DNMT3A mutations (P=0.005) and more rapid progression to AML (P=0.007), suggesting that DNMT3A mutation status may have prognostic value in de novo MDS.