An integrated approach utilizing artificial neural networks and SELDI mass spectrometry for the classification of human tumours and rapid identification of potential biomarkers.

MOTIVATION: MALDI mass spectrometry is able to elicit macromolecular expression data from cellular material and when used in conjunction with Ciphergen protein chip technology (also referred to as SELDI-Surface Enhanced Laser Desorption/Ionization), it permits a semi-high throughput approach to be taken with respect to sample processing and data acquisition. Due to the large array of data that is generated from a single analysis (8-10000 variables using a mass range of 2-15 kDa-this paper) it is essential to implement the use of algorithms that can detect expression patterns from such large volumes of data correlating to a given biological/pathological phenotype from multiple samples. If successful, the methodology could be extrapolated to larger data sets to enable the identification of validated biomarkers correlating strongly to disease progression. This would not only serve to enable tumours to be classified according to their molecular expression profile but could also focus attention upon a relatively small number of molecules that might warrant further biochemical/molecular characterization to assess their suitability as potential therapeutic targets. RESULTS: Using a multi-layer perceptron Artificial Neural Network (ANN) (Neuroshell 2) with a back propagation algorithm we have developed a prototype approach that uses a model system (comprising five low and seven high-grade human astrocytomas) to identify mass spectral peaks whose relative intensity values correlate strongly to tumour grade. Analyzing data derived from MALDI mass spectrometry in conjunction with Ciphergen protein chip technology we have used relative importance values, determined from the weights of trained ANNs (Balls et al., Water, Air Soil Pollut., 85, 1467-1472, 1996), to identify masses that accurately predict tumour grade. Implementing a three-stage procedure, we have screened a population of approximately 100000-120000 variables and identified two ions (m/z values of 13454 and 13457) whose relative intensity pattern was significantly reduced in high-grade astrocytoma. The data from this initial study suggests that application of ANN-based approaches can identify molecular ion patterns which strongly associate with disease grade and that its application to larger cohorts of patient material could potentially facilitate the rapid identification of validated biomarkers having significant clinical (i.e. diagnostic/prognostic) potential for the field of cancer biology. AVAILIBILITY: Neuroshell 2 is commercially available from ward systems.

Anatomic variants of the coracoacromial ligament.

Cadaveric anatomic dissections of 50 shoulders have been done with measurement and histologic analysis of the coracoacromial ligament. In subjects older than 50 years of age the coracoacromial ligament does not have a constant form. Three main types were identified: quadrangular, Y-shaped, and a broad band. A previously unreported type of coracoacromial ligament the multiple banded ligament, was found. It had the largest coracoid attachment. This ligament was similar to the Y form but with an additional band extending inferiorly and medially toward the base of the coracoid. Histologic analysis indicates the multiple banded type could be more common than this study suggests.

Granulation tissue polyposis associated with carcinoid tumours of the small intestine.

We report two patients with ileal carcinoid tumours which were associated with polyps due to mucosal granulation tissue proliferation. In both cases the tumours had extensively infiltrated the small bowel wall and mesentery, and one had hepatic metastases. The mucosal surface of each specimen showed numerous, pale brown, sessile polyps which were restricted to the intestinal segment involved by carcinoid tumour, although not always closely related to neoplastic cells. The polyps were formed by the proliferation of capillaries, smooth muscle cells and myofibroblasts as demonstrated by immunohistochemistry and electronmicroscopy.

A histological and electronmicroscopic study of intracorneal melanin in benign and malignant melanocytic lesions.

Intracorneal melanin is a feature quite frequently encountered in a range of melanocytic lesions, yet has rarely been described in the literature. We examined a variety of melanocytic lesions with increasing degrees of melanocytic atypia for this feature. The distribution and amount of intracorneal melanin is described and it was shown to be entirely within keratinocytes. In general, the amount of intracorneal melanin was related to increasing melanocytic atypia and was typically distributed in a disorderly fashion in malignant lesions.

Multiple and recurrent inflammatory fibroid polyps in a Devon family ('Devon polyposis syndrome'): an update.

Inflammatory fibroid polyps are uncommon but well documented as solitary polyps occurring typically in the stomach or ileum. A Devon family has previously been reported in which a female in three successive generations has presented with multiple polyps requiring repeated surgery over a number of years. A further two female family members, both siblings from the 3rd generation, who required surgery for the same condition are now reported.

Pulmonary endocrine cells in chronic bronchitis and emphysema.

Pulmonary endocrine cells have been studied according to their immunoreactivity for neuron-specific enolase, gastrin-releasing peptide (GRP), calcitonin, leucine-enkephalin, and serotonin in the lungs of subjects with chronic bronchitis and emphysema. The overall population was significantly greater in comparison with matched controls. The change was most marked in lobes affected by pneumonic consolidation, and did not affect equally the sub-populations of cells as identified by their content of peptide; the difference was much greater for calcitonin-containing cells than for those immunoreactive for GRP. This change may be the basis of the hypercalcitoninaemia and hypercalcitoninuria which have been reported in patients with inflammatory pulmonary disease.

Neuroendocrine cell populations in normal human lungs: a quantitative study.

Pulmonary neuroendocrine cells, identified by their positive immunochemical reaction for neurone specific enolase, were readily demonstrable and uniformly distributed in 15 pairs of normal adult human lungs. About 65% contained gastrin releasing peptide and nearly all the rest contained calcitonin. Leucine-enkephalin was not found. Serotonin containing cells were few, and cells immunoreactive for adrenocorticotrophin and antidiuretic hormone were absent. About one in 10 cells was argyrophilic, and costorage of peptides was not seen.