Performance of BRCA1/2 mutation prediction models in male breast cancer patients.

To establish whether existing mutation prediction models can identify which male breast cancer (MBC) patients should be offered BRCA1 and BRCA2 diagnostic DNA screening, we compared the performance of BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm), BRCAPRO (BRCA probability) and the Myriad prevalence table ("Myriad"). These models were evaluated using the family data of 307 Dutch MBC probands tested for BRCA1/2, 58 (19%) of whom were carriers. We compared the numbers of observed vs predicted carriers and assessed the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) for each model. BOADICEA predicted the total number of BRCA1/2 mutation carriers quite accurately (observed/predicted ratio: 0.94). When a cut-off of 10% and 20% prior probability was used, BRCAPRO showed a non-significant better performance (observed/predicted ratio BOADICEA: 0.81, 95% confidence interval [CI]: [0.60-1.09] and 0.79, 95% CI: [0.57-1.09], vs. BRCAPRO: 1.02, 95% CI: [0.75-1.38] and 0.94, 95% CI: [0.68-1.31], respectively). Myriad underestimated the number of carriers in up to 69% of the cases. BRCAPRO showed a non-significant, higher AUC than BOADICEA (0.798 vs 0.776). Myriad showed a significantly lower AUC (0.671). BRCAPRO and BOADICEA can efficiently identify MBC patients as BRCA1/2 mutation carriers. Besides their general applicability, these tools will be of particular value in countries with limited healthcare resources.

Prospective BCR-ABL analysis by polymerase chain reaction (RT-PCR) in adult acute B-lineage lymphoblastic leukemia: reliability of RT-nested-PCR and comparison to cytogenetic data.

The reliability of routine BCR-ABL RT-nested-PCR was evaluated in 1453 B-lineage ALL or hybrid leukemia at initial diagnosis by RT-nested-PCR. All BCR-ABL-positive (n = 642) and 176 BCR-ABL-negative samples underwent a second RT-PCR. In 518 patients, karyotyping and/or FISH was compared to the BCR-ABL status. The second RT-PCR revealed in 155/642 initially positive samples a divergent result (153 BCR-ABL-negative, two other transcripts) that in most cases turned out to be caused by contaminations in the first RT-nested-PCR. Confirmatory RT-PCR detected 2/176 false negative first RT-nested-PCR results. Thirty-nine specimens remained ambiguous despite different RT-PCR approaches. As far as cytogenetic evaluation and FISH is available (n = 23), the majority but not all patients with an ambiguous RT-PCR result were Ph-negative (n = 18). RT-nested-PCR and cytogenetics yielded in 346 of 383 evaluable samples a concordant result. Differing results are given and account in part to the lower sensitivity of karyotyping. Taken together, confirmed RT-PCR detected BCR-ABL fusion transcripts consistently in 487 out of 1453 ALL samples (c-ALL: 43%, pre-B ALL: 34%, pro-B ALL: 5%, B-ALL: 0%, hybrid leukemia: 5/11). Since false positive initial RT-nested-PCR data were frequent, either confirmatory second RT-PCR or FISH analysis is warranted to guarantee sensitive and reliable results of utmost clinical relevance.

High rate of chromosome abnormalities detected by fluorescence in situ hybridization using BCR and ABL probes in adult acute lymphoblastic leukemia.

The value of dual-color fluorescence in situ hybridization (FISH) with BCR and ABL probes for the detection of the Philadelphia (Ph) translocation and of other alterations involving ABL and/or BCR was evaluated in adult acute lymphoblastic leukemia (ALL). One hundred and four patients were studied prospectively using interphase nuclei FISH, chromosome analysis (CA), and PCR assays for the chimeric BRC/ABL transcript. FISH detected a Ph translocation in 24 cases (23.1%), as was confirmed by CA and/or PCR. FISH revealed a false positive diagnosis of a Ph translocation in four cases (5% false positive rate). Among 54 cases with combined FISH, CA and PCR assays, FISH failed to establish a correct diagnosis in 3.7%, PCR in 5.6%, and CA in 7.4%. The combination of two screening methods led to discrepant results in 9.3% (FISH + PCR), 11.1% (FISH + CA), or 13% (CA + PCR) of the cases. In seven of 80 (8.8%) Ph-negative patients, gain of BCR and/or ABL was identified. Overall, FISH detected alterations of the BCR and/or ABL genes with an incidence of 29.8% of the current study. Due to the possibility of false positive diagnosis of a Ph translocation using dual-color FISH the combination with chromosome and/or RT-PCR analyses is recommended in adult ALL patients.

Isoflurane-fentanyl anesthesia for coronary bypass surgery in patients with good left ventricular function.

The hemodynamic effects of a balanced anesthetic technique where a moderate dose of fentanyl (32 micrograms/kg) is supplemented with isoflurane were studied in 15 patients with good left ventricular function. Mean inspired isoflurane concentration was 0.63% during induction and 0.74% during maintenance. Induction of anesthesia was associated with a significant decrease (p less than 0.05) in systolic and diastolic pressure and left ventricular stroke work index (LVSWI). During maintenance systolic blood pressure and LVSWI remained significantly depressed. It is concluded that isoflurane-fentanyl anesthesia has myocardial depressant properties. There is a reduced incidence of break-through hypertension during noxious stimuli, when compared with high-dose fentanyl anesthesia. During maintenance, clinical signs that could reflect myocardial ischemia were not observed. Heart enzymes remained within normal range postoperatively in all patients and ECG morphology was unchanged.

Acquired left ventricular hypertrabeculation/noncompaction in myotonic dystrophy type 1.

Congenital left ventricular hypertrabeculation/noncompaction (LVHT) is a common feature of neuromuscular disorders (NMDs). Most commonly LVHT is located in the apex and the lateral wall. Acquired LVHT has been only occasionally reported. In myotonic dystrophy type 1 (MD1) acquired LVHT has not been described. In a 48-year-old female with MD1 due to a CTG-repeat expansion of 700-800 repeats in blood lymphocytes echocardiography at the age of 48 years revealed LVHT in the apex and the mid-ventricular septum. LVHT was interpreted as acquired since none of the previous echocardiograms, carried out to assess cardiac involvement in MD1, showed LVHT. Cardiac history and clinical cardiologic examination were normal. On ECG, non-specific ST-abnormalities and supraventricular ectopic beats were recorded. The AECG showed episodic sinus-bradycardia, ventricular ectopic beats, and was indicative of a sleep-apnea syndrome. This case is unique for the association of MD1 with acquired LVHT located in the apex and the mid-ventricular septum. In the absence of significant additional cardiac abnormalities no cardiac therapy was indicated.

Linkage investigation of three putative tuberous sclerosis determining loci on chromosomes 9q, 11q, and 12q. The Tuberous Sclerosis Collaborative Group.

Previous linkage studies in tuberous sclerosis have implicated three disease determining loci at 9q, 11q, and 12q. We have collated phenotypic and genotypic data on 1622 members of 128 families with tuberous sclerosis in order to evaluate simultaneously the evidence for these putative loci. Affection status in the family members has been reassessed using uniform diagnostic criteria and genotypic data extensively checked before analysis under alternative models of locus heterogeneity. One tuberous sclerosis determining locus, accounting for approximately 50% of the families studied, has been found to map in the region of D9S10 on 9q34 but no evidence has been found to support the existence of major loci on 11q or 12q. A locus, or loci, elsewhere in the genome is likely to account for tuberous sclerosis in most non-chromosome 9 linked families.

Computer simulation of linkage and heterogeneity in tuberous sclerosis: a critical evaluation of the collaborative family data.

The existence of locus heterogeneity for a genetic disease may complicate linkage studies considerably, especially when very few large families with the disease are available. In this situation a modest collection of families is unlikely to be sufficient for successful localisation of one or more disease genes. Recently, eight research groups working on tuberous sclerosis (TSC) brought together linkage data pertaining to the candidate chromosomes 9, 11, and 12 for a large group of families. In a series of simulation studies we determined the probability of detecting linkage and linkage heterogeneity in this set of families. On average TSC families are very small; in most cases there are fewer than two informative meioses. The size distribution of chromosome 9 linked families was similar to that of non-linked families. This indicates that a dramatic difference in the clinical severity of major genetic forms of TSC is unlikely. The results of our simulation studies show that this set of families can generate highly significant evidence for linkage and heterogeneity. When two TSC genes are equally common, the strongest evidence for linkage and heterogeneity could be obtained using a method based on the incorporation of multiple candidate regions in a single analysis, with an average lod score of 24.27.

Low-dose sufentanil-isoflurane anaesthesia for coronary artery surgery.

Haemodynamic changes and catecholamine responses were measured during anaesthesia with sufentanil (total dose 7 micrograms kg-1) supplemented with isoflurane in 14 patients undergoing coronary artery surgery. Isoflurane was used to control systolic arterial pressure, which was allowed to decrease to 100 mm Hg. Mean inspired isoflurane concentration was 0.22 (SD 0.19)% (induction), 0.34 (0.18)% (pre-bypass) and 0.22 (0.17)% (post-bypass). During cardiopulmonary bypass 0.22 (0.13)% isoflurane was administered to control mean perfusion pressure. During induction and the pre-bypass period, significant decreases in systolic and diastolic arterial pressure, systemic vascular resistance and left ventricular stroke work index (LVSWI) (P less than 0.01) were noted. The decrease in LVSWI with unchanged filling pressures indicated myocardial depression. Serum catecholamine concentrations remained at the pre-induction value until cardiopulmonary bypass, when a significant increase was noted. Tracheal intubation, sternotomy and sternal spread were not associated with hypertension or tachycardia. Clinical signs that could reflect myocardial ischaemia were not observed peroperatively. After operation, cardiac enzymes were within the normal clinical range and ECG was unchanged.

Propofol-fentanyl anaesthesia for coronary bypass surgery in patients with good left ventricular function.

The haemodynamic effects of propofol-fentanyl anaesthesia for elective coronary bypass surgery were studied in 15 patients with good left ventricular function. The induction dose of propofol was 1.5 mg kg-1. The mean infusion rate during maintenance was 5.15 mg kg-1 h-1 (range 4.05-8.82 mg kg-1 h-1). The total dose of fentanyl given in the pre-bypass period was 32 micrograms kg-1. Induction of anaesthesia was associated with significant (P less than 0.05) decreases in systolic (-28%) and diastolic (-23%) pressures, systemic vascular resistance (-25%) and left ventricular stroke work index (LVSWI) (-32%). The decrease in LVSWI (P less than 0.05) during induction and maintenance with unchanged filling pressures, indicated myocardial depression. Clinical signs that could reflect myocardial ischaemia were not observed during the operation. There were no changes in the concentrations of the cardiac enzymes in the postoperative period and ECG morphology was unchanged.

Genetic heterogeneity in tuberous sclerosis.

Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by widespread hamartosis. Preliminary evidence of linkage between the TSC locus and markers on chromosome 9q34 was established, but subsequently disputed. More recently, a putative TSC locus on chromosome 11 has been suggested and genetic heterogeneity seems likely. Here we describe an approach combining multipoint linkage analysis and heterogeneity tests that has enabled us to obtain significant evidence for locus heterogeneity after studying a relatively small number of families. Our results support a model with two different loci independently causing the disease. One locus (TSC1) maps in the vicinity of the Abelson oncogene at 9q34 and a second locus (TSC2) maps in the region of the anonymous DNA marker Lam L7 and the dopamine D2 receptor gene at 11q23.