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SummaryGenetic diseases such as familial polyposis, human non-polyposis colon carcinoma and the multiple endocrine neoplasia are already diagnosed using molecular biology techniques. Clea

Das Pankreaskarzinom zeichnet sich nach wie vor durch eine auβerst ungiinstige Prognose aus. Selbst bei den wenigen Fallen, die unter kurativen Gesichtspunkten reseziert werden konnen, ist die 5-Jahres-Uberlebensrate selten hoher als 10%. Die meisten adjuvanten chemotherapeutischen Ansatze mit zumeist 5-Fluorouracil (FU) als Basistherapeutikum fuhrten nicht zu einer uberzeugenden Verlangerung der medianen Uberlebenszeiten. Neuere multizentrische Studien (z.B. ESPAC-1) uberprufen derzeit den Stellenwert der adjuvanten Radiochemotherapie beim Pankreaskarzinom. Durch die adjuvante regionale Chemotherapie via Truncuscoeliacus-Infusionen konnte die mediane Uberlebenszeit im Vergleich zu einer historischen Kontrollgruppe verdoppelt werden.

In pancreatic cancer median survival times range around 6, 6 to 6,9 months. Here we retrospectively analyzed the outcome of immunotherapy in the additional palliative treatment of pancreatic cancer with long antigen exposition dendritic cell therapy (LANEX-DC(®)) in 138 patients who were treated at our institution.Data were available of 134 patients (97.1%). The median interval between first diagnosis and start of treatment was 1.4 months.Therapy was well tolerated and no serious side effects were observed. The survival rate after 6 months was 72.2 % and afters 9 month 50.4%. The median survival time according to Kaplan- Meier regression analysis was 8.9 months. Median survival was significantly higher in the group of patients who started immunotherapy within 2 months following diagnosis (p=0.029) or repeated immunotherapy (p=0.027). Interestingly, younger patients= 60 years of age lived significantly longer as patients60 years of age (p = 0.022).We were able to demonstrate in a large retrospective analysis that additional treatment with dendritic cells (LANEX-DC(®)) is highly effective and extends the median survival times up to 8.9 months. Furthermore we were able to demonstrate that median survival can be increased by early beginning and repetition of LANEX-DC(®) treatment.

Thirty-two patients with advanced nonresectable pancreatic cancer of UICC stages III (17 patients) and IV (15 patients; palliative group) received regional chemotherapy with mitoxantrone, 5-FU + folinic acid, and cisplatin via celiac axis infusion with the Seldinger technique. Twenty patients received this treatment after resection of their primary tumors (adjuvant group). Overall 202 cycles [4(1-11)/patient] were applied. Toxicities in all cycles were as follows: gastrointestinal ulcers 6%, gastritis 5%, severe stomatitis 0.5%, nausea/vomiting WHO I+ 11 44%, leukopenia WHO I+ II 11% and WHO III 0.5%. A false aneurysm and a hematoma developed in 1 patient each. The median survival times were 7.5 months in the palliative group (UICC III 12 months, UICC IV 4 months) and 15.1 months in the adjuvant group. Pain decreased significantly in the palliative group.

Infection of pancreatic necrosis (IN) has a major impact on management and outcome in acute pancreatitis (AP). Currently, guided fine-needle aspiration (FNA) is the only means for an accurate diagnosis of IN. Procalcitonin (PCT), a 116 amino acid pro-peptide of calcitonin has been found in high concentrations in patients with sepsis. In the present study we analyzed the clinical value of serum PCT for predicting IN in AP and compared the results to guided FNA.Clinical study.A collaborative study between the Departments of General Surgery and Clinical Chemistry/ Pathobiochemistry of the University of Ulm, Germany.61 patients with AP entered this study and were stratified into three groups according to morphological and bacteriological data: I. 22 patients with edematous pancreatitis (AIP), II. 18 patients with sterile necrosis (SN), III. 21 patients with IN.During an observation period of 14 days PCT was measured by immunoluminometry, CRP was determined by lasernephelometry on a routine base. In patients with IN overall PCT concentrations were significantly higher than in those with SN, whereas CRP levels did not differ in both groups. In contrast, only low concentrations of both parameters were found in patients with AIP. By ROC analysis the best PCT cut-off level for predicting IN or persisting pancreatic sepsis was obtained ator =1.8 ng/ml. If this cut-off was reached on at least two consecutive days, IN could be predicted with a sensitivity of 95%, a specificity, of 88%, and an accuracy of 90%. Guided FNA achieved a sensitivity, specificity, and accuracy of 91%. 79%, and 84% in differentiating IN from SN, respectively. After surgical treatment of IN median PCT values continued to be significantly higher in patients with persisting pancreatic sepsis (n=12) compared to those with an uneventful postoperative course (n=7). Our results demonstrate that monitoring of serum PCT could serve as a noninvasive and accurate method to predict IN in AP as well as to select patients with persisting septic complications after surgical debridement.

Oxygen radicals and nitric oxide are involved in a variety of regulative processes especially with regard to inflammation, immunoregulation and regulation of the vascular tone. The aim of our study was to investigate the effects of both these highly reactive molecules on the proliferation of human fibroblasts. We therefore cultured WI38 cells under various culture conditions like exposure to oxygen radicals and endogenously produced as well as exogenously applied nitric oxide. Exposure of WI38 to oxygen radicals led to a reduction of cell proliferation. Similarly induction of endogenous nitric oxide production by cytokines induced an inhibition in cell proliferation. Interestingly exogenously applied nitric oxide increased proliferation rates of WI38 cells. These data could point to a functional role of oxygen radicals and nitric oxide in the regulation of fibroblast growth.

In the present study we investigated the prognostic relevance of molecular and immunological changes in pancreatic carcinoma. 82 tissue specimens of adenocarcinoma of the pancreas were stained immunohistochemically with following factors: p53, p21WAF1, Cyklin D, EGF, EGF-R, cERB-B2, CD95, BCL-2 and Cathepsin D. We further determined the serum levels of sCD44, sCD44v6, neopterin and IL-2R. Except Cyclin D none of the immunohistochemically determined factors had prognostic significance. Interestingly all of the immunological serum parameters were of high prognostic significance. These data demonstrate the prognostic relevance of immunological parameters in human adenocarcinoma of the pancreas and could raise the possibility of an early immunological intervention in pancreatic cancer.

Beta-catenin is a component of the E-cadherin-catenin cell adhesion complex. It plays also a role in intracellular signaling and can function as an oncogene when it binds to the T-cell factor 4 (Tcf4)-binding site in the promoter region of cyclin D1 and transactivates genes after translocation to the nucleus. We evaluated the immunohistochemical expression pattern of beta-catenin in relationship with cyclin D1 overexpression, tumor grade, clinicopathologic parameters and patients' survival in 43 ductal adenocarcinomas of the pancreas and 5 normal pancreatic tissues. We were able to show that, both reduced membranous beta-catenin expression (25 of 43, 58.1%) and accumulation of beta-catenin in the cytoplasm (28 of 43, 65.1%) correlated significantly with cyclin D1 overexpression (both p0.0005). Furthermore, we could show a clear correlation between reduced membranous expression and ectopic cytoplasmic expression of beta-catenin (p0.0005). Among patients with carcinomas showing no cytoplasmic expression, the 1-year survival was 86.6% whereas among patients with carcinomas showing cytoplasmic expression only 35.7% survived 1 year (p0.01). Co-precipitation experiments revealed reduced beta-catenin bound to the E-cadherin-catenin complex in pancreatic tumor tissues compared with normal pancreatic tissues. These results suggest that beta-catenin may be involved in the tumorigenesis of pancreatic cancer and exhibited its effects mainly by the transactivation of cyclin D1.

Background: In recent studies we demonstrated the overexpression of cysteine protease ICE (caspase-1) in pancreatic carcinoma tissue and the significant correlation with factors associated with poor prognosis, pointing to possible aspects of ICE in proliferative processes in human pancreatic carcinoma. In this study we investigated the influence of ICE inhibition on the cell cycle of pancreatic carcinoma cells. Methods: For cell cycle analysis and Western blot analysis, pancreatic cells (AsPC-1, BxPC-3, MiaPaCa-2 and Panc-1) were incubated with the specific ICE-inhibitor Ac-AAVALLPAVLLALLAP-YVAD.CHO (p-YVAD.CHO) for 24 h. Results: We found that incubation with p-YVAD.CHO (25 µM) induces a non-apoptotic/necrotic-like cell death in pancreatic AsPC-1 (24.5 ± 10.3%), BxPC-3 (21.9 ± 6.9%), MiaPaCa-2 (32.0 ± 16.2%) and Panc-1 (15.3 ± 1.1%) cells. Western blot analysis revealed an ICE-dependent modulation of the expression levels of the proteins of the bcl-2 family, known to play a key role in the regulation of cell death. Conclusion Our observations support our previous findings that ICE may be involved in antiapoptotic processes in pancreatic carcinoma and may provide new aspects in its role in proliferation and cell death.

Recent studies have demonstrated that various tumors express enhanced levels of the radical scavenger glutathione (GSH). Moreover, there are grounds for claiming that GSH plays a crucial role in cell proliferation and tumor resistance. In the current study, we investigated the relation between cell growth and GSH levels in the pancreatic adenocarcinoma cell line, AsPC-1, and the significance of GSH in tumor resistance to chemotherapy.Cell growth in AsPC-1 was initiated through transforming growth factor-alpha (TGF-alpha) or fetal calf serum (FCS). Then, cell cycle, cell proliferation, and cellular GSH content were analyzed at different times in the presence or absence of buthionine sulfoximine (BSO). The impact of GSH on chemotherapy-induced apoptosis was studied using 5-fluorouracil or melphalan in the presence or absence of BSO. Finally, we compared the GSH content of 15 pancreatic tumor specimens with 10 normal pancreatic tissue specimens.Analysis of GSH in pancreatic tissues demonstrated increased GSH levels in cancerous compared with normal tissue (17.5 +/- 2.3 vs. 8. 8 +/- 1.4 nmol/mg protein; P0.004). Incubation of AsPC-1 with TGF-alpha or FCS resulted in cell proliferation and cell cycle activity, whereas GSH content was not altered. Incubation of GSH-depleted cells with TGF-alpha did not stimulate cell growth. In addition, GSH-depletion resulted in an increased rate of apoptosis after melphalan (6.3 +/- 0.3 % vs. 11.2 +/- 0.3 %; P0.001), but not after 5-fluorouracil treatment.Taken together, our results show enhanced GSH levels in pancreatic carcinoma and an essential role of GSH in cell proliferation and in resistance of AsPC-1 cells. Therefore, GSH-depletion may improve the efficacy of adjuvant therapy in pancreatic carcinoma.

It is suggested that interleukin-1beta-converting enzyme (ICE) and ICE-related proteases play an important role in programmed cell death (apoptosis). We investigated ICE expression in the human pancreatic carcinoma cell line AsPC-1 after stimulation with epidermal growth factor and found a time-dependent expression of active ICE induced by epidermal growth factor. Interestingly, ICE expression does not lead to apoptosis. Cell cycle analyses revealed that acetyl-Tyr-Val-Ala-Asp-chloromethylketone-specific and acetyl-Ala-Ala-Val-Ala-Leu-Leu-Pro-Ala-Val-Leu-Leu-Ala-Leu-Leu-Ala-Pro-T yr-Val-Ala-Asp-aldehyde-specific cell-permeable inhibitors of ICE significantly reduced the proliferation of AsPC-1 cells, which suggested a positive influence of ICE on the proliferation in human pancreatic carcinoma cells.

The FRAP-p70s6K signaling pathway was found to be constitutively phosphorylated/active in MiaPaCa-2 and Panc-1 human pancreatic cancer cells and a pancreatic cancer tissue sample as judged by the retarded electrophoretic mobility of the two major FRAP downstream targets, p70s6K and 4E-BP1. Treatment of cells with rapamycin, a selective FRAP Inhibitor, inhibited basal p70s6K kinase activity and induced dephosphorylation of p70s6K and 4E-BP1. Moreover, rapamycin inhibited DNA synthesis as well as anchorage-dependent and -independent proliferation in MiaPaCa-2 and Panc-1 cells. Finally, rapamycin strikingly inhibited cyclin D1 expression in pancreatic cancer cells. Thus, inhibitors of the constitutively active FRAP-p70s6K pathway may provide a novel therapeutic approach for pancreatic cancer.

To identify the impact of treatment factors on overall survival in patients with pancreatic carcinoma.We performed a follow-up study on 38 patients with adenocarcinoma of the pancreas treated from 1984 to 1998. 18/38 patients were resected. Irradiated volume included the primary tumor (or tumor bed) and regional lymph nodes. Thirty-seven patients received in addition chemotherapy consisting of mitoxantrone, 5-fluorouracil and cis-platin, either i.v. (14/38) or i.a. (23/38). The influence of treatment related factors on the overall survival was tested. Biologically effective dose was calculated by the linear-quadratic model (alpha/beta = 25 Gy) and by losing 0.85 Gy per day starting accelerated repopulation at day 28.Treatment factors influencing overall survival were resection (p = 0.02), overall treatment time (p = 0.03) and biologically effective dose (p0.002). Total dose and kind of chemotherapy had no significant influence. Treatment volume had a negative correlation (r = -0.5, p = 0.06) with overall survival, without any correlation between tumor size, tumor stage, and treatment volume. In multivariate analysis only biologically effective dose remained significant (p = 0.02).Among with surgery, biologically effective dose strongly influences overall survival in patients treated for pancreatic carcinoma. Treatment volume should be kept as small as possible and all efforts should be made to avoid treatment splits in radiation therapy.

Although expression of intercellular adhesion molecule-1 (ICAM-1) expression has been demonstrated in many human malignancies, very little is known about the ICAM-1 expression in human pancreatic cancer. We have examined ICAM-1 expression in pancreatic cancer cell lines and the induction of ICAM-1 in these cells by flow cytometry. The degree of baseline ICAM-1 expression was most significant in Panc-1, followed by PMH-2, Capan-2, Bx-PC-3, Capan-1, and PMH-3 in that order. PaCa-2 and AsPC-1 showed very low levels of baseline ICAM-1 expression. After tumor necrosis factor alpha and interferon gamma stimulation, five cell lines exhibited distinct ICAM-1 induction. The degree of induction was remarkable in AsPC-1 (32-fold), and moderate in PMH-3 (6.5-fold), PaCa-2 (3.2-fold), Capan-1 (1.6-fold), and BxPC-3 (1.5-fold). The ICAM-1 expression levels of PMH-2 and Capan-2 after stimulation were nearly the same as those before stimulation (1.2-fold and 1.1-fold, respectively). These results suggest that ICAM-1 is overexpressed and inducible by tumor necrosis factor alpha and interferon gamma in pancreatic cancer cell lines.

Patients with pancreatic cancer expect an extremely low 5-year survival rate of 1%. Resection of the primary tumour at an early stage may offer the only chance for cure, although this treatment result is rare, since only 5% of resected patients live beyond 5 years after surgery with curative intent. The overall fatal outcome of this disease is due to the fact that frequently the tumour has either already metastasised at the time of diagnosis or is locally advanced, so that resection without residual tumour is not possible. In spite of the large surgical experience of our own institution, resection could be performed in only 36% of 471 patients between 1982 and 1993; the 5-year survival rate was 8% and median survival time 11.3–12.1 months (1).

Gallstone ileus is a rare disorder, which, because it is often misdiagnosed preoperatively, may become life-threatening. The classic triad of Rigler (aerobilia, small bowel ileus and a calcified, dystopic stone) is visualized on abdominal plain films in only 14-35% of cases. Further work-up includes ultrasound, upper gastrointestinal series with water soluble contrast medium and computed tomography (CT). CT is especially reliable in demonstrating all three criteria.

Recent studies have shown that several splice variants of CD44, might be involved in tumor progression. Since chronic pancreatitis is suggested to be a risk factor for pancreatic cancer we investigated the splice pattern of CD44 in chronic pancreatitis to elucidate the role of CD44 in pancreas tumorigenesis. The expression of CD44-isoforms was examined in 40 specimens of chronic pancreatitis and 12 specimens of normal pancreas by immunohistochemistry, Westernblotting and exon specific RT-PCR. Pancreatic cancer tissue from two patients who developed pancreatic cancer 2 and 3 years following surgery for chronic pancreatitis were analyzed. Strong expression of CD44s was found in all cells, whereas the expression of CD44v6 was restricted to ductal cells. Westernblotting revealed an overexpression of CD44v6 in chronic pancreatitis as compared to normal pancreas. Exon specific analysis revealed an altered splice pattern of CD44, similar to that in pancreatic cancer, in 12.5% of the chronic pancreatitis specimens. Both patients who developed pancreatic cancer after chronic pancreatitis exhibited this altered splice pattern in both, chronic pancreatitis and pancreatic cancer. These results suggest that variant forms of CD44-mRNA might be expressed in early dysplastic alterations in chronic pancreatitis.

Nitric oxide (NO) is a messenger molecule with various biological activities including DNA damage. In the present study, we examined the influence of endogenously produced NO on human pancreatic cell lines. In response to cytokine stimulation (tumor necrosis factor alpha, IFN-gamma, and interleukin 1beta), human pancreatic carcinoma cell lines expressed the inducible NO synthase that synthesizes NO, detectable as nitrate and nitrite in the culture supernatants. Endogenously produced NO induced apoptosis in all of the tested pancreatic carcinoma cell lines. In cell cycle analysis, endogenous production of NO revealed a G1-arrest in all of the tested cell lines. This G1-arrest was blockable by addition of NG-monomethyl-L-arginine. These data indicate that NO induces a G1-arrest followed by apoptosis in pancreatic carcinoma cell lines.

In order to improve the dismal prognosis of patients suffering from advanced pancreatic cancer we treated 20 patients with adjuvant regional chemotherapy following resection of the tumor.All tumors were classified UICC stage III (TxN1M0). Regional chemotherapy consisted of Mitoxantrone 10 mg/m2 day 1, Folinic Acid 170 mg/m2 and 5-FU 600 mg/m2 days 2-4, and cis-Platinum 60 mg/m2 day 5 for up to 6 cycles. In a total of 101 cycles toxicities WHO III occurred in 6%, WHO IV in 0%.The median survival times, compared to institutional historical controls (treated vs. controls) were 18.5 vs. 9.3 months (p0.0006). Hepatic disease progression seemed to be suppressed.In conclusion regional chemotherapy seems to be effective for adjuvant treatment in resected pancreatic cancer.

We investigated the expression of interleukin 1beta-converting enzyme (ICE; caspase-1) in human adenocarcinomas of the pancreas. Immunohistochemistry and Western blot analyses revealed an overexpression of ICE in 71 and 80% of tumor cells, respectively. Also, on a mRNA level, ICE mRNA was overexpressed in 45% of the cases, as compared to normal pancreatic tissue. Interestingly, the overexpression of ICE in tumor cells correlated significantly with the overexpression of cyclin D1, epidermal growth factor, and epidermal growth factor receptor (P0.0005, P0.05, and P0.002, respectively), which are involved in cell cycle progression and proliferation in human pancreatic carcinoma. This is the first report concerning ICE expression in human carcinomas; however, the exact mechanism underlying these close correlations warrant further research.

This study investigated a total number of 120 colorectal malignant tumor tissues by applying a new quantitative luminometric assay (LIA)-mat, immunohistochemistry (IHC) (n=100), PCR/SSCP (n=42), and sequencing (n=7). Sera were collected from 235 patients suffering from colorectal carcinoma in addition to 195 healthy individuals as a control group. Manual ELISA kit was developed to detect p53 autoantibodies in the sera of those patients. Our data demonstrated that the LIA-mat yields reliable estimates of p53 expression in soluble cell extracts as compared with results obtained by immunohistochemistry which showed positive immunostaining in 63% of the studied cases. Using a cut-off value of 1.8 ng/mg protein, 65 tumors out of 120 (54%) were classified to be positive by LIA-mat, manifesting protein overexpression, while 22 out of 42 (52%) tumor samples showed p53 gene alteration when applying single strand conformation polymorphism (SSCP) analysis on polymerase chain reaction products. In tumor samples without a p53 gene alteration, the median soluble p53 protein level was 4.3 ng/mg protein, whereas the median p53 protein level for tumor samples with p53 gene alteration was 7.5 times higher. Despite a significant correlation between the outcome of LIA and SSCP, a disagreement was found in 30% of cases. We found no significant correlation between p53 protein overexpression and clinicopathological findings except for distant metastasis (p=0.33), indicating p53 immunoreactivity to be an independent prognostic factor. Our data showed that 18% of patients suffering from colorectal cancer developed autoantibodies against p53 in their sera which might be an early indicator for tumor development and distant metastasis.

In a study compiling the data in a prospective manner, the value of the pylorus-preserving duodenopancreatectomy (PPPD) compared to partial duodenopancreatectomy (PD) in patients suffering from ductal pancreatic carcinoma was assessed. Postoperative morbidity, mortality and overall prognosis were analysed. From May 1990 to April 1995 130 patients entered the study; 61 underwent PD, 69 patients had PPPD. The patients were regularly followed up every 6 months and the median follow-up period for all patients was 36 months. PPPD in patients with ductal pancreatic head carcinoma without infiltration of the duodenum is the technically simpler and faster operation method with significantly less blood loss. Moreover, PPPD did not lead to increased postoperative complications. The median survival rate of patients in the PD group was 10.8 months, in the PPPD group 21 months. This significant difference derives from the fact that the tumor stages were unevenly distributed. Regarding the most common stage (stage III according to UICC) the median survival times were almost identical (PD group 10.1 months, PPPD group 11.2 months). The PPPD operation seems to be a sufficiently radical procedure which does not worsen the prognosis of the disease.

Increased glycolysis is a characteristic metabolic feature of a malignant transformed phenotype. In cultured cells transformed by viruses or activated oncogenes, enhanced glycolytic metabolism is mediated by the overexpression of glucose transporter 1 (Glut-1) and key regulatory glycolytic enzymes. Whether increased glucose metabolism in solid human malignant tumors is related to the overexpression of key regulatory proteins of glucose metabolism is presently unknown. We thus studied the expression of Glut-1 and glucose uptake, assessed with 2-fluorodeoxyglucose (FDG) and PET in human pancreatic carcinoma (PC) and chronic mass-forming pancreatitis (MFP).Glucose uptake was measured in the fasting state with FDG and PET in 12 patients with PC and 15 patients with MFP. The standardized uptake value (SUV) of FDG was determined as a global quantitative measure of tissue glucose utilization in cancer tissue or MFP. The expression of Glut-1 and Glut-4 was analyzed from operatively removed cancer or MFP tissue by Northern analysis or semiquantitative reverse transcriptase-polymerase chain reaction. The count ratio of Glut-1 to Glut-4 transcripts was used as an indicator of selective Glut-1 up-regulation.The SUVs of FDG in patients with cancer and MFP were 2.98 +/- 1.23 and 1.25 +/- 0.51 (p0.01), respectively. Northern analysis showed intense Glut-1 expression in four of five patients with cancer but not in any of the five patients with MFP that were tested. In PC, Glut-1 and Glut-4 transcripts were found in five of five and three of 10 patients, respectively, using reverse transcriptase-polymerase chain reaction, whereas in MFP, Glut-1 was detected in one of five and Glut-4 was detected in all five patients. The Glut-1-to-Glut-4 transcript ratios were 6.17 +/- 1.27 in patients with cancer and 0.42 +/- 0.12 in patients with MFP. The mean Glut-1 concentration in eight patients with cancer was 1.71 nmol of Glut-1 mRNA/microg of mRNA (range, 0.0446-9.43) and 0.15 (range, 0-1.55) (p0.05) in 13 patients with MFP.The concomitant enhancement of glucose utilization and selective overexpression of Glut-1 mRNA in pancreatic cancer but not in MFP suggested constitutive activation of Glut-1 gene or decreased degradation of Glut-1 mRNA in human pancreatic cancer. These findings may imply a potential for the early detection of pancreatic cancer with FDG and PET and identify new targets for anticancer therapy.

We have investigated the expression of cyclin D1 in adenocarcinoma of the pancreas and the relevance of cyclin D1 expression to clinical outcome. In comparison to normal pancreas, Southern blot analyses revealed amplification of the cyclin D1 coding gene in 25% of the cases, whereas with reverse transcription-PCR, overexpression of mRNA was observed in 82% of the examined tissues. Immunohistochemically, we could demonstrate nuclear overexpression in tumor cells in 68.4%, and this protein accumulation correlated significantly with poor prognosis [median survival, 18.1 versus 10.5 months; P0.01 (chi2 test)].

Charakteristisch fur die akute Pankreatitis ist die grose Variabilitat des klinischen Bildes und im naturlichen Verlauf. Von besonderer klinischer Bedeutung sind die etiologischen Faktoren Alkohol und Gallensteinerkrankung sowie die hereditare Pankreatitis. Nach klinischen Kriterien, insbesondere nach Art und Haufigkeit auftretender Komplikationen, werden zwei klinische Phasen im Verlauf der akuten Pankreatitis unterschieden [1]. Innerhalb der ersten 14 Tage kommt es infolge von Flussigkeitssequestration in das Entzundungsgebiet und Freisetzung vasoaktiver und toxischer Substanzen zur Hypovolamie; es konnen Herz-Kreislauf-Komplikationen, insbesondere Rhythmusstorungen, Nieren- und Lungenfunktionsstorungen auftreten. Die Spatphase der akuten Pankreatitis wird von septischen Komplikationen bestimmt, insbesondere bei nekrotisierender Pankreatitis. Lokale und systemische septische Komplikationen bestimmen die Spatphase; Sepsis ist die haufigste Todesursache der schweren akuten Pankreatitis [2].

Mit dem Ausspruch: „Die Medizin wird Wissenschaft sein oder sie wird nicht sein“ hat sich der Internist Naunyn um die Jahrhundertwende in einer Rede vor den Deutschen Naturforschern und Arzten zum naturwissenschaftlichen Modell der Medizin bekannt. Dieses Wissenschaftspostulat gilt auch fur die Chirurgie, die ein auf die klinische Praxis orientiertes, technikbestimmtes und von handwerklicher Leistung abhangiges Fach der klinischen Medizin ist.

A prospective decision-aiding trial was performed to select drugs for regional chemotherapy of various liver tumors (n = 36) by individual drug testing. The drugs were chosen for hepatic artery infusion according to the individual chemosensitivity of tumor biopsies in the human tumor colony-forming assay (HTCA). In vitro HTCA sensitivity correlated with complete response (CR) + partial response (PR) + no change (NC) 93% of the time and with CR + PR 55% of the time. The test sensitivity was 90%, and the specificity was 67% for CR + PR + NC versus progressive disease (PD), whereas the sensitivity and specificity were 89% and 28%, respectively, for CR + PR versus NC + PD. The overall predictive accuracy of the test was 86% for CR + PR + NC versus PD and 58% for CR + PR versus NC + PD. Overall, 83% of this heterogenous patient group with various tumors achieved CR + PR + NC and a 50% clinical response (CR + PR). In vitro-sensitive patients showed a significantly lower intrahepatic progression rate (7% PD) than in vitro-resistant patients (57%; P0.05). These results indicate that the HTCA could identify active drugs for individualized hepatic artery infusion, and patients may profit from the use of in vitro-sensitive drugs.

We have investigated the expression of angiogenin (ANG) in pancreatic cancer and the relevance of ANG expression to the progression of pancreatic cancer. In comparison to normal pancreas, increased ANG mRNA expression was observed in 80.0% of the cases of pancreatic cancer by in situ hybridization, and increased ANG protein expression was observed in 86.7% of the cases of pancreatic cancer using Western blot analysis. The mean serum ANG concentration of pancreatic cancer patients (566.6 +/- 191.9 ng/ml) was significantly higher (P2.0 x 10(-8)) than that of healthy volunteers (359.0 +/-t 59.9 ng/ml). Increased ANG mRNA expression as well as elevated serum ANG concentration correlated with poor prognosis. These findings suggest that ANG expression is up-regulated in pancreatic cancer patients and that ANG contributes to the aggressiveness of pancreatic cancer.

Systemic chemotherapy in patients who underwent resection of pancreatic carcinoma has not been significantly improved median survival times. We investigated whether regional chemotherapy administered via celiac trunc infusion increases survival rates in patients with locally advanced pancreatic carcinoma after resection of the primary. From 12/1992 to 2/1995 we treated 18 patients with regional chemotherapy consisting of mitoxantrone (d1), 5-FU + folinic acid (d2-4) and CDDP (d5) on five consecutive days. This cycle was repeated up to 6 times. Besides non-symptomatic GI-ulcerations (3/18) no severe side effects were observed. The median survival is actually 17.8 months (regression analysis). Compared to a historical control of our department survival times are significantly prolonged (17.8 vs. 9.3 months, p0,0003). In conclusion we state that adjuvant regional chemotherapy in patients with advanced pancreatic cancer is well tolerated and prolongs survival significantly.

Whether chronic pancreatitis is a risk factor for the development of pancreatic cancer is still under discussion. 395 patients operated for chronic pancreatitis with enlargement of the head of the pancreas between 1982 and 1994 were evaluated retrospectively. The frequency of pancreatic cancer in pre-existing chronic pancreatitis was 3.8% (n = 15). This frequency was significantly elevated in comparison to the estimated cancer frequency of the normal population (p0.001). The time interval between first diagnosis of chronic pancreatitis and diagnosis of pancreatic carcinoma was 33.3 month in the mean. 474 patients with pancreatic carcinoma without pre-existing chronic pancreatitis were operated in the same period. Histological examination revealed signs of chronic obstructive pancreatitis due to tumor obstruction of the main pancreatic duct in 11.1% (n = 53). The relative risk of patients suffering primarily from chronic pancreatitis to develop pancreatic carcinoma is elevated by a factor of more than 50 in comparison to normal population.

Immunohistochemical screening of pancreatic adenocarcinomas from 24 different patients and 9 pancreatic carcinoma cell lines revealed variant CD44 expression in all specimens tested. In contrast to normal pancreatic tissue, carcinomas were strongly positive for epitopes encoded by variant exons v5, whereas v6 was expressed on carcinoma cells as well as normal ductal pancreatic cells. Analysis of RNA expression revealed clear differences between normal pancreatic tissue and tumor specimens. In normal pancreas, v6 and v3 solely and one major chain consisting of v6-v10 were expressed, whereas in pancreatic carcinoma, multiple splice variants were detected. In about 80% of all carcinoma cases and all cell lines tested, the exon v5 appeared in the chain containing at least v4-v10. These data thus far suggest that not the presence alone but the chain composition of the CD44 variant chains could be important for their altered function because one of the major differences between normal and cancer tissue is the linkage of CD44v5 to the CD44v6-containing chain.

Even after resection median survival times in advanced pancreatic carcinoma are seldom more than one year. The aim of our study was to evaluate the effectivity of regional chemotherapy in patients suffering from unresectable pancreatic cancer.From 2/92 until 11/94 32 patients with unresectable pancreatic cancer (17 patients stage III, 15 patients stage IV) were treated by celiac trunc infusion. One cycle consisted of mitoxantrone (d 1), 5-FU, folinic acid (d 2 to 4) and cisplatinum (d 5).Besides a few severe complications, therapy was well tolerated in 101 cycles. In unresected patients with stage III tumors the median survival is 12 months compared to 4.8 months in patients with biliodigestive bypasses (p0.006) and 4 months in regionally infused patients stage IV compared to 2.7 months in untreated patients (n.s.).Regional chemotherapy in advanced pancreatic carcinoma is well tolerated and increases median survival in patients with stage III tumors.

Das zunehmend haufige Pankreaskarzinom ist durch eine schlechte Prognose, auch nach chirurgischer Therapie, gekennzeichnet [1]. Die Ursachen fur die Aggressivitat dieses Tumors sind weitgehend ungeklart. In der Vergangenheit wurde durch zahlreiche Studien die Bedeutung von Wachstumsfaktoren fur die maligne Transformation und Progression des Pankreaskarzinoms nachgewiesen [2].