Characterization of novel, recurrent genomic rearrangements as sensitive MRD targets in childhood B-cell precursor ALL.

B-cell precursor (BCP) ALL carry a variety of classical V(D)J rearrangements as well as genomic fusions and translocations. Here, we assessed the value of genomic capture high-throughput sequencing (gc-HTS) in BCP ALL (n = 183) for the identification and implementation of targets for minimal residual disease (MRD) testing. For TRδ, a total of 300 clonal rearrangements were detected in 158 of 183 samples (86%). Beside clonal Vδ2-Dδ3, Dδ2-Dδ3, and Vδ2-Jα we identified a novel group of recurrent Dδ-Jα rearrangements, comprising Dδ2 or Dδ3 segments fused predominantly to Jα29. For IGH-JH, 329 clonal rearrangements were identified in 172 of 183 samples (94%) including novel types of V(D)J joining. Oligoclonality was found in ~1/3 (n = 57/183) of ALL samples. Genomic breakpoints were identified in 71 BCP-ALL. A distinct MRD high-risk subgroup of IGH-V(D)J-germline ALL revealed frequent deletions of IKZF1 (n = 7/11) and the presence of genomic fusions (n = 10/11). Quantitative measurement using genomic fusion breakpoints achieved equivalent results compared to conventional V(D)J-based MRD testing and could be advantageous upon persistence of a leukemic clone. Taken together, selective gc-HTS expands the spectrum of suitable MRD targets and allows for the identification of genomic fusions relevant to risk and treatment stratification in childhood ALL.

Rapid Capture Next-Generation Sequencing in Clinical Diagnostics of Kinase Pathway Aberrations in B-Cell Precursor ALL.

Comprehensive next-generation sequencing (NGS) applications have recently identified various recurrent kinase and cytokine receptor rearrangements in Ph-like B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) amenable to tyrosin kinase inhibitor treatment. For rapid diagnostics of kinase pathway aberrations in minimal residual disease (MRD) high-risk BCP-ALL, we developed a PCR-independent NGS custom enrichment capture panel targeting recurrent genomic alterations, which allows for the identification of unknown 5' fusion partner genes and precise mapping of variable genomic breakpoints. Using a standardized bioinformatics algorithm, we identified kinase and cytokine receptor rearrangements in the majority of ALL patients with high burden of postinduction MRD and enrichment of IKZF1 mutation or deletion (IKZF1(del) ).

Percutaneous aortic valvuloplasty in inoperable symptomatic severe aortic stenosis in the very elderly.

Aortic valve replacement is the first therapeutic option in patients with symptomatic severe aortic stenosis. Given the fact that percutaneous aortic valve implantation is a relatively new procedure and the need for palliative treatment in symptomatic patients with a high surgical risk, percutaneous balloon aortic valvuloplasty is still employed. The authors describe two cases of percutaneous balloon aortic valvuloplasty in very elderly patients with severe calcified aortic stenosis not suitable for cardiac surgery, exacerbated in one case by significant coronary artery disease and left ventricular systolic dysfunction. The authors also review the role of this procedure in current interventional cardiology.

Anomalous origin of the circumflex coronary artery--two case reports.

As shown in many series, congenital coronary artery anomalies are found in 0.6 to 1.5% of patients undergoing coronary angiography. Various types of coronary anomalies have been described, many involving the circumflex artery. The second most common anomaly is of the circumflex arising from the right sinus of Valsalva, while origin in the right coronary artery is also frequent. The most common anomaly is absence of the left main coronary artery, the anterior descending and circumflex arteries originating separately in the left coronary sinus. Such anomalies are usually benign, although earlier and more aggressive atherosclerosis is more likely than in normal coronaries and myocardial ischemia can result. Although rare, this can manifest as sudden death. Conventional coronary angiography may be unable to determine the three-dimensional course of the anomalous vessel. The development of multislice computed tomography and its application to cardiac imaging mean that it is now possible to visualize the coronary arteries non-invasively and to obtain more accurate information on their proximal course. We present two cases of congenital anomaly of the circumflex coronary artery diagnosed with the aid of multislice computed tomography.

Small coronary arteries treated with sirolimus-eluting stents: one-year results of the PORTO multicentre registry.

AIMS: To assess the effectiveness and safety of sirolimus-eluting stents (SES) in de novo native coronary lesions in small vessels (/= 23 mm).The mean (SD) reference vessel diameter of the treated segment was 2.08 (0.33) mm and lesion length 11.04 (6.0) mm. After six months, LL was 0.07 (0.37) mm. BR was 5.1% in-stent and 9.1% in-segment. At one year, TLR was 5.6% and TVR was 9.0%. MACE rate was 2.6% at six months and 8.6% at one year with 2.3% cardiac death and 1.5% non-fatal myocardial infarction. Stent thrombosis rate at one year was 0.8% per protocol. There were more MACE in diabetic patients (12.8%) than in non-diabetic (5.4%, p=0.046), but no other significant differences in clinical and angiographic parameters were noted between the subgroups analysed. CONCLUSIONS: The use of SES for lesions in very small coronary arteries proved to be safe and efficacious, irrespective of the size and length of the stents, with low restenosis and repeat revascularisation rates at one year.

Percentage of coronary anomalies in a population of patients undergoing coronary angiography: a retrospective study.

Coronary artery anomalies, although less frequent than congenital anomalies of the heart chambers and valve morphology, should be considered in a wide range of ages, in both sexes and as a possible etiology in myocardial ischemia, infarction, and sudden death, as well as in the planning of heart surgery for coronary revascularization, correction of congenital heart malformations or valve replacement. Between January 1996 and June 2002 we reviewed our catheterization database and carried out a retrospective study of the 3660 angiographies performed in our cardiology department. The patients were referred for positive ischemic test, acute coronary syndrome and/or valvular heart disease. From the 3660 angiographies we identified 25 patients (0.68%) with coronary artery anomalies and report the prevalence and types of these anomalies in the population studied. We also assessed the presence of coronary artery disease.

Acute coronary syndromes in smokers: clinical and angiographic characteristics.

UNLABELLED: Smoking is a major and reversible risk factor for coronary artery disease. The present work aims to define the risk factors, angiographic and clinical characteristics and evolution of acute coronary syndromes in smokers. METHODS: We studied 521 consecutive patients with acute coronary syndrome admitted to the intensive care unit who underwent catheterization. We assessed the population in terms of risk factors, pathology (unstable angina or acute myocardial infarction), coronary morphology, left ventricular function, the need for intervention, evolution and complications over a one-year period. The characteristics of smokers were then compared with those of non-smokers. RESULTS: Of the 521 patients with acute coronary syndrome (391 men), 182 (35 %) were smokers. The smokers were younger than the non-smokers (56.3+/-9.5 versus 66.4 +/- 7.8; p < 0.001), were more frequently male (91 versus 66%; p < 0.001), and presented more risk factors (43% with 3 or more risk factors versus 17% in non-smokers; p < 0.001), more obesity (11 versus 5%; p < 0.01), and less diabetes (19 versus 37%; p < 0.001). Smokers presented greater prevalence of acute myocardial infarction (57 versus 40%; p < 0.001) and less unstable angina. Coronary morphology was not significantly different in smokers compared to non- smokers and left ventricular function after the aculte coronary syndrome was similar in both groups. Smokers less frequently underwent surgery during hospitalization (22% versus 35%; p < 0.01) but needed angioplasty as often as non-smokers (48% versus 16%; NS). Smokers presented more frequent complications (angina, heart failure, re-infarction or CABG) than non-smokers (26% versus 17%; p < 0.01), during the first year of follow-up. One-year mortality was similar in both groups. The results were not significantly different when adjusted for gender. CONCLUSIONS: On average, acute coronary syndrome occurred 10 years earlier in smokers than in non-smokers. The former generally presented more risk factors, lower prevalence of diabetes and higher of obesity, more myocardial infarctions and less unstable angina. After the acute coronary syndrome, at one year, smokers presented more complications than non-smokers but had similar mortality.

New classification of aortic dissection with reference to a case report.

The authors present a case report of a patient who was diagnosed with aortic dissection during a hemodynamic exam following acute myocardial infarction. With reference to this case, the European Society of Cardiology's latest classification of aortic dissection, published in 2001, is also presented. The patient had the usual risk factors described for aortic dissection, which are simultaneously those for coronary disease. The patient reported an isolated episode in the past of retrosternal pain, radiating to the back, which may have been caused by the aortic dissection. Since then he had been asymptomatic. Four years later, the patient was admitted to hospital following an anteroseptal acute myocardial infarction; fibrinolysis was contraindicated due to recent episodes of rectal bleeding and the patient underwent hemodynamic study (coronary angiography). Due to difficulties in manipulating the guide wire during this exam, aortography was performed, which showed aneurysm and Stanford type B aortic dissection of the thoracic aorta. During hospitalization, a thoracic-abdominal CT scan was performed, which confirmed chronic type B aortic dissection (with intraluminal thrombi). The authors present their reasons for considering this case to be Class 4 according to the new sub-types/classes of aortic dissection of the European Society of Cardiology (ESC): Class 1--Classical aortic dissection Class 2--Intramural hematoma/hemorrhage Class 3--Subtle/discrete aortic dissection Class 4--Plaque rupture/ulceration Class 5--Iatrogenic/traumatic aortic dissection. The authors consider this case to be of interest because of its rarity, the risk that fibrinolysis could have represented, and its categorization according to the latest classification of aortic dissection by the ESC.

Left main coronary artery originating in the right sinus of Valsalva.

A forty-one-year-old male, with no risk factors for coronary artery disease (CAD) and with moderate alcohol intake, was admitted in 1992 to Portalegre Hospital with heart failure due to viral cardiomyopathy. He was re-admitted in 1998 with acute pulmonary edema and was put on mechanical ventilation for 48 hours, and transferred to Pulido Valente Hospital when stable. The physical exam was without abnormalities. ECG showed first degree AV block, left ventricular hypertrophy and 2 mm ST depression in the precordial leads. The echocardiogram revealed left ventricular dilatation and depressed systolic function. Coronary angiography showed single-vessel CAD and coronary artery anomaly. Dobutamine stress echocardiography was halted due to hypertension, making it impossible to evaluate ischemic response. Holter monitoring showed five-complex ventricular tachycardia. The patient was discharged medicated with amiodarone, with indication for cardiac scintigraphy and electrophysiological study.