PROGNOSTIC VALUE OF MIB-1 IN NEUROENDOCRINE TUMOURS OF THE LUNG

The spectrum of neuroendocrine lung tumours ranges from highly aggressive small cell carcinomas (SCLC) to carcinoid tumours (CD) of low malignant potential. Between these two extremes, the ‘well-differentiated neuroendocrine carcinomas’ (WDNEC) form a transitional group with uncertain biological behaviour. This study investigated the prognostic value of the proliferation marker MIB-1 (paraffin Ki-67) in 59 neuroendocrine lung tumours (32 SCLC, 13 WDNEC, 14 CD) by immunostaining of routinely processed paraffin sections. Morphometric evaluation was done by semi-automatic image analysis. The results were compared with survival data (mean follow-up: 42 months). The proliferation rates of the tumours as determined by MIB-1 immunoreactivity (MIB-1-PR) were significantly different between the tumour types (SCLC>WDNEC>CD) and showed a strong inverse correlation with survival time. In CD, the percentage of MIB-1-labelled nuclei never exceeded 1·1 per cent; higher values would therefore favour the diagnosis of WDNEC over that of CD. Among WDNEC, MIB-1 was able to differentiate a subgroup with excellent prognosis (MIB-1-PR: 0·3–3·4 per cent) from another subgroup with a death rate of 50 per cent (MIB-1-PR: 7·3–20·3 per cent). Within each tumour type, all patients without distant metastases at diagnosis survived when MIB-1-PR was ⩽9·4 per cent, suggesting a potential threshold for prognosis. Although the status of metastases was the dominant prognostic factor in these neoplasms, MIB-1 was able to provide additional prognostic information allowing the definition of prognostically different subgroups of patients. In conclusion, MIB-1 and the status of metastases are complementary prognostic indicators and are best used in combination to characterize the biological behaviour of neuroendocrine lung tumours.     

COMPARATIVE GENOMIC HYBRIDIZATION (CGH) ANALYSIS OF NEUROBLASTOMAS—AN IMPORTANT METHODOLOGICAL APPROACH IN PAEDIATRIC TUMOUR PATHOLOGY

Comparative genomic hybridization (CGH) was applied to 35 neuroblastomas to obtain a global view of genetic imbalances. Results were validated by means of Southern blot hybridization (detection of N-myc amplification), loss of heterozygosity (LOH) studies (detection of deletion 1p), and interphase cytogenetics [dual labelling fluorescence in situ hybridization (FISH) of centromeric 17 and erbB-2]. CGH allowed sensitive detection of N-myc amplification and chromosome 1p deletion, representing the most established prognostic markers of neuroblastoma. In addition, a high rate of chromosome 17 aberrations (63 per cent) with possible prognostic relevance was observed. Previously unreported high level copy number increases indicating oncogene amplification were mapped to chromosome subbands 2p13–14 and 3q24–26. Other recurrent regional chromosomal aberrations were localized on 11q, 12q, 13q, 14q, and 15q. CGH results were fully consistent with data of Southern blot analysis and LOH study, as well as interphase cytogenetics. These results show that CGH is a sensitive method for the detection of all prognostically relevant genetic alterations in neuroblastomas; that CGH considerably simplifies the detection of these alterations, resulting in a single methodological approach; and that CGH is a powerful tool to elucidate previously unknown genetic changes in neuroblastomas. © 1997 by John Wiley & Sons, Ltd.     

THE INFLUENCE OF THE METHOD OF DELIVERY AND THE CLAMPING TECHNIQUE ON THE RED CELL VOLUME IN INFANTS OF DIABETIC AND NON-DIABETIC MOTHERS

The red cell volume has been investigated in 35 infants of diabetic mothers and in 18 infants of non-diabetic mothers. It is shown that not only the clamping technique but also, the method of delivery has an influence on the red cell volume of the infant. Thus the red cell volume is less in infants delivered vaginally with early clamping, compared with infants delivered by caesarean section with early clamping. These findings support the theory that during vaginal delivery a temporary change in It is suggested that IDM during vaginal delivery with early clamping deposit more blood in the placenta than do the non-IDM, since we found a smaller red cell volume per kg the distrfbution of. the foeto-placental blood volume between placenta and child occurs.     

EFFECTS OF SEGMENTAL THORACIC EXTRADURAL ANALGESIA ON SYMPATHETIC BLOCK IN CONSCIOUS DOGS

To test the hypothesis that segmental thoracic extradural blockcauses sympathetic denervation caudally beyond dermatomes renderedanalgesic, we have measured regional skin temperatures in sixconscious dogs after upper thoracic, mid thoracic, and lumbarextradural injection of 0.5% bupivacaine 0.5, 1 and 2 ml cumulatively(total dose: 3.5 ml) given at 45-min intervals. Dogs were studiedat constant ambient and rectal temperatures. Upper thoracicextradural injections resulted in a significant increase inskin temperatures on both the front (+ 1.4 (SEM 0.2) °C)and hind paw (+ 1.4 (0.3) °C), while the area of analgesiawas confined to the upper trunk. With lumbar extradural injection,skin temperatures increased significantly (+2.0 (0.5) °C)on the lower extremities only. Mid thoracic injection significantlyincreased both front (+2.4 (0.9) °C) and hind paw (+2.2(0.6) °C) skin temperatures, but decreased temperatureson the thorax (–0.9 (0.2) °C) and abdomen (–1.0(0.2) °C), reversing the normal temperature gradient alongthe body axis. Irrespective of the injection site, skin temperatureson the trunk failed to increase or even decreased significantly.These data suggest that small doses of local anaesthetics appliedto the extradural space of conscious dogs cause increased lowerextremity skin temperatures caudal to areas unresponsive topinprick stimulation when injected at a high thoracic level,and decreased trunk skin temperature even in analgesic areas,so that skin temperature measurements are unlikely to reflectpurely sympathetic efferent activity on the trunk. Upper thoracicsegmental extradural analgesia induced a decrease in sympathetictone distal to the area of analgesia.     

PLACENTAL TRANSFUSION IN INFANTS OF DIABETIC MOTHERS ELUCIDATED BY PLACENTAL RESIDUAL BLOOD VOLUME

The influence of the method of delivery and the clamping technique on the placental transfusion is investigated by measurement of the placental residual blood volume in 58 infants of diabetic mothers and in 65 infants of nondiabetic mothers. It is shown that infants of diabetic mothers delivered vaginally compared with infants of diabetic mothers delivered by caesarean section, have a larger placental residual blood volume, if early clamping is employed. This relation suggests that also in infants of diabetic mothers, a temporary deposition of the distribution of the foeto-placental blood volume between the infant and the placenta occurs during vaginal delivery, because of the impaired venous backflow to the infant. The difference in the placental residual blood volume is more pronounced for infants of diabetic mothers than for infants of non-diabetic mothers. Further, it is shown that the placental residual blood volume is significant larger in infants of diabetic mothers but only after vaginal delivery with early clamping, compared with the same group of infants of non-diabetic mothers.     

Synthesis,biological activity and isomerism of guanylate cyclase C-activating peptides guanylin and uroguanylin

Recently, the peptides guanylin and uroguanylin were identified as endogenous ligands of the membrane-bound guanylate cyclase C (GC-C) that is mainly expressed in the intestinal epithelium. In the present study, bioactive guanylin and uroguanylin have been prepared by solid-phase methodology using Fmoc/HBTU chemistry. The two disulfide bonds with relative 1/3 and 2/4 connectivity have been introduced selectively by air oxidation of thiol groups and iodine treatment of Cys(Acm) residues. Using this strategy, several sequential derivatives were prepared. Temperature-dependent HPLC characterization of the bioactive products revealed that guanylin-related peptides exist as a mixture of two compounds. The isoforms are interconverted within approximately 90 min, which prevents their separate characterization. This effect was not detected for uroguanylin-like peptides. Synthetic peptides were tested for their potential to activate GC-C in cultured human colon carcinoma cells (T84), known to express high levels of GC-C. The results obtained show that both disulfide bonds are necessary for GC-C activation. The presence of the amino-terminally neighboring residues of Cys104 for guanylin and Cys100 for uroguanylin has been found to be essential for GC-C stimulation. Unexpectedly, a hybrid peptide obtained from substitution of the central tripeptide AYA of guanylin by the tripeptide VNV of uroguanylin was not bioactive. © Munksgaard 1997.     

Pacing System Analyzers: Different Systems—Different Results

When a pacemaker is implanted, several electrophysiological parameters are measured using pacing system analyzers (PSA). Different PSAs may use different filter settings and measuring techniques when compared to the implanted pacemaker. In order to determine if there were significant differences in measurements obtained with different PSAs, we obtained measurements in a group of 99 patients with three different PSAs and a manual method. The results show that with each of the three different PSAs tested, different amplitudes of intracardiac electrograms are obtained and that they are usually higher than those obtained by manual measurement of recorded electrograms. Despite significant differences, however, all methods correlate well with each other. Following common practice of pacemaker programming, the use of a PSA for the implantation of a pacemaker that uses different sensing technique does not lead to clinical complications.