Enalapril and ASS inhibit tumor growth in a transgenic mouse model of islet cell tumors.

Accumulating evidence suggests a role for angiotensin-converting enzymes involving the angiotensin II-receptor 1 (AT1-R) and the cyclooxygenase pathway in carcinogenesis. The effects of ASS and enalapril were assessed in vitro and in a transgenic mouse model of pancreatic neuroendocrine neoplasms (pNENs). The effects of enalapril and ASS on proliferation and expression of the AGTR1A and its target gene vascular endothelial growth factor (Vegfa) were assessed in the neuroendocrine cell line BON1. Rip1-Tag2 mice were treated daily with either 0.6 mg/kg bodyweight of enalapril i.p., 20 mg/kg bodyweight of ASS i.p., or a vehicle in a prevention (weeks 5-12) and a survival group (week 5 till death). Tumor surface, weight of pancreatic glands, immunostaining for AT1-R and nuclear factor kappa beta (NFKB), and mice survival were analyzed. In addition, sections from human specimens of 20 insulinomas, ten gastrinomas, and 12 non-functional pNENs were evaluated for AT1-R and NFKB (NFKB1) expression and grouped according to the current WHO classification. Proliferation was significantly inhibited by enalapril and ASS in BON1 cells, with the combination being the most effective. Treatment with enalapril and ASS led to significant downregulation of known target genes Vegf and Rela at RNA level. Tumor growth was significantly inhibited by enalapril and ASS in the prevention group displayed by a reduction of tumor size (84%/67%) and number (30%/45%). Furthermore, daily treatment with enalapril and ASS prolonged the overall median survival compared with vehicle-treated Rip1-Tag2 (107 days) mice by 9 and 17 days (P=0.016 and P=0.013). The AT1-R and the inflammatory transcription factor NFKB were abolished completely upon enalapril and ASS treatment. AT1-R and NFKB expressions were observed in 80% of human pNENs. Enalapril and ASS may provide an approach for chemoprevention and treatment of pNENs.

Inflammatory response during abdominal and thyroid surgery: a prospective clinical trial on mediator release.

Several studies have been demonstrated that endotoxin is a potent stimulus of the acute inflammatory response following traumatic injury. Although numerous studies have indicated that the extent of surgical intervention correlates well with the inflammatory response, the potential role of endotoxin as a trigger under those conditions still remains unknown. Therefore, the aim of this study was to elucidate whether or not the up-regulated inflammatory mediators are paralleled by increased endotoxin plasma levels during and following surgery, and whether the extent of surgical intervention represents a crucial factor under those conditions. To study this, plasma was collected at various time points during and after surgery from 52 patients subjected to abdominal surgery (i.e., major surgery) and 25 patients subjected to thyroid surgery (i.e., minor surgery). Plasma was assessed for endotoxin, endotoxin neutralizing capacity (ENC), and inflammatory mediators (leucotriene-C4 [LTC4]-, 6-keto-prostaglandin-F-1-alpha [PGF]-, thromboxane-B2 [TxB2], interleukin-6 [IL-6], and C-reactive protein [CRP]). Furthermore, splanchnic blood circulation was measured by determination of the intraluminal pH of the stomach and sigma (pHi) by intraluminal tonometry. Mesenteric lymph nodes were also collected at the time point of organ mobilization in the major surgery group and were assessed for bacterial translocation. Among all parameters investigated, endotoxin showed the most rapid changes. A significant increase in plasma levels of endotoxin and a decrease of ENC were found in the major surgery groups following induction of anesthesia and in the minor surgery groups after skin incision. Moreover, the incidence of elevated endotoxin levels was significantly higher (89% with elevated endotoxin levels) than the incidence of bacterial translocation (35% with gram-negative bacteria) in mesenterial lymph nodes of the major surgery group. pHi decreased significantly in both groups after skin incision, but no difference was observed between the major and minor surgery groups. Plasma mediators of the arachidonic acid cascade (LTC4, PGF, and TxB2) were only elevated in individual patients during and following surgery in both groups. Conversely, the post-operative increase in the acute phase mediators was significantly different in the major and minor surgery groups. IL-6 plasma levels peaked higher and earlier after major surgery than after minor surgery and the delayed increase of CRP was significantly greater in the major surgery group. In conclusion, the results indicate that plasma levels of endotoxin significantly correlate with the severity of the surgical intervention and may play an important role in inducing mediators of the acute phase reaction under such conditions.

[Age and sex distribution of primary thyroid cancer in relation to histological type]. / Alters- und Geschlechtsverteilung beim primären Schilddrüsenmalignom in Abhängigkeit vom Tumortyp.

METHOD: Data of all (239) patients suffering from thyroid carcinoma and operated on between January 1st, 1982, and December, 31st, 1997 in our center, were analyzed retrospectively with respect to age- and sex-distribution in relation to the histological type of cancer. The change of frequency in the histological groups was observed over a 16 years period. RESULTS: From all 239 cases, 202 (84.5%) were females and 37 (15.5%) males. The most common histological type with 70.3% in both male and female was the papillary carcinoma, followed by follicular carcinoma with 21.6% of male and 17.8% of female patients. A medullary carcinoma was seen in 8.1% and 5.9%, respectively and an anaplastic carcinoma in only 5.9% of female patients. There was no significant gender difference regarding the histological type. In male patients there was also no influence of age on histological groups. Females with papillary and medullary cancer were significantly younger than those suffering from follicular and anaplastic cancer. Beside, we observed an increase in papillary and a decrease in anaplastic carcinoma during the examination period. CONCLUSIONS: Although the relation of 1 male to 5 females with thyroid carcinoma shows a clear dependence on sex, the histological type distribution is identical in both male and female. Therefore, several different factors seem to influence the development of thyroid carcinoma. One of these factors depends on sex and supports an increased development of carcinoma in female patients. Another factor doesn't depend on sex and causes different histological types. Causes for that could be as well hormonal and reproductive ones as regional differences in iodine availability.

[Exsanguination caused by liver cell adenoma and rupture of the hepatic capsule as cause of maternal death]. / Verblutung bei Leberzelladenom und Leberkapselriss als mütterliche Todesursache.

In the 35th week of a twin-pregnancy fatal bleeding to death due to liver-cell adenoma and rupture of liver capsule could not be prevented despite immediate caesarean section, enucleation of the adenoma and intensive treatment.