Solitary bronchioloalveolar carcinoma: CT criteria

The computed tomographic (CT) scans of 30 patients with solitary bronchioloalveolar carcinoma were reviewed. Common features at CT included the peripheral or subpleural location of a pulmonary mass (25 cases), pseudocavitation (18 cases), heterogeneous attenuation (17 cases), irregular margins forming a star pattern (22 cases), and pleural tags (21 cases). Using these CT criteria, four independent observers attempted to identify cases of bronchioloalveolar carcinoma from a larger sample of lung cancers and benign lesions by categorizing a series of test cases into four probability categories. Although the bronchioloalveolar carcinomas were correctly ranked in the two highest probability categories 75% of the time (in 45 of 60 cases), there was considerable overlap with other lung lesions, particularly with adenocarcinoma and large cell undifferentiated carcinoma. However, even though the typical features of bronchioloalveolar carcinoma are not invariable or highly specific, they are characteristic enough to suggest the diagnosis.     

Identification of a gene disrupted by a microdeletion in a patient with X-linked retinitis pigmentosa (XLRP)

The gene for the most frequent from of X-linked retinitis pigmentosa (XLRP), RP3, has been assigned by genetic and physical mapping to a segment of less than 1000 kbp, which is flanked by the marker DXS1110 and the ornithine transcarbamylase (OTC) gene. In search of microdeletions, we have screened the DNA of 30 unrelated patients with XLRP by employing a representative set of YAC-derived DNA fragments that were generated by restriction enzyme digestion and PCR amplification. In one of these patients, a 6.4 kbp microdeletion was detected which was not present in the DNA of 444 male controls. A cosmid contig spanning the deletion was constructed and used to isolate cDNAs from retina-specific libraries. Exons corresponding to these expressed sequences as well as other putative exons were identified by sequencing more than 30 kbp of the critical region. So far, no point mutations in these putative exon sequences have been identified.      

Positional cloning of the gene for X-linked retinitis pigmentosa 3: homology with the guanine-nucleotide-exchange factor RCC1

The gene for retinitis pigmentosa 3 (RP3), the most frequent form of X- linked RP (XLRP), has been mapped previously to a chromosome interval of less than 1000 kbp between the DXS1110 marker and the OTC locus at Xp21.1-p11.4. Employing a novel technique, YAC Representation Hybridization (YRH)', we have recently identified a small XLRP associated microdeletion in this interval, as well as several putative exons including the 3' end of a gene that was truncated by the deletion. cDNA library screening and sequencing of a cosmid centromeric to the deletion has now enabled us to identify numerous additional exons and to detect several point mutations in patients with XLRP. The predicted gene product shows homology to RCC1, the guanine-nucleotide- exchange factor (GEF) of the Ras-like GTPase Ran. Our findings suggest that we have cloned the long-sought RP3 gene, and that it may encode the GEF of a retina-specific GTP-binding protein.      

Comprehensive mutational scanning of the p53 coding region by two- dimensional gene scanning

A comprehensive mutational scanning test for the p53 coding region based on multiplex PCR and two-dimensional DNA electrophoresis was designed and evaluated. In a 2-step multiplex PCR, the p53 coding region (exons 2-11) was amplified as a single 8646-bp fragment by long- distance PCR in step one. This fragment served as a template for the subsequent co-amplification of the individual exons in two multiplex groups in step two. The multiplex products were then separated, first on the basis of size in non-denaturant polyacrylamide gels and then on the basis of sequence by denaturing gradient gel electrophoresis (DGGE). Primers for optimal PCR, melting behavior and 2-D gel distribution were designed using a recently developed computer program. The resulting two-dimensional gene scanning (TDGS) test was evaluated by screening, in a blinded fashion, 29 coded DNA samples from Li- Fraumeni syndrome patients with previously identified germline mutations. All mutations were correctly detected. This assay provides an accurate, cost-effective and non-radioactive method for simultaneous mutational scanning of all p53 coding exons.      

Associations between both genetic and environmental biomarkers and lung cancer: evidence of a greater risk of lung cancer in women smokers

This molecular epidemiologic case-control study of lung cancer incorporated three complementary biomarkers: the glutathione S- transferase M1 (GSTM1) null genotype, a potential marker of susceptibility, and polycyclic aromatic hydrocarbon-DNA adducts (PAH- DNA) and sister chromatid exchanges (SCE), both indicators of environmentally induced genetic damage. Associations between biomarkers and lung cancer were investigated, as were possible gene-environment interactions between the GSTM1 null genotype and tobacco smoke exposure. Subjects included 136 primary non-small cell lung cancer surgical patients and 115 controls at the Columbia Presbyterian Medical Center. Questionnaire and Tumor Registry data, pre-treatment blood samples and biomarker measurements on blood were obtained. Overall, GSTM1 null genotype was significantly associated with lung cancer [odds ratio (OR) = 2.04, 95% confidence interval (CI) = 1.13-3.68]. ORs for GSTM1 and lung cancer were significant in females (2.50, 1.09-5.72) and smokers (2.25, 1.11-4.54) and not significant in males (1.4, 0.58-3.38) and non-smokers (0.88, 0.18-4.33). However, ORs for males versus females and smokers versus non-smokers did not differ significantly. The OR for GSTM1 and lung cancer in female smokers was 3.03 (1.09- 8.40), compared with 1.42 (0.53-4.06) in male smokers. In contrast to PAH-DNA adducts in leukocytes, SCE did not differ between cases and controls. Neither biomarker differed significantly between the two GSTM1 genotypes. The combined effect of elevated PAH-DNA adducts and GSTM1 genotype on case-control status (16.19, 1.2-115) appeared multiplicative. Results suggest that the effect of the GSTM1 null genotype is greatest in female smokers, which is consistent with other evidence that indicates that women are at higher risk of lung cancer than males, given equal smoking. Persons with both the GSTM1 deletion and elevated PAH-DNA adducts may represent a sensitive subpopulation with respect to carcinogens in tobacco smoke and other environmental media.      

Impact of the acute cardiac ischemia time-insensitive predictive instrument (ACI-TIPI) on the speed of triage decision making for emergency department patients presenting with chest pain

Objective: Emergency department (ED) triage for acute cardiac ischemia in the primary teaching hospital in Geneva, Switzerland, is very accurate, but at the cost of very long ED stays. Thus, the authors sought: 1) to determine the impact of the acute cardiac ischemia time-insensitive predictive instrument (ACI-TIPI), incorporated into a computerized electrocardiograph, on length of stay and speed of triage decision making for ED patients presenting with symptoms suggesting acute cardiac ischemia, and 2) to study the ACI-TIPI’s impact on physicians of different training levels. Design: A seven-month prospective clinical trial with alternating-month experimental and control periods. Setting: An urban major teaching hospital in Geneva, Switzerland. Participants: Patients over the age of 18 years presenting to the ED with chest pain or other symptoms suggesting acute cardiac ischemia (acute myocardial infarction or unstable angina pectoris). Emergency department physicians, classified as novice (those in their first ED rotations) and experienced (those in their second or later ED rotations). Patients staying overnight in the ED (n=111) were excluded from the analysis. Intervention: During the experimental months, the computerized electrocardiograph printed the ACI-TIPI probability of acute cardiac ischemia at the top of each subject’s electrocardiogram. During control months, the probability was not provided. Measurements and main results: Among the 418 study subjects, for patients with acute ischemia seen by novice clinicians, the use of the ACI-TIPI decreased ED time from presentation to triage decision and ED release by 0.7 hour (19%) (p=0.007). Subgroup analyses for patients with acute myocardial infarction, patients with unstable angina pectoris, and patients given thrombolytic therapy also showed analogous decreases in ED time consistent with this finding. Other key determinants of ED length of stay included: age, whether the coronary care unit was full, whether patients received thrombolytic therapy, and whether admission was during the night shift. The experimental and control groups did not differ in triage disposition appropriateness or mortality. Conclusions: For ED patients with acute cardiac ischemia evaluated by novice clinicians, the ACI-TIPI substantially speeded ED decision making and triage. The suggestion of an impact on different cardiac ischemia subgroups and mortality deserves further larger clinical trials.     

A diaphragmatic retroperitoneal cyst

Diaphragmatic lesions are usually congenital bronchogenic cysts. A patient with a known diaphragmatic cyst presented with new onset right upper quadrant pain. Repeat imaging showed enlargement of the cyst, the CA19–9 cancer marker was raised at 312iu/ml (normal: <27iu/ml) and positron emission tomography combined with computed tomography showed focally increased uptake in the cystic wall. In view of symptoms and risk of neoplasia, the lesion was excised. Histology showed a benign epidermoid cyst. Features falsely suggesting neoplasia have been reported previously with benign splenic cysts but not with a benign diaphragmatic epidermoid cyst.     

Prophylactic antithrombotic therapy for patients with systemic lupus erythematosus with or without antiphospholipid antibodies: do the benefits outweigh the risks? A decision analysis

BACKGROUND: A high incidence of both arterial and venous thromboembolic events has been reported in patients with systemic lupus erythematosus (SLE), but the risks and benefits of primary prophylactic antithrombotic therapy have not been assessed. We measured the clinical benefit of 3 antithrombotic regimens in patients with SLE without antiphospholipid antibodies, with anticardiolipin antibodies, or with lupus anticoagulant. METHODS: A Markov decision analysis was used to evaluate prophylactic aspirin therapy, prophylactic oral anticoagulant therapy, and observation. Input data were obtained by literature review. Clinical practice was simulated in a hypothetical cohort of patients with SLE who had not experienced any previous episode of arterial or venous thromboembolic events. For each strategy, we measured numbers of thromboembolic events prevented and major bleeding episodes induced, and quality-adjusted survival years. RESULTS: Prophylactic aspirin therapy was the preferred strategy in all settings, the number of prevented thrombotic events exceeding that of induced bleeding episodes. In the baseline analysis (40-year-old patients with SLE), the gain in quality-adjusted survival years achieved by prophylactic aspirin compared with observation ranged from 3 months in patients without antiphospholipid antibodies to 11 months in patients with anticardiolipin antibodies or lupus anticoagulant. Prophylactic oral anticoagulant therapy provided better results than prophylactic aspirin only in patients with lupus anticoagulant and an estimated bleeding risk of 1% per year or less. CONCLUSIONS: Prophylactic aspirin should be given to all patients with SLE to prevent both arterial and venous thrombotic manifestations, especially in patients with antiphospholipid antibodies. In selected patients with lupus anticoagulant and a low bleeding risk, prophylactic oral anticoagulant therapy may provide a higher utility.