Experimentelle Untersuchungen zur Frage der Seltenheit von Geschwulstmetastasen in der Skeletmuskulatur

Summary Authors injected a suspension of Brown-Pearce cancer cells into the left ventricle of 10 rabbits. The venous blood of the lower extremities of these first rabbits was injected into the ear vein of 20 intact second rabbits. In the surviving 7 first rabbits metastases in the skeletal muscles frequently developed. The majority of second rabbits developed tumors indicating a transmuscular passage of tumour cells emboli in the first rabbits. Transmuscular passage of tumour cell was found not only immediately after the injection of the tumour cells, but also three minutes later.These facts contradict the rather speculative theory according to which the skeletal muscle is an unsuitable soil for the development of secondary tumours.     

The ability of heat stress and metabolic preconditioning to protect primary rat cardiac myocytes

Primary rat cardiocytes were subjected to either thermal preconditioning for 30 min at 43°C or 20 min metabolic preconditioning (10 mM deoxyglucose, 20 mM lactate, pH 6.5). Eighteen hours later cells were analysed either for hsp 70i expression or subjected to a subsequent lethal heat stress or simulated ischaemia (10 mM deoxyglucose, 20 mM lactate, 0.75 mM sodium dithionite, 12 mM potassium chloride, pH 6.5) for 2 hours and assessed for survival by trypan blue exclusion.Hsp 70i was induced over 100 fold by thermal preconditioning and 30 fold by metabolic preconditioning (p<0.001, p<0.05), hsp 90 was induced 2.71 fold and 2.24 fold (p<0.001, p<0.001) by thermal and metabolic preconditioning respectively, while hsp 60 was not induced by either treatment. Preconditioned cultures had improved survival against subsequent lethal heat stress or simulated ischaemia: Thermal preconditioning reduced death from 69.22% to 52.46% upon subsequent lethal heat stress and from 49.13% to 36.66% upon subsequent lethal simulated ischaemia. Metabolic preconditioning reduced cell death from 51.29% to 33.8% against subsequent lethal heat stress, and from 69.09% to 55.61% upon subsequent lethal simulated ischaemia. A second marker of cell death, the release of lactate dehydrogenase activity into the culture media, was reduced to 65% and 60% of control values for thermally preconditioned cells subjected to lethal heat or lethal simulated ischaemia respectively. Metabolically preconditioned cells demonstrated lactate dehydrogenase activity of 59% and 51% that of control values, when subjected to lethal heat or lethal simulated ischaemia respectively.Abbreviations hsp heat stress protein - hsp 70i inducible 70 kDa heat stress protein - LDH lactate dehydrogenase - PBS phosphate buffered saline     

Follow-up of “non-diabetic” relatives of diabetics by retesting oral glucose tolerance after 5 years

Summary Of 743 first degree relatives of diabetics in whom oral glucose tolerance tests had been performed in 1967 488 were re-tested in 1972. Among the original normals (n = 353) 17.6% had developed a subclinical and 1.3% an overt diabetes within 5 years. The original subclinical diabetics (n = 118) showed a remission to normal in 35.6% and a progression to overt diabetes in 13.6%. 3 out of the 17 formerly overt diabetics were found to be normal after 5 years and 3 were subclinical diabetics. Thus the performance of an oral glucose tolerance test is of limited prognostic value in the individual case. In both studies a higher prevalence of abnormal test results occurred in the older age groups and in overweight subjects. Remission or deterioration did not depend, however, on age or on weight changes. The frequency of abnormal tests was higher in males than in females, but the tendency towards the development of diabetes was more pronounced in females, in accordance with a previous observation of a higher age dependance of glucose tolerance in females.     

Prognostic relevance of histological findings on bone marrow biopsy in myelodysplastic syndromes

Summary Bone marrow biopsy (BMB) has aroused growing interest as a possible aid in the diagnostic and prognostic evaluation of myelodysplastic syndromes (MDS). Previous reports have pointed out that MDS patients with blastic aggregates or severe bone marrow (BM) fibrosis are characterized by a worse clinical outcome. BMBs of 106 MDS patients were retrospectively reviewed, and relationships among the different histological parameters as well as clinicopathological correlations were looked for. Three patterns of BM blastic infiltration (diffuse, cluster, and large) were recognized. Overt leukemic transformation and overall survival were selected as prognostic end points. BM infiltration was diffuse in 18, cluster in 48, and large in 40 cases. RAEB-t patients accounted for about half of the large cases, and none had a diffuse pattern (p<0.01). Nineteen patients showed extensive BM fibrosis; most of them were characterized by cluster blastic infiltration and megakaryocyte hyperplasia. Leukemic transformation occurred in 67% of large cases (p<0.001) and in none of the cluster cases with severe BM fibrosis (p<0.01); however, survival was equally poor in these two groups because of early leukemic transformation (large cases) and BM failure (cluster cases). The FAB classification did not significantly correlate with prognosis. Patients with cluster BM infiltration and severe fibrosis can be regarded as a true separate MDS subset characterized by unique clinicopathological and prognostic features. Because of the subacute clinical behavior of most cases, and the poor performance status of many elderly patients, there is still controversy as to the best therapeutic approach in MDS. Histological analysis allowed two groups of MDS patients to be identified, both characterized by poor life expectancy, who could benefit from early aggressive chemotherapy.     

Immunoglobulin production and secretion in bence jones protein myeloma and “nonsecretory” myeloma

Summary Using our electron microscopic method for polysome analysis and an immunofluorescent technique we studied Ig production and secretion by tumor cells in seven BJP myeloma patients and seven nonsecretory myeloma patients.In BJP myeloma Ig production and secretion is of three types: Type 1, only L-chains are synthesized and secreted; Type 2, the myeloma cells show fluorescence for H-chains, but upon polysome analysis there is no peak at polysomes corresponding to H-chain production; Type 3, the myeloma cells show fluorescence for H-chains, and polysome analysis shows two peaks corresponding to L- and H-chain production.Polysome analysis of nonsecretory myelomas show the presence of only very few membrane-bound polysomes and their distribution curves are entirely different from those of ordinary myeloma. Furthermore, the distribution patterns vary among seven cases. Results obtained by polysome analysis and immunofluorescent technique suggest that the nonsecretory myeloma could be divided into several subtypes.Supported in part by grants-in-aid for scientific Research (748103, 867050, 167092, 267108, 777124) from the Ministry of Education, Science and Culture of Japan     

Insulin and growth hormone responses to glucose loading in treated acromegalics

Summary The insulin and growth hormone responses to oral glucose load (100 g) in 23 acronaegalic patients, previously treated by external irradiation, are described. Based on current clinical findings, sixteen acromegalics were considered inactive and seven patients active. Two of the latter were treated diabetics. Thirteen healthy, non-obese subjects formed the control group. Five inactive acromegalics had blood glucose values exceeding the upper limits of normal after the glucose load. Both the inactive and active acromegalics had hyperinsulinemia in the fasting state and after glucose load. The observation of an exaggerated serum insulin response to glucose load in clinically inactive acromegalics suggested that chronically elevated levels of circulating growth hormone may have led to permanent changes in the responsiveness of the pancreatic islets to glucose stimulation. The mean fasting value of serum growth hormone was about the same in the controls and the inactive acromegalics; the latter did not show suppression in serum growth hormone levels after glucose load.Research Fellow, Medical Research Council of Canada     

The value of tumour spread,grading and growth pattern as morphological predictive parameters in bladder carcinoma. A critical revision of the 1987 TNM classification

A group of 343 patients with bladder carcinomas was uniformly staged, both clinico-radiologically and pathologically. In accordance with pathological staging, they were treated from 1983 to 1990 and follow-up was closed on January 1992. No systemic chemotherapy regime was used. The present study was designed to assess the value of classical morphological parameters (tumour extension, histological subtype, grade and growth pattern) in the prediction of prognosis, and also to evaluate the adequacy of the current TNM classification (4th edition, 1987) of bladder cancer. The initial tumour stage appears the most useful criterion in the prediction of prognosis. Nevertheless, survival analysis confirms the necessity to modify the present TNM classification for routine clinical practice. In fact, stage III proves to be heterogeneous, and the difference in survival between categories pT3a and pT3b is even more statistically significant (logrankP<0.01) than the difference between pT2 and pT3 as a whole (log-rankP<0.02). Consequently, invasion of the muscular layer should be reclassified into a common stage II, equivalent to the B category in the ABCD system. Moreover, stage IV is also heterogeneous in terms of survival. Despite the overall life-expectancy being rather poor for a patient with bladder carcinoma, three subsets with different prognosis (log-rankP<0.001) can be identified: pT4N0M0; pTxN1-3M0; pTxNyM1, wherex andy represent any number. Therefore, we believe that various subgroups should be distinguished in a future edition of the TNM classification. Current treatment modalities, involving the role of systemic chemotherapy and aimed at bladder preservation, make such innovations even more convenient for a new edition of the TNM classification of bladder cancer. Apart from tumour staging, several microscopic morphological parameters are valuable in distinguishing patients with different prognosis. Pure transitional-cell histology, papillar growth, and low grade, are favourable data. In fact, tumour grade, although somewhat subjective, is a factor of major prognostic importance. Pauwels' distinction of intermedium grade 2 into 2A and 2B is also helpful in the assessment of a population of intermediate prognosis. Similarly, with regard to superficial tumours, the division of infiltration levels of subepithelial connective tissue into superficial or deep into the muscularis mucosae, is also relevant, even after stratification by grade.Abbreviations TCC transitional-cell carcinoma - TUR transurethral resection - MM muscularis mucosae The Journal of Cancer Research and Clinical Oncology publishes in loose succession Editorials and Guest editorials on current and/or controversial problems in experimental and clinical oncology. These contributions represent exclusively the personal opinion of the authorThis work has been supported by an institutional grant from the Health Department of the Basque Government, and is also part of the doctoral thesis of one of the authors (J. C. Angulo)     

The efficacy of neuraminidase treatment in studies on red cell aging

Summary An in vitro system was developed to test the propensity of rat erythrocytes (RBC) toward phagocytosis by homologous peritoneal macrophages after in vivo aging or after in vitro surface modification. Old RBC obtained from erythrocyte populations separated into fractions on the basis of their density were found to be phagocytosed to a significantly greater extent than cells obtained from young cell fractions. Neuraminidase treatment of RBC resulted in extensive phagocytosis in comparison to control cells representing the whole population or old cells. Galactose oxidase treatment of neuraminidase treated RBC afforded no protection from uptake by macrophages. In contrast, treatment of RBC with neuraminidase immobilized on Sepharose 4B, leading to removal of up to 25% of the total membrane sialic acid, did not lead to phagocytosis above control values. These results indicate that extreme caution is necessary in the interpretation of experiments in which neuraminidase is utilized to produce simulated aged RBC.     

Unspezifische Phosphatasen und Esterasen im Melanoblastom der Chorioidea

Zusammenfassung Melanoblastome der Chorioidea bestehen aus wenig pigmentierten Melanocyten und stark pigmentierten als Makrophagen bezeichneten perivasculären Zellen. In sieben histochemisch untersuchten Melanoblastomen der Chorioidea besaßen die Makrophagen eine starke Aktivität unspezifischer Esterasen und saurer Phosphatasen, in den Melanocyten war die Aktivität schwach. Ein Melanoblastom vom epitheloiden Typ enthielt vorwiegend Zellen mit starker Enzymaktivität und zeigt außerdem alle Übergänge zwischen Melanocyten und Makrophagen. In allen Melanoblastomen waren die Fraktionen der isodynamen Esterasen und sauren Phosphatasen (Zymogramme nach Agarelektrophorese des Tumorextraktes) gleichartig, lediglich die Aktivität der einzelnen Fraktionen ist etwas verschieden. Die als Makrophagen bezeichneten Zellen sind ebenso wie die Melanocyten tumoreigene Zellen. Die starke Phosphataseaktivität wird auf den verstärkten Einbau von Phosphat (P³²) in die Tumorzellen bezogen.

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Summary The malignant melanoma of the choroid consists of melanocytes with slight pigmentation and of tumor cells (macrophage-like) that are heavily pigmented and perivascularly localized. In 7 malignant melanomas of the choroid belonging to the spindle cell and epithelioid type (Reese), the macrophage-like tumor cells histochemically showed a high activity of nonspecific esterases and acid phosphatases; the activity in melanocytes was low. A malignant melanoma of the epithelioid type chiefly contained tumor cells with high enzymatic activity and showed all transitional cells from melanocytes to macrophages. Zymograms of all melanomas (electrophoresis of tumor extract on agar-agar) showed similar fractions of isodynamic esterases and acid phosphatases which differed only in activity. The macrophage-like cells and the melanocytes were tumor cells. A relation presumably existed between the high activity of phosphatases and the increased incorporation of phosphate (P³²) into the tumor cells.

     

Effect of insulin on glucagon enhanced lipolysis in vitro

Summary Glucagon in concentrations similar to those found in human plasma markedly stimulates lipolysis in rat adipose tissuein vitro. The effects of these physiological concentrations of glucagon are reduced or abolished by insulin at concentrations of 25 and 100U/ml. Considering the marked insulinogenic effect of glucagon these observations may provide an explanation for the delayed increase of blood FFA observed after glucagon injectionin vivo.This work was supported by the Fonds National de la Recherche Scientifique and the Fonds de la Recherche Scientifique Médicale, Belgium.     

Zur Epidemiologie und Ätiologie des Oesophaguscarcinoms in China

Ohne Zusammenfassung

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The epidemiology and etiology of esophageal cancer in China

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Stipendiaten der Alexander von Humboldt-Stiftung aus der Volksrepublik China

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The Journal of Cancer Research and Clinical Oncology publishes in loose succession Editorials and Guest Editorials on actual and/or controversial problems in experimental and clinical oncology. These contributions represent exclusively the personal opinion of the author.Die Zeitschrift Journal of Cancer Research and Clinical Oncology bringt in zwangsloser Folge Editorials zu aktuellen und/oder kontroversen Problemen der experimentellen und klinischen Onkologie. Diese Beiträge geben ausschließlich die persönliche Meinung des Autors wieder.     

Circulating lupus type anticoagulant and pulmonary hypertension associated with mixed connective tissue disease

Summary We report the case of a young woman, with mixed connective tissue disease (MCTD), associated with disabling pulmonary hypertension and presence of the lupus anticoagulant. The lupus anticoagulant, an antibody directed against phospholipid components, was linked in our patient to extensive thrombophlebitis and premature labor. Raynaud's phenomenon progressed towards finger necrosis in spite of optimal vasodilating treatment. The part played by the lupus anticoagulant in pulmonary hypertension remains to be established. Both these complications responded to prednisolone therapy, but the improvement was limited and short-lived.     

Dosis-Wirkungs-Beziehungen bei der Erzeugung von Hämangioendotheliomen der Leber bei Mäusen durch Diäthylnitrosamin

Zusammenfassung Quantitative Fütterungsversuche bei Mäusen des DBA-Stammes mit Diäthyl-nitrosamin ergaben, daß bei Verkleinerung der Tagesdosis auch die zur Erzeugung von Hämangioendotheliomen der Leber benötigte Gesamtdosis kleiner wird. Die Krebserzeugung verläuft auch bei Mäusen nach der allgemeinen Formel d · t ⁿ=konst. als beschleunigter Vorgang nach Art einer Verstärkerwirkung.

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Summary Quantitative feeding experiments in mice of the DBA strain with di-ethyl-nitrosamine disclosed that with a reduction of the daily dose the total dosage needed for the induction of hepatic hemangioendotheliomata also became smaller. The induction of cancer in mice occurs according to the general formula d · t ⁿ=K, as an accelerated process much like an intensifier action.

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Mit 1 Textabbildung

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Die Arbeit wurde durch die Deutsche Forschungsgemeinschaft unterstützt.     

The problem of thresholds in chemical carcinogenesis some views on theoretical and practical aspects

Conclusions I have tried to show that the threshold problem for carcinogens is still unsolved and that this unsatisfactory situation creates many problems for the scientific evaluation of the carcinogenesis problem as well as for its regulative aspects. In view of the extremely low acceptance of cancer risks in the general population, which is justified as well as understandable, carcinogenesis research must present new ideas to come nearer to a solution of such problems. More sound data on dose-time-effect curves in the low incidence range of 10-0.1% tumor incidences could indicated whether the established linearity in the higher incidence range might eventually by interrupted. Increase of animal numbers could also increase reliability of carcinogenicity experiments and allow the detection of low-dose effect; the disadvantages of this approach (mega-mouse experiment) however, in regard to cost and space necessary are evident. Increases of the mean life span by optimization of animal husbandry still would be another way of approach. However, no real breakthrough is to be expected here.The most promising approach seems to be the use of other indicators for carcinogenicity instead of tumor formation. Binding studies of carcinogens to biopolymers (Neumann 1980), especially DNA, as well as the determination of preneoplastic, enzyme-deficient islands (Kunz et al. 1978) have been shown to give dose-response curves parallel to the corresponding curves from carcinogenicity studies (Kunz) and extendable over 6 orders of magnitude of doses, without deviation from linearity (Neumann). Additional parameters might be found, which, altogether, might prove to be an important step toward further knowledge in this important field of carcinogenesis research.Oh König, das kann ich dir nicht sagen, und was du frägst, das wirst du nie erfahren R. Wagner, Tristan und IsoldeJournal of Cancer Research and Clinical Oncology publishes in loose succession Editorials and Guest Editorials on actual and/or controversial problems in experimental and clinicial oncology. These contributions represent exclusively the personal opinion of the author. The Editors Die Zeitschrift Journal of Cancer Research and Clinical Oncology bringt in zwangloser Folge Editorials und Guest Editorials zu aktuellen und/oder kontroversen Problemen der experimentellen und klinischen Onkologie. Diese Beiträge geben ausschließlich die persönliche Meinung des Autors wieder.     

Histomorphologische und cytologische Befunde bei einem Fall von Gewebsmastzell-Retikulose mit akutem leukämieartigem Verlauf

Zusammenfassung Es wird über einen Krankheitsfall berichtet, welcher nach der bisherigen Nomenklatur als Gewebsmastzellen-Leukämie oder als maligne Mastocytose mit leukämieartigen Manifestationen (Efrati et al., 1957) bezeichnet worden ist; er muß als akute subleukämische Gewebsmastzellen-Reticulose klassifiziert werden.

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Summary The author reports a case which, according to the past nomenclature, was designated as tissue-mast-cell leukemia or as malignant mastocytosis with leukemia-like manifestations (Efrati et al., 1957). This case must be classified as an acute subleucemic tissue-mast-cell reticulosis.

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Vortrag auf dem 12. Kongreß der Deutschen Gesellschaft für Hämatologie, Berlin 1966.     

“Mini-perforation” of the colon—Not all postpolypectomy perforations require laparotomy

In a 10-year experience with 4,784 consecutive colonoscopic polypectomies, the need for operative intervention in just two of seven perforations indicates that patients with specially defined, limited perforations can usually be treated nonoperatively. This specific complication, which has been termed mini-perforation, is generally detected within 6–24 hours of polypectomy, and is characterized by local pain and tenderness, without signs of diffuse or spreading peritoneal irritation. Free intra-abdominal or retroperitoneal air on x-ray documents the actual perforation. Complete resolution of symptoms within 24–48 hours confirms the diagnosis of mini-perforation. Success depends on good bowel preparation for colonoscopy, and early recognition of perforation, with institution of bowel rest and intravenous antibiotics. The mini-perforation spontaneously closes, probably by omental adherence. Frequent serial clinical examinations are mandatory so that frank perforation with advancing peritonitis will be promptly recognized and treated surgically. An understanding of the three levels of cautery injury to the colon wall—serosal burn, mini-perforation, and frank perforation are essential in managing the complications of colonoscopic polypectomy.Read at the meeting of The American Society of Colon and Rectal Surgeons, St. Louis, Missouri, April 29–May 4, 1990.     

Heterogeneous glycaemic and insulinaemic responses to oral glucose in non-diabetic men: interactions between duration of obesity,body fat distribution and family history of diabetes mellitus

Summary The interaction between environmental and genetic factors in the alterations of glucose-insulin homeostasis was studied in 104 non-diabetic men. Family history of diabetes mellitus was used as an index of genetic predisposition to diabetes. Body composition was measured by under-water weighing whereas subcutaneous and visceral adipose tissue areas were measured at the abdominal and femoral levels by computed tomography. The sample was first divided into two groups. The first group included subjects with normal glycaemic and insulinaemic responses during a 75 g oral glucose tolerance test. The second group was composed of subjects either with a high glucose response or high insulin response or both. Men included in the second group were different from the normal subjects for almost all body fatness variables. They also presented a prevalence of a positive family history of diabetes which was significantly higher than normal subjects. The second group was then divided into three distinct subgroups based on insulin and glucose responses of the subjects during the oral glucose tolerance test. Subjects with high insulin but normal glucose responses were characterized by significantly higher levels of total body fat and deep abdominal adipose tissue when compared to the normal group (p<0.05). Men with both high insulinaemic and glycaemic responses displayed higher body fatness values and higher deep and subcutaneous abdominal adipose tissue areas (p<0.05) in comparison with normal subjects. They also had a higher body mass index at age 20 years than control subjects and subjects with high insulin but normal glucose responses. In contrast, subjects with normal insulin but with high glucose responses were not different from the normal group with regard to body fat and adipose tissue areas. These results show the heterogeneous origin of altered glucose-insulin homeostasis in non-diabetic men. Finally, subjects in the altered glucose-insulin homeostasis group with no family history of diabetes displayed a higher body mass index at age 20 years (p<0.05) in comparison with subjects who had a positive family history of the disease. They also presented a greater abdominal-to-thigh fat ratio measured by computed tomography. These results suggest that in men with alterations of glucose-insulin homeostasis, the relationship of body fat distribution to glucose tolerance and plasma insulin levels is different in those with no family history of diabetes than in subjects with a positive family history of diabetes.     

Some actual aspects of tumor induction and promotion

Summary Quantitative data on chemical carcinogenesis illustrate how difficult it is to decide whether there are thresholds for complete carcinogens. With tumor promoters there probably are safe levels, but these are difficult to determine. The results recorded in the experiments of Fibiger, in which tumors of the stomach were seen, could have been caused by the tumor-promoting effects of a biological agent.The Journal of Cancer Research and Clinical Oncology publishes in loose succession Editorials and Guest Editorials on current and/or controversial problems in experimental and clinical oncology. These contributions represent exclusively the personal opinion of the authorDedicated to Professor Hermann Druckrey on the occasion of his 80th birthday     

Use of cultured human tissues and cells in carcinogenesis research

Summary A variety of approaches are used to study carcinogenesis. Recent advances in techniques for culture of human tissues and cells have provided additional experimental systems of study the process of carcinogenesis and the genetics of cancer.The Journal of Cancer Research and Clinical Oncology publishes in loose succession Editorials and Guest Editorials on current and/or controversial problems in experimental and clinical oncology. These contributions represent exclusively the personal opinion of the author.     

Acute insulin response to intravenous glucose,glucagon and arginine in some subjects at risk for Type 1 (insulin-dependent) diabetes mellitus

Summary The relationships between first-phase insulin secretion to i.v. glucagon and i.v. arginine were studied in 19 healthy adult volunteers (Group I) and in 21 subjects at risk for Type 1 (insulin-dependent) diabetes mellitus with either a normal (n=11; Group II a) or a low insulin response to i.v. glucose (n=10; Group II b). Groups I and II a displayed similar insulin responses to the three secretagogues. In contrast, Group II b demonstrated lower insulin responses to both glucagon and arginine than control subjects (p}<0.007 and (p}<0.04 respectively) orthan normo-responders to glucose (#x007D;<0.007 and p<0.04 respectively). In Group II b however, arginine-stimulated insulin release was increased compared to the response to glucose (p}<0.006), while glucagon and glucose led to non-statistically different responses. Five low-responders developed Type 1 diabetes. As a group, they displayed lower responses to glucagon and to arginine than subjects who up to now have not developed the disease (p<0.05 and p<0.0003 respectively). In the subjects who progressed to diabetes, the responses to glucose and glucagon were similarly blunted. In the low-responders who have not developed the disease, no statistical difference could be detected between mean responses to glucagon and glucose, but four out of these five subjects had a glucagon-stimulated response within the control range and higher than their corresponding response to glucose. Arginine led to a higher stimulation than glucose, in subgroups that either progressed to diabetes (p<0.006) or did not (p<0.002). Finally, low-responders who did not develop diabetes displayed similar responses to both glucagon and arginine than normo-responders to glucose. A progressive decrease of arginine-stimulated insulin response may be a later event during pre-Type 1 diabetes than a blunted response to glucose, while a loss of glucagon-stimulated insulin release may be intermediate. Diminished response to all secretagogues may offer better prediction than a low response to glucose alone.