Nichtsteroidale Antirheumatika (NSAR) haben heute aufgrund ihrer analgetischen und antiphlogistischen Wirksamkeit in der Behandlung von zahlreichen akuten und chronischen Schmerzformen einen zentralen Stellenwert. In der Akutschmerztherapie, zum Beispiel peri- und postoperativ, ist der i.v.-Einsatz von NSAR bedeutsam. Hier spielen insbesondere NSAR mit kurzer Halbwertszeit, die aufgrund einer leichteren Steuerbarkeit entsprechend dem jeweiligen Krankheitszustand eingesetzt werden können, eine Rolle, ggf. als Kombinationspräparat mit einem zentral wirksamen Muskelrelaxans oder Orphenadrinzitrat.

PURPOSE:A complication after restorative rectal surgery with a straight anastomosis is low-anterior resection syndrome with a postoperatively deteriorated anorectal function. The colonic J-reservoir is sometimes used with the purpose of reducing these symptoms. An alternative method is to use a simple side-to-end anastomosis or a coloplasty.MATERIAL AND METHODS:Three-hundred fiftyseven patients with rectal cancer undergoing total mesorectal excision (TME). Three-hundred (84.0%) received a low anterior resection with primary anastomosis and colo-rectal n = 194 (64.6%) or colo-anal anastomosis n = 106 (35.3%). A colonic pouch using the descending colon was created in 24 patients and in 75 patients respectively. Surgical results and complications were recorded. Patients were followed with a functional evaluation at 6 and 12 months postoperatively.RESULTS:Patient characteristics in both groups were very similar regarding gender, age, tumor level, and Dukes' stages. A large proportion of the patients received short-term preoperative radiotherapy (72%). There was no significant difference in surgical outcome between the 2 techniques with respect to anastomotic height, perioperative blood loss, postoperative complications, reoperations, hospital stay or pelvic sepsis rates except the anastomotic stricture rate in the colonic J-Pouch group after coloanal anastomosis (p < 0.02).CONCLUSIONS:These data show that either a colonic J-pouch or a straight anastomosis performed on the descending colon in low-anterior resection with TME are methods that can be used with similar expected surgical and functional results.

To evaluate the feasibility, effectiveness, and long-term bowel function of preoperative hyperfractionated accelerated radiotherapy in primary resectable rectal cancer. A total of 184 consecutive patients (median age 65 years, male : female=2 : 1) with clinical T3Nx rectal adenocarcinoma received preoperative pelvic radiation therapy with single fractions of 2.5 Gy twice daily (interval 6 h between fractions) to a total dose of 25 Gy within 1 week. Surgery was conducted the following week. Postoperative histology revealed UICC stage I in 33%, stage II in 26%, stage III in 34%, and stage IV in 7% of the patients. Median follow-up was 43 months (53 months for surviving patients). The actuarial 4-year-local-recurrence rate was 2.1%, overall recurrence 23%. Disease-specific and disease-free survivals at 4 years (excluding stage IV) were 82 and 69%, respectively. Overall survival for 4 years was 68%. Postoperative mortality was 0.5% (one patient), early anastomotic leakage occurred in 11.4%, and anastomotic stenosis requiring treatment in 6%, of 132 patients with primary anastomosis. Seven of 184 patients (3.8%) died of abdominal complications, all within the first year. Bowel function was satisfactory after more than 5 years. Local control in primarily resectable rectal cancer after 10 x 2.5 Gy is excellent, warranting further evaluation of this treatment.

The aim of this study was to investigate the activation of the p53 pathway and the induction of apoptosis during preoperative radiotherapy in normal human rectal tissue and in rectal carcinoma. Twelve patients with rectal cancer of the lower third were enrolled in this study. Tumor specimens and adjacent normal tissue were obtained before radiation, after the third radiation cycle and from the surgically removed rectum. All specimens were analyzed be means of immunohistochemistry for expression of p53 and its downstream target genes MDM2 and p21. In normal mucosal crypts, irradiation led to p53 accumulation and MDM2 induction in more than 70% of the cells. The accumulation of p53 in basal crypts was associated with high expression of p21. Apoptosis was also induced in crypts and occurred in 15% of the cells. Activation of the p53 pathway was not seen in the resting cells at the luminal border of the epithelium. In interstitial cells, p21 was highly upregulated, whereas p53 and MDM2 showed weak expression. The level of bcl-2 was not altered during radiotherapy in healthy tissue. In rectal carcinoma cells, p53 expression was unaltered by irradiation in 11 out of 12 tumors. The p53 non-functional tumors were characterized by a weak induction of MDM2 and p21 and by the lack of apoptosis in the presence of bcl-2. Our findings demonstrate that sequential immunohistochemical analysis is suitable to detect a deregulation of the p53 pathway in human rectal cancer cells during radiotherapy. Further investigations are necessary to elucidate its value as a prognostic marker and potential predictor of therapy responsiveness.

Multidetector computed tomography (CT) offers new opportunities in imaging of the gastrointestinal tract. When thin collimation is used, near-isotropic imaging of the stomach is possible, allowing high-quality multiplanar reformation and three-dimensional reconstruction of gastric images. Proper distention of the stomach and optimally timed administration of intravenous contrast material are required to detect and characterize disease. In contrast to gastroscopy and double-contrast studies of the stomach, CT provides information about both the gastric wall and the extragastric extent of disease. Preoperative staging of gastric carcinoma appears to be the main clinical indication for multidetector CT. In addition, multidetector CT allows detection of other gastric malignancies (lymphoma, carcinoid tumors, metastases, gastrointestinal stromal tumors) and benign gastric tumors (neural tumors, polyps). Gastric inflammation (gastritis, ulcers, Ménétrier disease) and miscellaneous gastric conditions (emphysema, gastric outlet obstruction, varices) can also be visualized with multidetector CT. Multidetector CT is a valuable tool for the evaluation of gastric wall disease and serves as an adjunct to endoscopy.

Objective To evaluate and compare the predictive power of p53 gene analysis versus p53 immunohistochemical staining in terms of response to preoperative short-term radiotherapy using 25 Gy in operable rectal cancer.Summary Background Data Recent studies show that p53 may be a determinant of radiosensitivity being required for induction of apoptosis in case of radiation-induced DNA damage.Methods Preirradiation biopsy samples of 64 patients with rectal carcinoma were analyzed, Genetic alterations of the p53 gene were detected by complete direct sequencing of exons 2 to 10. Expression of the nuclear phosphoprotein p53 was assessed by immunohistochemical staining. Results were correlated with histopathology of resected specimens and follow-up data, respectively.Results Mutations of the p53 gene were present in 45% of tumors. Patients with a normal p53 gene had a significant survival advantage. Comparing pre- and post radiotherapy T category, a reduction was seen in patients with normal p53 genotype only. A mutant p53 genotype was highly specific in indicating stable disease concerning T category after irradiation, Protein overexpression was detected in 61%. Overexpression of the p53 protein was not related to survival or response. The concordance between immunohistochemistry and sequencing was only 0.51.Conclusions The authors show that downstaging after short-term radiation may occur but is seen in tumors with normal p53 gene only. Moreover, p53 genotype but not p53 immunohistochemistry is predictive for response to preoperative short-term radiotherapy and patient survival.

Aromatic fatty acids such as phenylbutyrate (PB) and its metabolite phenylacetate (PA) induce growth arrest, differentiation and apoptosis in solid tumor cells. Despite their antiproliferative action they were reported to exhibit a synergistic effect in combination with cytotoxic drugs like topotecan, and others. Since the activity of the camptothecines (CPTs) depends on local pH conditions, we investigated, whether PB/PA modulate CPT effects indirectly by affecting intracellular pH in SW620 and SW480 colon cancer cells. The results for the colon carcinoma cells show an antagonistic interaction for the combination of CPT and 0.25-5 mM PA in viability assays, resulting in an approximately 3-fold increase in IC50 (control: 20+/-7 nM). A synergistic effect with significantly increased numbers of late apoptotic/necrotic cancer cells (difference +21+/-4%) and 1.4-fold sensitization were detected upon inclusion of 2.5 mM PA during a 4-h CPT (10 micro;M) loading phase. In response to 0.25-1 mM PA/PB the cells exhibit a reversible decrease of pHi (0.1-0.31 pH units) in HEPES- or bicarbonate-buffered media. Dose-dependent acidification and pHi-recovery occurred following addition of PA and PB after an acid load and inhibition of the Na+/H+-antiporter and bicarbonate exchangers, pointing to a possible intracellular mechanism of cytoplasmic acidification. It is concluded that the synergistic modulation of CPT toxicity by short-term PA/PB treatment in colon carcinoma cells is caused by changes in intracellular pH, possibly affecting quantity and localization of the active closed lactone form of this drug.

Immunohistochemistry (IHC) is a cheap and rapid method to detect p53 inactivation but the results are often discordant with gene mutation analysis. This study aimed to investigate whether there is a difference in the immunohistochemical staining patterns of p53-positive cells on comparing tumours with inactivating gene mutations with those without. Tissues of 142 colorectal cancers were investigated for p53 inactivation simultaneously by IHC and gene analysis using SSCP of exons 4-9 and sequencing. In addition, tumours were investigated immunohistochemically for the expression of mdm-2 protein, known to be transcriptionally transactivated by the wild-type (wt) p53 gene. p53-positive cells of tumours without detectable p53 gene mutations were microdissected using a PALM laser microscope system and subjected to p53 sequence analysis. Among the 142 cases of colorectal cancer (male/female=88/54; mean age 66a+/-11 years, range 24-90 years), 74% (n=105) of tumours were positive by p53 IHC and mutations in the p53 gene were found in 51% (73 patients). In 16% (12 patients) with mutations in the p53 gene, IHC for p53 was negative. In tumours with mutations in the p53 gene and positive p53 IHC, staining of all nuclei of the tumour was more frequently (57/61, 93%) found than in tumours without p53 gene mutations, where staining of scattered single cells was predominantly seen (29/44, 66%; p<0.0001). mdm-2 positivity (n=33) showed only staining of scattered single cells, predominantly (24/33, 82%; p<0.0001) in tumours without gene mutations. Single cell microdissection followed by mutation analysis of scattered p53-positive cells revealed no gene mutations. A scattered positive immunohistochemical reactivity of p53 in colorectal cancer cells might therefore represent a functionally active non-mutated p53 gene and should not be considered as a marker of gene mutation and inactivation.

Levamisole (LEV) weakly activates CFfR, the apical Cl channel of cAMP-mediated Cl secretion, via effects on an alkaline phosphatase.Despite activating CFrR, we found that LEV inhibits

The purpose of this study was to compare the diagnostic sensitivity of unenhanced magnetic resonance (MR) imaging, and MR imaging with a new superparamagnetic iron oxide (SPIO)-enhanced contrast agent (SHU 555 A) with biphasic helical computed tomography during arterial portography (CTAP) in patients with focal liver lesions. Eighteen patients with a total of 91 (78 malignant, 13 benign) proven liver lesions underwent unenhanced short tau inversion recovery (STIR), T2-weighted (T2-w) TSE, and SHU 555 A-enhanced T2-w turbo spin-echo (TSE) MR imaging and biphasic helical CTAP. The standard of reference was histopathologic analysis of resected specimens in 59 lesions, intraoperative ultrasound with biopsy in 20 lesions, and CT-guided biopsy and follow-up in 12 lesions. Diagnostic performance of the imaging modalities was compared quantitatively and qualitatively by assessing lesion Involvement in liver segments. There were 68 lesions detected on unenhanced T2-w TSE, which resulted in a sensitivity of 75%. With the STIR sequence, 76 lesions were detected, for a sensitivity of 84%, and with SHU 555 A-enhanced AM, 84 lesions were detected, for a sensitivity of 92%. CTAP detected 88 lesions, for a sensitivity of 97%. The accuracy for unenhanced T2-w TSE was 98%, for STIR 99%, for enhanced-NM 100%, and for CTAP 95%. The specificity was 100% for SHU 555 A-enhanced MRI and 95% for CTAP. SHU 555 A-enhanced MRI was superior to nonenhanced MRI (P < 0.05) and equivalent to CTAP in terms of sensitivity. Due to the absence of false-positive results on SHU 555 A-enhanced MRI, the specificity and accuracy of enhanced MRI were higher than those of CTAP, but the difference was not statistically significant (P = 0.134). J. Magn. Reson. Imaging 2000;11:665-672. (C) 2000 Wiley-Liss, Inc.

BACKGROUND Strains of Bacteroides fragilis producing a 20 kDa protein toxin ( B fragilis toxin (BFT) or fragilysin) are associated with diarrhoea in animals and humans. Although in vitro results indicate that BFT damages intestinal epithelial cells in culture, the effects of BFT on native human colon are not known. AIMS To examine the electrophysiological and morphological effects of purified BFT-2 on human colonic mucosa in vitro. METHODS For resistance (R) measurements, colonic mucosa mounted in Ussing chambers was exposed to luminal or serosal BFT-2 (1.25–10 nM) and after four hours morphological damage was measured on haematoxylin and eosin stained sections using morphometry. F actin distribution was assessed using confocal microscopy. RESULTS Serosal BFT-2 for four hours was four-, two-, seven-, and threefold more potent than luminal BFT-2 in decreasing resistance, increasing epithelial 3 H-mannitol permeability, and damaging crypt and surface colonocytes, respectively (p<0.05). Confocal microscopy showed reduced colonocyte F actin staining intensity after exposure to BFT-2. CONCLUSIONS BFT-2 increases human colonic permeability and damages human colonic epithelial cells in vitro. These effects may be important in the development of diarrhoea and intestinal inflammation caused by B fragilis in vivo.

Previous studies indicated that the peptide substance P (SP) causes Cl--dependent secretion in animal colonic mucosa. We investigated the effects of SP in human colonic mucosa mounted in Ussing chamber. Drugs for pharmacological characterization of SP-induced responses were applied 30 min before SP. Serosal, but not luminal, administration of SP (10(-8) to 10(-6) M) induced a rapid, monophasic concentration and Cl--dependent, bumetanide-sensitive short-circuit current (Isc) increase, which was inhibited by the SP neurokinin 1 (NK1)-receptor antagonist CP-96345, the neuronal blocker TTX, the mast cell stabilizer lodoxamide, the histamine 1-receptor antagonist pyrilamine, and the PG synthesis inhibitor indomethacin. SP caused TTX- and lodoxamide-sensitive histamine release from colonic mucosa. Two-photon microscopy revealed NK1 (SP)-receptor immunoreactivity on nerve cells. The tyrosine kinase inhibitor genistein concentration dependently blocked SP-induced Isc increase without impairing forskolin- and carbachol-mediated Isc increase. We conclude that SP stimulates Cl--dependent secretion in human colon by a pathway(s) involving mucosal nerves, mast cells, and the mast cell product histamine. Our results also indicate that tyrosine kinases may be involved in this SP-induced response.

We previously reported (Gastroenterology 112: A1183, 1997) that the peptide SP stimulates chloride secretion in human colon in vitro.Our aim was to examine the mechanism(s) of this SP-mediated response.Methods: Ussing chambered colonic mlJcosae were exposed to SP in the presence or absence of chloride-containing buffer.Drugs for pharmacologic characterization of SP-induced changes were applied 30 min prior to SP. Results: Serosal administration of SP (10-8-10 .6M) induced a rapid, monophasic, dose-and chloride-dependent short circuit current (Isc)-increase (p<0.001), which was dramatically inhibited by 10 -6 M of the SP-receptor antagonist CP-96,345, the neuronal blocker tetrodotoxin, the mast cell stabilizer !odnxamide, the H-1 receptor antagonist pyrilamine, the prostaglandin synthesis inhibitor indomethacine, or by pharmacologic inhibition of ion transport pathways required for chloride secretion (almost complete inhibition by bumetanide, ouabain, and charybdotoxin).Serosal SP (10 --6 M) caused histamine release from human colonic mueosa, which was inhibited by TTX and lodoxamide.Two photon microscopy revealed NK-1 (SP) receptor immunoreactive cells on nerve cells, but not on colonic epithelium.The tyrosine-kinase inhibitor genistein completely blocked SP-induced Isc increase without impairing forskolin and carbachol-mediated Isc increase.Conclusions: SP-mediatedchloride secretion in human colon is mediated by mueosal nerves, mast cells and histamine and could possibly involve a tyrosine kinase-dependent signal transduction pathway.

A case of intestinal splenosis in a splenectomized patient is presented. 111In-DTPA-D-Phe-1-octreotide (111In-OCT) scintigraphy, computed tomography, as well as magnetic resonance imaging suggested a tumor in the small intestine. The histopathogical finding after operation revealed an intestinal splenosis. This case illustrates that intestinal splenosis may mimic a tumor by 111In-OCT scan. In a splenectomized patient, a splenosis should therefore be considered.

Epidermal growth factor (EGF) exhibits a cytoprotective effect on gastrointestinal epithelia via a receptor-mediated mechanism. We investigated the effect of EGF on Clostridium difficile toxin A (TxA)- and toxin B (TxB)-induced damage of human colon. Ussing-chambered colonic mucosa was exposed serosally to EGF before and during luminal exposure to TxA and TxB. Resistance was calculated from potential difference and short-circuit current. Epithelial damage was assessed by light microscopy and alteration of F-actin by fluoresceinated phalloidin. Luminal exposure of colonic strips to TxA and TxB caused a time- and dose-dependent decrease in electrical resistance, necrosis and dehiscence of colonocytes, and disruption and condensation of enterocyte F-actin. These effects were inhibited by prior, but not simultaneous, serosal application of EGF (20 nM). Administration of the tyrosine kinase inhibitor genistein (10-6 M) inhibited the protective effects of EGF. We conclude that EGF protects against TxA and TxB probably by stabilizing the cytoskeleton, the main target of these toxins.

BACKGROUND Epithelial restitution enables resurfacing of epithelial discontinuities by enterocyte migration. This study investigated the effect of basic fibroblast growth factor (bFGF), insulin-like growth factor (IGF-1), and epidermal growth factor (EGF) on restitution of human colonic mucosa in vitro. METHODS After base-line incubation human colonic mucosal strips, mounted in Ussing chambers, were luminally exposed to 0.5 mM sodium deoxycholate (NaDOC) for 10 min. Thereafter tissues were incubated with buffer alone or luminal buffer containing various concentrations of bFGF, IGF-1, and EGF for 3 h. Resistance (R) was calculated from potential difference (PD) and short-circuit current (Isc). All tissues were processed for light microscopy. Extent of damage was measured by morphometry. RESULTS Luminal 0.5 mM NaDOC for 10 min caused R to drop by 43% (n = 4; P < 0.05). Compared with controls 50 ng/ml EGF induced an approximately 30% R increase until the end of the experiments (P < 0.05, n = 4, paired). Ten minutes after injury 50.2 +/- 4% of the mucosa was damaged (n = 6), and after 3 h damage was significantly reduced by EGF (17.2 +/- 3% versus 31.7 +/- 4%, 50 ng/ml EGF versus controls) (P < 0.05, n = 6 per group). Histology showed that EGF stimulated enterocyte migration over the basal lamina. Various doses of bFGF and IGF-1 did not impair restitution when compared with controls. CONCLUSION In contrast to bFGF and IGF-1, EGF was shown to promote epithelial restitution of human colonic mucosa in vitro.

Planar scintimammography (SMM) with 99Tcm-sestamibi (99Tcm-MIBI) has proved to be a useful method in the evaluation of breast lesions. The aim of our study was to determine the diagnostic value of planar and single photon emission tomograpic (SPET) SMM in different age group. We investigated women with breast lesions for which the surgeon recommended biopsy or careful follow-up. Seventy consecutive patients underwent supine planar SMM, while supine SPET was performed in 68 of the patients. Twenty-seven carcinomas in 23 patients and 35 benign lesions in 31 patients were confirmed histologically. In the remaining 16 patients, the findings were classified as benign at follow-up. The carcinomas and benign lesions had a mean (+/- S.D.) diameter of 25 +/- 17 and 17 +/- 11 mm respectively (P < 0.05). A sensitivity/specificity of 67/96% and 88/91% was obtained with the planar and SPET techniques respectively. The accuracy of both techniques was 90%. In patients aged 40 years or less, SPET increased the sensitivity from 50 to 100% (P < 0.01), whereas it decreased the specificity and accuracy from 94 to 81% and 91 to 81% respectively (N.S.). In patients aged 41-50 years, the sensitivity increased from 63 to 100% (P < 0.01), whereas there was a small decrease in specificity and an increase in accuracy (from 91 to 89% and 86 to 91% respectively, N.S.) We conclude that, in younger patients, a negative SPET SMM study indicates the need for careful follow-up rather than biopsy. However, the addition of SPET in supine scintimammography does-not change the overall accuracy significantly.