A transgenic mouse line that develops early-onset invasive gastric carcinoma provides a model for carcinoembryonic antigen-targeted tumor therapy.

In an attempt to obtain suitable in vivo models for optimizing new tumor therapy strategies for intestinal adenocarcinomas, carcinoembryonic antigen (CEA) promoter/SV40 T antigen gene constructs have been used to generate transgenic mice. One transgenic line (L5496), which contains a 424-bp CEA promoter/SV40 T antigen transgene, exclusively developed multi-focal carcinomas in the pyloric region of the stomach in 100% of the offspring. Tumors were already observable in 37-day-old animals as dysplastic cell foci within the mucosal layer. In 50-day-old mice, the tumor mass was mainly restricted to the mucosa with invasive growth into the submucosal tissue. The animals became moribund at 100-130 days of age due to blockage of the pylorus. At this time, the tumor had penetrated into the duodenum and had invaded all tissue layers within the stomach. In contrast to most other stomach tumor models, this one perfectly matches the development of the most common stomach cancers found in humans. Furthermore, after crossing these mice with mice that are transgenic for the human CEA gene, the double transgenic offspring revealed expression of CEA in the resulting tumors. Thus, as well as being a model for studying gastric carcinoma development and prevention, this system should provide a useful preclinical model for CEA-targeted gastric tumor therapy.

Carcinoembryonic antigen family members CEACAM6 and CEACAM7 are differentially expressed in normal tissues and oppositely deregulated in hyperplastic colorectal polyps and early adenomas.

Four members of the carcinoembryonic antigen (CEA) family, CEA, CEACAM1 (BGP), CEACAM6 (NCA-50/90), and CEACAM7 (CGM2), are coexpressed in normal colorectal epithelia but are deregulated in colorectal cancers, where they could play a role in tumorigenesis. As a basis for functional studies, their expression patterns in normal tissues first need to be clarified. This is well documented for CEACAM1 and CEA but not for CEACAM6 or CEACAM7. We have now carried out immunohistochemical expression studies on 35 different organs, using CEACAM6-specific (9A6) and CEACAM7-specific (BAC2) monoclonal antibodies. CEACAM7 was only found on the apical surface of highly differentiated epithelial cells in the colorectal mucosa and on isolated ductal epithelial cells within the pancreas. CEACAM6 was expressed in granulocytes and epithelia from various organs. CEACAM6 and CEACAM7 expression correlated with apoptosis at the table region of the normal colon, and both were absent from highly proliferating cells at the base of colonic crypts. CEACAM6 revealed a broader expression zone in proliferating cells in hyperplastic polyps and adenomas compared with normal mucosa, whereas CEACAM7 was completely absent. Down-regulation of CEACAM7 and up-regulation of CEACAM6 expression in hyperplastic polyps and early adenomas represent some of the earliest observable molecular events leading to colorectal tumors.

Expression of the von Hippel-Lindau-binding protein-1 (Vbp1) in fetal and adult mouse tissues.

The von Hippel-Lindau (VHL) tumour suppressorgene product is believed to be involved in the down-regulation of transcriptional elongation by preventing the association of elongin B and C with the catalytic subunit elongin A. Alterations in the human VHL gene lead to VHL disease which is associated with various rare neoplasias, including haemangioblastoma of the central nervous system, retinal angioma, clear cell renal carcinoma and pheochromocytoma. Recently, a protein (VBP1) was isolated that was found to bind to the VHL protein in vivo. We have used the murine Vbp1 homologous cDNA to investigate the expression of the Vbp1 mRNA in the mouse by in situ hybridization and northern blot analysis. In fetal stages between days 9 and 18 of gestation, Vbp1 was expressed mainly in the central nervous system, retina and liver. In addition, at day 12, high expression was observed in the labyrinthine region of the placenta. In later stage placentas, Vbp1 expression was, however, considerably reduced. Northern blot analysis of adult mouse tissues showed that Vbp1 was ubiquitously expressed. In situ analysis on several adult tissues showed that in most tissues, transcripts were evenly distributed. In brain, eye, kidney and intestine, however, Vbp1 was expressed in specific cell types. Moreover, expression of the human VBP1 gene was investigated in cerebellum and in various tumours of VHL patients encompassinghaemangioblastomas, renal cell carcinomas and pheochromocytomas. In all of these tissues, VBP1 was ubiquitously expressed at low levels. However, no consistent differences in VBP1 expression levels could be detected between tumours and normal tissue. Mapping of the murine Vbp1 gene revealed conserved chromosomal localization between mouse and human in a region homologous to human Xq28.

Prevalence, morphology and biology of renal cell carcinoma in von Hippel-Lindau disease compared to sporadic renal cell carcinoma.

PURPOSE: Renal cell carcinoma occurs as a sporadic tumor but may be part of the autosomal dominant von Hippel-Lindau disease, characterized by retinal and central nervous system hemangioblastoma, pheochromocytoma, pancreatic cysts and renal cell carcinoma. We determine the prevalence of von Hippel-Lindau disease in a series of unselected renal cell carcinoma cases by molecular genetic analysis, and compare sporadic to von Hippel-Lindau renal cell carcinoma with respect to morphology and biology. MATERIALS AND METHODS: We established registers comprising 63 subjects with von Hippel-Lindau renal cell carcinoma, belonging to 30 distinct families (register A), and 460 unselected patients operated on for renal cell carcinoma in an 11-year period (register B). Molecular genetic analysis of the von Hippel-Lindau gene was performed for living patients of register A, representing 80% of von Hippel-Lindau families, and register B, 62% living patients, to identify von Hippel-Lindau germline mutations. In addition, register B was evaluated by a questionnaire (95% response) for familial occurrence of von Hippel-Lindau disease. RESULTS: The prevalence of von Hippel-Lindau renal cell carcinoma was 1.6% in 189 consenting unselected renal cell carcinoma patients. Risk factors for occult germline von Hippel-Lindau gene mutations in register B included familial renal cell carcinoma in 3 of 3 patients (100%), multifocal or bilateral renal cell carcinoma in 1 of 10 (10%) and age younger than 50 years at diagnosis in 1 of 33 (3%). Compared to sporadic von Hippel-Lindau renal cell carcinoma was characterized by an occurrence 25 years earlier, association with renal cysts, multifocal and bilateral tumors, cystic organization and low grade histology, and a better 10-year survival (p < 0.001 each). In von Hippel-Lindau disease metastases occurred only in tumors larger than 7 cm. CONCLUSIONS: von Hippel-Lindau differs from sporadic renal cell carcinoma in morphology and biology. Our data provide arguments for planning surgery for von Hippel-Lindau renal cell carcinoma and should stimulate future investigations.

[Excessive tissue storage of colloids in the reticuloendothelial system]. / Exzessive Gewebespeicherung von Kolloiden im retikuloendothelialen System.

In addition to renal elimination and gastrointestinal metabolism (amylase; splenic and hepatic dextranase) colloid plasma solutions like dextran and hydroxyethyl starch deposit in tissues, especially in the reticuloendothelial system (RES). This tissue storage is limited in time (weeks to months), is influenced by the employed solution and other factors (lysosomes) and has usually no clinical importance (no RES blockade). We report here a case study of a patient with sepsis (lung, liver and kidney failure) who had an overload of the RES with colloids while being treated with dextran (molecular weight 40,000 and 70,000 daltons) and hydroxyethyl starch (mw 450,000 daltons, molar substitution 0,7) for 5 weeks. Autopsy showed parenchymal and reticuloendothelial cells of liver, lung, kidney and spleen with a large amount of colloid mass inclusions and altered organ morphology. This storage may have impaired ventilation, transport of bile acids and renal function. A possible role of tissue storage of colloids in organ failure is discussed.

Renal angiomyolipomas, cysts, and cancer in tuberous sclerosis complex.

Tuberous sclerosis is a multisystem syndrome characterized by neurological symptoms and tumors in multiple organs, including kidney, brain, skin, eyes, heart, and lung. The kidney and brain are the two most frequently affected organs in TSC, and renal disease is a leading cause of death in TSC patients. Three types of tumors occur in TSC kidneys: (1) angiomyolipomas, which are benign tumors composed of smooth muscle, fat, and vessels; (2) epithelial cysts; and (3) malignant tumors. This review focuses on the clinical, pathological, and molecular features of these tumors.

Incidental appendix carcinoid. Value of somatostatin receptor imaging.

PURPOSE: Somatostatin receptor scintigraphy is used to diagnose carcinoid of the gastrointestinal tract. Its sensitivity ranges from approximately 75%-100%. Therefore, it was hypothesized that it can be used in the postsurgical follow-up to detect residual carcinoid, recurrence, and metastatic disease. RESULTS: This article is concerned with the findings of somatostatin receptor imaging performed on a 12-year-old girl 8 weeks after appendectomy. Histologic examination showed an incidental appendix carcinoid. Somatostatin receptor scintigraphy performed for detection of lymph node metastatic spread of the carcinoid showed focal tracer accumulation at the former operative site; subsequently, a right hemicolectomy was performed. However, histologic examination of the surgical tissue showed no evidence for carcinoid. CONCLUSION: It is concluded that there are some potential pitfalls for somatostatin receptor imaging at least soon after surgery. Therefore, it should not be used to aid in reoperation.

[Early childhood angiofibroma in an unusual site]. / Das frühkindliche Angiofibrom in ungewöhnlicher Lokalisation.

Angiofibromas are usually characterized by their occurrences in adolescent males with a typical localization and involvement of the posterior nasal cavity and nasopharynx. Even the suspicion of an extranasopharyngeal angiofibroma or an angiofibroma in young children must be viewed in general with skepticism, although reports of angiofibromas with atypical localizations and manifestations in young children have appeared in the literature. Three cases of this fibro-vascular neoplasm with manifestations in the first decade of life and atypical localizations are presented: (1) an angiofibroma medial to the left lacrimal sac in a 15-month old boy, (2) a right paranasal localization in a 9-year-old boy and (3) an angiofibroma limited to the right sphenoid sinus in a 6-year old boy. In all three cases the neoplasm was resected via an endonasal, micro-endoscopic approach that avoided an external incision. According to the literature and based on our own experiences with typical histological findings in all three cases, the clinician has to be aware that the rare angiofibroma can occur in preadolescent children with atypical localizations. The endonasal surgical approach is without any doubt the least traumatic one and in selected cases allows resection of a circumscribed tumor considering functional and aesthetic aspects.

Roles of the imprinted gene Igf2 and paternal duplication of distal chromosome 7 in the perinatal abnormalities of androgenetic mouse chimeras.

Mouse chimeras made with androgenetic (two paternal genomes) ova or embryonic stem cells frequently die at the perinatal stage and exhibit a range of defects, the most noticeable being a pronounced overgrowth of rib cartilage. Excess concentrations of IGFII, a potent mitogen, has been suggested to play a major role in these defects, as androgenetic cells possess two active paternal copies of the imprinted Igf2 gene, rather than one inactive maternal and one active paternal copy as in normal cells. Here, we show that chimeras made with androgenetic embryonic stem cells, homozygous for an Igf2 null mutation, do not develop rib cartilage hyperplasia, demonstrating the dependence of this defect on Igf2 activity produced by androgenetic cells. In contrast, in these same chimeras, many other defects, including whole body overgrowth and perinatal death, are still prevalent, indicating that the abnormal expression of one or more imprinted genes, other than Igf2, is also capable of inducing most of the defects of androgenetic chimeras. Many of these genes may reside on distal chromosome 7, as we also show that perinatal chimeras made with embryonic stem cells possessing paternal duplication of distal chromosome 7 exhibit a range of defects similar to those of androgenetic chimeras. The relevance of these findings for the human imprinting-related disorder, Beckwith-Wiedemann syndrome, is discussed.

[Weil's disease and necrotizing herpes pneumonia as the cause of death of a 39-year-old sewage drain worker]. / Weil'sche Erkrankung und nekrotisierende Herpespneumonie als Todesursache bei einem 39 Jahre alt gewordenen Kanalarbeiter.

Acute leptospirosis in Europe (Weil's disease) is a rare and in more than 90% of the cases undiagnosed febrile, self-limited disease. We report the case of a 39-year-old sewerage worker, who was admitted to our hospital with fever, jaundice, pain in his calves and acute renal failure. Serology revealed elevated antibody titers against Leptospira canicola, L. icterhaemorrhagica and L. sejroe. The patient developed disseminated intravascular coagulation (DIC) with diffuse gastrointestinal bleeding due to thrombocytopenia. The ECG showed atrial fibrillation with irregularly irregular rhythm. Cardiac arrest developed, most likely due to hypoxia, with a drop in the blood pressure. Despite immediate resuscitation efforts the patient developed severe hypoxic brain damage and died a few days later. Autopsy disclosed histologic signs of a generalized leptospiral infection, signs of shock and within the lungs a necrotizing herpes simplex virus pneumonia causing the death of the patient. The virus pneumonia most probably was caused by retrograde canalicular dissemination of oral secretions since herpetic tracheitis and esophagitis were found and herpetic lesions were readily identified on the lips and tongue. A medical opinion asked for by the professional association having liability for occupational safety and insurance was given, the disease being recognized as an occupational disease.

Polymorphous high-grade B cell lymphoma is the predominant type of spontaneous primary cerebral malignant lymphomas. Histological and immunomorphological evaluation of computed tomography-guided stereotactic brain biopsies.

In this retrospective study, a series of 54 patients (1982-1989) with sporadic primary cerebral malignant lymphomas is presented. All diagnoses were uniformly done on computed tomography-guided stereotactic brain biopsies according to histological criteria and immunomorphological data. In this series, the tumors were predominantly (25 of 48; 52%) classified as polymorphous high-grade blastic B cell lymphomas. This lymphoma type is therefore regarded as the most common type of sporadic primary cerebral non-Hodgkin's lymphoma. Severe regression (++/ ), which may dramatically alter the morphological appearance of a brain lymphoma, was found in 24 of 28 (86%) of cases with glucocorticoid administration prior to stereotactic brain biopsy.

[Metastasizing gastrinoma and tuberous sclerosis complex. Association or coincidence?]. / Metastasierendes Gastrinom und der Tuberöse-Sklerose-Komplex. Assoziation oder Koinzidenz?

We report about the case of a 34-year-old male patient suffering from a combination of Bourneville-Pringle disease and a metastasizing gastrinoma. As far as we know this association has hitherto not been described in the literature. We believe that a gastrinoma could develop against the background of the general tissue dysplasia which tuberous sclerosis represents. In our opinion, gastrinomas should be included into the tuberous sclerosis complex as a new form of possible association.

Primary cerebral malignant non-Hodgkin's lymphomas: a retrospective clinical study.

In this retrospective study a series of 54 patients (seen from 1982 to 1989) with sporadic primary cerebral malignant lymphomas (PCML), which were uniformly classified with the support of immunocytochemical data, is presented. The analysis shows that on CT PCML are shown as cirumscribed, homogeneous, contrast-enhanced multifocal (70%) or solitary (30%) mass lesions within the subcortical white matter; they were found mainly close to the ventricular system or the subarachnoid space. To prove the histological diagnosis and for the purposes of differential diagnosis, low-risk CT-stereotactic biopsy is necessary and is the method of choice. Immunomorphological techniques are valuable adjuncts to confirm the histological diagnosis of PCML. In the series presented these tumours have been predominantly classified as high-grade blastic B-cell lymphomas. For this reason, this type should be regarded as the prevalent variant of malignant brain lymphomas. The evaluation of possible prognostic factors suggests that age at admission and morphological features of regression are relevant determinants of survival time. A correlation between neuroradiological evidence of a decrease in tumour size, morphological signs of regression and glucocorticoid administration has been found. Thus, patients suspected of having PCML require rapid diagnosis prior to corticosteroid administration. PCML have been shown to be radioresponsive, but not curable. Because of the lack of uniformity in management of this rate brain neoplasm, the different treatment protocols are not comparable, and hence the optimum therapy has not been satisfactorily determined.(ABSTRACT TRUNCATED AT 250 WORDS)

[Pilot study of the metabolism of codeine to morphine and a possible modification by benzodiazepines]. / Pilotstudie zur Metabolisierung von Codein zu Morphin und eine mögliche Beeinflussung durch Benzodiazepine.

After administration of high-dose codeine we found that in two cases 20-40% of the total morphine-equivalents in the 24-hour urine sample were free morphine. After another 24 hours the proportion of free morphine was up to 70% and after roughly 96 hours even went up to 96%. Although 10% of the administered codeine was eliminated as morphine. In contrast to the values reported in literature we found that even with codeine/morphine ratios greater than 0.5 and morphine concentrations of up to 2000 ng/ml urine one cannot naturally conclude that morphine/diamorphine has been consumed. The short half-life of codeine in serum was 2-4 hours, the final half-life was 9-11 hours. In urine we found a short half-life of 1-6 hours as well as a long half-life of 7-12 hours. When diazepam was administered simultaneously with codeine the expected half-life in serum was up to 1.5 times and in urine 2.5 times. The codeine/morphine ratios were hardly affected so far as evidence goes which they give of preceding drug-intake.

Purification of human monocytes by adherence to polymeric fluorocarbon. Characterization of the monocyte-enriched cell fraction.

Human mononuclear cells were obtained from peripheral blood by density gradients. Monocytes can be purified after cultivation of 2 hours by a modified adherence procedure on membranes of gas-permeable polymeric fluorocarbon (teflon). After further cultivation of 24-48 hours, monocyte-enriched cell fraction can be easily detached from the membranes with a viability greater than 98% and a final cell yield of approximately 50% of the peripheral monocyte count. The cells showed the morphological and cytochemical characteristics of human monocytes and differentiated into dense monolayers of macrophages within 10 days of cultivation. Immune-autoradiography with iodine-125-labelled xenogeneic antimonocytic antisera and staining with several monoclonal antisera in an indirect immunofluorescence technique revealed up to 92% of these cells to carry monocytic characteristics. To show their functional integrity, monocytes obtained by this procedure were activated by 48 hours' cultivation with synthetic alkyl-lysophospholipids to inhibit the proliferation of autologous tumor cells.