LONG‐TERM FOLLOW UP OF PATIENTS WITH SMALL GASTROINTESTINAL STROMAL TUMORS IN THE STOMACH USING ENDOSCOPIC ULTRASONOGRAPHY‐GUIDED FINE‐NEEDLE ASPIRATION BIOPSY

Background: Gastrointestinal stromal tumors (GIST) are one of the most common mesenchymal tumors of the gastrointestinal tract. GIST are defined by positive immunohistochemical staining for KIT or CD34 and thus are generally diagnosed after surgery. Because small GIST are rarely diagnosed before surgery, the clinical course of these small tumors is not clear. The aim of the present study was to follow changes in size and configuration of small GIST that were pathologically confirmed using endoscopic ultrasonography‐guided fine‐needle aspiration biopsy (EUS‐FNAB). Methods: Between July 1997 and December 2003, 16 tumors in 16 patients (10 men and 6 women) with an immunohistochemical diagnosis of GIST were regularly followed in our hospital. The median patient age when EUS‐FNAB was performed was 62 years (range 26–82 years) and the median follow‐up period was 4.9 years (range 0.5–9.6 years). Results: Fourteen tumors showed no remarkable changes in size and shape during follow up compared with the initial diagnosis. Two tumors enlarged: one tumor approximately doubled its diameter in 8 years and the other tumor increased from 1.8 cm at diagnosis to up to 10 cm after only 2 years. Doubling time of the latter tumor was calculated as 3.1 months. Conclusions: We conclude that EUS‐FNAB might be a good modality for final diagnosis of GIST without surgery, and that GIST without rapid growth on follow up can be endoscopically followed.     

Fungal infections in cancer patients: An international autopsy survey

In an attempt to estimate the frequency of fungal infections among cancer patients, a survey of autopsy examinations was conducted in multiple institutions in Europe, Japan and Canada. Fungal infections were identified most often in leukemic patients and transplant recipients (25 % each). Fifty-eight percent of fungal infections were caused byCandida spp. and 30 % byAspergillus spp. There was considerable variability in the frequency of fungal infections in different countries. Nevertheless, this study clearly demonstrates that fungal infections represent a common complication in cancer patients, especially in patients with leukemia.     

Diffuse intermyocardiocytic fibrosis in uraemic patients

At post-mortem we examined heart tissue of (i) 31 patients with uraemia not on dialysis, (ii) 42 patients on haemodialysis for less than 6 months, (iii) 60 patients on haemodialysis for more than 6 months, (iv) 16 patients after renal transplantation, and (v) 11 patients on CAPD. Patients with stenosing coronary lesions were excluded. Diffuse non-coronary intermyocardiocytic fibrosis, assessed by a score system in trichrome-stained sections, was found in 91% of chronically uraemic patients, but not in non-hypertensive, non-diabetic controls. The lesion was present even in non-dialysed uraemic patients; in dialysed patients its severity was related to the duration of dialysis; it was demonstrable even years after renal transplantation. On electron-microscopy, collagen fibres were seen, while beta 2-M amyloid was consistently absent. Logistic regression analysis showed that uraemia was a determinant of intermyocardiocytic fibrosis independent of hypertension, diabetes mellitus, anaemia, heart weight, and presence or absence of dialysis procedure.     

Competitive control of the self-renewing T cell repertoire

We develop a mathematical model for the self-renewing part of the T cell repertoire. Assuming that self-renewing T cells have to be stimulated by immunogenic MHC-peptide complexes presented on the surfaces of antigen-presenting cells, we derive a model of T cell growth in which competition for MHC-peptide complexes limits T cell clone sizes and regulates the total number of self-renewing T cells in the animal. We show that for a sufficient diversity and/or degree of cross-reactivity, the total T cell number hardly depends upon the diversity of the T cell repertoire or the diversity of the set of presented peptides. Conversely, for repertoires of lower diversity and/or cross-reactivity, steady-state total T cell numbers may be limited by the diversity of the T cells. This provides a possible explanation for the limited repertoire expansion in some, but not all, mouse T cell re-constitution experiments. We suggest that the competitive interactions described by our model underlie the normal T cells numbers observed in transgenic mice, germ-free mice and various knockout mice.      

Morphometric observations on the rat heart after high-dose treatment with cortisol

Summary Male Wistar rats were treated with high cortisol doses for 1 week. The dose administered daily was 15 mg per animal in group 1 (7 animals) and 30 mg in group 2 (7 animals). 7 rats served as control group. After cortisol treatment the body weights decreased due to skeletal muscle catabolism and the heart weights increased. Morphometric analysis of the left ventricular posterior papillary muscles gave evidence that the increased heart weights resulted from an increased number of mitochondria and an increased volume of the cytoplasm, whereas the myofibrillar mass was not affected. The surface area of inner mitochondrial membranes (+cristae mitochondriales) per myofibrillar unit volume increased from 15.7 ²/³ to 21.3 ²/³ in group 1 and 21.4 ²/³ in group 2. Ultrastructural changes indicating myocardial cell damage were absent. Similar quantitative results have been reported to occur in the early phase of cardiac overload. For elucidating the hemodynamic effects of glucocorticoid a second experiment was performed: 7 Wistar rats were treated with cortisol in the same way as group 1, 7 others of the same body weight served as control. The systolic arterial pressure was significantly elevated in the cortisol group. Though myocardial tissue is known to be able to accumulate large quantities of glucocorticoids our results indicate that the application of high cortisol doses for a short time does not produce myocardial cell damage and does not suppress the myocardial adaption to the glucocorticoid-induced hypertension, i.e. hypertrophy. On the contrary, it seems to be possible that the adaption process is itself facilitated or accelerated by the presence of high cortisol concentrations in the heart. This thesis is supported by the considerably higher relative heart weights in the cortisol groups and is in agreement with observations reported by other authors.Dedicated to Professor Dr. W. Doerr on the occasion of his 65th birthdayThe results have been partially reported in 1977 (cf. G. Mall and H. Reinhard, Verh. Dtsch. Ges. Path. 61, 445)This investigation was supported by the Sonderforschungsbereich 90 of the Deutsche Forschungsgemeinschaft.     

Transformationsvorgänge in der Frühphase der Entstehung des arteriellen Thrombus

Zusammenfassung In unserer ultrastrukturell durchgeführten Studie wurden Thromben in der Arteria carotis communis von Ratten nach einer zuerst von Meng und Seuter (1977) beschriebenen Methode experimentell erzeugt. Induktion der Thrombusbildung erfolgte in vivo durch Unterkühlung eines kleinen Gefäßabschnittes unter konstantem Druck und kurzfristiger Stase. Eine Änderung des Blutflusses wurde durch einen Silberclip erzeugt. Die geschädigten Gefäßsegmente einschließlich der Thromben bzw. deren Vorstufen wurden nach 5, 10, 30 min und 1, 4 und 24 h nach der Thrombosestimulation entnommen und fixiert. Semidünnschnitte und Ultradünnschnitte wurden im Licht- und Elektronenmikroskop morphologisch untersucht.Den Transformationsvorgängen im Thrombus konnten exakte Zeitmarken zugeordnet werden. Als wichtigstes histopathologisches Merkmal für die Altersbestimmung arterieller Thromben in der Frühphase der Thrombogenese werteten wir die Querstreifung der Fibrinfasern. Diese trat bereits nach 5 min auf, erreichte nach 30 min ein Maximum und verschwand als Folge der zunehmenden Verdichtung der Fasern nach einer Stunde. Nach 4 h sahen wir eine weitgehende Retraktion der Fibrinfasern, die nach 24 h zur Bildung des Fibrinfasergerüstes mit Einmauerung korpuskulärer Elemente führte. Überdies beobachteten wir zwei Thrombocytenaggregate von differenter Struktur. Wir unterschieden ein fibrinarmes Aggregat, in dem die Thrombocyten dichtgepackt und pseudopodienreich erschienen von einem thrombocytenarmen Aggregat mit reichlich interponierten Fibrinfasern. Die nach 5 min im Zentrum des Thrombus auftretende Agglutination der Plättchen im thrombocytenreichen Aggregat führte nach 30 min zur Thrombocytorrhexis und ergab daher einen weiteren Anhalt für die Altersbestimmung des Coagulum. Der entstandene celluläre Abraum stimulierte mononucleäre Zellen und Leukocyten zur Phagocytose. Daher sahen wir nach 4 h eine massive Leukocytose als Folge der frühen Thrombocytorrhexis. Nach 24 h war die viscöse Metamorphose im fibrinreichen und fibrinararmen Aggregat weitgehend abgeschlossen. Innerhalb des beobachteten Zeitraumes entstand eine Verballung und bizarre Deformierung der Erythrocyten, die bereits nach 5 min vom Zentrum des Thrombus ausging und nach 24 h die Peripherie erreichte. Eine Hämolyse der Erythrocyten war nach dieser Zeit noch nicht erkennbar.

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Evolution in the early changes in the establishment of arterial thrombi

Summary Ultrastructural studies of thrombi were carried out on the common carotid artery of the rat using a method first described by Meng and Seuter (1977). Induction of thrombus formation in vivo was achieved by chilling of a small vessel segment under constant pressure and short-termed stasis. Disturbance of the blood flow was produced by a silver clip. The damaged vessel segments with the thrombotic deposits were removed 5, 10, 30 min, and 1, 4 and 24 h after stimulation of thrombosis. They were fixed and samples were studied as semithin and ultrathin sections morphologically using light and electronmicroscopy.In the maturation of thrombi exact time intervals could be determined. The most important histopathological characteristics for age determination of arterial thrombi in the early period of thrombogenesis were the cross stripes of fibrin fibres. They appeared after 5 min, reaching a maximum after 10 min and disappeared as a result of increasing fibre density after 1 h. After 4 h nearly complete retraction of fibrin fibres was found which led after 24 h to the formation of a corresponding frame walling in the corpuscular elements. Apart from this aggregation of thrombocytes, which were of two different types were observed, one showing a fibrin-poor aggregate in which the thrombocytes appeared densely packed with numerous pseudopods, and one showing a thrombocyte poor aggregate with abundant interposed fibrin fibres. Agglutination of platelets which occurred in the thrombocyte-rich aggregate in the centre of the thrombus after 5 min led to thrombocytorrhexis after 30 min. The resulting cellular waste stimulated phagocytosis by mononuclear cells and leucocytes. Because of this a massive leucocytosis was found as a result of the early thrombocytorrhexis after 4 h. After 24 h the viscous metamorphosis in the fibrin-rich and in the fibrin-poor aggregate was largely completed. Clumping and deformation of erythrocytes was observed in the middle of the thrombus after 5 min and at the periphery of the thrombus after 24 h. Haemolysis did not occur within this time interval.

Frau Antoni, Herrn Ing. grad. Derks und Herrn Rieger sei für ausgezeichnete technische Assistenz herzlichst gedankt.     

Effects of combined renovascular hypertension and diabetes mellitus on myocardial cells,non-vascular interstitium and capillaries: a stereological study on rat hearts

Summary The effects of combined renovascular hypertension and diabetes mellitus on the rat heart were investigated in order to detect possible synergistic effects of the two conditions. Hypertensive diabetic and hypertensive non-diabetic animals were compared to diabetic and non-diabetic controls. Hypertension was established for 12 weeks by a surgical stenosis of the left renal artery; diabetes mellitus was maintained for 8 weeks by a single intraperitoneal injection of 60 mg/kg streptozotocin. Light microscopic stereology did not reveal significant divergences between diabetic hypertensives and non-diabetic hypertensives. Hypertension induced a focal perivascular and interstitial fibrosis with increased volume densities of non-vascular interstitium and fibrosis (P<0.001). Capillary density (Q_A) was decreased in transverse sections (P<0.01) and increased in longitudinal sections (P<0.01). This indicates a three-dimensional remodelling of the capillary bed with an increased number of obliquely running capillaries. At least the length density (L_V) of capillaries (mm/mm³) tends to be normalized in long-term renovascular hypertension. At the ultrastructural level, a synergism of hypertension and diabetes mellitus was observed: the volume ratio of mitochondria to myofibrils was significantly decreased in hypertensive diabetics, but not in non-diabetic hypertensives or in diabetics. This may enhance the risk of cardiac deterioration. We conclude that the primary target of the synergistic damage in hypertensive diabetic heart muscle disease is the myocardial cell and not the cardiac interstitium.Preliminary results of this study have been published in: Mall G (1991) Morphometric study on the rat heart in combined renovascular hypertension and diabetes mellitus. In: Nagano N, Dhalla NS (eds) The diabetic heart. Raven Press, New York, pp 115–124Dedicated to Prof. Dr. med. G. Seifert on the occasion of his 70th birthday