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In Europe, mitral regurgitation and aortic stenosis are the most common valve lesions requiring interventions. In advanced stages, these valve pathologies affect patients' quality of life and prognosis. The prevalence of mitral regurgitation and aortic stenosis is increasing with age. In view of an aging population and the comorbidities associated with age, these valve defects represent an increasing challenge to health care providers. Nowadays, surgical as well as catheter-based treatment options are available to treat affected patients. Therapeutic strategies suitable to the individual patient should be discussed in interdisciplinary heart teams. The aim of the present article is to give an overview of possible guideline-conform heart team decisions based on patient examples. [ABSTRACT FROM AUTHOR]

The preoperative cardiovascular risk management accounts for patient related risk factors, the circumstances leading to the surgical procedure, and the risk of the operation. While urgent operations should not be delayed for cardiac testing, an elective surgical intervention should be postponed in unstable cardiac conditions. In stable cardiac situations, prophylactic coronary interventions to reduce the risk of perioperative complications are rarely indicated. Therefore, in most cases, the planned operation can be performed without previous cardiac stress testing or coronary angiography. Preoperative imaging stress testing is recommended for patients with poor functional capacities that are at high cardiovascular risk prior to a high-risk operation. According to the literature, preoperative prophylactic administration of beta-blockers and aspirin is controversial. Preoperative discontinuation of dual anti-platelet therapy within six months following drug-eluting stent implantation is not recommended. [ABSTRACT FROM AUTHOR]

Purpose: The ironman (IM) triathlon is a popular ultraendurance competition, consisting of 3.8 km of swimming, 180.2 km of cycling, and 42.2 km of running. The aim of this study was to investigate the predictors of IM race time, comparing echocardiographic findings, anthropometric measures, and training characteristics. Methods: Amateur IM athletes (ATHL) participating in the Zurich IM race in 2010 were included. Participants were examined the day before the race by a comprehensive echocardiographic examination. Moreover, anthropometric measurements were obtained the same day. During the 3 months before the race, each IM-ATHL maintained a detailed training diary. Recorded data were related to total IM race time. Results: Thirty-eight IM finishers (mean ± SD age = 38 + 9 yr, 32 men [84%]) were evaluated. Total race time was 684 ± 89 min (mean + SD). For right ventricular fractional area change (45% ± 7%, Spearman p = -0.33, P = 0.05), a weak correlation with race time was observed. Race performance exhibited stronger associations with percent body fat (15.2 ± 5.6%, p = 0.56, P = 0.001), speed in running training (11.7 ± 1.2 km⋅h-1, p = -0.52, P = 0.002), and left ventricular myocardial mass index (98 + 24 g⋅m-2, p = -0.42, P = 0.009). The strongest association was found between race time and right ventricular end-diastolic area (22 ± 4 cm2, p= -0.64, P< 0.0001). In multivariate analysis, right ventricular end-diastolic area (Β = -16.7, 95% confidence interval = -27.3 to -6.1, P = 0.003) and percent body fat ((Β = 6.8, 95% confidence interval = 1.1-12.6, P = 0.02) were independently predictive of IM race time. Conclusions: In amateur IM-ATHL, RV end-diastolic area and percent body fat were independently related to race performance. RV end-diastolic area was the strongest predictor of race time. The role of the RV in endurance exercise may thus be more important than previously thought and needs to be further studied. [ABSTRACT FROM AUTHOR]

Background: Lung cancer in never smokers would rank as the seventh most common cause of cancer death worldwide. Methods and Findings: We performed high-resolution array comparative genomic hybridization analysis of lung adenocarcinoma in sixty never smokers and identified fourteen new minimal common regions (MCR) of gain or loss, of which five contained a single gene (MOCS2, NSUN3, KHDRBS2, SNTG1 and ST18). One larger MCR of gain contained NSD1. One focal amplification and nine gains contained FUS. NSD1 and FUS are oncogenes hitherto not known to be associated with lung cancer. FISH showed that the amplicon containing FUS was joined to the next telomeric amplicon at 16p11.2. FUS was over-expressed in 10 tumors with gain of 16p11.2 compared to 30 tumors without that gain. Other cancer genes present in aberrations included ARNT, BCL9, CDK4, CDKN2B, EGFR, ERBB2, MDM2, MDM4, MET, MYC and KRAS. Unsupervised hierarchical clustering with adjustment for false-discovery rate revealed clusters differing by the level and pattern of aberrations and displaying particular tumor characteristics. One cluster was strongly associated with gain of MYC. Another cluster was characterized by extensive losses containing tumor suppressor genes of which RB1 and WRN. Tumors in that cluster frequently harbored a central scar-like fibrosis. A third cluster was associated with gains on 7p and 7q, containing ETV1 and BRAF, and displayed the highest rate of EGFR mutations. SNP array analysis validated copy-number aberrations and revealed that RB1 and WRN were altered by recurrent copy-neutral loss of heterozygosity. Conclusions: The present study has uncovered new aberrations containing cancer genes. The oncogene FUS is a candidate gene in the 16p region that is frequently gained in never smokers. Multiple genetic pathways defined by gains of MYC, deletions of RB1 and WRN or gains on 7p and 7q are involved in lung adenocarcinoma in never smokers. [ABSTRACT FROM AUTHOR]

Abstract: The role of acquired chromosomal rearrangements in oncogenesis (cytogenomics) and tumor progression is now well established. These alterations are multiple and diverse and the products of these rearranged genes play an essential role in the transformation and growth of cancer cells. The validity of this assumption is demonstrated by the development of specific inhibitors or antibodies that eliminate tumoral cells by targeting some of these changes. Imatinib, an inhibitor of the tyrosine kinase ABL, the prototype of these targeting drugs, is yielding complete remissions in most CML patients. Knowledge of chromosomal abnormalities is becoming an essential contribution to the diagnosis and prognosis of cancers but also for monitoring minimal residual disease or relapse. The concept of the “cytogenetic uniqueness” of each cancer has resulted in personalized treatment. This investigation will expound upon, besides the recurrent genomic alterations, the numerous products of perverted Darwinian selection at the cellular level. [ABSTRACT FROM AUTHOR]

Limited information exists regarding the significance of dyspnea in patients who are unable to exercise and the contribution of myocardial ischemia to this symptom. To assess this, we evaluated results of dobutamine stress echocardiography (DSE) and long-term outcome of patients with dyspnea referred for DSE. We studied 6,376 consecutive patients who were unable to perform an exercise test and were referred for DSE. Patients were classified according to presenting symptoms and followed for 5.5 ± 2.8 years. End points were cardiac ischemic events (myocardial infarction or revascularization), hospitalization for heart failure (HF), and death. Dobutamine stress echocardiogram was positive for ischemia in 19% of patients with dyspnea versus 24% (p = 0.002) of those with typical angina and 17% (p = 0.2) of asymptomatic patients. In multivariate analysis, risk of death was increased in dyspneic patients versus asymptomatic patients (hazard ratio [HR] 1.14, p = 0.02) and patients with chest pain (HR 1.20, p <0.001). Hospitalization for HF occurred more often in patients with dyspnea (HR 1.26, p = 0.05 vs asymptomatic; HR 1.24, p = 0.06 vs chest pain), especially in the subset without previous HF (HR 1.45, p = 0.006 vs chest pain). Risk of cardiac ischemic events in patients with dyspnea was similar versus asymptomatic patients (HR 0.92, p = 0.39) and decreased versus patients with chest pain (HR 0.70, p <0.001). In conclusion, in patients referred for DSE, dyspnea was associated with a poor outcome. This increased hazard seems not to be linked to myocardial ischemia, but instead to HF and death. [Copyright &y& Elsevier]

OBJECTIVE: To evaluate the effects of resection of hepatic carcinold metastases on progression and prognosis of carclnold heart disease. PATIENTS AND METHODS: From our database of 265 consecutive patients diagnosed as having carcinold heart disease from January 1, 1980, through December 31, 2005, we calculated survival from first diagnosis of cardiac involvement. Hepatic resection during follow-up was entered as a time-dependent covariable in a multi-variable analysis. In patients with serial echocardiograms more than 1 year apart without intervening cardiac surgery, a previously validated cardiac severity score was calculated. A score Increase that exceeded 25% was considered relevant progression. RESULTS: Hepatic resection was performed In 31 patients (12%) during follow-up. Five-year survival was significantly higher In these patients (86.5%; 95% confidence interval [CI], 73.5%-100.0%) than In patients without hepatic resection (29.0%; 95% Cl, 23.3%- 36.1%; univariable hazard ratio for hepatic resection, 0.25; 95% CI 0.12-0.53; P<.001). Hepatic resection remained strongly associated with Improved prognosis in multivariable analysis (hazard ratio, 0.31; 95% Cl, 0.14-0.66; P=.003). Among 77 patients (29%) with serial echocardiograms, 10 (13%) underwent hepatic resection during follow-up; resection was independently associated with decreased risk of cardiac progression (odds ratio, 0.29; 95% Cl, 0.06-0.75; P=.03). CONCLUSION: Despite the limitations of this retrospective nonrandomized study, our data suggest that patients with carcinold heart disease who undergo hepatic resection have decreased cardiac progression and improved prognosis. Eligible patients should be considered for hepatic surgery. [ABSTRACT FROM AUTHOR]

The article presents information on a study which analyzes the impact of exercise and altitude-induced increase in pulmonary artery pressures on left ventricular (LV) diastolic function in patients with high-altitude pulmonary edema (HAPE). The study included 29 HAPE susceptible (HAPE-S) and 10 control subjects.

Objectives: We aimed to compare the hemodynamic effects of right-atrial-paced (DDD) and right-atrial-sensed (VDD) biventricular paced rhythm on cardiac resynchronization therapy (CRT). Background: Cardiac resynchronization therapy improves hemodynamics in patients with severe heart failure and left ventricular (LV) dyssynchrony. However, the impact of active right atrial pacing on resynchronization therapy is unknown. Methods: Seventeen CRT patients were studied 10 months (range: 1 to 46 months) after implantation. At baseline, the programmed atrioventricular delay was optimized by timing LV contraction properly at the end of atrial contraction. In both modes the acute hemodynamic effects were assessed by multiple Doppler echocardiographic parameters. Results: Compared to DDD pacing, VDD pacing resulted in much better improvement of intraventricular dyssynchrony assessed by the septal-to-posterior wall motion delay (VDD 106 ± 83 ms vs. DDD 145 ± 95 ms; p = 0.001), whereas the interventricular mechanical delay (difference between onset of pulmonary and aortic outflow) did not differ (VDD 20 ± 21 ms vs. DDD 18 ± 17 ms; p = NS). Furthermore, VDD pacing significantly prolonged the rate-corrected LV filling period (VDD 458 ± 123 ms vs. DDD 371 ± 94 ms; p = 0.0001) and improved the myocardial performance index (VDD 0.60 ± 0.18 vs. DDD 0.71 ± 0.23; p &#60; 0.01). Conclusions: Our findings suggest that avoidance of right atrial pacing results in a higher degree of LV resynchronization, in a substantial prolongation of the LV filling period, and in an improved myocardial performance. Thus, the VDD mode seems to be superior to the DDD mode in CRT patients. [Copyright &y& Elsevier]

Most carcinoid tumors originate in the gut. Carcinoid heart disease typically occurs when tumor progression results in the formation of hepatic metastases, which allow vasoactive substances to reach the heart without being metabolized in the liver. Except for patients with primary ovarian carcinoid tumors, the occurrence of carcinoid heart disease without hepatic metastases has been reported only anecdotally. From a retrospective analysis of 265 patients, 4 patients were identified who developed carcinoid heart disease in the absence of liver metastases or primary tumors located in the ovaries. All 4 patients had metastases to the retroperitoneal lymph nodes and had carcinoid syndrome. The reasons for referral to cardiac evaluation by transthoracic echocardiography were findings on auscultation in 3 patients and exertional dyspnea in 1 patient. In conclusion, cardiac symptoms or findings on auscultation should prompt further evaluation by transthoracic echocardiography in these patients, although the classic prerequisites for development of carcinoid heart disease are lacking. [Copyright &y& Elsevier]

Background: In most patients with secundum atrial septal defects (ASD), transcatheter closure is the preferred treatment strategy, but whether device size affects clinical outcomes is unknown. We sought to study the efficacy and safety of large closure devices compared to the use of smaller devices. Methods: Using a single-center, prospective registry of adult patients undergoing transcatheter ASD closure, patients receiving a large closure device (waist diameter ≥25 mm, n = 41) were compared to patients receiving smaller devices (waist diameter ≤24 mm, n = 66). We analyzed pre-interventional clinical, hemodynamic and echocardiographic data, interventional success and complication rates, and 6-month clinical and echocardiographic outcomes. The primary efficacy outcome was successful ASD closure achieved by a single procedure and confirmed by lack of a significant residual shunt at 6 months. The primary safety outcome was a composite of device embolization, major bleeding, and new-onset atrial arrhythmia occurring within 6 months. Results: Transcatheter ASD closure using large devices was successful in 90 % compared to 97 % of patients receiving smaller devices as defined by the primary efficacy outcome (p = 0.20). The primary safety outcome occurred in 4 patients of the large and 6 patients of the small device group, resulting in an event-free rate of 90 and 91 %, respectively (p = 0.89). Similar significant symptomatic improvement was observed in both treatment groups after 6 months, indicated by a 50 % increase in the fraction of patients in NYHA class I (p < 0.0001 vs. baseline). Conclusions: Transcatheter closure in this cohort of patients with large or small ASD was effective with similar complication rates during short-term follow-up irrespective of the size of the implanted device. [ABSTRACT FROM AUTHOR]

In France gamete donation and notably sperm donation are anonymous. It has been claimed that anonymous artificial insemination by donor (AID) could highly contribute to an increase in the level of consanguinity and the incidence of autosomal recessive diseases, due to the unions between offspring of anonymous donors, unaware of their biological kinship, with the special case of unions between half-siblings. The actual incidence of consanguinity due to AID was compared with that resulting from the two other main sources of consanguinity and recessive diseases, i.e. voluntary unions between related individuals or inadvertent unions between the offspring of a common unknown male ancestor (false paternity). From these data, we estimated that expected unions in France between half sibs per year are 0.12 between offspring of sperm donors (1.2 every 10 years) and 0.5 between offspring of common male ancestors through false paternity (5 every 10 years). More generally, the inadvertent unions between false paternity offspring are roughly four times more frequent than those resulting from anonymous AID. We estimated that in the future, when AID has been in practice for several generations, out the 820 000 annual births in France, respectively, 6 and 25 births will be consanguineous through an unknown common ancestor related to anonymous AID and to a false paternity, both of which are negligible when compared with the 1256 children born from first-degree cousins. About 672 children per year are born with a recessive genetic disease due to the panmictic risk and additional affected cases due to consanguinity would be 34.54 for first-cousin offspring, 0.33 for offspring of individuals related due to false paternity and 0.079 for offspring of individuals related due to anonymous AID. Anonymous AID would therefore be responsible for 0.46% of consanguineous births and for 0.01% of recessive diseases. Therefore, the effect of anonymous AID on half-sibling unions, consanguinity and recessive disease incidence can be regarded as marginal. [ABSTRACT FROM AUTHOR]

This article presents the results of an 18 month study on the cost-effectiveness of drug-eluting stents in patients at high or low risk of major cardiac events. To assess the value of these medical devices, the authors looked at cost of the procedure and the rate of follow-up events which were usually vessel revascularisations avoided by placement of the stents. The study found that overall costs were higher for patients with drug-eluting stents over those with bare metal stents due to the higher price of the drug-eluting stent. If used in all patients, the drug-eluting stents would not be good value for the money. They are cost effective in patients who need small vessel or bypass graft stenting but not in those who need larger vessel stenting.

Aims: Myeloblastosis Associated Virus type 1 (N) [MAV 1(N)] induces specifically nephroblastomas in 8-10 weeks when injected to newborn chicken. The MAV-induced nephroblastomas constitute a unique animal model of the pediatric Wilms' tumor. We have made use of three independent nephroblastomas that represent increasing tumor grades, to identify the host DNA regions in which MAV proviral sequences were integrated. METHODS Cellular sequences localized next to MAV-integration sites in the tumor DNAs were used to screen a Bacterial Artificial Chromosomes (BACs) library and isolate BACs containing about 150 kilobases of normal DNA corresponding to MAV integration regions (MIRs). These BACs were mapped on the chicken chromosomes by Fluorescent In Situ Hybridization (FISH) and used for molecular studies. Results: The different MAV integration sites that were conserved after tumor cell selection identify genes involved in the control of cell signaling and proliferation. Syntenic fragments in human DNA contain genes whose products have been involved in normal and pathological kidney development, and several oncogenes responsible for tumorigenesis in human. Conclusion: The identification of putative target genes for MAV provides important clues for the understanding of the MAV pathogenic potential. These studies identified ADAMTS1 as a gene upregulated in MAV-induced nephroblastoma and established that ccn3/nov is not a preferential site of integration for MAV as previously thought. The present results support our hypothesis that the highly efficient and specific MAV-induced tumorigenesis results from the alteration of multiple target genes in differentiating blastemal cells, some of which are required for the progression to highly aggressive stages. This study reinforces our previous conclusions that the MAV-induced nephroblastoma constitutes an excellent model in which to characterize new potential oncogenes and tumor suppressors involved in the establishment and maintenance of tumors. [ABSTRACT FROM AUTHOR]

Aims: While the conditions of heart failure (HF) with reduced (HFrEF, LVEF < 40%) and preserved (HFpEF, LVEF ≥ 50%) left ventricular ejection fraction (LVEF) are well characterized, it is unknown whether patients with HF and mid-range LVEF (HFmrEF, LVEF 40-49%) have to be regarded as a separate clinical entity. The aim of this study was to characterize these three populations and to compare outcome and response to therapy.Methods and Results: The analysis was based on the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF) comprising a population with established HF including the whole spectrum of LVEF. Of the 622 patients, 108 (17%) were classified as having HFmrEF. This group was in general found to be 'intermediate' regarding clinical characteristics with a comparable and high burden of comorbidities and equally impaired quality of life but was more likely to have coronary artery disease as compared with the HFpEF group. During a median follow-up of 794 days, mortality was 39.7% without significant differences between groups. N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided as compared with standard therapy resulted in improved survival free of HF hospitalizations in HFrEF and HFmrEF, but not in HFpEF.Conclusion: Although the 'intermediate' clinical profile of HFmrEF between HFrEF and HFpEF would support the conclusion that HFmrEF is a distinct clinical entity, we hypothesize that HFmrEF has to be categorized as HFrEF because of the high prevalence of coronary artery disease and the similar benefit of NT-proBNP-guided therapy in HFrEF and HFmrEF, in contrast to HFpEF. [ABSTRACT FROM AUTHOR]

Aims While the conditions of heart failure (HF) with reduced (HFrEF, LVEF < 40%) and preserved (HFpEF, LVEF ≥ 50%) left ventricular ejection fraction (LVEF) are well characterized, it is unknown whether patients with HF and mid-range LVEF (HFmrEF, LVEF 40–49%) have to be regarded as a separate clinical entity. The aim of this study was to characterize these three populations and to compare outcome and response to therapy. Methods and results The analysis was based on the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF) comprising a population with established HF including the whole spectrum of LVEF. Of the 622 patients, 108 (17%) were classified as having HFmrEF. This group was in general found to be ‘intermediate’ regarding clinical characteristics with a comparable and high burden of comorbidities and equally impaired quality of life but was more likely to have coronary artery disease as compared with the HFpEF group. During a median follow-up of 794 days, mortality was 39.7% without significant differences between groups. N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided as compared with standard therapy resulted in improved survival free of HF hospitalizations in HFrEF and HFmrEF, but not in HFpEF. Conclusion Although the ‘intermediate’ clinical profile of HFmrEF between HFrEF and HFpEF would support the conclusion that HFmrEF is a distinct clinical entity, we hypothesize that HFmrEF has to be categorized as HFrEF because of the high prevalence of coronary artery disease and the similar benefit of NT-proBNP-guided therapy in HFrEF and HFmrEF, in contrast to HFpEF. [ABSTRACT FROM AUTHOR]

Background In chronic heart failure, left ventricular ejection fraction (LVEF) is considered to be stable. Intensified therapy may improve survival, but little is known whether this is associated with reverse remodeling and dependent on age and NT-proBNP guidance. We aimed to define the evolution of LVEF under intensified therapy in relation to age and NT-proBNP guidance. Methods and results Echocardiography was performed at baseline, 12 and 18 months in TIME-CHF, a trial comparing NT-proBNP versus symptom-guided therapy in patients aged 60 to 74 and ≥ 75 years. LVEF, LV end diastolic volume index (LVEDVI) and end systolic volume index (LVESVI) were assessed. LVEF increased from 31.3 ± 10.7% to 39.1 ± 11.8% at 18 months (p < 0.001) in symptom-guided, and from 30.3 ± 11.7% to 44.0 ± 13.2% (p < 0.001) in NT-proBNP-guided patients. The increase in LVEF was significantly larger in the NT-proBNP-guided treatment group (p for interaction = 0.006), which was true for both age groups (p for interaction in both = 0.091). LVEDVI and LVESVI decreased without influence by study group allocation. Conclusions In elderly heart failure patients, intensified medical therapy leads to an improvement in LVEF and to reverse remodeling. NT-proBNP guided therapy was associated with a larger improvement in LVEF than symptom guided therapy both in patients aged 60 to 74 and ≥ 75 years. [ABSTRACT FROM AUTHOR]

Neuroblastoma has a very diverse clinical behaviour: from spontaneous regression to a very aggressive malignant progression and resistance to chemotherapy. This heterogeneous clinical behaviour might be due to the existence of Cancer Stem Cells (CSC), a subpopulation within the tumor with stem-like cell properties: a significant proliferation capacity, a unique self-renewal capacity, and therefore, a higher ability to form new tumors. We enriched the CSC-like cell population content of two commercial neuroblastoma cell lines by the use of conditioned cell culture media for neurospheres, and compared genomic gains and losses and genome expression by array-CGH and microarray analysis, respectively (in CSC-like versus standard tumor cells culture). Despite the array-CGH did not show significant differences between standard and CSC-like in both analyzed cell lines, the microarray expression analysis highlighted some of the most relevant biological processes and molecular functions that might be responsible for the CSC-like phenotype. Some signalling pathways detected seem to be involved in self-renewal of normal tissues (Wnt, Notch, Hh and TGF-β) and contribute to CSC phenotype. We focused on the aberrant activation of TGF-β and Hh signalling pathways, confirming the inhibition of repressors of TGF-β pathway, as SMAD6 and SMAD7 by RT-qPCR. The analysis of the Sonic Hedgehog pathway showed overexpression of PTCH1, GLI1 and SMO. We found overexpression of CD133 and CD15 in SIMA neurospheres, confirming that this cell line was particularly enriched in stem-like cells. This work shows a cross-talk among different pathways in neuroblastoma and its importance in CSC-like cells. [ABSTRACT FROM AUTHOR]

Eleven samples of DNA from choriocarcinomas were studied by high resolution CGH-array 244 K. They were studied after histopathological confirmation of the diagnosis, of the androgenic etiology and after a microsatellite marker analysis confirming the absence of contamination of tumor DNA from maternal DNA. Three cell lines, BeWo, JAR, JEG were also studied by this high resolution pangenomic technique. According to aCGH analysis, the de novo choriocarcinomas exhibited simple chromosomal rearrangements or normal profiles. The cell lines showed various and complex chromosomal aberrations. 23 Minimal Critical Regions were defined that allowed us to list the genes that were potentially implicated. Among them, unusually high numbers of microRNA clusters and imprinted genes were observed. [ABSTRACT FROM AUTHOR]

Therapy-related acute leukemia (t-AML), is a severe complication of cytotoxic therapy used for primary cancer treatment. The outcome of these patients is poor, compared to people who develop de novo acute leukemia (p-AML). Cytogenetic abnormalities in t-AML are similar to those found in p-AML but present more frequent unfavorable karyotypes depending on the inducting agent. Losses of chromosome 5 or 7 are observed after alkylating agents while balanced translocations are found after topoisomerase II inhibitors. This study compared t-AML to p-AML using high resolution array CGH in order to find copy number abnormalities (CNA) at a higher resolution than conventional cytogenetics. More CNAs were observed in 30 t-AML than in 36 p-AML: 104 CNAs were observed with 63 losses and 41 gains (mean number 3.46 per case) in t-AML, while in p-AML, 69 CNAs were observed with 32 losses and 37 gains (mean number of 1.9 per case). In primary leukemia with a previously ''normal'' karyotype, 18% exhibited a previously undetected CNA, whereas in the (few) t-AML with a normal karyotype, the rate was 50%. Several minimal critical regions (MCRs) were found in t-AML and p-AML. No common MCRs were found in the two groups. In t-AML a 40kb deleted MCR pointed to RUNX1 on 21q22, a gene coding for a transcription factor implicated in frequent rearrangements in leukemia and in familial thrombocytopenia. In de novo AML, a 1Mb MCR harboring ERG and ETS2 was observed from patients with complex aCGH profiles. High resolution cytogenomics obtained by aCGH and similar techniques already published allowed us to characterize numerous non random chromosome abnormalities. This work supports the hypothesis that they can be classified into several categories: abnormalities common to all AML; those more frequently found in t-AML and those specifically found in p-AML. [ABSTRACT FROM AUTHOR]

Additional chromosomal abnormalities are currently detected in Burkitt's lymphoma. They play major roles in the progression of BL and in prognosis. The genes involved remain elusive. A whole-genome oligonucleotide array CGH analysis correlated with karyotype and FISH was performed in a set of 27 Burkitt's lymphoma-derived cell lines and primary tumors. More than half of the 145 CNAs,2 Mb were mapped to Mendelian CNVs, including GSTT1, glutathione s-transferase and BIRC6, an anti-apoptotic protein, possibly predisposing to some cancers. Somatic cell line-specific CNVs localized to the IG locus were consistently observed with the 244 K aCGH platform. Among 136 CNAs .2 Mb, gains were found in 1q (12/27), 13q (7/27), 7q (6/27), 8q(4/27), 2p (3/27), 11q (2/27) and 15q (2/27). Losses were found in 3p (5/27), 4p (4/27), 4q (4/27), 9p (4/27), 13q (4/27), 6p (3/27), 17p (3/27), 6q (2/27),11pterp13 (2/27) and 14q12q21.3 (2/27). Twenty one minimal critical regions (MCR), (range 0.04-71.36 Mb), were delineated in tumors and cell lines. Three MCRs were localized to 1q. The proximal one was mapped to 1q21.1q25.2 with a 6.3 Mb amplicon (1q21.1q21.3) harboring BCA2 and PIAS3. In the other 2 MCRs, 1q32.1 and 1q44, MDM4 and AKT3 appeared as possible drivers of these gains respectively. The 13q31.3q32.1 ,89.58-96.81. MCR contained an amplicon and ABCC4 might be the driver of this amplicon. The 40 Kb 2p16.1 ,60.96- 61. MCR was the smallest gained MCR and specifically encompassed the REL oncogene which is already implicated in B cell lymphomas. The most frequently deleted MCR was 3p14.1 ,60.43-60.53. that removed the fifth exon of FHIT. Further investigations which combined gene expression and functional studies are essential to understand the lymphomagenesis mechanism and for the development of more effective, targeted therapeutic strategies. [ABSTRACT FROM AUTHOR]

Oncogene (2003) 22, 1907. doi:10.1038/sj.onc.1206225 [ABSTRACT FROM AUTHOR]

Stable and safe corrective gene transfer in stem keratinocytes is necessary for ensuring success in cutaneous gene therapy. There have been numerous encouraging preclinical approaches to cutaneous gene therapy in the past decade, but it is only recently that a human volunteer suffering from junctional epidermolysis bullosa could be successfully grafted using his own non-selected, genetically corrected epidermal keratinocytes. However, ex vivo correction of cancer-prone genetic disorders necessitates a totally pure population of stably transduced stem keratinocytes for grafting. Antibiotic selection is not compatible with the need for full respect for natural cell fate potential and avoidance of immunogenic response in vivo. In order to surmount these problems, we developed a strategy for selecting genetically modified stem cell keratinocytes. Driving ectopic expression of CD24 (a marker of post-mitotic keratinocytes) at the surface of clonogenic keratinocytes permitted their full selection. Engineered keratinocytes expressing CD24 and the green fluorescent protein (GFP) tracer gene were shown to retain their original growth and differentiation potentials both in vitro and in vivo over 300 generations. Also, they did not exhibit signs of genetic instability. Using ectopic expression of CD24 as a selective marker of genetically modified human epidermal stem cells appears to be the first realistic approach to safe cutaneous gene therapy in cancer-prone disease conditions.Molecular Therapy (2007) 15 12, 2186–2193. doi:10.1038/sj.mt.6300292 [ABSTRACT FROM AUTHOR]

Purpose: To investigate a potential link between telomere length, chromosomal instability, and the advent of a second cancer (SC) in patients with Hodgkin’s lymphoma (HL), who are known to be at risk for SCs. This study was premised on the finding that telomere dysfunction and DNA repair pathways were related to many pathologic conditions. Methods and Materials: Three cohorts of patients with HL were studied: 73 who were prospectively followed >5 years after diagnosis (prospective HL cohort), 28 who developed a SC (SC HL cohort), and 18 long-term survivors with no evidence of disease or complication since their initial treatment (NED HL cohort). Telomere length was analyzed by a telomeric restriction fragment assay in peripheral blood lymphocytes. Thirty healthy donors and 70 patients with a newly diagnosed solid tumor were the control population. Results: Compared with controls, patients from the prospective HL cohort, before any treatment, showed age-independent shorter telomeres (mean, 8.3 vs. 11.7 kb in healthy donors; <6 kb in 18% in HL patients), increased spontaneous chromosomal abnormalities, and increased in vitro radiation sensitivity (p < 10−4 each). After treatment, telomere shortening was associated with cytogenetic profiles characterized by the persistence of complex chromosomal rearrangement and clonal aberrations. Moreover, the two cases of SC in the prospective HL patients had short telomeres and CCR initially. In addition, the SC HL cohort was characterized by markedly short telomeres (6.6 vs. 9.7 kb in the NED HL cohort), the presence of complex chromosome rearrangements, and increased in vitro radiation sensitivity. Conclusions: An intimate relationship between pre-treatment telomere shortening, chromosomal instability, radiation sensitivity and occurrence of SC was found in HL patients. [Copyright &y& Elsevier]

Background: Carcinomas of unknown primary site (CUP) are epithelial malignancies revealed by metastatic lesions in the absence of any detectable primary tumor. Although they often adopt an aggressive clinical pattern, their basic biology remains poorly understood. Laboratory research on their biology have been hampered so far by the absence of cell lines representative of CUPs. Methods: We attempted xenografts of CUP clinical specimens in immunodeficient mice and subsequent in vitro culture of transplanted malignant cells. Whenever possible, malignant xenografted or cultured cells were characterized by microsatellite genotyping, immunohistology, electron microscopy, multifish chromosome analysis and search of TP 53 gene mutations. Results: Successful xenografts were achieved in 2 cases out of 4. One of them (Capi1) was lost after 3 passages whereas the other one (Capi3) has been adapted to in vitro culture and is currently available to the scientific community with reliable identification based on microsatellite genotyping. Both Capi1 and Capi3 have histological characteristics of adenocarcinomas and display intense expression of EMA, CEA and cytokeratin 7. Multifish chromosome analysis demonstrated a translocation involving chromosomes 4 and 21 in both specimens. Distinct rare missense mutations of the TP53 gene were detected in Capi1 (codon 312) and Capi3 (codon 181); the codon 181 mutation is consistent with a previously reported similar finding in a small series of CUP specimens. Finally, intense membrane expression of c-kit was recorded in Capi3. Conclusion: Our data suggest that xenografted tumors can be obtained from a substantial fraction of CUP clinical specimens. The hypothesis of a preferential association of CUPs with TP 53 mutations of codon 181 deserves further investigations. The Capi3 cell line will be a useful tool for assessment of novel c-kit inhibitors. [ABSTRACT FROM AUTHOR]

Background: High-altitude pulmonary edema (HAPE) is caused by exaggerated hypoxic pulmonary vasoconstriction associated with decreased bioavailability of nitric oxide in the lungs and by impaired reabsorption of alveolar fluid.Objective: To investigate whether dexamethasone or tadalafil reduces the incidence of HAPE and acute mountain sickness (AMS) in adults with a history of HAPE.Design: Randomized, double-blind, placebo-controlled study performed in summer 2003.Setting: Ascent from 490 m within 24 hours and stay for 2 nights at 4559 m.Patients: 29 adults with previous HAPE.Intervention: Prophylactic tadalafil (10 mg), dexamethasone (8 mg), or placebo twice daily during ascent and stay at 4559 m.Measurements: Chest radiography was used to diagnose HAPE. A Lake Louise score greater than 4 defined AMS. Systolic pulmonary artery pressure was measured by using Doppler echocardiography, and nasal potentials were measured as a surrogate marker of alveolar sodium transport.Results: Two participants who received tadalafil developed severe AMS on arrival at 4559 m and withdrew from the study; they did not have HAPE at that time. High-altitude pulmonary edema developed in 7 of 9 participants receiving placebo and 1 of the remaining 8 participants receiving tadalafil but in none of the 10 participants receiving dexamethasone (P = 0.007 for tadalafil vs. placebo; P < 0.001 for dexamethasone vs. placebo). Eight of 9 participants receiving placebo, 7 of 10 receiving tadalafil, and 3 of 10 receiving dexamethasone had AMS (P = 1.0 for tadalafil vs. placebo; P = 0.020 for dexamethasone vs. placebo). At high altitude, systolic pulmonary artery pressure increased less in participants receiving dexamethasone (16 mm Hg [95% CI, 9 to 23 mm Hg]) and tadalafil (13 mm Hg [CI, 6 to 20 mm Hg]) than in those receiving placebo (28 mm Hg [CI, 20 to 36 mm Hg]) (P = 0.005 for tadalafil vs. placebo; P = 0.012 for dexamethasone vs. placebo). No statistically significant difference between groups was found in change in nasal potentials and expression of leukocyte sodium transport protein messenger RNA.Limitations: The study involved a small sample of adults with a history of HAPE.Conclusions: Both dexamethasone and tadalafil decrease systolic pulmonary artery pressure and may reduce the incidence of HAPE in adults with a history of HAPE. Dexamethasone prophylaxis may also reduce the incidence of AMS in these adults. ClinicalTrials.gov identifier: NCT00274430. [ABSTRACT FROM AUTHOR]

Background: High-altitude pulmonary edema (HAPE) is caused by exaggerated hypoxic pulmonary vasoconstriction associated with decreased bioavailability of nitric oxide in the lungs and by impaired reabsorption of alveolar fluid. Objective: To investigate whether dexamethasone or tadalafil reduces the incidence of HAPE and acute mountain sickness (AMS) in adults with a history of HAPE. Design: Randomized, double-blind, placebo-controlled study performed in summer 2003. Setting: Ascent from 490 m within 24 hours and stay for 2 nights at 4559 m. Patients: 29 adults with previous HAPE. Intervention: Prophylactic tadalafil (10 mg), dexamethasone (8 mg), or placebo twice daily during ascent and stay at 4559 m. Measurements: Chest radiography was used to diagnose HAPE. A Lake Louise score greater than 4 defined AMS. Systolic pulmonary artery pressure was measured by using Doppler echocardiography, and nasal potentials were measured as a surrogate marker of alveolar sodium transport. Results: Two participants who received tadalafil developed severe AMS on arrival at 4559 m and withdrew from the study; they did not have HAPE at that time. High-altitude pulmonary edema developed in 7 of 9 participants receiving placebo and 1 of the remaining 8 participants receiving tadalafil but in none of the 10 participants receiving dexamethasone (P = 0.007 for tadalafil vs. placebo; P < 0.001 for dexamethasone vs. placebo). Eight of 9 participants receiving placebo, 7 of 10 receiving tadalafil, and 3 of 10 receiving dexamethasone had AMS (P = 1.0 for tadalafil vs. placebo; P = 0.020 for dexamethasone vs. placebo). At high altitude, systolic pulmonary artery pressure increased less in participants receiving dexamethasone (16 mm Hg [95% CI, 9 to 23 mm Hg]) and tadalafil (13 mm Hg [CI, 6 to 20 mm Hg]) than in those receiving placebo (28 mm Hg [CI, 20 to 36 mm Hg]) (P = 0.005 for tadalafil vs. placebo; P = 0.012 for dexamethasone vs. placebo). No statistically significant difference between groups was found in change in nasal potentials and expression of leukocyte sodium transport protein messenger RNA. Limitations: The study involved a small sample of adults with a history of HAPE. Conclusions: Both dexamethasone and tadalafil decrease systolic pulmonary artery pressure and may reduce the incidence of HAPE in adults with a history of HAPE. Dexamethasone prophylaxis may also reduce the incidence of AMS in these adults. [ABSTRACT FROM AUTHOR]

Summary Background No prospective trial-based data are available for incremental cost-effectiveness of drug-eluting stents (DES) compared with bare-metal stents (BMS) in unselected patients, as treated in everyday practice. Methods The Basel stent cost-effectiveness trial (BASKET) included 826 consecutive patients treated with angioplasty and stenting for 1281 de-novo lesions, irrespective of indication for angioplasty. Patients were randomised to one of two DES (Cypher, n=264; Taxus, n=281) or to a cobalt-chromium-based BMS (Vision, n=281) and followed up for 6 months for occurrence of major adverse cardiac events and costs. Analysis was by intention-to-treat. The primary endpoint was cost-effectiveness after 6 months, with effectiveness defined as reduction of major adverse cardiac events. Findings Cardiac death, myocardial infarction, or target vessel revascularisation occurred in 39 of 544 (7·2%) patients with DES and 34 of 280 (12·1%) with BMS (odds ratio 0·56, 95% CI 0·35-0·91; p=0·02), without significant differences between the two DES. Total costs at 6 months were higher with DES (mean &z.euro;10 544, SD 6849) than with BMS (&z.euro;9639, 9067; p<0·0001); higher stent costs of DES were not compensated for by lower follow-up costs. Incremental cost-effectiveness ratio of DES compared with BMS to avoid one major event was &z.euro;18 311, and costs per quality-adjusted life-year gained were more than &z.euro;50 000. Subgroup analyses showed that DES were more cost-effective for elderly patients in specific high-risk groups. Interpretation In a real-world setting, use of DES in all patients is less cost effective than in studies with selected patients. Use of these stents could be restricted to patients in high-risk groups. [ABSTRACT FROM AUTHOR]

Background: Loss of left ventricular capture in patients with cardiac resynchronization devices may account for worsening heart failure and can be difficult to diagnose without a programmer.Objective: To determine whether distinct morphologic changes on the surface electrocardiogram indicate loss of left ventricular capture.Design: After analysis of the R-S spike ratio in the 12-lead electrocardiogram during right ventricular and biventricular pacing in 10 patients, an algorithm to detect loss of left ventricular capture was developed.Setting: University hospital.Patients: 54 patients with a cardiac resynchronization device and underlying left bundle-branch block.Measurements: Leads V1 and I of a 12-lead electrocardiogram were assessed after biventricular pacing was confirmed and after the device was programmed to right ventricular pacing only (simulating loss of left ventricular capture).Results: The sensitivity of the algorithm to correctly identify loss of left ventricular capture was 94% (95% CI, 88.2% to 97.7%), and the specificity was 93% (CI, 86.3% to 95.8%). The likelihood ratio of a positive test result was 12.8 (CI, 6.443 to 23.310), and the likelihood ratio of a negative test result was 0.06 (CI, 0.024 to 0.137).Limitations: The algorithm was tested in patients in whom the right ventricular electrode was placed in the apex of the right ventricle only.Conclusion: Presence of biventricular capture--the prerequisite for successful cardiac resynchronization therapy--and loss of left ventricular capture can be accurately detected by an algorithm based on analysis of the R-S ratio on leads V1 and I of the surface electrocardiogram. [ABSTRACT FROM AUTHOR]

Background: Loss of left ventricular capture in patients with cardiac resynchronization devices may account for worsening heart failure and can be difficult to diagnose without a programmer. Objective: To determine whether distinct morphologic changes on the surface electrocardiogram indicate loss of left ventricular capture. Design: After analysis of the R-S spike ratio in the 12-lead electrocardiogram during right ventricular and biventricular pacing in 10 patients, an algorithm to detect loss of left ventricular capture was developed. Setting: University hospital. Patients: 54 patients with a cardiac resynchronization device and underlying left bundle-branch block. Measurements: Leads V1 and I of a 12-lead electrocardiogram were assessed after biventricular pacing was confirmed and after the device was programmed to right ventricular pacing only (simulating loss of left ventricular capture). Results: The sensitivity of the algorithm to correctly identify loss of left ventricular capture was 94% (95% CI, 88.2% to 97.7%), and the specificity was 93% (CI, 86.3% to 95.8%). The likelihood ratio of a positive test result was 12.8 (CI, 6.443 to 23.310), and the likelihood ratio of a negative test result was 0.06 (CI, 0.024 to 0.137). Limitations: The algorithm was tested in patients in whom the right ventricular electrode was placed in the apex of the right ventricle only. Conclusion: Presence of biventricular capture the prerequisite for successful cardiac resynchronization therapy-and loss of left ventricular capture can be accurately detected by an algorithm based on analysis of the R-S ratio on leads V1 and I of the surface electrocardiogram. [ABSTRACT FROM AUTHOR]

Abstract: Renal cell carcinomas (RCC) in adults are histologically heterogeneous solid tumors with specific chromosomal abnormality patterns included in the World Health Organization (WHO) classification. To overcome some of the drawbacks of cytogenetic and comparative genomic hybridization (CGH) analyses, we designed a first-generation cytogenetic diagnostic test using four-color fluorescence in situ hybridization (FISH) on interphase nuclei. We selected 51 bacterial artificial chromosome and P1-derived artificial chromosome clones covering 17 chromosomal regions involved in the abnormalities of the adult RCC histologic subtypes. An initial set of probes allowed the identification of clear-cell RCC, papillary RCC, and other RCC on a single slide. A second test allowed the detection of additional chromosomal abnormalities or aberrations specific to chromophobic RCC and oncocytomas. We tested 25 cases of RCC, and the results were in agreement with those of cytogenetic techniques and/or CGH methods. The techniques appeared to be very sensitive, because small tumoral cell clones that were undetected by other cytogenetic methods were identified with this method. It was concluded that the multicolor FISH test was specific and sensitive, easy to perform, and could be part of the investigation process in RCC. [Copyright &y& Elsevier]

Myelodysplastic syndromes (MDS) are clonal malignant stem cell disorders characterized by inefficient hematopoiesis. The role of the marrow microenvironment in the pathogenesis of the disease has been controversial and no study has been performed so far to characterize mesenchymal cells (MC) from MDS patients and to analyse their ability to support hematopoiesis. To this end, we have isolated and characterized MC at diagnostic marrow samples (n=12) and have purified their CD34+CD38-and CD34+CD38+counterparts (n=7) before using MC as a short- and long-term hematopoietic support. We show that MC can be readily isolated from MDS marrow and exhibit a major expansion potential as well as an intact osteoblastic differentiation ability. They do not harbor the abnormal marker identified by FISH in the hematopoietic cells and they stimulate the growth of autologous clonogenic cells. Conversely, highly purified stem cells and their cytokine-expanded progeny harbor the clonal marker with variable frequencies, and both normal and abnormal long-term culture-initiating cell-derived progeny can be effectively supported by autologous MC. Thus, we demonstrate that MDS marrow is an abundant source of MC appearing both cytogenetically and functionally noninvolved by the malignant process and able to support hematopoiesis, suggesting their possible usefulness in future cell therapy approaches.Oncogene (2005) 24, 2441-2448. doi:10.1038/sj.onc.1208405 Published online 7 February 2005 [ABSTRACT FROM AUTHOR]

Neuroblastomas, tumors of the sympathetic nervous system, account for 7–10% of the cancers of childhood. Genetic studies have shown, and this study has confirmed, that neuroblastomas are very heterogeneous; no single genetic change common to all neuroblastomas has yet been identified. One genetic aberration found frequently in this pediatric tumor is MYCN gene amplification. Recently we identified a new subset of tumors showing MYCN gain (small increases in gene number arising from unbalanced translocation). To investigate whether gain precedes amplification or is an independent event, we surveyed 200 primary tumors for MYCN copy number with fluorescence in situ hybridization; 152 of 200 (76%) were MYCN single-copy tumors, whereas 48 of 200 (24%) tumors harbored MYCN abnormalities: 36 of the 48 (75%) had MYCN amplification and 12 (25%) had MYCN gain. Among the 36 with MYCN amplified gene, we found four that also showed gain. In three tumors exhibiting simultaneous gain and amplification, these two events were detected in neighboring cells. In the fourth case we detected only MYCN gain in metastatic neuroblasts in the bone marrow, but both MYCN amplification and gain in the primary tumor. The detailed study of these four cases suggests that there may be several different mechanisms leading to increase in MYCN copy number. Further studies in other human malignancies are necessary to determine whether simultaneous gain and amplification are specific to neuroblastoma or constitute a general mechanism by which tumor cells can acquire selective growth advantage. [Copyright &y& Elsevier]

Hoyeraal-Hreidarsson syndrome (HHS) is a severe infantile variant of X-linked dyskeratosis congenita (DC). The authors report evidence of increased in vitro sensitivity to radiation and alkylating agent in circulating lymphocytes and fibroblasts obtained from a 7-year-old boy with HHS. A major telomere shortening was also found (3 kb) as compared to healthy donors (10 kb). The standard treatments, chemotherapy regimens, and radiation therapy were not possible. The data suggest that conditioning regimens including TBI should not be used when a bone marrow transplantation procedure is planned in these patients. [ABSTRACT FROM AUTHOR]

Objectives: This study investigated the combination of maximal and low-intensity exercise testing in predicting prognosis in chronic heart failure (CHF), using one single exercise test (two-step protocol).Background: Risk assessment based on any single factor has limited accuracy and reproducibility.Methods: Treadmill exercise testing was performed in 202 consecutive CHF patients (174 male; mean age 52 +/- 11 years) using "breath-by-breath" gas exchange monitoring. Oxygen uptake (VO(2)) kinetics were defined as oxygen deficit (DeltaVO(2) x time [rest to steady state] - Sigma VO(2) [rest to steady state]) and mean response time (MRT = oxygen-deficit/DeltaVO(2)). Peak VO(2) (VO(2)max) was defined as the highest VO(2). Mean follow-up was 873 +/- 628 days. The primary end point was cardiac mortality and the need for urgent heart transplantation.Results: Forty-four patients (22%) died and 15 (7%) were urgently transplanted. In both univariate and multivariate analyses, MRT >50 s was the most powerful predictor of the primary end point (hazard ratio [HR] 4.44), followed by predicted VO(2)max <50% (HR 3.50) and resting systolic blood pressure <105 mm Hg (HR 2.49, all p < 0.001). A majority (n = 130 [64%]) had one or none of these risk factors, with a one-year event rate of only 3%. Patients with two risk factors (n = 45 [22%]) were at medium risk (one-year event rate of 33%). Twenty-seven patients (13%) had all three risk factors, with a one-year event rate of 59%. The area under the curve, using the number of risk factors, was 0.86 +/- 0.04 for the primary end point at one year. These results were independent of medication, in particular, beta-blockade.Conclusions: A combination of low-intensity and maximal exercise test results improves assessment of prognosis in patients with CHF. [ABSTRACT FROM AUTHOR]

: ObjectivesThis study investigated the combination of maximal and low-intensity exercise testing in predicting prognosis in chronic heart failure (CHF), using one single exercise test (two-step protocol).: BackgroundRisk assessment based on any single factor has limited accuracy and reproducibility.: MethodsTreadmill exercise testing was performed in 202 consecutive CHF patients (174 male; mean age 52 ± 11 years) using “breath-by-breath” gas exchange monitoring. Oxygen uptake (Vo2) kinetics were defined as oxygen deficit (ΔVo2 × time [rest to steady state] − Σ Vo2 [rest to steady state]) and mean response time (MRT = oxygen-deficit/ΔVo2). Peak Vo2 (Vo2max) was defined as the highest Vo2. Mean follow-up was 873 ± 628 days. The primary end point was cardiac mortality and the need for urgent heart transplantation.: ResultsForty-four patients (22%) died and 15 (7%) were urgently transplanted. In both univariate and multivariate analyses, MRT >50 s was the most powerful predictor of the primary end point (hazard ratio [HR] 4.44), followed by predicted Vo2max <50% (HR 3.50) and resting systolic blood pressure <105 mm Hg (HR 2.49, all p < 0.001). A majority (n = 130 [64%]) had one or none of these risk factors, with a one-year event rate of only 3%. Patients with two risk factors (n = 45 [22%]) were at medium risk (one-year event rate of 33%). Twenty-seven patients (13%) had all three risk factors, with a one-year event rate of 59%. The area under the curve, using the number of risk factors, was 0.86 ± 0.04 for the primary end point at one year. These results were independent of medication, in particular, beta-blockade.: ConclusionsA combination of low-intensity and maximal exercise test results improves assessment of prognosis in patients with CHF. [Copyright &y& Elsevier]

Summary. To evaluate the incidence and the predictive signs of therapy-related myelodysplasia and/or acute myeloid leukaemia (tMDS/tAML), we undertook a prospective study over a 4-year period of 221 patients who underwent autologous haematopoietic progenitor cell transplantation. Only seven patients (3·1%) were identified to have tMDS/tAML. Peripheral cytopenia was the first sign; diagnosis could be achieved by cytological analysis of bone marrow smears using World Health Organization criteria. All patients presented with bi- or trilineage dysplasia. Haematopoietic reconstitution was significantly delayed in patients progressing to tMDS/tAML compared with the control group. Typical cytogenetic abnormalities were observed in five of seven patients. The mean time interval between transplantation and cytological diagnosis, or detection of cytogenetic abnormalities, was 20·0 months and 31·2 months respectively. Pantelomeric fluorescence analysis using quantitative fluorescence in situ hybridization enabled us to make two major observations: (i) the fluorescence intensity in metaphases of all autografted patients was weak, and highly variable between tMDS patients; (ii) a drastic reduction of the telomere fluorescence intensity was observed in two patients who rapidly evolved to acute leukaemia. In conclusion, early detection of tMDS/tAML could be achieved by close follow-up of the bone marrow repopulation, and confirmed by cytological bone marrow examination and cytogenetic study. Our results address the implication of several factors, such as the initial telomeric status, and the effect of cytogenetic abnormalities and clonal expansion on bone marrow repopulation. [ABSTRACT FROM AUTHOR]

Describes a novel mechanism by which anti-tumor IgG might directly regulate tumor development. Information on human melanoma tumors and cell lines; Data on the development of human melanomas.

To discriminate among the chromosomal abnormalities associated with the etiology of hepatocellular carcinoma (HCC), we performed a comparative genomic hybridization (CGH) analysis on 34 HCCs resected on non-cirrhotic livers from patients serologically negative for both hepatitis B (HBV) and C (HCV) viruses. The results were compared to those of a previous analysis of 50 HCCs selected on the basis of their positivity for HBV infection. The majority of the abnormalities found in the HBV positive cases (losses of chromosome arms 1p, 8p, 6q, 13q and 14q and gains of 1q, 8q, 6p and 17q) were similarly detected in the virus negative specimens. In contrast, a significant decrease (40% on average) was observed for losses at 4q, 16q and 17p in non-viral HCC samples, suggesting that these abnormalities are tightly associated with HBV infection. Thus, in addition to a common pathway towards malignancy, a subset of alterations may preferentially contribute to virus-induced carcinogenesis. In a parallel CGH study of 10 fibrolamellar carcinomas, a rare subtype of HCC, we found in six out of the seven informative cases, gains of chromosome arm 1q. This region, which is also preferentially amplified in non fibrolamellar tumors (58%), may contain an essential proto-oncogene commonly implicated in liver carcinogenesis. Oncogene (2000) 19, 3733–3738 [ABSTRACT FROM AUTHOR]

Molecular cytogenetic analysis of several sporadic papillary renal cell carcinomas and of their xenografts in immunodeficient mice had previously allowed us to delimit a minimal overrepresented region of chromosome 7 shared by all of them to band 7q31. We have refined the location of the overlapping region to the junction of the subbands 7q31.2 and 7q31.3 by reverse painting with two differently labelled probes prepared from the small chromosome 7 derivatives microdissected from the cells of two distinct tumours. This small region was shown to contain the MET proto-oncogene, present at three to four copies per cell as determined by Southern blot analysis. The increased copy number of the MET gene was found to be associated with its overexpression at the mRNA level. However, no change in MET copy number or expression level was observed in the cells from two xenografted tumours serially transplanted into immunodeficient mice, as compared to those from the corresponding initial tumours. Our results indicate that expression of the MET proto-oncogene above a critical threshold is required for the maintenance of the tumorigenic phenotype of at least some papillary renal cell carcinomas, but does not further increase during tumour progression. Oncogene (2000) 19, 754–761. [ABSTRACT FROM AUTHOR]

A letter to the editor about the lymphoblastic lymphoma with initial bilateral breast lesions is presented.

Background: Gain of genetic material from chromosome arm 17q (gain of segment 17q21–qter) is the most frequent cytogenetic abnormality of neuroblastoma cells. This gain has been associated with advanced disease, patients who are ≥1 year old, deletion of chromosome arm 1p, and amplification of the N-myc oncogene, all of which predict an adverse outcome. We investigated these associations and evaluated the prognostic importance of the status of chromosome 17. Methods: We compiled molecular cytogenetic analyses of chromosome 17 in primary neuroblastomas in 313 patients at six European centers. Clinical and survival information were collected, along with data on 1p, N-myc, and ploidy. Results: Unbalanced gain of segment 17q21–qter was found in 53.7 percent of the tumors, whereas the chromosome was normal in 46.3 percent. The gain of 17q was characteristic of advanced tumors and of tumors in children ≥1 year of age and was strongly associated with the deletion of 1p and amplification of N-myc. No tumor showed amplification of N-myc in the absence of either deletion of 1p or gain of 17q. Gain of 17q was a significant predictive factor for adverse outcome in univariate analysis. Among the patients with this abnormality, overall survival at five years was 30.6 percent (95 percent confidence interval, 21 to 40 percent), as compared with 86.0 percent (95 percent confidence interval, 78 to 91 percent) among those with normal 17q status. In multivariate analysis, gain of 17q was the most powerful prognostic factor, followed by the presence of stage 4 disease and deletion of 1p (hazard ratios, 3.4, 2.3, and 1.9, respectively). Conclusions: Gain of chromosome segment 17q21–qter is an important prognostic factor in children with neuroblastoma. (N Engl J Med 1999;340:1954-61.) [ABSTRACT FROM AUTHOR]