Morphological predictors of survival in early and advanced gastric carcinoma.

In 351 patients with gastric carcinomas resected for cure, the relationship between macroscopic and microscopic features and survival was studied by univariate and multivariate analyses. In the multivariate survival analysis with covariates according to the Cox regression model, in early cancer all significant correlations to survival rate are covered by the stage grouping according to the UICC schedule of 1987. In advanced gastric carcinoma the UICC stage and, in addition, the Borrmann type and the intensity of cellular infiltration are effective. By additional consideration of these two variables an extended pathological staging schedule is proposed. It has the advantage of better discrimination between patients who differ in prognosis and seems to improve the prognostic prediction of outcome. Testing of this extended staging system in larger collectives is recommended.

Morphological predictors of survival in colorectal carcinoma: univariate and multivariate analysis.

In 150 curative resected adenocarcinomas of the large bowel we analyzed the morphological parameters of the primary tumor and lymph node involvement which most efficiently expressed the relationship to survival time. Using univariate survival analysis (product limit estimator according Kaplan-Meier), several macroscopical and microscopical parameters of the primary tumor and lymph node involvement significantly correlated with survival time. A multivariate survival analysis of covariates according to the Cox regression model revealed that the significant correlations of all these parameters were expressed by a set of five variables: pT stage, number of inflammatory cells, sex, age, and pN stage. As shown by the Kaplan-Meier test, this set of variables allowed a more precise prediction of survival time than mere staging according to the TNM system. Parametric multiple stepwise survival analysis was inefficient. No distinct relationship was found between the morphology of the primary tumor and the involvement of lymph nodes.

Morphological predictors of survival in advanced gastric carcinoma univariate and multivariate analysis.

In 76 curative resected advanced gastric carcinomas, the relationships between macro- and microscopy of the carcinoma and the survival rate were studied by univariate and multivariate survival analyses. In the Kaplan-Meier survival analysis (product limit estimator), significant influence on survival rate was found for tumor size, Laurén type, number of lymphocytes, tumor fibrosis, and N stage. In the multivariate survival analysis of covariates according to the Cox regression model, in macroscopically evaluable variables the tumor size was effective, in bioptically evaluable variables the number of plasma cells and the histological type. Concerning the primary tumor, the same set of variables presents significant correlations to survival time. Adding the involvement of lymph nodes, Laurén type, and N stage express all significant correlations of the tumor to survival rate. In parametric multivariate stepwise regression analyses of survival time, all variables working in the Cox proportional hazard model were very ineffective. But adaption of the Kaplan-Meier test to the effective variables of multivariate survival analysis elucidates the tight relationships between survival rate and these variables. No distinct relationships are present between variables of primary tumor and presence of lymph nodes metastases or N stage respectively.

Influence of vitamin A deficiency on the excretion of uromucoid and other substances in the urine of rats.

Male Fü-albino rats were weaned at the age of four weeks and maintained on a vitamin A-deficient diet. When they were 14-18 and 21-26 weeks old, the concentration of uromucoid, calcium and other substances possibly important for the pathogenesis of urinary calculi were determined. Reduced uromucoid excretion with hypercalciuria and reduced phosphate levels were observed. Subsequent examination of the kidneys did not demonstrate the presence of nephrocalcinosis or lithiasis. The relation between vitamin A, the synthesis of uromucoid and AMPS and calcium metabolism in the renal tubules is discussed.

Comparative radiological and morphological study of the human pancreas. IV. Acute necrotizing pancreatitis in man.

In 40 patients with massive acute pancreatitis the pancreata (autoptical 30, surgical 6, surgical + autoptical 4) were studies by ductography and extensive histology. The study shows that in man acute pancreatitis starts with fat necrosis around and within the pancreas. In second step acinar cell necorsis as well as vascular destruction and thrombosis arise in the immediate neighbourhood of the fat necorsis. In about 25% the vascular lesions are followed by infarction-like necrosis of the pancreas. The study strongly suggests that the pancreatic lipase is the key-enzyme in the development acute pancreatitis by releasing membrane-toxical fatty acids.

Does quantitative histology of rectal biopsy improve the differential diagnosis of Crohn's disease and ulcerative colitis in adults?

The aim of this study was to clear up, whether in adults morphometric investigation of rectal biopsies could improve the differential diagnosis of Crohn's disease and ulcerative colitis. Rectal biopsies were available of 63 normal controls, of 65 patients suffering from Crohn's disease and 72 patients with ulcerative colitis. The serially cut biopsies were investigated histologically both by morphometric methods and by subjective rules of daily practice in five randomly chosen sections. The data were evaluated by multivariate discriminate analysis. Morphometric analysis on the basis of 16 variables brought a significantly better discrimination between Crohn's disease and ulcerative colitis than evaluation by means of 5 criteria of conventional daily routine. This improved discrimination, however, is at least partially produced by incidental variations between the subsets under study. Therefore, the functions of our multivariate discriminate analyses cannot be used for differentiation of chronic inflammatory bowel disease in daily routine. But the variables, most effective in these analyses, may be helpful for valid discrimination of Crohn's disease and ulcerative colitis in adults. These variables are "deformation of crypt", "stromal fibrosis" and "number of eosinophils".

Tissue damage by fatty acids released by lipolysis. Contribution to the pathogenesis of acute pancreatitis.

Local application of a mixture of emulsified olive oil and pancreatic lipase produces massive necrosis in liver, kidney, pancreas, skeletal muscle, and perivascular sheath within 3 hours with subsequent spread. The necrosis is accompanied by a marked leucocytic reaction and, - after 16-24 hours -, involves the walls of veins and arteries resembling the vascular necrosis of acute hemorrhagic pancreatitis. Electron microscopy shows necrosis of emigrated leucocytes after only 120 minutes. Vascular necrosis is not seen before the second day. The results clearly demonstrate the ability of free fatty acids to damage cells and tissue, and support the hypothesis that the morphological change of necrotizing pancreatitis are mainly produced by the release of fatty acids by active lipase.

Histology of the lower intestinal tract in Crohn's disease of children and adolescents. Multicentric Paediatric Crohn's Disease Study.

Serial sections of 1047 colonic and rectal biopsies from 385 children and adolescents suffering from Crohn's disease were studied histologically. Inflammatory alterations were seen in 76% of the biopsies and 84% of the patients. Incidence of inflammatory infiltration, of crypt abscesses, of erosions, and of ulcers decrease from caecum to rectum were studied. The incidence of granulomas falls along the colon but rises in the rectum. The occurrence of granuloma depends rather on the severity of the inflammation than on the biopsy site. Granulomas are present in 26% of the biopsies and 42% of the patients. Compared to adults, the incidence was twofold in children. Discontinuous type of infiltration, density of infiltration, crypt abscesses, rectal erosions prevail in children, diffuse type of infiltration, and colonic ulcers in adults. Incidence of granulomas is reduced after the second year of illness and after the 16th year of life. The number of granulomas per mm3 biopsy is increased in children, their average size in adults.

Probability of detecting a granuloma in a colorectal biopsy of Crohn's disease.

In serial sections of 75 rectal and colonic biopsies of 42 patients with Crohn's disease the number and size of epithelioid cell granulomas as well as the size of the biopsies were measured. From these data the number of serial sections necessary to detect a possibly existing granuloma was calculated. This number depends on the average size of the sections. A statistical probability of 100% to detect one granuloma is reached by 900 running sections for an average size of 2 mm2 and by 35 running sections for an average size of the sections of 50 mm2.

Lipomatosis of the pancreas. A morphometrical investigation.

The study was performed in 50 human autoptic pancreata. After postmortem ductography and formalin fixation the organs were cut in slices of 8 mm thickness. After paraffinembedding histological sections were made from these slices. In photographical magnification (20 X) of these sections the amount of adipose tissue and pancreatic parenchyma were measured by morphometric means. The length of the pancreatic duct was determined in the radiographs. The data were evaluated by statistical methods. The share of the adipose tissue and the total weight of the pancreata are positively correlated depending on age and body weight. In contrast the weight of the pancreatic parenchyma shows no correlation to age, body length and weight. The amount of lipomatosis is the same in the various parts of the dorsal pancreatic anlage. On the other hand, the amount is clearly diminished in the ventral anlage. In the lipomatous pancreata the main duct is longer than in the normal. The lipomatosis of the pancreas is not correlated with a loss of parenchyma, which means, that there is not a true lipomatous atrophy. Even if the parenchyma in the lipomatous pancreata is replaced by fat tissue, which includes the undestroyed pancreatic islets, the parenchymal weight of the pancreas remains unchanged. This and the lengthening of the pancreatic duct in lipomatous organs allow the conclusion that the loss of parenchyma may be compensated by new parenchymal growth.

Endoscopic and bioptic study of the upper gastrointestinal tract in Crohn's disease patients.

In the present study, virtually all of 225 patients suffering from Crohn's disease of the lower gastrointestinal tract (small and/or large bowel) were subjected to endoscopic examination of the upper gastrointestinal tract (esophagus, stomach, duodenum); while histologic examination of the upper gastrointestinal tract was performed in a portion of the patients (54 initial esophageal, 221 initial gastric and 210 initial duodenal examinations). Statistical evaluation of the findings from the upper gastrointestinal tract revealed that: Endoscopic lesions were observed in the esophagus of 15%, the stomach of 49%, and the duodenum of 34% of the 225 Crohn's disease patients. Of the 54 patients from which esophageal biopsies were taken, 31 (57%) revealed histopathologic alterations. Of the 221 patients from which gastric biopsies were obtained, 60% revealed histopathologic alterations; the rate was 53% in the 210 patients from which duodenal biopsies were taken. Calculated from the present data, noncaseating granulomas, i.e., Crohn's disease, were present only in the stomach of 29.4% of the patients, only in the duodenum in 3.4% of patients, and in both the stomach and duodenum in 4.9% of patients. Gastric granulomas were confined to the region of the stomach body and fundus in 3.4% of the patients from which gastric biopsies were obtained and to the antrum in 15.6% of the respective patients. Both gastric regions were involved in 8.3% of the respective patients. The incidence of gastric granulomas was significantly increased in young patients, patients with enterocolic manifestations of Crohn's disease, and those with brief duration of disease. Patient sex or previous drug therapy had no effect on the incidence of granulomas. The most frequent endoscopic findings in the stomach of patients with Crohn's disease were mucosal edema, mucosal redness, and acute or chronic erosions. Only chronic erosions were of significant predictive value for the presence of granulomas, i.e., diagnosis of Crohn's disease. The most frequent endoscopic lesion in the duodenum was mucosal redness, followed by mucosal edema and aphthous lesions. Ulcers, stenosis, and mucosal redness had significant predictive values for the presence of granulomas.

Relationships between blood chemistry and histology of the rectal mucosa in Crohn's disease.

In the scope of the ECCDS, established to test the efficacy of prednisolone and/or sulfasalazine in Crohn's disease, the relationships of blood chemistry and CDAI to histology of rectal mucosa were studied in 115 patients by means of univariate and multivariate statistical analyses. Laboratory and histologic markers of inflammation tend to be correlated. But these correlations are definitively weak. Thus, the predictive value of histology for blood chemistry or CDAI is very low. Laboratory indices and CDAI are relatively inaccurate means of assessing disease severity at tissue level and vice versa.

Relationships between drug regime and histology of rectal mucosa in Crohn's disease.

In the scope of the ECCDS, testing the efficacy of prednisolone and/or sulfasalazine in Crohn's disease, the relationships between drug regime and histology of rectal mucosa were studied. Rectal biopsies, gained at start and after termination of treatment were available in 57 patients. Additionally, biopsies of 20 normal controls were studied. The biopsies, cut completely in serial sections, were investigated by quantitative histological methods. The data were evaluated by multivariate discriminant analyses. The nearest approach of histologic pattern to normal was found after combined treatment with prednisolone and sulfasalazine, followed by prednisolone monotherapy. The effect of sulfasalazine as monotherapy was poor. The degree of normalisation in histologic pattern agrees very well with the CDAI in our subsets. Overall, effective therapy was reflected in histology of rectal mucosa by a decrease of acute inflammatory alterations and an increase of mononuclear infiltration. Only minor individual effects of the various drug regimes were found.

Morphometric studies of normal and inflamed duodenal mucosa.

Corresponding and differing parameters in normal and inflamed duodenal mucosa are compared in a morphometric, histologic study. Results of this study show that the density of cellular infiltration into the lamina propria is decisive for the diagnosis of duodenitis, in particular the composition of plasma cells and lymphocytes. This diagnosis is supported by dilatation of Brunner's glands, cellular infiltration of the muscularis mucosae, and by gastric metaplasia of the duodenal epithelium. The length and width of the villi and crypts, the number of goblet cells and Paneth cells, the mitotic rate, and hemorrhage and hyperemia are inappropriate differential diagnosticc criteria.

[Studies of lipase-induced fat necrosis in rats (author's transl)]. / Untersuchungen zur lipaseinduzierten Fettgewebsnekrose bei der Ratte.

Disseminated fat necrosis can be produced by intraperitoneal injection of porcine pancreatic lipase. They get detecable by intravital staining with Phosphine 3R about 15 min after injection. The earliest fine structural findings are spotty destruction of the pinocytic invaginations and vesicles, combined with alterations of the cell membrane. Later there is a complete destruction and disintegration of the cytoplasm and its organels as well as the nucleus, whereas the cell membrane partly remains visible. At the same time the central lipid droplet shows cloudy disintegration and clumping as well as cristalline and granular structures. In the beginning the necrosis is limited to single cells. Later the adjacent fat cells also undergo necrosis, even when the applicated lipase has been removed after 30 min. In light microscopic studies fat necrosis are detectable 30 min after the application of lipase. During the first 48 hours they get demarcated by leucocytes. In the following days resorption and organisation take place. Lipolytic drugs facilitate the development of fat necrosis, whereas antilipolytic drugs inhibit it. In starvation the number of fat necrosis rises, after feeding it decreases. In the diurnal rhythm there is a maximum after midnight and a minimum in the early afternoon. The results support the hypothesis that pancreatic lipase only attacks fat cells, which are lipolytically active.

The granuloma in Crohn's disease. A bioptical study.

Serial sections of 1434 colonic and rectal biopsies of 347 patients with Crohn's disease were performed. The relationship between the incidence of granulomas and the inflammatory alterations of the mucosa and some clinical parameters was studied. The presence of granulomas depends on the severity of inflammatory alterations and not on the site of the biopsy. The number of granulomas per mm3 increases from caecum to rectum. The incidence of granulomas decreases with age, duration of illness and under a conservative therapy. If several biopsies, taken at the same or at different times, are studied, granulomas can be found in 40-50% of these patients.

Quantitative histological study of duodenitis in biopsies.

In 48 patients, suffering from an endoscopically verified ulcerative or nonulcerative duodenitis, biopsies of the bulb and of the lower duodenum have been studied with quantitative histological methods. The evaluation of the data with simple and multivariate statistical methods revealed: In healthy duodenal mucosa the height of the villous epithelium significantly decreases with rising age, while the cellular infiltration of the stroma increases. Conclusive, sex dependent differences are not present. Many histological variables are significantly correlated to the endoscopical degree of inflammation, if the endoscopically normal mucosa of the lower duodenum is used as normal control. In contrast, the endoscopically normal bulb mucosa histologically showed inflammatory alterations in the majority of cases. As shown by a multivariate discriminant analysis, a correct histological diagnosis of duodenitis will be reached in nearly all patients, if a biopsy of the endoscopically normal lower duodenum of the same patients is used as matched control. As shown by a multiple stepwise regression analysis, the same procedure results in a good correspondence of the endoscopically estimated degree of inflammation and the values, calculated from histology. In some patients, the lower duodenum slightly takes part in the inflammation of the bulb. But no significant correlation was found between the calculated degree of inflammation of the bulb and of the lower duodenum, neither in ulcerative duodenitis nor in nonulcerative duodenitis. From a practical point of view, our findings elucidate, that the simultaneous histological examination of mucosa of the bulb and of endoscopically healthy mucosa of the lower duodenum will be an essential help in the diagnosis and grading of duodenitis and should be introduced as routine method.

Patho-anatomical demonstration of lymph node metastases in a surgical specimen.

The prognosis of malignant disease is mainly determined by the demonstration or exclusion of lymph node metastases. However, other findings must also be considered, e.g., the number of lymph nodes examined and involved by tumor, differentiation between micro- and macrometastases, intranodal and perinodal growth, and non-neoplastic changes. These findings cannot be established with certainty when conventional examination methods (lamination and palpation) are used. Satisfactory results can only be obtained by employing a clearing technique and by processing the lymph nodes in step sections. For the speedy clearing of adipose tissue two devices have been developed in which hot acetone and xylene act on the tissue. In the transparent adipose tissue the lymph nodes can be easily recognized and accurately correlated topographically. In comparison to the routine method, the number of lymph nodes and nodal metastases detected can be doubled or tripled with this technique and with step sections. In particular, lymph nodes less than 5 mm in size and micrometastases (less than 2 mm) are visualized.

Prognostic significance of nucleolar organizing regions (NORs) in carcinomas of the sigmoid colon and rectum.

The prognostic significance of silver-binding nucleolar organizing regions (AgNORs) has been evaluated in tissue sections of biopsies taken from 70 primary adenocarcinomas of the colon sigmoid (n = 25) and rectum (n = 45) prior to their curative resection. A significant correlation between five-year survival rate and the mean AgNOR number per tumour cell (p less than 0.001) and the mean size of silver stained dots (p less than 0.05) was found according to the univariate Kaplan-Meier survival analysis. There was no significant relationship between AgNOR content and grade of malignancy, pT categories or pN categories. Multivariate survival analysis of covariates (Cox regression model) revealed a set of five variables that significantly influenced the patients' outcome: pN categories, AgNOR content, pT categories, maximum grade of malignancy and number of inflammatory cells. From the clinical and pathological parameters studied, pN and pT categories as well as the mean AgNOR number were the most important variables predicting death from colorectal carcinoma. Since the analysis of AgNORs can be performed on routinely processed paraffin-embedded tissue, this method may be of potential use in pretherapeutic assessment of the biologic aggressiveness of the disease.

The role of certain habits and various diseases in the occurrence of gastritis.

Four biopsy specimens of antral and body mucosa were taken from the greater and lesser curvature of the stomach in 557 Germans and 46 Turks with no gastric or duodenal lesions. The age-adjusted gastritis score in each area was related to various habits and clinical diagnoses. In contrast to the Germans the Turks had advanced antral gastritis at an early age which did not progress with age. Patients of low social class were more prone to antral gastritis than academics and civil servants. Hypertension was associated with a lower incidence of antral gastritis. Patients who had had a cholecystectomy had advanced gastritis in antral and body mucosa as compared with those with gallstones but intact gallbladders. The incidence of fundic gastritis was higher in patients with degenerative joint disease than in the controls. It is concluded that alcohol, nicotine, drug abuse and various diseases do not play an important role in the frequency of occurrence of gastritis.