Artificial intelligence and bladder cancer arrays.

Non-muscle invasive bladder cancer is a heterogenous disease whose management is dependent upon the risk of progression to muscle invasion. Although the recurrence rate is high, the majority of tumors are indolent and can be managed by endoscopic means alone. The prognosis of muscle invasion is poor and radical treatment is required if cure is to be obtained. Progression risk in non-invasive tumors is hard to determine at tumor diagnosis using current clinicopathological means. To improve the accuracy of progression prediction various biomarkers have been evaluated. To discover novel biomarkers several authors have used gene expression microarrays. Various statistical methods have been described to interpret array data, but to date no biomarkers have entered clinical practice. Here, we describe a new method of microarray analysis using neurofuzzy modeling (NFM), a form of artificial intelligence, and integrate it with artificial neural networks (ANN) to investigate non-muscle invasive bladder cancer array data (n=66 tumors). We develop a predictive panel of 11 genes, from 2800 expressed genes, that can significantly identify tumor progression (average Logrank p = 0.0288) in the analyzed cancers. In comparison, this panel appears superior to those genes chosen using traditional analyses (average Logrank p = 0.3455) and tumor grade (Logrank, p = 0.2475) in this non-muscle invasive cohort. We then analyze panel members in a new non-muscle invasive bladder cancer cohort (n=199) using immunohistochemistry with six commercially available antibodies. The combination of 6 genes (LIG3, TNFRSF6, KRT18, ICAM1, DSG2 and BRCA2) significantly stratifies tumor progression (Logrank p = 0.0096) in the new cohort. We discuss the benefits of the transparent NFM approach with respect to other reported methods.

Glucocorticoid receptor expression in inflammatory bowel disease: evidence for a mucosal down-regulation in steroid-unresponsive ulcerative colitis.

BACKGROUND: Glucocorticoids (GC) play a major role in the attenuation of inflammation. Glucocorticoid receptor (GR) expression is an important determinant of steroid sensitivity. AIMS: To investigate whether GR mRNA expression is altered in inflammatory bowel disease, and whether GR mRNA expression correlates with disease activity and may predict response to GC therapy. METHODS: Mucosal biopsies were taken from 33 patients with ulcerative colitis, 21 with Crohn's disease and 11 controls. Peripheral blood mononuclear cells were isolated from 24 ulcerative colitis and 18 Crohn's disease patients and 11 controls. GR mRNA was measured by quantitative reverse transcriptase polymerase chain reaction (RT-PCR), and correlated to endoscopic findings, clinical activity and outcome of GC therapy. In a subset of subjects GR localisation was shown by immunohistochemistry. RESULTS: In patients with inflammatory bowel disease GR expression was not different from controls. However, GR was decreased in biopsies from ulcerative colitis patients with impaired GC response. The inhibitory subtype GRbeta was expressed 100-1000 times lower than GRalpha. GR immunoreactivity was identified in immune and epithelial cells except for colonic crypts. CONCLUSION: In inflammatory bowel disease systemic and mucosal GR mRNA expression is not altered. However, in ulcerative colitis patients, low mucosal GR expression may predict the outcome of GC therapy. The low expression of GRbeta challenges its role in steroid refractoriness in inflammatory bowel disease.

Acute cyclosporine-induced nephrotoxicity in renal transplant recipients: the role of the transplanted kidney.

Cyclosporine A causes an acute reduction in GFR. The interindividual variable reduction in GFR is most likely the result of arteriolar vasoconstriction. Vasoconstriction is attributable either to a local effect of cyclosporine on renal blood vessels (intrinsic mechanism) or to a systemic effect of cyclosporine on circulating and/or neuronal factors (extrinsic mechanism). The aim of the investigation presented here was to establish whether intrinsic or extrinsic mechanisms account for the interindividual differences in the susceptibility to acute cyclosporine-induced nephrotoxicity. For that purpose, this study took advantage of the clinical transplant situation in which two (intrinsically identical) kidneys from a cadaveric donor are transplanted into two (extrinsically) different subjects. The preexisting regular daily cyclosporine doses were raised by 25% for 2 wk and by 50% for another 2 wk in 16 patients with stable renal graft function, representing eight pairs of patients, each of whom had received kidneys from the same donor. In these patients, a mean (+/- SD) maximum cyclosporine-induced increase in serum creatinine concentration of 13 +/- 11% (P < 0.001) and in serum BUN of 27 +/- 33% (P < 0.01), together with a decline in the fractional uric acid excretion of 51 +/- 89% (P < 0.02) were observed. The percentage change in serum creatinine concentrations after increased dosing of cyclosporine paralleled within the subjects receiving their kidneys from the same donor, i.e., when one recipient experienced a large percentage of change after increases of cyclosporine dosing, the corresponding recipient of a kidney from the same donor had a change of the same magnitude. Seven of eight pairs showed a consistent response with respect to a clinically significant increase in serum creatinine concentration of > 15%, with a consistent response purely by chance being < 5%. Thus, the transplanted kidney itself rather than the recipient determines the susceptibility to acute cyclosporine-induced nephrotoxicity.

Inhaled nitric oxide in advanced paraquat intoxication.

No effective treatment is available for adult respiratory distress syndrome, pulmonary hypertension and progressive lung fibrosis in severe paraquat poisoning. A potentially beneficial effect of nitric oxide inhalation on the mean pulmonary artery pressure and gas exchange in a subject with advanced paraquat intoxication is reported. Eight days after the suicidal ingestion of an unknown dose of paraquat, a 52-year-old female had a PaO2 < or = 50 mm Hg despite ventilation with an FiO2 of 1 and a positive end-expiratory pressure of 14 to 18 cm H2O. After administration of 25 ppm nitric oxide, PaO2 increased and the mean pulmonary artery pressure and the right-to-left shunt decreased. Discontinuation of nitric oxide resulted in rapid reversal. Ventilatory function was stabilized for three days during nitric oxide inhalation but the patient developed massive pleural effusions and died on d 11 during an interruption of nitric oxide therapy. The response of serious paraquat intoxications to nitric oxide therapy may merit further study. A remarkable post-mortem finding was extensive myonecrosis supporting prolonged muscular retention of paraquat with toxic myopathy or neuromyopathy as a late manifestation of paraquat toxicity.

[Radiological findings in periosteal reaction due to inflammation (author's transl)]. / Radiologische Befunde des Periostes bei entzündlichen Knochenerkrankungen.

Presentation of radiographically apparent periosteal changes due to inflammation. Solid periosteal reaction is being distinguished from an interrupted-type reaction. Some cases of acute and chronic osteomyelitis, congenital and acquired lues, bony tuberculosis, leprosy and fungal disease serve to demonstrate the different types of periosteal reaction; and a differential diagnosis is being discussed. The diagnostic evaluation should include bone scanning in addition to routine radiography with special views and follow up examinations.

[Malignant metastases to the periphery of the skeleton (author's transl)]. / Zur Metastasierung maligner Tumoren in die Skelettperipherie.

Metastases from malignant tumours beyond the knee and elbow are uncommon and represent only 1 to 2% of all bone metastases. Four cases of peripheral skeletal metastases are described, with primaries in the cervix, epipharynx, parotid and breast.

[Repeated contrast cisternography after previous use of an oily contrast medium (author's transl)]. / Möglichkeit der wiederholten Kontrastzisternographie nach einmaliger Applikation von öligem Kontrastmittel.

Twenty-four control cisternograms were carried out at two to 22 months after lumbar injection of 1.0 to 1.5 ml. Duroliopaque; 20 of these were successfully performed without a fresh lumbar puncture. In most cases, the amount of contrast medium available was less than at the original examination, but was sufficient for definite exclusion of a space-occupying lesion. In four cases only the contrast medium could not be mobilised or manoeuvred into the cisterns and a fresh lumbar puncture was required for further contrast injection.

[Malignant tumors of the small intestine (author's transl)]. / Maligne Dünndarmtumoren.

Tumors of the small intestine are rare as compared to other tumors of the gastrointestinal tract; clinical symptoms are unrevealing for long time, thwarting an early diagnosis. Detection of these tumors by x-ray examination is successful often only after several attempts. Case reports are given of 7 patients and difficulties of making a diagnosis are discussed. Radiological methods are described; differential diagnosis of x-ray findings is expecially difficult. A histological diagnosis by endoscopic or intraoperative biopsy should always be tried. Surgery is necessary in every case in order to restore normal passage.

[The diagnosis of cerebellopontine tumours by tomography after positive contrast cisternography (author's transl)]. / Die Diagnostik von Kleinhirnbrückenwinkel-Tumoren mittels Tomographie nach positiver Kontrastzisternographie

Forty-one tumours in the cerebello-pontine angle were found as a result of 207 Duroliopaque cisternograms. In all 37 patients who came to operation, the position and size of the tumour, as shown radiologically, could be confirmed. The value of positive contrast cisternography was greatest in the smaller tumours. 35 tumours were less than 2.5 cm. in their vertical diameter. Twenty-four tumours were predominantly extra-meatal, were predominantly extra-meatal, four predominantly intra-meatal and 13 extra- and intra-meatal as well. In only 23 patients was there enlargement of the internal acoustic meatus, either absolutely or by comparison with the other side. In 18 patients there was no significant difference in the meati on the two sides. These facts and the observation that there may be idiopathic meatal widening in the presence of typical symptoms of an acoustic neuroma, but without a tumour being present, underlines the importance of positive contrast cisternography. A high degree of accuracy for tumour less than 2.5 cm. can only be obtained by using the method in conjunction with multi-dimensional tomography.