Linkage map of a region of human chromosome band 11q13 amplified in breast and squamous cell tumors.

DNA amplification involving markers on human chromosome band 11q13 is a consistent feature of several major cancers, notably adenocarcinoma of the breast and squamous cell carcinoma of the head, neck, lung, and esophagus. Since the presence of the amplification may be clinically significant, by defining a subset of patients at increased risk, it is important to establish which of the several genes on the amplified DNA provides the selective force. Here we describe a physical map of the centromeric end of the amplified DNA as it exists in a particular squamous carcinoma cell line (UMSCC2) and establish an unambiguous order for several known markers in the region, including pMS51/D11S97, pHB159/D11S146, BCL1, PRAD1/D11S287, HSTF1/FGF4 and INT2/FGF3. Significantly, PRAD1 is within 120-150 kb of the BCL1 translocation breakpoint and the data identify a new CpG island (D11S814) between PRAD1 and HSTF1. The ordering of the HSTF1 and INT2 genes and the clustering of CpG islands in the region have important implications in assessing whether the frequently observed amplifications at 11q13 are centered on one or more genes.     

Discriminative power of visual evoked potential characteristics in multiple sclerosis

To investigate the discriminative power of pattern-reversal visual evoked potential characteristics (peak latencies and amplitude) and to test whether the addition of visual evoked potential amplitude can increase the power of the visual evoked potential in the diagnosis of multiple sclerosis, we retrospectively studied visual evoked potentials in 59 patients with definite multiple sclerosis and 126 control subjects. Two check sizes (17 and 10) were used. Females had significantly higher amplitudes and shorter latencies than males. N80 latency showed a gradual increase and P100 amplitude a decrease with age. P100 latency was stable between the ages of 20 and 55 years but was increased in childhood and the elderly. The significance of visual evoked potential peak latencies and amplitude in separating the two groups was investigated by means of a (multivariate) discriminant analysis. The visual evoked potential with a pattern of 10 could be measured in 58% of patients with multiple sclerosis. The exclusive use of the P100 amplitude in the discriminant analysis resulted in a percentage of correctly classified cases of 84%, whereas for P100 and N80 latency it was 85% and 90%, respectively. With the 17 pattern, the N80 latency yielded also a higher correct percentage than did the P100 latency. Although N80 latency is, to a greater extent than P100 latency, influenced by age, sex and size of stimulus pattern, when these influences are accounted for, the N80 latency is a more sensitive measure than P100 latency in the classification of multiple sclerosis. Combined use of latency and amplitude for discriminant analysis yielded no significant improvement of the percentage of correctly classified cases.Abbreviations MS multiple sclerosis - SD standard deviation     

Chromosome 11q13 markers and D-type cyclins in breast cancer

Summary One in six primary human breast cancers has DNA amplification centered on the cyclin D1 gene (CCND1) on chromosome 11q13. This genetic abnormality is preferentially associated with estrogen-receptor positive tumors and may define a sub-class of patients with an adverse prognosis. AlthoughCCND1 has the credentials of a cellular oncogene, being a target for chromosomal translocation and retroviral integration, the 11q13 amplicon encompasses several other markers andCCND1 is not the only candidate for the key gene on the amplified DNA. To assess their relative importance, we have constructed a physical map of the amplified DNA and compared the extent and frequency of amplification across the region. Since it is likely that the gene providing the selective force for amplification will be expressed at elevated levels, we have also examined expression of both RNA and protein. By these criteria, cyclin D1 remains the strongest candidate for the key oncogene on the amplicon and we are currently investigating the functional consequences of its over-expression.Presented by Gordon Peters at the 16th Annual San Antonio Breast Cancer Symposium, San Antonio TX, USA, November 4, 1993; Minisymposium on Molecular Genetics in Breast Cancer.     

Validity of clinical criteria for the diagnosis of dementia with Lewy bodies

OBJECTIVE: To assess the clinical validity of clinical diagnostic criteria for dementia with Lewy bodies (DLB). METHODS: We assessed the sensitivity, specificity, and positive and negative predictive values of the clinical criteria of the Consortium on dementia with Lewy Bodies (CDLB) in 18 patients with autopsy-proven DLB and in 76 patients with dementia not associated with Lewy bodies, using postmortem diagnosis as a gold standard. RESULTS: CDLB criteria had either high sensitivity or high specificity, but no set of criteria simultaneously provided both high sensitivity and high specificity. Clinical criteria had higher predictive validity in patients with pure DLB than in patients with DLB and AD. Seventy-eight percent of patients with pure DLB had two or more major criteria, compared with 44% of patients with DLB and AD (p<0.02). If the nine patients with DLB and AD were excluded from the DLB group, the CDLB criteria for probable DLB had sensitivity of 78% and specificity of 85%. CDLB criteria for probable DLB (two or more major criteria) distinguished DLB from AD with a sensitivity of 78% and a specificity of 64%. CONCLUSIONS: The proposed CDLB criteria have high negative predictive value and thus do well at excluding patients with DLB. Positive predictive value of 75% can be achieved by a combination of any three major or minor criteria, providing the analysis is confined to patients with mild to moderate dementia. Criteria were most accurate if confined to patients with pure DLB who had mild to moderate dementia.     

Neurochemical diversity of dystrophic neurites in the early and late stages of Alzheimer's disease

We examined the neurochemical and morphological diversity of abnormal neurites associated with beta-amyloid plaque formation in the early and late stages of Alzheimer's disease. Preclinical Alzheimer's disease was characterised by the presence of abnormal neurites containing either neurofilament or chromogranin A immunoreactivity. All clustered dystrophic neurites in these cases were associated with beta-amyloid plaques. Neurofilament immunoreactive dystrophic neurites in preclinical Alzheimer's disease could be further subclassified into bulb- and ring-like structures, and these abnormal neurites contained both phosphorylated and dephosphorylated neurofilament epitopes. Dystrophic neurites in Alzheimer's disease could be subdivided into predominantly neurofilament, tau, or chromogranin A immunolabeled forms. Some neurofilament immunoreactive neurites had a core region labeled for tau. The neurofilaments of the dystrophic neurites in Alzheimer's disease had the same complement of phosphorylation- and dephosphorylation-dependent epitopes as observed in preclinical cases. Therefore, an abnormal accumulation of variably phosphorylated neurofilaments represent the earliest cytoskeletal alteration associated with dystrophic neurite formation. Furthermore, these data indicate that dystrophic neurites may "mature" through neurofilament-abundant forms to the neurites containing the profoundly altered filaments labeled for tau. The precise morphological and neurochemical changes associated with dystrophic neurite formation suggests that beta-amyloid plaques are causing physical damage to surrounding axons. The resultant axonal sprouting and profound cytoskeletal alterations would follow the chronic stimulation of the stereotypical reaction to such physical trauma.     

Blood crossmatching for burn surgery: potential for reduced wastage using a modified dye formula

Estimating the perioperative crossmatch requirement (CMR) of burn patients is difficult, as losses are variable and hard to predict. Accuracy is important, however, as over-provision risks wasting blood. Blood ordering tariffs have increased efficiency and reduced blood wastage in other branches of surgery. Dye has published a tariff for burn patients in the form of a formula, relating CMR to weight and percentage total body surface area (TBSA) excised. This study examines the efficiency of blood ordering and use among 72 burn patients and compares outcomes with the predictions of Dye's and a modified Dye's formula, for the same patients. All patients were crossmatched, but only 34 patients were transfused. The crossmatch:transfusion ratio was 2.1, with 52% of crossmatched blood being unused. Dye's formula would have reduced the total volume crossmatched for the same patients by 13%. The crossmatch:transfusion ratio would be 1.8, with 44% of cross-matched blood remaining unused. A modified form of Dye's formula was designed to reduce the high rate of blood non-use. This would reduce the total volume crossmatched by 40% and the rate of blood non-use to 20%. The crossmatch:transfusion ratio would be 1.24.     

Anti-invasion drugs

Summary Most of the pharmaceuticals in clinical practice today for treatment of breast and other cancers are cytotoxic or cytostatic inhibitors of tumor growth. While this type of drug has found its place, along with surgery and radiotherapy, in treatment of disease, the breast cancer death rate has not decreased. This appears to be the result of rising incidence, resistance to therapy, and metastasis of the disease. Since distant metastasis (usually indicated by lymph node involvement) of breast cancer is related only indirectly to tumor size, it would appear that a concerted effort should be made to discover drugs which directly interfere with this complex process. Metastasis appears to depend upon tumor cell motility, dedifferen-tiation, local invasion, and angiogenesis. Significant progress has been recently made in the creation of new animal models of metastasis and in identifying several new drugs which may be suitable for clinical inhibition of this process. This article reviews current findings on anti-invasion/metastasis drugs with a focus on breast cancer.Presented at the symposium "New Approaches in the Therapy of Breast Cancer", Georgetown University Medical Center, Washington DC, October 1994, generously supported by an education grant from Bristol-Myers Squibb.