The clinical efficacy of adjuvant systemic chemotherapy with gemcitabine and NSC-631570 in advanced pancreatic cancer.

A study of 30 patients with resected advanced pancreatic cancer shows that combining Gemcitabine with NSC-631570 in adjuvant chemotherapy is safe and may significantly extend survival. The median survival time reached 33.8 months, with 23.3% of patients surviving five years. Toxicity was mild (no severe grade III/IV events). These promising results suggest the potential of this combination therapy to improve outcomes, though further studies are needed to confirm its efficacy.

Systemic immune dysfunction in pancreatic cancer patients.

This study reveals systemic immune dysfunction in pancreatic cancer patients, marked by decreased lymphocyte responsiveness and a shift toward an immune-suppressive profile. Elevated levels of immunosuppressive cytokines (e.g., TNF-alpha, TGF-beta, IL-10) and reduced IL-2 were observed. These findings highlight the immunological challenges in pancreatic cancer and underscore the potential for targeting immune dysregulation in future therapeutic approaches.

Pancreatic cancer. The relative importance of neoadjuvant therapy.

Neoadjuvant radiochemotherapy, combining 50-54 Gy of radiotherapy with 5FU as a radiosensitizer, shows promise in improving outcomes for resectable pancreatic cancer, particularly in UICC stage II. Median survival increases to 15-30 months, with 15% of cases achieving tumor downstaging. Coupled with R0 resection, it reduces local recurrence. However, controlled clinical trials are needed to confirm its benefits and establish standardized protocols.

Pancreatic cancer--low survival rates.

Pancreatic cancer remains largely incurable, with less than 2% of patients surviving five years. Long-term survival is possible only for those with TNM stage I/II disease undergoing R0 resection, with median survival of 17-28 months, extended modestly by adjuvant chemotherapy. Smoking and chronic alcohol consumption are key preventable risk factors, accounting for 30% of cases. Early surgical removal of cystic lesions and targeted follow-up for high-risk individuals are essential preventive strategies.

CAM 17.1--a new diagnostic marker in pancreatic cancer.

The monoclonal antibody CAM 17.1, which detects a mucus glycoprotein, is overexpressed in pancreatic cancer but not in normal pancreas or chronic pancreatitis. A new CAM 17.1/WGA serum assay demonstrated high specificity (90%) and comparable sensitivity (67%) to the established marker CA 19-9. Its higher specificity in distinguishing pancreatic cancer from chronic pancreatitis suggests CAM 17.1/WGA as a promising diagnostic tool for improving pancreatic cancer detection.

Epidermal growth factor induces cyclin D1 in human pancreatic carcinoma: evidence for a cyclin D1-dependent cell cycle progression.

Cyclin D1 is overexpressed in pancreatic carcinoma cells, correlating with poor prognosis. This study shows that cyclin D1 expression is driven, in part, by epidermal growth factor (EGF) signaling through the EGF receptor (EGFR). Overexpression of EGF, EGFR, and cyclin D1 was observed in over half of tumor samples, while absent in normal pancreas. These findings highlight the EGF/EGFR-cyclin D1 pathway as a potential target for therapeutic intervention in pancreatic cancer.

The role of anti-p53-autoantibodies in pancreatic disorders.

Anti-p53 autoantibodies (a-p53-aabs) appear to suppress distant metastases but not lymph node metastases in pancreatic cancer. Patients with UICC stage III tumors and a-p53-aabs showed significantly improved survival compared to those without these antibodies. This study found a-p53-aabs in 15.9% of pancreatic cancer patients, correlating with p53 overexpression, tumor grading, and survival. These findings suggest a-p53-aabs may serve as a prognostic marker, highlighting their potential role in pancreatic cancer progression and outcomes.

Antibiotic prophylaxis in severe acute pancreatitis.

Severe acute pancreatitis, characterized by local and systemic complications, is strongly influenced by the extent of pancreatic necrosis and bacterial infection. While mortality ranges from 5-25% in sterile necrosis, it increases to 15-28% with infection. Prophylactic antibiotics have shown mixed results, with the largest randomized controlled trial finding no overall benefit of ciprofloxacin and metronidazole in reducing infection or mortality. Prophylaxis may be beneficial in select high-risk subgroups, emphasizing the need for tailored approaches.

The use of antibiotics for acute pancreatitis: is there a role?

Infections occur in one-third of severe acute pancreatitis (SAP) cases, but antibiotic prophylaxis has proven ineffective in reducing infected necrosis or mortality. Antibiotics, particularly carbapenems and quinolones, are recommended for SAP patients with multiorgan failure, hemodynamic shock, or associated infections like cholecystitis, cholangitis, bacteremia, or urinary tract infection. Late prophylactic antibiotic use in necrotizing pancreatitis is unsupported by evidence. Further trials are needed to assess early antibiotic prophylaxis within 24-48 hours of SAP onset.

Duodenum-preserving total pancreatic head resection for cystic neoplasm: a limited but cancer-preventive procedure.

Duodenum-preserving total pancreatic head resection is an effective, limited surgical option for monocentric cystic neoplastic lesions in the pancreatic head, such as main-duct IPMN and MCN, without invasive cancer. This procedure offers low hospital mortality (?1%) and avoids removing the duodenum. Long-term outcomes depend on complete resection and absence of advanced cancer. For lesions with signs of malignancy, a Kausch-Whipple resection is preferred. Intraoperative frozen section analysis is crucial for surgical decision-making.

Release of histamine in whole blood by oxygen radicals: division between specific and unspecific processes.

Oxygen-derived free radicals contribute to pathological conditions by inducing lipid peroxidation and damaging cellular membranes. In this study, radicals generated by the xanthine oxidase/hypoxanthine system triggered histamine release in human blood cell cultures. Initial release was calcium-independent, caused by membrane perturbation, while later release involved calcium-dependent processes likely mediated by platelet-activating factor (PAF). Oxygen radicals also altered leukocyte adhesion molecule (LECAM-1) expression, though histamine itself did not affect LECAM-1 regulation. These findings highlight the complex role of free radicals in inflammatory processes.

Pathophysiologic role of oxygen free radicals in acute pancreatitis: initiating event or mediator of tissue damage?

This study confirms that oxygen free radicals (OFRs) are key mediators of tissue damage in acute pancreatitis but not the sole triggers of the disease. In a rat model, oxidative stress from exogenous OFR generation caused changes in glutathione metabolism and inflammatory markers but did not induce the hallmark enzymatic and structural changes of acute pancreatitis. Antioxidant treatment (SOD/CAT) reduced oxidative damage, inflammatory infiltration, and acinar cell injury, highlighting the role of OFRs in disease progression rather than initiation. Other factors are required to trigger acute pancreatitis in vivo.

Modulation of endogenous nitric oxide synthase in experimental acute pancreatitis: role of anti-ICAM-1 and oxygen free radical scavengers.

In an experimental model of acute pancreatitis, increased nitric oxide (NO) production and inducible NO synthase (NOS-2) expression were observed, with oxygen free radicals and neutrophils playing critical regulatory roles. While NO contributes to toxicity during severe pancreatitis, it appears to play a secondary role in local pancreatic damage. Treatments targeting oxidative stress (SOD/CAT) and neutrophil adhesion (aICAM-1) reduced tissue damage, inflammation, and NO levels, suggesting their potential to mitigate disease severity by modulating the interplay between NO and oxidative stress.

NSC-631570 (Ukrain) in the palliative treatment of pancreatic cancer. Results of a phase II trial.

A study of 90 patients with unresectable pancreatic cancer demonstrated that NSC-631570 (Ukrain), alone or combined with gemcitabine, significantly improved survival. Median survival was 5.2 months with gemcitabine alone, 7.9 months with NSC-631570, and 10.4 months with the combination therapy. Both NSC-631570 regimens showed higher response rates and better 6-month survival (65% and 74%) compared to gemcitabine alone (26%). These findings suggest that NSC-631570, particularly in combination with gemcitabine, offers a promising therapeutic approach for advanced pancreatic cancer.

Influence of PMN leukocyte-mediated pancreatic damage on the systemic immune response in severe acute pancreatitis in rats.

The progression of severe acute pancreatitis is influenced by polymorphonuclear (PMN) leukocyte activity and systemic inflammation. In a rat model, PMN respiratory burst and tissue damage were reduced by anti-ICAM-1 antibody and oxygen radical scavengers after 24 hours. Acute pancreatitis also caused immunological shifts, including reduced peripheral helper T cells, increased lymphocyte homing, and a higher CD45RC(high)/CD45RC(low) helper T cell ratio, driven by a reduction in regulatory T cells. Anti-ICAM-1 treatment partially mitigated these immune changes, suggesting that early PMN-mediated damage contributes but does not fully account for the systemic immune dysregulation in necrotizing pancreatitis.

p53 in relation to therapeutic outcome of locoregional chemotherapy in pancreatic cancer.

Adjuvant celiac artery infusion (CAI) chemotherapy significantly improved survival in patients with resected advanced pancreatic cancer, with a median survival of 21 months compared to 10.5 months in those without adjuvant treatment. CAI involved angiographically placed catheters delivering mitoxantrone, 5-FU, folinic acid, and cis-platinum over five cycles. While p53 overexpression was associated with poorer outcomes, it is not a reliable prognostic marker due to its higher prevalence in undifferentiated and palliative cases, underscoring the complexity of prognostic evaluation in pancreatic cancer.

Adjuvant regional chemotherapy in advanced pancreatic cancer: results of a prospective study.

Adjuvant regional chemotherapy significantly improved survival in UICC stage III pancreatic cancer patients after tumor resection, with median survival extended to 18.5 months compared to 9.3 months in untreated controls (p < 0.0006). The regimen, including mitoxantrone, folinic acid, 5-FU, and cis-platinum over six cycles, was well-tolerated, with severe toxicity (WHO III) in only 6% of cases and no grade IV toxicity. Hepatic disease progression appeared suppressed, highlighting the potential of regional chemotherapy as an effective adjuvant treatment for resected pancreatic cancer.

Multimodal therapies in ductal pancreatic cancer. The future.

Intra-arterial infusion chemotherapy via the celiac axis combined with external beam radiotherapy shows promise as a multimodal approach for managing pancreatic cancer, including both resectable and nonresectable cases. A review of palliative, adjuvant, and neoadjuvant therapies highlights its potential to improve outcomes in UICC-III nonresectable pancreatic cancer and as part of a combined neoadjuvant/adjuvant strategy for resectable cases. Further refinement and studies of this approach aim to enhance its efficacy and broaden its application.

Molecular oncology in pancreatic cancer.

Pancreatic cancer remains highly aggressive, with a poor prognosis despite advancements in diagnosis and treatment. Molecular studies have identified frequent mutations in p53 and K-ras, as well as altered expression of growth factors and adhesion molecules, contributing to disrupted cell-cell interactions and growth regulation. Tumor markers such as CA19-9 and CEA aid in diagnosis and monitoring but are limited in scope. Emerging molecular biological techniques provide insights into the mechanisms of pancreatic cancer and offer potential avenues for improved diagnosis, prognostic tools, and targeted therapies.

Intraarterial adjuvant chemotherapy after pancreaticoduodenectomy for pancreatic cancer: significant reduction in occurrence of liver metastasis.

Adjuvant celiac artery infusion (CAI) chemotherapy significantly improved outcomes in resected pancreatic cancer patients. In a study of 24 patients, CAI extended median survival to 23 months compared to 10.5 months without adjuvant therapy. Patients with R0 resections and CAI achieved a 4-year survival rate of 54%, versus 9.5% without CAI. Liver metastases were reduced to 17%, and CAI was well tolerated, with only 8% experiencing WHO grade III toxicities and none grade IV. These findings suggest CAI as a promising adjuvant therapy to improve survival and reduce disease progression in pancreatic cancer.

Regional chemotherapy of nonresectable colorectal liver metastases with mitoxantrone, 5-fluorouracil, folinic acid, and mitomycin C may prolong survival.

A new hepatic artery infusion (HAI) protocol combining mitoxantrone, 5-FU with folinic acid, and mitomycin C (MFFM) achieved a 54% objective response rate in patients with isolated, nonresectable colorectal liver metastases (CRLM). Median survival was 25.7 months from diagnosis and 23.7 months from HAI initiation, with 11% of patients surviving over 40 months. Toxicity was manageable, with grade 3 events in 34.9% and no cases of sclerosing cholangitis or treatment-related deaths. This protocol shows promise as a more effective and safer alternative to traditional HAI with 5-FUDR or systemic chemotherapy, warranting further comparison in Phase III trials.

Celiac artery adjuvant chemotherapy. Results of a prospective trial.

Adjuvant celiac artery infusion (CAI) chemotherapy significantly improved survival in resected pancreatic cancer patients, with a median survival of 21 months compared to 9.3 months in historical controls (p < 0.0003). This well-tolerated treatment involved six cycles of mitoxantrone, folinic acid, 5-FU, and cisplatin via celiac artery catheters. Toxicity was low, with only 8% of cycles causing WHO grade III side effects and no grade IV toxicity. These findings highlight CAI as a promising and effective adjuvant therapy to extend survival in pancreatic cancer patients following tumor resection.

Overexpression of cyclin D1 in human pancreatic carcinoma is associated with poor prognosis.

Cyclin D1 is overexpressed in pancreatic adenocarcinoma, with gene amplification observed in 25% of cases and mRNA overexpression in 82%. Immunohistochemical analysis revealed nuclear overexpression in 68.4% of tumor cells, significantly correlating with worse outcomes. Patients with cyclin D1 overexpression had a median survival of 10.5 months compared to 18.1 months for those without (P < 0.01). These findings suggest cyclin D1 as a potential prognostic marker and therapeutic target in pancreatic cancer.

Levels of serum neopterin are increased in pancreatic cancer patients and correlate with the prognosis.

This study highlights serum neopterin as a potential prognostic marker in pancreatic cancer (PC). Elevated neopterin levels (>2 pmol/ml), indicative of cellular immune activation, were associated with significantly better survival across all stages of PC, particularly in advanced stages (p < 0.001). In resectable cases, elevated neopterin also correlated with increased survival and was an independent prognostic factor. These findings suggest that an active immune response positively influences outcomes in PC and point to the potential benefit of supportive immunotherapy in this patient group.

Pancreatic cancer: who benefits from curative resection?

Surgical resection remains the only curative option for pancreatic cancer, primarily benefiting patients with UICC stage I or II disease. Achieving an R0 resection, requiring extensive removal of surrounding tissues and lymphatic structures, significantly extends median survival compared to standard resection. However, even histologically negative lymph nodes often harbor cancer cells, detected by molecular techniques in 50% of cases. Aggressive surgical approaches may be considered for stage III patients, though long-term survival is rare. Postoperative challenges include severe diarrhea from nerve plexus resection and frequent recurrence in the liver and peritoneum. Adjuvant radiochemotherapy offers modest survival benefits, but overall prognosis remains poor.

Regulation of cell growth and cyclin D1 expression by the constitutively active FRAP-p70s6K pathway in human pancreatic cancer cells.

The FRAP-p70s6K signaling pathway is constitutively active in pancreatic cancer cells (MiaPaCa-2, Panc-1) and tissues, promoting cancer cell proliferation. Inhibition of this pathway with rapamycin dephosphorylated key downstream targets (p70s6K, 4E-BP1), suppressed DNA synthesis, reduced anchorage-dependent and -independent growth, and significantly decreased cyclin D1 expression. These findings suggest that targeting the FRAP-p70s6K pathway with inhibitors like rapamycin could represent a promising therapeutic strategy for pancreatic cancer.

Loss of the Y chromosome is a frequent chromosomal imbalance in pancreatic cancer and allows differentiation to chronic pancreatitis.

Loss of the Y chromosome is a frequent event in male pancreatic cancer, observed in 8/11 pancreatic cancer cell lines and primary tumor cells through interphase FISH analysis. In contrast, the Y chromosome remains intact in benign conditions like chronic pancreatitis. Although no functional role for this loss has been established, it effectively differentiates malignant pancreatic tumors from benign conditions, suggesting potential diagnostic utility in identifying malignancy in male pancreatic patients.

Carcinoma of the head of the pancreas arising from the uncinate process.

Carcinoma of the uncinate process (CUP) of the pancreatic head is rare, accounting for 8% of evaluated pancreatic cancer cases. CUP presents with upper abdominal pain and weight loss, while jaundice is uncommon and not an early symptom. Diagnosis is often delayed, with advanced disease characterized by vascular involvement (48% vs. 19% in ventral pancreatic head carcinoma, VPC) and distant metastasis. Computed tomography (CT) is the most effective diagnostic tool (93% sensitivity), unlike endoscopic retrograde cholangiopancreatography (21% sensitivity). CUP has a lower resection rate (64% vs. 92% in VPC) and significantly poorer median survival (5 vs. 11 months). Elevated CA19-9 levels alongside clinical symptoms should prompt early CT imaging for timely diagnosis.

The clinical value of procalcitonin in the prediction of infected necrosis in acute pancreatitis.

This study highlights serum procalcitonin (PCT) as a valuable, noninvasive biomarker for predicting infection of pancreatic necrosis (IN) in acute pancreatitis (AP). PCT levels were significantly higher in patients with IN compared to those with sterile necrosis (SN), while CRP levels did not distinguish between the groups. A PCT cut-off of ?1.8 ng/ml on two consecutive days predicted IN with 95% sensitivity, 88% specificity, and 90% accuracy, comparable to guided fine-needle aspiration (FNA). Additionally, persistently elevated PCT levels post-surgery indicated ongoing pancreatic sepsis. PCT monitoring provides a reliable alternative for diagnosing IN and assessing postoperative complications.

Increased angiogenin expression in obstructive chronic pancreatitis surrounding pancreatic cancer but not in pure chronic pancreatitis.

This study highlights the distinct role of angiogenin (ANG) in pancreatic cancer compared to chronic pancreatitis. ANG expression is absent in chronic pancreatitis and normal pancreas tissues, with no significant difference in serum ANG levels between chronic pancreatitis patients (352.1 ng/ml) and healthy individuals (357.6 ng/ml). In contrast, pancreatic cancer tissues show elevated ANG mRNA in acinar cells and interstitial fibroblasts, increased protein expression, and higher serum ANG levels. These findings suggest that ANG is specifically involved in the tumor microenvironment of pancreatic cancer rather than in chronic pancreatitis, underscoring its potential as a cancer-specific biomarker or therapeutic target.

Serum and correspondent tissue measurements of epidermal growth factor (EGF) and epidermal growth factor receptor (EGF-R). Clinical relevance in pancreatic cancer and chronic pancreatitis.

This study concludes that routine serum measurements of epidermal growth factor (EGF) and its receptor (EGF-R) are ineffective for screening pancreatic cancer, despite frequent tissue overexpression of these markers in ductal pancreatic cancer. Serum EGF and EGF-R levels were not significantly elevated in pancreatic cancer patients compared to controls and showed no correlation with tumor markers or disease stage. Interestingly, chronic pancreatitis patients exhibited significantly decreased EGF and EGF-R levels, correlating with exocrine insufficiency. While not suitable for routine screening, serum EGF and EGF-R measurements may aid in distinguishing pancreatic cancer from chronic pancreatitis in diagnostically challenging cases.

Overexpression of caspase-1 in pancreatic disorders: implications for a function besides apoptosis.

This study highlights distinct overexpression patterns of caspase-1 in pancreatic cancer and chronic pancreatitis, suggesting roles beyond apoptosis. In pancreatic cancer, 71% of samples showed cytoplasmic overexpression of caspase-1 in tumor cells, correlating significantly with known prognostic markers such as cyclin D1, EGF, and EGF-R. Chronic pancreatitis exhibited high caspase-1 expression in atrophic acinar cells (nuclear), hyperplastic ducts, and dedifferentiating acinar cells (cytoplasmic). Western blot analysis confirmed the presence of the 45 kDa precursor in 80% of cancer and 86% of pancreatitis samples, with the active 30 kDa form detected in 60% and 14%, respectively. These findings suggest caspase-1 may play a novel role in tumor proliferation alongside its apoptotic functions.

Nuclear accumulation of p53 correlates significantly with clinical features and inversely with the expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) in pancreatic cancer.

This study demonstrates a significant correlation between p53 overexpression and p21(WAF1/CIP1) expression in pancreatic adenocarcinoma, observed in both tissue samples and cell lines (P < 0.005). p53 overexpression also correlated with tumor stage, size, grading, and lymph node metastases, while p21(WAF1/CIP1) expression was linked only to tumor size. These findings suggest that p21(WAF1/CIP1) expression is primarily dependent on active p53, but the presence of p53-independent pathways may modulate p21(WAF1/CIP1) induction, potentially affecting its association with clinicopathological features. This dual regulation highlights the complexity of p21(WAF1/CIP1) expression in pancreatic cancer.

Serum amyloid A versus C-reactive protein in acute pancreatitis: clinical value of an alternative acute-phase reactant.

This study evaluates serum amyloid A (SAA) as an alternative to C-reactive protein (CRP) for assessing acute pancreatitis severity. While both SAA and CRP peaked within 4 days of symptom onset, SAA rose faster and exhibited a wider dynamic range (676 mg/L vs. 313 mg/L median in pancreatitis patients). SAA was effective in distinguishing necrotizing pancreatitis from interstitial edematous pancreatitis, but CRP offered earlier differentiation and superior overall accuracy. SAA levels were nonspecifically elevated in other abdominal disorders but remained low in healthy individuals. Despite SAA's rapid response and applicability, CRP remains the preferred marker for early, accurate stratification of complicated pancreatitis cases.

Altered expression of extracellular matrix molecules and their receptors in chronic pancreatitis and pancreatic adenocarcinoma in comparison with normal pancreas.

This study highlights distinct integrin and extracellular matrix (ECM) expression patterns in chronic pancreatitis (CP) and pancreatic adenocarcinoma (PC) compared to normal pancreas (NP). In CP, integrin expression largely mirrored NP, except for alpha V, which was occasionally expressed in acinar cells. In PC, alpha 2, alpha 3, and alpha 6 were diffusely overexpressed, while alpha 5 was absent. The basement membrane (BM) exhibited continuous staining in CP but was disrupted or absent in PC, correlating with type IV collagen, laminin, and vitronectin loss. Fibronectin was diffusely expressed in the stroma of both CP and PC. Intracellular vitronectin was noted in some acinar, ductal, and carcinoma cells. These findings suggest that altered integrin and ECM expression patterns contribute to the inflammatory and malignant processes in the pancreas.

Cystic tumours of the pancreas: diagnostic accuracy, pathologic observations and surgical consequences.

Cystic pancreatic neoplasms, though rare (1% of primary pancreatic lesions), are increasingly diagnosed. This study of 51 patients treated for serous and mucinous cystadenomas and cystadenocarcinomas emphasizes the benefits of surgical resection. While computed tomography and ERCP were effective diagnostics, some serous tumors showed normal ERCP findings. Surgical resection was performed in all but one case, with no perioperative mortality. All patients with resected benign tumors survived, while mucinous cystadenocarcinomas had a 36% late mortality after 6 years. The findings support surgical resection for all cystic pancreatic tumors due to the potential for symptoms and malignant transformation.

Regional chemotherapy directed by individual chemosensitivity testing in vitro: a prospective decision-aiding trial.

This study demonstrates that the human tumor colony-forming assay (HTCA) effectively guides drug selection for hepatic artery infusion in liver tumors, improving treatment outcomes. HTCA sensitivity correlated with stable or responsive disease (CR + PR + NC) in 93% of cases and with clinical response (CR + PR) in 55%. Patients with in vitro-sensitive tumors had significantly lower intrahepatic progression rates (7% vs. 57%, P < 0.05) compared to in vitro-resistant cases. Overall, 83% achieved CR + PR + NC, with a 50% clinical response rate. These findings suggest that HTCA can optimize individualized regional chemotherapy, enhancing its efficacy.

Distributional and functional alterations of immunocompetent peripheral blood lymphocytes in patients with chronic pancreatitis.

This study reveals that chronic pancreatitis significantly alters immune function, increasing CD3(+) T cells, including CD4(+) and CD8(+) subsets, while reducing the blastogenic response to immune stimulation. Natural killer cells and B lymphocytes remained unaffected. Remarkably, one year after pancreatic head resection, immune cell distribution and function returned to normal. These findings suggest that chronic inflammation in pancreatitis impairs immune competence and that surgical removal of the inflammatory focus can restore immune function, highlighting the benefits of surgery in select patients.

Cyclooxygenase-2 is overexpressed in chronic pancreatitis.

This study highlights the role of cyclooxygenase-2 (COX-2) in chronic pancreatitis, showing its overexpression in atrophic acinar cells (80%), hyperplastic ductal cells (86%), and islet cells (97%), but not in normal pancreatic tissues. COX-2 overexpression significantly correlated with the frequency of acute pancreatitis attacks, with higher levels in patients experiencing more than five episodes (p = 0.004). No correlation was observed with other clinical features like disease duration, diabetes, alcohol use, or smoking. These findings suggest COX-2 as a key mediator of inflammation in chronic pancreatitis and its potential role in disease progression.

Inhibition of caspase-1 induces cell death in pancreatic carcinoma cells and potentially modulates expression levels of bcl-2 family proteins.

This study reveals that inhibiting caspase-1 in pancreatic carcinoma cells induces a non-apoptotic, necrotic-like cell death in various cell lines, including AsPC-1, BxPC-3, MiaPaCa-2, and Panc-1. Treatment with a cell-permeable caspase-1 inhibitor increased the expression of pro- and anti-apoptotic proteins bcl-2 and bax, while bcl-x(L) levels remained unchanged. These findings suggest that caspase-1 may play a role in anti-apoptotic mechanisms in pancreatic carcinoma, highlighting its complex contribution to tumor cell survival and its potential as a therapeutic target.

Comparative analysis of extracellular matrix proteins in chronic pancreatitis: differences between pancreatic head and tail.

This study shows that in chronic pancreatitis (cP) with an inflammatory mass, fibrosis is more pronounced in the pancreatic head compared to the tail. Fibrosis levels were 64% versus 47% in alcohol-induced cP and 40% versus 32% in idiopathic cP. Collagen type IV and laminin were more strongly expressed in the pancreatic head, particularly in ductal epithelia, while other extracellular matrix proteins (ECMPs) showed no significant difference between regions. These findings suggest that the pancreatic head acts as the 'pacemaker' of cP, with collagen type IV and laminin potentially driving localized fibrotic and inflammatory processes.

Increased oxidative stress in the RAW 264.7 macrophage cell line is partially mediated via the S-nitrosothiol-induced inhibition of glutathione reductase.

This study demonstrates that nitric oxide (NO), whether produced endogenously or applied exogenously, can inhibit glutathione reductase (GR) in macrophage-like RAW 264.7 cells via S-nitrosothiol formation. This inhibition decreases cellular glutathione (GSH) levels, leading to increased oxidative stress marked by elevated superoxide production. The specificity of this effect was confirmed using NO-synthase inhibitors and hemoglobin variants. These findings identify GR as a critical target of S-nitrosothiols, linking NO to oxidative stress regulation in macrophages.

Low serum levels of CD44, CD44v6, and neopterin indicate immune dysfunction in chronic pancreatitis.

This study reveals that chronic pancreatitis is associated with reduced immune activity, as evidenced by significantly lower serum levels of CD44, CD44v6, and neopterin, and a non-significant reduction in IL-2 receptor levels compared to controls. These findings are independent of immunosuppressive factors such as alcohol use, smoking, or diabetes, suggesting that the chronic inflammatory process directly contributes to impaired T-lymphocyte and macrophage activation. The results indicate that surgical resection may help restore immune function in these patients.

The splice-pattern of CD44 is altered in chronic pancreatitis exhibiting dysplastic changes.

This study highlights the potential role of CD44 splice variants in the progression from chronic pancreatitis to pancreatic cancer. CD44s was widely expressed in all pancreatic cells, while CD44v6 expression was limited to ductal cells and overexpressed in chronic pancreatitis compared to normal pancreas. An altered CD44 splice pattern, resembling that in pancreatic cancer, was observed in 12.5% of chronic pancreatitis cases. Notably, this pattern was also present in two patients who developed pancreatic cancer after chronic pancreatitis. These findings suggest that CD44 variants may represent early dysplastic changes and could play a role in pancreatic tumorigenesis.

Basal expression and cytokine induction of intercellular adhesion molecule-1 in human pancreatic cancer cell lines.

This study reveals that intercellular adhesion molecule-1 (ICAM-1) is variably expressed in pancreatic cancer cell lines and can be significantly induced by tumor necrosis factor-alpha (TNF-?) and interferon-gamma (IFN-?). Panc-1 showed the highest baseline ICAM-1 expression, while PaCa-2 and AsPC-1 exhibited low baseline levels. Upon stimulation, AsPC-1 displayed a remarkable 32-fold increase, with moderate induction in other lines like PMH-3 and PaCa-2. These findings suggest that ICAM-1 overexpression, particularly under inflammatory stimuli, may play a role in pancreatic cancer progression and immune interactions.

The role of immunocytes in acute and chronic pancreatitis: when friends turn into enemies.

NOT FOUND

Increased etheno-DNA adducts in affected tissues of patients suffering from Crohn's disease, ulcerative colitis, and chronic pancreatitis.

This study reveals that chronic inflammation, as seen in conditions like chronic pancreatitis and inflammatory bowel disease, leads to elevated levels of promutagenic etheno-DNA adducts, particularly epsilondC and epsilondA. These adducts, caused by oxidative stress and lipid peroxidation, were significantly higher in inflamed tissues compared to non-inflamed ones, with epsilondC levels especially elevated. This suggests that chronic inflammation generates DNA damage that may drive mutations in genes like K-ras and p53, contributing to cancer development in these high-risk conditions.

CD44v6 cell surface expression is a common feature of macrophages and macrophage-like cells - implication for a natural macrophage extravasation mechanism mimicked by tumor cells.

This study explored the origins of soluble CD44standard (sCD44s) and CD44v6, found in both pancreatic cancer patients and healthy individuals. Experiments demonstrated that monocytes and macrophages express and secrete these molecules upon stimulation, with macrophage-differentiated cells showing the highest levels. These findings suggest that sCD44s and sCD44v6 are general adhesion molecules associated with macrophages and macrophage-like cells, offering insights into their broader physiological and pathological roles.

Dendritic Cell Therapy in the palliative Treatment of Pancreatic Cancer Patients. Experience in 200 Patients

Pancreatic cancer's median survival remains poor despite advancements. A retrospective analysis of 200 patients treated with LANEX-DC® dendritic cell therapy in addition to palliative care showed promising results. Median survival was 9.1 months, with significant improvement in patients starting therapy early (11.8 vs. 7.9 months, p=0.009) and those receiving multiple cycles (17.5 vs. 7.4 months, p=0.001). Younger patients (<65 years) also had better outcomes (p=0.004). The therapy was well-tolerated, suggesting a viable approach to prolong survival in this challenging disease.

Duodenum-Preserving Subtotal and Total Pancreatic Head Resections for Inflammatory and Cystic Neoplastic Lesions of the Pancreas

Limited surgical procedures such as subtotal or total pancreatic head resection offer effective alternatives to the Whipple procedure for inflammatory and benign neoplastic lesions of the pancreatic head. These techniques preserve the stomach, duodenum, and bile ducts while achieving complete tumor removal and preventing carcinogenesis. They are associated with lower morbidity, faster recovery, and better quality of life compared to Whipple resection, making them preferred options for suitable cases.

Duodenum-preserving total pancreatic head resection for cystic neoplastic lesions in the head of the pancreas

Duodenum-preserving pancreatic head resection (DPPHRt) with segmental duodenal resection is a safe and effective surgical option for managing cystic neoplastic pancreatic lesions, including IPMN, MCN, and cystic EN. Among 15 patients treated, complications such as delayed gastric emptying and acute pancreatitis were observed, but hospital mortality was 0%. This procedure not only ensures oncological completeness but also acts as a preventive strategy against pancreatic cancer, demonstrating its long-term benefit.

Chronic Pancreatitis: Inflammatory Mass in the Head of the Pancreas — Pacemaker of Chronic Pancreatitis

Chronic pancreatitis, primarily linked to chronic alcohol abuse, affects the exocrine pancreas and involves complex pathological processes. The leading theory attributes the disease to protein plaque formation from alcohol consumption, obstructing pancreatic ducts and inducing chronic inflammation. Another hypothesis suggests it stems from repeated acute pancreatitis episodes, causing necrosis, fibrosis, and ductal obstruction. Smoking is also a significant factor, contributing to calcified chronic pancreatitis. Despite these insights, the exact causative and pathological mechanisms remain unresolved.

Effect of early and late antibiotic treatment in experimental acute pancreatitis in rats

In a rat model of necrotizing pancreatitis, early and late antibiotic treatments with ciprofloxacin/metronidazole and imipenem effectively reduced pancreatic infection rates. However, extrapancreatic infections were significantly reduced only with early antibiotic therapy. Ciprofloxacin/metronidazole also reduced gut bacterial counts, unlike imipenem. These findings highlight the importance of early intervention in preventing complications, warranting further clinical investigation to optimize antibiotic timing and effectiveness in human pancreatitis.

Down-Regulation of BRCA1 in Chronic Pancreatitis and Sporadic Pancreatic Adenocarcinoma

Altered BRCA1 expression, but not BRCA2, plays a role in chronic pancreatitis and sporadic pancreatic adenocarcinoma. BRCA1 expression was significantly reduced in chronic alcoholic pancreatitis and pancreatic cancer. Patients with regular BRCA1 expression demonstrated better 1-year survival compared to those with reduced or absent expression. These findings suggest BRCA1 contributes to pancreatic cancer progression and may serve as a prognostic marker, highlighting its importance in noninherited pancreatic carcinogenesis.

Treatment of Pancreatic Cancer: Challenge of the Facts

Pancreatic adenocarcinoma remains the most lethal gastrointestinal cancer, with long-term survival rates below 3% despite advancements in surgical techniques and reduced perioperative complications. Even after R(0) resection, most patients experience recurrence due to undetected or unremoved cancer cells, such as in lymph nodes or nerve plexuses. Adjuvant chemotherapy or radiochemotherapy can extend median survival by 6-10 months but fails to yield substantial long-term benefits. Improved trial metrics, such as actual survival rates, progression-free survival, and quality of life assessments, are critical for evaluating treatment efficacy. While surgery remains the only curative option, it is viable for only 10-15% of patients, emphasizing the need for better therapeutic approaches and potential neoadjuvant protocols.

The Beger procedure

Adjuvant Regional Infusion Therapy

Biglycan is overexpressed in pancreatic cancer and induces G1-arrest in pancreatic cancer cell lines

Biglycan (PG-I), a component of the extracellular matrix, is overexpressed in pancreatic cancer and may inhibit tumor growth. PG-I levels were higher in cancer samples compared to normal or chronic pancreatitis tissues. Transforming growth factor-beta (TGF-?) stimulated PG-I expression in fibroblasts and cancer cells. PG-I induced G1 cell cycle arrest in pancreatic cancer cells by increasing p27 and reducing cyclin A and PCNA, partially suppressing Ras and ERK signaling. PG-I may represent a natural defense mechanism to slow tumor progression.

Anti-ICAM-1 Antibody Modulates Late Onset of Acinar Cell Apoptosis and Early Necrosis in Taurocholate-Induced Experimental Acute Pancreatitis

In severe acute pancreatitis (SAP), acinar cell death initially occurs via necrosis, followed by apoptosis in the later stages. In a rat model, necrosis began immediately after pancreatitis induction, with widespread parenchymal damage and neutrophil infiltration by 6 hours, alongside TNF-? mRNA upregulation. Apoptosis was rare early on but increased significantly by 24 hours. Anti-ICAM-1 pretreatment reduced neutrophil infiltration, TNF-? expression, and necrosis, while suppressing apoptosis. Neutrophils, through TNF-?, appear to contribute to both necrosis and apoptosis in SAP.

Overexpression of Caspase-1 (Interleukin-1? Converting Enzyme) in Chronic Pancreatitis and Its Participation in Apoptosis and Proliferation

Caspase-1, formerly designated interleukin-1beta converting enzyme, was the first described member of a group of cysteine proteases called caspases. It is suggested that caspases play an important role in apoptosis, but recent observations could show that caspase-1 might also be involved in cellular proliferation. We investigated the expression of caspase-1 in 38 chronic pancreatitis tissues, six pancreatitis tissues from patients with pancreatic carcinoma and nine normal pancreatic tissues by immunohistochemistry. Western blot analysis was used to confirm the immunohistochemical findings. We found a clear expression of caspase-1 in chronic pancreatitis, but not in normal pancreatic tissues. Interestingly, we found expression of caspase-1 in three distinct morphologic compartments: (i) in atrophic acinar cells (31 of 35; 89%), (ii) proliferating cells of ductal origin (33 of 38; 87%), and (iii) in acinar cells redifferentiating to form tubular structures (26 of 31; 83%). These immunohistochemical findings were confirmed by Western blot analysis, which showed an expression of caspase-1 in 85% of the tissues. No correlation was found between any of the examined clinicopathologic features and the caspase-1 expression in chronic pancreatitis. In conclusion, the expression of caspase-1 is a frequent event in chronic pancreatitis and its distribution pattern may reflect two functions of this protease: on one hand its participation in the apoptotic pathway in atrophic acinar cells and, on the other hand, its role in proliferation and differentiation in proliferating duct cells.

Loss of the Y chromosome is a frequent chromosomal imbalance in pancreatic cancer and allows differentiation to chronic pancreatitis

In a study for the identification of genomic alterations in pancreatic cancer, representational difference analysis was used and led to the isolation of 2 distinct fragments, deleted on the Y chromosome in the xenografted tumor DNA of a male patient with an adenocarcinoma of the pancreas. Loss of Y chromosomal material was further studied in 11 pancreatic cancer cell lines of male origin, using PCR amplification of 5 sequence tagged sites (STSs) distributed along the Y chromosome; 8/11 cell lines exhibited a complete loss of the Y chromosome and 3 had deletions. To examine the status of the Y chromosome in situ, interphase FISH analysis was performed on paraffin sections from pancreatic carcinoma (n=7) and chronic pancreatitis (n=7) tissues, and the loss of Y-chromosomal STS-markers was studied in 6 xenograft tumors obtained from male pancreatic cancer patients. This analysis revealed that a loss of the Y chromosome occurs in vivo in primary pancreatic tumor cells, whereas the Y chromosome was intact in chronic pancreatitis. Our data suggest that loss of Y is a frequent event occurring in male pancreatic tumors. Although there is no evidence for a functional implication of Y chromosome loss, it effectively differentiates between a malignant and a benign condition as e.g. chronic pancreatitis. Thus, this genetic alteration may be of diagnostic use. © 2001 Wiley-Liss, Inc.

Inflammatory mediators in human acute pancreatitis: clinical and pathophysiological implications

The time course and relationship between circulating and local cytokine concentrations, pancreatic inflammation, and organ dysfunction in acute pancreatitis are largely unknown. In a prospective clinical study, we measured the proinflammatory cytokines interleukin (IL)-1 beta, IL-6 and IL-8, the anti-inflammatory cytokine IL-10, interleukin 1 beta receptor antagonist (IL-1RA), and the soluble IL-2 receptor (sIL-2R), and correlated our findings with organ and systemic complications in acute pancreatitis. In 51 patients with acute pancreatitis admitted within 72 hours after the onset of symptoms, these parameters were measured daily for seven days. In addition, 33 aspirates from ascites and the lesser sac were measured. Sixteen patients had mild acute pancreatitis (AP) and 35 severe AP (Atlanta classification); 18 patients developed systemic complications requiring treatment. All mediators were increased in AP. sIL-2R, IL-10, and IL-6 were significantly elevated in patients with distant organ failure. An imbalance in IL-1 beta/IL-1RA was found in severe AP and pulmonary failure. Peak serum sIL-2R predicted lethal outcome and IL-1RA was an early marker of severity. IL-6 was the best prognostic parameter for pulmonary failure. Our results suggest that local mediator release, with a probable IL-1 beta-IL-1RA imbalance in severe cases, is followed by the systemic appearance of pro- and anti-inflammatory mediators. The pattern of local and systemic mediators in complicated AP suggests a role for systemic lymphocyte activation (triggered by local release of mediators) in distant organ complications in severe AP.

Glutathione depletion causes cell growth inhibition and enhanced apoptosis in pancreatic cancer cells

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; P < 0.004). 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 %; P < 0.001), 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.

Multiple organ failure in human acute pancreatitis is associated with increased local and systemic inflammatory mediators

A possible mechanism for metastasation and invasion of cancer cells by mimicking macrophage invasiveness

The Clinical Value of Procalcitonin in the Prediction of Infected Necrois in Acute Pancreatitis

Objective: 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.¶Design: Clinical study.¶Setting: A collaborative study between the Departments of General Surgery and Clincal Chemistry/Pathobiochemistry of the University of Ulm, Germany.¶Patients: 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.¶Measurements and Results: 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 at S 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.

Tumor of the ampulla of Vater: experience with local or radical resection in 171 consecutively treated patients

This study was designed to evaluate prospectively oncological factors determining survival after resection of tumors of the papilla, comparing local and radical oncological resection. We hypothesized that, in malignant lesions of the ampulla, the T and N stages are major determinants of the patient's long-term outcome. The frequency of malignant lesions in adenomas of the papilla is about 26%. Villous adenoma of the ampulla is considered a premalignant lesion. Local excision has been recommended for benign adenoma and pancreatoduodenectomy for malignant lesions. From January 1, 1982, through June 30, 1997, 171 patients with tumors of the ampulla of Vater were surgically treated. Demographics, intraoperative factors, tumor pathological findings, and postoperative short- and long-term follow-up data were documented prospectively. Of the patients, 45 had adenoma of the papilla and 126 had malignant lesions of the ampulla. Local resection was performed in 40 of the 45 patients with adenoma. In 98 of the 126 patients with malignant lesions, a radical Kausch-Whipple resection or pylorus-preserving pancreatoduodenectomy was used. Of the patients with benign adenoma, 40 had local resection and 5 had pylorus-preserving pancreatic head resection, with a hospital mortality of 0%. Thirty of 35 patients had villous adenoma, 9 (30%) of the 30 with severe dysplasia. Of the 126 patients with malignant lesions, 98 had partial pancreatoduodenectomy and 10 had ampullectomy, with an overall hospital mortality of 3.1% for patients who underwent resection. Seventy-eight of the 98 patients had an R0 resection. The 5-year survival probability for all patients who underwent resection was 84% for cancer stage I, 70% for stage II, and 27% for stage III. In 8 patients with villous adenoma and carcinoma in situ and in 10 patients with cancer in the adenoma, ampullectomy with local lymph node dissection was performed. In 4 of the patients who had villous adenoma and a carcinoma in stage pT1 N0, an R0 resection was performed, resulting in cure of cancer. On the basis of a multivariate regression analysis, the prognosis after oncological resection of cancer of the ampulla is determined by the absence of lymph node metastasis (P<.05), the absence of infiltration into the pancreatic head tissue (P<.05), and the application of an R0 resection. In patients with villous adenoma of the ampulla, ampullectomy was an adequate surgical treatment. In patients with a low-risk cancer in stages pTis and pT1 N0 M0, G1 or G2, a local resection with ampullectomy including local lymph node dissection is justified. An oncological resection of cancer of the ampulla by means of a pylorus-preserving partial pancreatoduodenectomy or the Kausch-Whipple resection is the surgical procedure of choice; the 3- and 5-year survival rates were 72% and 52%, respectively, in patients with R0 resections.

Overexpression of endothelium-derived nitric oxide synthase isoform 3 in the vasculature of human pancreatic tumor biopsies

Cellular nitric oxide (NO) synthesis determines whether NO has cytoprotective or cytotoxic effects at anatomic sites; thus it is important to identify potential NO synthase isoforms in tumor tissue and tumor cell lines which might be involved in tumor development or destruction. Incubation of human pancreatic adenocarcinoma cell lines (AsPc-1, BxPc-3, CaPan-2) with cytokines resulted in increased NO formation, indicating the existence of the NOS2 isoform. This was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) and western blot analysis. Furthermore, we identified the presence of the endothelium-derived NOS isoform 3 by RT-PCR analysis and immunohistochemistry in normal and pancreatic tumor biopsies. NOS3 was markedly overexpressed in the vasculature of the tumor tissue. RT-PCR analysis of tumor biopsies identified NOS isoform 2 mRNA in 60% of cases, but western blot analysis or immunohistochemistry scored negative for this isoform. It is noteworthy that the NOS enzyme activity in pancreatic tumor cell lines and tumor biopsies was inhibited by EGTA by approximately 30% and 65%, respectively. Our results suggest that increased endothelium-derived NOS isoform 3 expression in pancreatic adenocarcinomas regulates blood flow and is therefore involved in the vascularization and neovascularization of human pancreatic tumors.

Interleukin 1?-converting Enzyme (Caspase-1) Is Overexpressed in Adenocarcinoma of the Pancreas

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 (P < 0.0005, P < 0.05, and P < 0.002, 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.

Cystic tumours of the pancreas: Diagnostic accuracy, pathologic observations and surgical consequences

Cystic neoplasms of the pancreas account for only 1% of primary pancreatic lesions. However, patients with these tumors are diagnosed more frequently. Up to now, nonsurgical management is still the established form of treatment of benign cystic tumours of the pancreas. Between 1987 and 1996 we treated 51 patients with serous and mucinous cystadenoma and their malignant counterparts, serous and mucinous cystadenocarcinoma. Eighty-five percent of the patients presented symptoms. Computed tomography and endoscopic cholangiopancreatography (ERCP) were the most sensitive diagnostic techniques; however, in three patients with serous cystadenoma and in one patient with serous cystadenocarcinoma, ERCP findings were completely normal. The tumour was resected in all but one patient. There was no perioperative mortality. After dismissal from the hospital, all patients in whom benign tumours had been resected are still alive; however, the late mortality of mucinous cystadenocarcinoma was 36% after a median follow-up of 6 years. Surgical resection is recommended in all cystic tumours, even in serous cystic tumours, because symptoms may develop and malignant transformation to serous cystadenocarcinoma is possible.

Prognostic significance of molecular alterations in human pancreatic carcinoma – an immunohistological study

Background: During the last decade, many molecular alterations have been described for pancreatic carcinomas. However, the clinical and prognostic value of these alterations has been discussed and is controversial. Methods: An immunohistochemical study was performed in 82 cases of adenocarcinoma of the pancreas. Using specific antibodies, expression of EGF, EGF-receptor, cERB-B2, p53, p21CIP1, cyclin-D1, BCL-2, CD95 and KI67 was evaluated. Results: Overexpression of the different molecules was found in 44-69% of the pancreatic carcinomas. With regard to clinico-pathological features, p53 positivity was more frequently found in advanced and undifferentiated tumours (P<0.05), EGF overexpression was significantly more frequent in advanced tumours (P<0.05) and CD95 overexpression was observed to a greater extent in undifferentiated tumours (P<0.05). Besides cyclin-D1, none of the molecules tested was of prognostic significance. Patients whose tumours expressed cyclin-DI lived significantly shorter than patients with cyclin-D1-negative tumours. However, in subgroup analyses of patients with the same tumour stage or tumour grade, even cyclin-D1. expression had no prognostic significance. Conclusion: These results demonstrate that the prognostic significance of the molecules tested here is low. Nevertheless, with regard to tumorigenesis and tumour biology of pancreatic carcinoma, determination of molecular alterations could provide important information about pancreatic cancer.

K-Ras Mutations at Codon 12 Are Rare Events in Chronic Pancreatitis

The activation of the K-ras gene at codon 12 is thought to be an early genetic event in the multistep pathogenesis of pancreatic cancer. Since the risk of pancreatic cancer is significantly elevated in subjects with chronic pancreatitis, the aim of the present study was to determine the frequency of K-ras mutations in chronic pancreatitis. Pancreatic DNA from intraoperatively resected tissues of 60 patients with chronic pancreatitis and 11 patients with histologically confirmed pancreatic carcinoma was evaluated by PCR amplification and restriction fragment length polymorphism analysis. In none of the 60 samples of chronic pancreatitis could K-ras mutations be identified using two independent PCR assays. In 5 of 11 patients with pancreatic carcinoma, K-ras mutations in codon 12 were detected. These data indicate that K-ras mutations are rare events in chronic pancreatitis. Alternatively, it is possible that the time span between the occurrence of K-ras mutations and malignant transformation is rather short.

The potential role of procalcitonin and interleukin 8 in the prediction of infected necrosis in acute pancreatitis

Infection of pancreatic necrosis has a major impact on clinical course, management, and outcome in acute pancreatitis. Currently, guided fine needle aspiration is the only means for an early and accurate diagnosis of infected necrosis. Procalcitonin (PCT), a 116 amino acid propeptide of calcitonin, and interleukin 8 (IL-8), a strong neutrophil activating cytokine, are markers of severe inflammation and sepsis. To analyse the clinical value of PCT and IL-8 as biochemical parameters for predicting infected necrosis in acute pancreatitis. Fifty patients with acute pancreatitis entered this prospective study and were stratified into three groups according to morphological and bacteriological findings: 18 patients with oedematous pancreatitis (group I), 14 patients with sterile necrosis (group II), and 18 patients who developed infected necrosis a median of 13.5 days after the onset of symptoms (group III). After admission serum samples were drawn daily for two weeks. Concentrations of PCT and IL-8 were measured by chemoluminescent immunoassays (upper reference range 0.5 ng/ml for PCT and 70 pg/ml for IL-8). The routine parameter C-reactive protein was determined by laser nephelometry (upper reference range 10 mg/l). Median concentrations of PCT and IL-8 were significantly higher in patients with infected necrosis than in those with sterile necrosis during the observation period, whereas there was no difference in C-reactive protein. In oedematous pancreatitis overall median concentrations of all three parameters were low. By receiver operating characteristics best cut off levels for predicting infected necrosis or persisting pancreatic sepsis were 1.8 ng/ml for PCT and 112 pg/ml for IL-8. If these cut off levels were reached on at least two days, sensitivity, specificity, and accuracy for the prediction of infected necrosis were 94%, 91%, and 92% for PCT and 72%, 75%, and 74% for IL-8, respectively. After surgical treatment of infected necrosis median PCT and IL-8 values continued to be significantly higher in patients with persisting pancreatic sepsis (n = 11) compared with those having an uneventful postoperative course (n = 7). For the preoperative differentiation between infected necrosis and sterile necrosis guided fine needle aspiration was performed in 24 patients with necrotising pancreatitis and reached a diagnostic accuracy of 84% compared with 87% for PCT, and 68% for IL-8. There was no correlation between the aetiology of acute pancreatitis or the extent of necrosis and PCT or IL-8. PCT and IL-8 are found in high concentrations in infected necrosis and associated systemic complications in patients with acute pancreatitis. The course of PCT shows the closest correlation with the presence of infected necrosis. Monitoring of serum PCT is a potential new marker for the non-invasive and accurate prediction of infected necrosis as well as for the selection of patients with persisting septic complications after surgical debridement.

Low serum levels of soluble CD44 variant 6 are significantly associated with poor prognosis in patients with pancreatic carcinoma

Variant CD44 splice products, especially CD44 variant 6 (CD44v6), are expressed on activated lymphocytes and tumor cells. The soluble forms of CD44 standard (CD44s) and CD44v6 are present in the serum of normal individuals. The aim of the current study was to evaluate the concentrations and the prognostic potential of soluble CD44s and CD44v6 in patients with pancreatic carcinoma. The serum CD44s and CD44v6 levels were determined quantitatively by enzyme-linked immunosorbent assay. The molecular mass of CD44v6 isoforms was determined by immunoprecipitation and Western blot analysis. CD44 mRNAs were analyzed by reverse transcriptase polymerase chain reaction followed by exon specific analysis. Both serum CD44s and serum CD44v6 were significantly reduced in patients with pancreatic carcinoma (n = 93, P < 0.001 and P < 0.00005). The median survival in the group with CD44v6 serum concentrations below 100 ng/mL was significantly decreased compared with that in the group with serum concentrations higher than 100 ng/mL (6.7 vs. 15.1 months, P < 0.0005). The isoforms containing soluble CD44v6 (sCD44v6) that were detected in the sera of pancreatic carcinoma patients showed molecular masses comparable to the sCD44v6 isoforms detected in the supernatant of lymphocytes activated by phorbol myestral acetate, whereas the sCD44v6 isoforms detected in the supernatant of pancreatic carcinoma cell lines exhibited higher molecular masses. These results suggest that serum CD44v6 is significantly reduced in pancreatic carcinoma patients and could serve as a good prognostic marker for patients with this disease.

Palliative and adjuvant regional chemotherapy in pancreatic cancer

To improve the dismal prognosis of patients (pts) with pancreatic cancer we treated 32 patients with non-resectable (UICC III, 17 pts; UICC IV, 15 pts--group 1) and 20 patients with resected (UICC I, 1 pt; UICC II, 3 pts; UICC III, 16 pts--group 2) pancreatic cancer with palliative (group I) and adjuvant post-operative (group II) coeliac axis intra-arterial cyclic infusions (CAI). CAI consisted of mitoxantrone 10 mg/m2 on day 1, folinic acid 170 mg/m2 and 5-FU 600 mg/m2 during days 2-4, and cis-platinum 60 mg/m2 on day 5 for up to 11 (group I) or six (group II) cycles. In a total of 211 cycles toxicities at the level of WHO III occurred in 0-6% and of WHO IV in 0%. The median survival times, compared with institutional historical controls (treated vs controls), were 12 vs 4.8 months in UICC III (P < 0.006) and 4 vs 2.9 months in UICC IV (P < 0.05) group I pts, and 21 vs 9.3 months in group II (P < 0.0003). Hepatic disease progression appeared to be suppressed with CAI, which also appears to be effective for palliative and adjuvant treatment in non-resectable and resected pancreatic cancer.

Overexpression of glucose transporter 1 and increased FDG uptake in pancreatic carcinoma

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 (p < 0.01), 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) (p < 0.05) 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.

Exogenous, but not endogenous, nitric oxide increases proliferation rates in senescent human fibroblasts

We investigated the effects of endogenously produced and exogenously applied nitric oxide (NO) on cell proliferation rates and cell cycle regulation in senescent human fibroblasts (WI38). Induction of inducible nitric oxide synthase by tumor necrosis factor-alpha, interferon-gamma and interleukin-1beta inhibited cell proliferation and led to a G1 arrest. These effects were partially reversible by N(G)-monomethyl-arginine (NMA). Addition of the NO donors sodium nitroprusside (SNP) or S-nitroso-N-acetylpenicillamine (SNAP) increased cell proliferation rates as well as the S/G2 fraction. This points to a functional role of NO in cell cycle regulation and cell proliferation in human fibroblasts which depends on the mode of NO generation as well as the culture conditions used.

Overexpression of Intercellular Adhesion Molecule-1 (ICAM-1) in Pancreatic Adenocarcinoma in Comparison with Normal Pancreas

To elucidate the role of intercellular adhesion molecules (ICAMs), which has not been well understood in pancreas, we investigated the localization and expression of ICAM-1 by immunohistochemistry and in situ hybridization (ISH) in pancreatic adenocarcinoma and in normal pancreas. The localizations of ICAM-2 and ICAM-3 were also investigated by immunohistochemistry. In normal pancreas, acinar cells, duct epithelial cells, and Langerhans islet cells failed to stain with anti-ICAM-1, anti-ICAM-2, and anti-ICAM-3 antibodies. These cells showed no expression of ICAM-1 mRNA. On the other hand, various percentages of carcinoma cells were stained with anti-ICAM-1 antibody, while no carcinoma cells were stained with anti-ICAM-2 and anti-ICAM-3 antibodies. ICAM-1 mRNA expression was also observed in carcinoma cells, and ICAM-1 mRNA expression was associated with localization of the ICAM-1 protein. These results suggest that ICAM-1 expression is up-regulated in pancreatic adenocarcinoma cells and that ICAM-1 is involved in malignant processes in pancreas.

Regional Celiac Artery Infusion as Adjuvant Treatment after Pancreatic Cancer Resection

The dismal course of pancreatic adenocarcinoma patients after resection is determined by the biology of the disease preventing R-0 resections. In the spontaneous course after resection, patients frequently develop either local recurrences, liver metastases and/or peritoneal metastases. Postoperative radiochemotherapy may extend survival and reduce local recurrences without influence on hepatic progression. We performed adjuvant celiac artery infusion in pancreatic cancer, to find out whether this treatment prolongs survival and changes the biology of the disease after resection, especially by reducing liver metastasis. 20 patients received cyclic celiac artery infusions (CAI) after resection of their pancreatic cancer (18 ductal, 2 cystadenocarcinoma). The treatment consisted of 6 cycles intraarterial infusion using Seldinger's technique with mitoxantrone (Novantron, Wyeth-Lederle, Germany) 10 mg/m2 dl, 5-fluorouracil + folinic acid (Fluroblastin, Farmitalia, Germany + Leucovorin, Wyeth-Lederle) 600 mg/m2 + 170 mg/m2 d2-4, and cis-platinum (Cisplatin, Bristol, München, Germany) 60 mg/m2 d5. The patients were monitored for toxicity, development of disease progression and survival. The median survival time was 21 months, and only 15% of the patients developed liver metastases. The median survival time of the CAI-treated patient group compared favorably to the median survival of 9.3 months in a matched historical control group. Adjuvant celiac artery infusion seemed to prolong median survival and the occurrence of liver metastases appeared to be delayed or reduced.

Increased angiogenin expression in pancreatic cancer is related to cancer aggressiveness

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 (P < 2.0 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.

Adjuvant regional chemotherapy in resected advanced pancreas carcinoma

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, p < 0,0003). In conclusion we state that adjuvant regional chemotherapy in patients with advanced pancreatic cancer is well tolerated and prolongs survival significantly.

Differential expression of CD44 splice variants in human pancreatic adenocarcinoma and in normal pancreas

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.

Alternative splicing of CD44 in human pancreatic cancer

Immunhistochemical 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 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.

Regional chemotherapy in advanced pancreatic carcinoma

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 (p < 0.006) 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.

Rationales for intraperitoneal chemotherapy: Chemosensitivity testing and pharmacokinetic considerations—Clinical experience with intraperitoneal chemotherapy

Background To facilitate drug selection for regional chemotherapy, we defined the concentration response behavior, and the dependence of drug cytotoxicity on time, using the 2 human colorectal carcinoma cell lines HT29 and NMG 64/84. In addition, the drugs' cytotoxic potencies for regional chemotherapy after a single drug exposure were preclinically defined with in vitro phase II studies, using single cell suspensions of human solid tumor biopsies in the Human Tumor Colony Assay (HTCA). Methods The drugs Doxorubicin (ADM), Cis-Platinum (CDDP), Epidoxorubicin (EPI), 5-FU, 5-FUDR, Mitomycin C (MMC), and Mitroxantrone (NOV) were incubated at increasing concentrations up to 1000 ?g/ml at 10, 30, 60, 360, and 1440 min with the cell lines. These drugs, as well as Vindesine (VDS) and Mafosfamide (MAF) were also tested in the HTCA at increasing concentrations. The HTCA response rates at 1 ?g/ml (5-FU and MAF at 10?g/ml) and at 10?g/ml (5-FU and MAF at 100 ?g/ml were used for in vitro phase II comparisons of the drugs' potential clinical activities. Results All test drugs showed a time and concentration dependent cytotoxicity against the cell lines. Based on the cytotoxicity test results with HT29 and NMG 64/84, specific times were recomended for clinical therapy with each drug. In the HTCA, the drugs differed in their activities at both concentrations. The HTCA results, which are clinically more relevant, showed that a 10 times higher concentration of the drug resulted in an increase of in vitro response rates by a factor of 2.1±0.7 (1.1 to 3.7). NOV was the drug which had a high cytotoxicity against the cell lines, a high HTCA-phase II activity (82% response at 10 ?g/ml), and clinical pharmacological advantages for intraperitoneal regional chemotherapy (IPRC). Therefore we used NOV for IPRC at 10?g/ml and with a minimal instillation time of 3 h and obtained a clinically relevant response (CR+ PR) in 56% of the patients with malignant ascites (N=16). In peritoneal carcinosis (N=11) these response rate was 45% with questionable clinical relevance. Conclusions In vitro tests with cell lines and with tumor cell suspensions in the HTCA helped to define the pharmacological basis for the drugs' use in regional chemotherapy. Mitoxantrone and its treatment concentration of 10 ?g/ml were successfully identified by HTCA phase II tests for IPRC.

Abstracts from the sixth meeting of the international association of pancreatology, November 2–4, 1994, Chicago, IL

Effectivity of long antigen exposition dendritic cell therapy (LANEXDC®) in the palliative treatment of pancreatic cancer.

A retrospective analysis of 134 pancreatic cancer patients suggests that immunotherapy with long antigen exposition dendritic cell therapy (LANEX-DC®) is effective, extending median survival to 8.9 months compared to the typical 6-6.9 months. Early initiation and repeated treatments significantly improved outcomes. Younger patients (?60 years) also showed longer survival. The therapy was well tolerated with no serious side effects, highlighting its potential to enhance survival in this challenging cancer.

Treatment of pancreatic cancer: challenge of the facts.

Pancreatic adenocarcinoma has the poorest prognosis among gastrointestinal cancers, with a cure rate under 3% despite surgical advances. R0 resection improves short-term survival but often fails to achieve long-term survival due to undetected residual cancer in lymph nodes, nerve plexuses, and perivascular tissues. Adjuvant treatments provide a modest survival benefit (6-10 months) and should be offered post-resection. Reliable evaluation metrics, including median survival and quality-of-life assessments, are critical for accurately assessing treatment efficacy. Neoadjuvant protocols remain undeveloped.

Duodenum-preserving total pancreatic head resection for cystic neoplastic lesions in the head of the pancreas.

Duodenum-preserving pancreatic head resection (DPPHRt) with segmental duodenal resection is a safe and effective surgical option for cystic neoplastic pancreatic lesions, including IPMN, MCN, SCA, and cystic EN. Among 15 patients, complications included recurrence of IPMN in two cases, gastric emptying delays, and mild pancreatitis, but no hospital mortality occurred. This procedure ensures oncological completeness while preserving pancreatic function and may serve as a preventive strategy against pancreatic cancer.

Low serum levels of soluble CD44 variant 6 are significantly associated with poor prognosis in patients with pancreatic carcinoma.

Serum levels of soluble CD44v6 are significantly reduced in pancreatic carcinoma patients and correlate with prognosis. Patients with CD44v6 levels below 100 ng/mL had markedly shorter median survival (6.7 months) compared to those with higher levels (15.1 months). These findings suggest CD44v6 as a promising prognostic marker, with potential for guiding disease assessment and management in pancreatic cancer.

Duodenum-preserving subtotal and total pancreatic head resections for inflammatory and cystic neoplastic lesions of the pancreas.

Subtotal and total pancreatic head resections offer a safe and effective alternative to the Whipple procedure for treating benign and inflammatory pancreatic head lesions. These techniques preserve the stomach, duodenum, and bile ducts, reducing postoperative morbidity and maintaining quality of life. Duodenum-preserving resections effectively manage conditions like chronic pancreatitis and mono-centric neoplasms (e.g., IPMN, MCN, SCA) while minimizing complications such as delayed gastric emptying and preserving endocrine function. These approaches improve recovery and reduce rehospitalization, making them a superior option in select cases.

Effect of early and late antibiotic treatment in experimental acute pancreatitis in rats.

In a rat model of acute necrotizing pancreatitis, early and late antibiotic treatment with ciprofloxacin/metronidazole or imipenem significantly reduced pancreatic infections (58% to 8-25%). However, only early antibiotic therapy effectively reduced extrapancreatic infections. Quinolones also reduced bacterial counts in the gut, unlike imipenem. These findings highlight the importance of early antibiotic intervention, warranting further clinical studies to confirm its benefits in human patients.

Exogenous, but not endogenous, nitric oxide increases proliferation rates in senescent human fibroblasts.

This study highlights the dual role of nitric oxide (NO) in regulating cell proliferation and the cell cycle in human fibroblasts. Endogenously produced NO, induced by inflammatory cytokines, inhibited proliferation and caused G1 arrest, partially reversible by N(G)-monomethyl-arginine. In contrast, exogenously applied NO donors enhanced proliferation and increased the S/G2 fraction. These findings suggest that NO's effects on cell cycle regulation depend on its source and cellular context, emphasizing its complex role in fibroblast biology.

The induction of apoptosis in proliferating human fibroblasts by oxygen radicals is associated with a p53- and p21WAF1CIP1 induction.

Reactive oxygen species (ROS) generated by hypoxanthine/xanthine oxidase (HX/XO) induce apoptosis in proliferating human fibroblasts (WI38) but not in senescent cells. Apoptosis, observed after 48 hours, was inhibited by catalase, implicating hydrogen peroxide in the process. ROS also caused G1 cell cycle arrest, evidenced by reduced S/G2 phase cells and increased levels of p53 and the cdk inhibitor p21WAF1/CIP1. These findings suggest that ROS selectively target proliferating cells for apoptosis, highlighting their role in cell cycle regulation and stress response.

The role of polymorphonuclear leukocytes and oxygen-derived free radicals in experimental acute pancreatitis: mediators of local destruction and activators of inflammation.

In a rat model of acute pancreatitis induced by sodium taurocholate, treatment with oxygen radical scavengers or anti-ICAM-1 antibody reduced tissue damage and PMN infiltration. These treatments also attenuated the activation of circulating PMNs. While local oxygen free radical production increased PMN infiltration, it did not induce pancreatitis on its own. These findings suggest that oxygen free radicals and PMNs amplify acute pancreatitis, serving as key mediators of local pancreatic damage and systemic PMN activation.

Anti-ICAM-1 antibody modulates late onset of acinar cell apoptosis and early necrosis in taurocholate-induced experimental acute pancreatitis.

Severe acute pancreatitis (SAP) involves early necrosis followed by late apoptosis of acinar cells. In a rat model, taurocholate-induced SAP triggered necrosis within minutes, characterized by zymogen degranulation and cell damage without DNA degradation, progressing to widespread parenchymal breakdown by 6 hours. Apoptosis became prominent after 24 hours in non-necrotic areas. Pretreatment with anti-ICAM-1 antibody reduced neutrophil infiltration, TNF-alpha expression, and necrotic damage while suppressing late apoptosis. These findings suggest that neutrophils, through TNF-alpha signaling, contribute to both necrosis and apoptosis, highlighting their dual role in SAP pathogenesis.

Palliative and adjuvant regional chemotherapy in pancreatic cancer.

A study of coeliac axis intra-arterial cyclic infusions (CAI) for pancreatic cancer demonstrated improved survival in both palliative (non-resectable, UICC III/IV) and adjuvant (resected, UICC I-III) settings. Median survival was significantly extended to 12 months (vs. 4.8) in UICC III, 4 months (vs. 2.9) in UICC IV, and 21 months (vs. 9.3) in resected patients. CAI was well-tolerated, with low severe toxicity rates (0-6% WHO III, 0% WHO IV). CAI also appeared to suppress hepatic progression, highlighting its potential as an effective treatment for pancreatic cancer.

Increased angiogenin expression in pancreatic cancer is related to cancer aggressiveness.

Angiogenin (ANG) expression is significantly upregulated in pancreatic cancer, with 80% of cases showing increased ANG mRNA and 86.7% elevated protein levels. Serum ANG concentrations were markedly higher in pancreatic cancer patients (566.6 ng/ml) compared to healthy individuals (359.0 ng/ml; P < 2.0 x 10??). Elevated ANG levels correlate with poor prognosis, suggesting ANG's role in promoting the aggressiveness of pancreatic cancer and its potential as a prognostic marker or therapeutic target.

Regional celiac artery infusion as adjuvant treatment after pancreatic cancer resection.

Adjuvant celiac artery infusion (CAI) chemotherapy improved outcomes in resected pancreatic cancer patients by extending median survival to 21 months compared to 9.3 months in a historical control group. Using a regimen of mitoxantrone, 5-fluorouracil, folinic acid, and cis-platinum over six cycles, the treatment showed low toxicity and reduced liver metastases to 15%. These findings suggest that CAI not only prolongs survival but may also alter the disease's progression by delaying or reducing hepatic metastases, warranting further investigation.

Glutathione depletion causes cell growth inhibition and enhanced apoptosis in pancreatic cancer cells.

This study highlights the critical role of glutathione (GSH) in pancreatic cancer, showing that GSH levels are significantly higher in cancerous tissues compared to normal pancreatic tissues (17.5 vs. 8.8 nmol/mg protein; P < 0.004). In the pancreatic adenocarcinoma cell line AsPC-1, GSH is essential for cell proliferation, as depletion of GSH inhibited growth even in the presence of growth factors like TGF-alpha. Additionally, GSH depletion increased sensitivity to melphalan-induced apoptosis but not to 5-fluorouracil. These findings suggest that targeting GSH could enhance the efficacy of chemotherapy in pancreatic cancer.

Biglycan is overexpressed in pancreatic cancer and induces G1-arrest in pancreatic cancer cell lines.

Biglycan (PG-I), an extracellular matrix protein overexpressed in pancreatic cancer, inhibits tumor cell growth by inducing G1 cell cycle arrest. This effect is associated with increased p27 levels, reduced cyclin A, and decreased Ras and ERK activity. Transforming growth factor-beta (TGF-beta) further induces PG-I expression in fibroblasts and pancreatic cancer cells. These findings suggest that PG-I may serve as a host defense mechanism, limiting pancreatic tumor progression and offering potential therapeutic insights for targeting tumor-matrix interactions.

Regional chemotherapy in advanced pancreatic carcinoma.

Regional chemotherapy via celiac artery infusion significantly improved median survival in patients with unresectable stage III pancreatic cancer, extending it to 12 months compared to 4.8 months in those receiving only biliodigestive bypass (p < 0.006). In stage IV patients, median survival was modestly increased to 4 months from 2.7 months in untreated cases, though not statistically significant. The therapy was well-tolerated despite occasional severe complications, highlighting its potential to improve outcomes in advanced pancreatic cancer, particularly in stage III disease.

Prognostic significance of soluble interleukin-2 receptor-alpha in adenocarcinoma of the pancreas.

Serum soluble interleukin-2 receptor-alpha (sIL-2R?) levels are significantly elevated in pancreatic cancer patients compared to those with chronic pancreatitis or healthy individuals. Interestingly, higher sIL-2R? levels (>500 U/ml) in adenocarcinoma patients were associated with longer survival, as shown by Kaplan-Meier analysis (P < 0.01). This suggests that sIL-2R? concentrations may serve as a valuable prognostic marker in pancreatic cancer, providing additional insights into patient outcomes independent of tumor size, grade, or lymph node involvement.

Prognostic significance of molecular alterations in human pancreatic carcinoma--an immunohistological study.

This study assessed the clinical and prognostic significance of molecular alterations in 82 cases of pancreatic adenocarcinoma. Overexpression of molecules such as p53, EGF, CD95, and cyclin-D1 was observed in 44-69% of cases, with p53, EGF, and CD95 linked to advanced or undifferentiated tumors (P<0.05). Among the markers, only cyclin-D1 overexpression correlated with shorter survival, but its prognostic significance diminished when controlling for tumor stage and grade. While these findings suggest limited prognostic utility, molecular alterations still offer valuable insights into the tumor biology and pathogenesis of pancreatic cancer.

Inhibition of epidermal growth factor-induced interleukin-1beta-converting enzyme expression reduces proliferation in the pancreatic carcinoma cell line AsPC-1.

Interleukin-1beta-converting enzyme (ICE) is expressed in the pancreatic carcinoma cell line AsPC-1 following epidermal growth factor (EGF) stimulation, but its activation does not induce apoptosis. Instead, ICE appears to positively influence cell proliferation. Specific ICE inhibitors significantly reduced AsPC-1 cell proliferation, suggesting a role for ICE in promoting tumor growth. These findings highlight ICE as a potential target for therapeutic intervention in pancreatic cancer by disrupting its pro-proliferative effects.

Effect of therapy on survival of patients with pancreatic carcinoma.

A follow-up study of 38 pancreatic adenocarcinoma patients identified key treatment factors influencing overall survival. Resection (p = 0.02), overall treatment time (p = 0.03), and biologically effective dose (BED; p < 0.002) were significant, with BED remaining the most critical factor in multivariate analysis (p = 0.02). Larger treatment volumes correlated negatively with survival (r = -0.5, p = 0.06), but tumor size or stage showed no correlation. These findings emphasize the importance of optimizing BED, minimizing treatment volume, and avoiding splits in radiation therapy to improve survival outcomes.

Differential expression of CD44 splice variants in human pancreatic adenocarcinoma and in normal pancreas.

Immunohistochemical and RNA analysis of pancreatic adenocarcinomas revealed distinct patterns of CD44 variant expression compared to normal pancreatic tissue. Variant exon v5 was strongly expressed in carcinoma cells but absent in normal tissue, while v6 was present in both but exhibited different chain compositions. In 80% of carcinoma cases and all cell lines tested, v5 was linked to a chain containing at least v4-v10, a feature absent in normal pancreas. These findings suggest that the altered chain composition of CD44 variants, rather than their mere presence, may contribute to the functional changes associated with pancreatic cancer progression.

Adjuvant regional chemotherapy in resected advanced pancreas carcinoma.

Adjuvant regional chemotherapy via celiac trunk infusion significantly improved survival in patients with locally advanced pancreatic carcinoma after resection. In a study of 18 patients treated with mitoxantrone, 5-FU with folinic acid, and cisplatin over six cycles, median survival was extended to 17.8 months compared to 9.3 months in historical controls (p < 0.0003). The treatment was well-tolerated, with only mild gastrointestinal side effects in a few cases. These findings highlight regional chemotherapy as an effective approach to prolong survival in advanced pancreatic cancer post-resection.

Overexpression of endothelium-derived nitric oxide synthase isoform 3 in the vasculature of human pancreatic tumor biopsies.

This study identifies nitric oxide synthase (NOS) isoforms involved in pancreatic adenocarcinoma. Tumor cell lines (AsPc-1, BxPc-3, CaPan-2) expressed NOS2 (inducible NOS) upon cytokine stimulation, confirmed by RT-PCR and Western blot. NOS3 (endothelial NOS) was overexpressed in tumor vasculature, as demonstrated by RT-PCR and immunohistochemistry in both normal and tumor biopsies. NOS activity was partially calcium-dependent, with EGTA reducing activity by 30% in cell lines and 65% in tumor biopsies. These findings suggest NOS3 plays a role in tumor vascularization and neovascularization, potentially contributing to pancreatic tumor growth and progression.

Overexpression of glucose transporter 1 and increased FDG uptake in pancreatic carcinoma.

This study highlights the metabolic distinction between pancreatic cancer (PC) and chronic mass-forming pancreatitis (MFP), with pancreatic cancer showing significantly increased glucose uptake and selective overexpression of glucose transporter 1 (Glut-1). FDG-PET scans revealed higher standardized uptake values (SUVs) in PC (2.98 ± 1.23) compared to MFP (1.25 ± 0.51, p < 0.01). Northern and RT-PCR analyses confirmed elevated Glut-1 expression in PC tissue but not in MFP, with Glut-1-to-Glut-4 transcript ratios markedly higher in PC (6.17 ± 1.27 vs. 0.42 ± 0.12). These findings suggest Glut-1 as a driver of enhanced glycolysis in pancreatic cancer and a potential target for early detection with FDG-PET and for therapeutic intervention.

Nitric oxide-induced apoptosis in human pancreatic carcinoma cell lines is associated with a G1-arrest and an increase of the cyclin-dependent kinase inhibitor p21WAF1/CIP1.

This study demonstrates that nitric oxide (NO), produced endogenously in response to cytokine stimulation, induces apoptosis in human pancreatic carcinoma cell lines. The inducible NO synthase (iNOS) was activated in the presence of tumor necrosis factor-alpha, IFN-gamma, and interleukin-1beta, leading to NO production. NO caused G1 cell cycle arrest in all tested cell lines, which was reversible with NG-monomethyl-L-arginine, an iNOS inhibitor. These findings suggest that NO triggers G1 arrest and subsequent apoptosis in pancreatic cancer cells, highlighting its potential role in therapeutic strategies targeting tumor growth.

Pancreatic carcinoma in chronic pancreatitis with inflammatory tumour of the head of the pancreas.

This retrospective study confirms a significant link between chronic pancreatitis and pancreatic cancer. Among 395 patients operated on for chronic pancreatitis, 3.8% (n = 15) developed pancreatic cancer, significantly higher than the general population (p < 0.001), with an average interval of 33.3 months between diagnoses. In a separate cohort of 474 patients with pancreatic cancer, 11.1% (n = 53) showed histological evidence of chronic obstructive pancreatitis caused by tumor-related duct obstruction. Patients with chronic pancreatitis have a more than 50-fold increased relative risk of developing pancreatic cancer, highlighting the importance of vigilant monitoring in this high-risk group.

Value of pylorus preserving partial duodenopancreatectomy in ductal pancreatic carcinoma.

This study compared pylorus-preserving duodenopancreatectomy (PPPD) with partial duodenopancreatectomy (PD) for ductal pancreatic carcinoma. Among 130 patients, PPPD was associated with reduced blood loss and similar postoperative complication rates compared to PD. Median survival was 21 months in the PPPD group and 10.8 months in the PD group, but this difference reflected uneven tumor stage distribution. For UICC stage III tumors, survival was nearly identical (10.1 vs. 11.2 months). PPPD appears to be an effective and less invasive alternative to PD, offering sufficient oncological radicality without compromising prognosis.

Tumor of the ampulla of Vater: experience with local or radical resection in 171 consecutively treated patients.

A study evaluating survival after resection of ampullary tumors found that surgical approach and tumor stage significantly influence outcomes. Local resection is effective for benign adenomas and low-risk cancers, while radical resection is essential for advanced malignant lesions. Key prognostic factors include absence of lymph node metastasis, pancreatic infiltration, and achieving an R0 resection. Five-year survival rates reached 84% for stage I and 27% for stage III. Tailored surgery offers optimal outcomes for these patients.

Reduced membranous and ectopic cytoplasmic expression of beta -catenin correlate with cyclin D1 overexpression and poor prognosis in pancreatic cancer.

This study highlights the role of beta-catenin in pancreatic ductal adenocarcinoma. Reduced membranous beta-catenin expression (58.1%) and cytoplasmic accumulation (65.1%) significantly correlated with cyclin D1 overexpression (p < 0.0005), suggesting beta-catenin’s involvement in tumorigenesis through cyclin D1 transactivation. Patients with cytoplasmic beta-catenin expression had a significantly lower 1-year survival rate (35.7% vs. 86.6%, p < 0.01). Co-precipitation experiments revealed reduced beta-catenin in the E-cadherin-catenin complex in tumors. These findings suggest beta-catenin contributes to pancreatic cancer progression by disrupting cell adhesion and enhancing oncogenic signaling.

Overexpression of intercellular adhesion molecule-1 (ICAM-1) in pancreatic adenocarcinoma in comparison with normal pancreas.

This study highlights the role of intercellular adhesion molecule-1 (ICAM-1) in pancreatic adenocarcinoma. While normal pancreatic tissues showed no ICAM-1, ICAM-2, or ICAM-3 expression, ICAM-1 was upregulated in various percentages of carcinoma cells. Immunohistochemistry and in situ hybridization confirmed ICAM-1 protein and mRNA localization in tumor cells. In contrast, ICAM-2 and ICAM-3 were absent in both normal and cancerous tissues. These findings suggest that ICAM-1 is specifically upregulated in pancreatic adenocarcinoma and may play a role in tumor malignancy and progression.

Interleukin 1beta-converting enzyme (caspase-1) is overexpressed in adenocarcinoma of the pancreas.

This study demonstrates significant overexpression of interleukin-1beta-converting enzyme (ICE; caspase-1) in pancreatic adenocarcinomas, observed in 71% of tumor cells via immunohistochemistry and 80% via Western blot. ICE mRNA was overexpressed in 45% of cases compared to normal pancreatic tissue. Notably, ICE overexpression correlated strongly with cyclin D1, epidermal growth factor (EGF), and EGF receptor (EGFR) expression (P < 0.0005, P < 0.05, and P < 0.002, respectively), which are key regulators of cell cycle progression. These findings suggest a potential role for ICE in tumor proliferation, warranting further investigation into its mechanistic contributions to pancreatic cancer.

Overexpression of caspase-1 (interleukin-1beta converting enzyme) in chronic pancreatitis and its participation in apoptosis and proliferation.

This study highlights the dual role of caspase-1 in chronic pancreatitis, with its expression observed in 85% of tissues but absent in normal pancreas. Caspase-1 was found in three key compartments: atrophic acinar cells (89%), proliferating ductal cells (87%), and redifferentiating acinar cells forming tubular structures (83%). These findings suggest that caspase-1 participates in both apoptosis and cellular proliferation/differentiation. Its expression pattern underscores a complex role in chronic pancreatitis pathology, potentially bridging inflammatory damage and tissue remodeling processes.

Prognostic value of molecular biologogy and immunologic parameters in human pancreatic carcinoma.

This study highlights the prognostic value of immunological markers in pancreatic adenocarcinoma. Among 82 tissue samples analyzed, only Cyclin D expression showed prognostic significance, while other molecular markers (e.g., p53, p21WAF1, EGF, EGF-R) did not. However, serum levels of immunological factors such as sCD44, sCD44v6, neopterin, and IL-2R were strongly associated with prognosis. These findings suggest that immunological parameters may be more predictive of outcomes than traditional molecular markers, potentially opening avenues for early immunological intervention in pancreatic cancer.

Inflammatory mediators in human acute pancreatitis: clinical and pathophysiological implications.

This study demonstrates that acute pancreatitis (AP) is characterized by elevated levels of both pro- and anti-inflammatory cytokines, with distinct patterns linked to disease severity and complications. Imbalances in IL-1?/IL-1RA were associated with severe cases and pulmonary failure, while elevated IL-6 and sIL-2R levels correlated with systemic organ failure and poor outcomes. IL-1RA served as an early severity marker, and IL-6 was the best predictor of pulmonary failure. These findings highlight the progression from local mediator release to systemic immune activation, which drives complications in severe AP.

Nitrogen monoxide and oxygen radicals work contrarily on proliferation behaviour of human fibroblasts.

This study highlights the distinct roles of oxygen radicals and nitric oxide (NO) in regulating fibroblast proliferation. Oxygen radicals and endogenously produced NO, induced by cytokines, inhibited the proliferation of WI38 human fibroblasts. In contrast, exogenously applied NO increased cell proliferation rates. These findings suggest that oxygen radicals and NO play dual roles in modulating fibroblast growth, potentially influencing processes such as inflammation and tissue repair.

The potential role of procalcitonin and interleukin 8 in the prediction of infected necrosis in acute pancreatitis.

This study highlights the potential of procalcitonin (PCT) and interleukin-8 (IL-8) as reliable biochemical markers for predicting infected pancreatic necrosis in acute pancreatitis. PCT showed high sensitivity (94%) and specificity (91%) for infected necrosis, outperforming IL-8 and C-reactive protein (CRP). Elevated PCT levels also correlated with persistent pancreatic sepsis post-surgery, making it a valuable non-invasive marker for early diagnosis and monitoring of complications, with accuracy comparable to fine-needle aspiration.

p53 genetic alterations, protein expression and autoantibodies in human colorectal carcinoma: A comparative study.

This study evaluated p53 expression and its clinical relevance in 120 colorectal cancer tissues using various methods, including a novel luminometric assay (LIA-mat), immunohistochemistry, PCR/SSCP, and sequencing. Serum from 235 cancer patients and 195 healthy controls was analyzed for p53 autoantibodies. Results showed p53 protein overexpression in 54% of tumors, with higher levels in cases with gene alterations. Despite correlation between methods, discrepancies occurred in 30% of cases. Notably, 18% of patients exhibited p53 autoantibodies, which may serve as early indicators for tumor development and metastasis, supporting p53's role as a prognostic biomarker.

K-ras mutations at codon 12 are rare events in chronic pancreatitis.

This study investigated the frequency of K-ras gene mutations at codon 12 in chronic pancreatitis, a condition linked to an elevated risk of pancreatic cancer. Using PCR and restriction fragment length polymorphism analysis, no K-ras mutations were detected in 60 chronic pancreatitis samples, while 5 of 11 pancreatic carcinoma samples showed mutations. These findings suggest that K-ras mutations are rare in chronic pancreatitis or occur shortly before malignant transformation, emphasizing their potential role as a late event in pancreatic cancer development.

Diagnosis of gallstone ileus.

Gallstone ileus is a rare but potentially life-threatening condition often misdiagnosed before surgery. The classic Rigler triad—aerobilia, small bowel obstruction, and a displaced calcified gallstone—is identified in only 14-35% of abdominal X-rays. Advanced diagnostic tools, including ultrasound, contrast-enhanced upper gastrointestinal imaging, and particularly computed tomography (CT), are effective in confirming all diagnostic criteria, with CT being the most reliable method.

Clinics in Oncology Additional Long Antigen Exposition Dendritic Cell Therapy (LANEX-DC ® ) in the Palliative Treatment of Stage IV Colorectal Cancer Patients OPEN ACCESS

Stage IV colorectal cancer (CRC) has a dismal prognosis, with 5-year survival rates below 10%. In a retrospective study of 73 patients, adjuvant LANEX-DC® dendritic cell therapy was evaluated alongside standard treatments. The therapy was well-tolerated with no severe side effects. Remarkably, 5-year survival increased to 23.3%, with a median survival of 27.8 months. These findings highlight the potential of dendritic cell immunotherapy to significantly improve outcomes for late-stage CRC patients.

Evaluation of long antigen exposition dendritic cell therapy (LANEX-DC®) in the adjuvant treatment of pancreatic cancer – results of a single center analysis

Despite advancements, gastric cancer's 5-year survival rates remain below one-third. A retrospective analysis of 16 patients treated with LANEX-DC® dendritic cell therapy as an adjuvant revealed significantly improved outcomes. The therapy, which was well-tolerated with no severe side effects, resulted in 5-year disease-free survival (DFS) of 62.5% and overall survival (OS) of 67.5%. These findings suggest that dendritic cell therapy may substantially extend survival in gastric cancer patients.

Effectivity of Long Antigen Exposition Dendritic Cell Therapy (LANEXDC®) in the Palliative Treatment of Pancreatic Cancer

A study evaluated the efficacy of Long Antigen Exposition Dendritic Cell Therapy (LANEX-DC®) as an additional palliative treatment for pancreatic cancer. Results showed the therapy is well tolerated, with no serious side effects. Median survival increased to 8.9 months, and patients starting treatment early or undergoing repeated cycles achieved significantly better outcomes. This highlights the potential of dendritic cell-based immunotherapy in extending survival and improving outcomes for pancreatic cancer patients.

ChemInform Abstract: Synthesis and in vitro Antitumor Activity of 2?-Deoxy-5-fluorouridylyl- (3? ? 5?)-2?-deoxy-5-fluoro-N4-octadecylcytidine (I): A New Amphiphilic Dinucleoside Phosphate

A novel amphiphilic dinucleoside phosphate was synthesized from the cancer drug 2?-deoxy-5-fluorouridine (5FdU) and its derivative, showing enhanced efficacy against pancreatic cancer cells. In vitro, this dimer outperformed the monomeric 5FdU, achieving significant tumor growth inhibition at lower concentrations (IC50: 10–12 ?g/ml), while 5FdU's IC50 was not reached. This suggests the dimer could offer a promising therapeutic advantage over its parent compound.

Duodenum-preserving total pancreatic head resection for cystic neoplasm - A limited but cancer-preventive procedure

Cystic pancreatic neoplasms, such as IPMN and MCN, carry a significant risk of malignancy (60% and 30%, respectively). For localized cystic lesions in the pancreatic head without advanced cancer signs, a duodenum-preserving total pancreatic head resection offers a minimally invasive alternative to more extensive surgeries. This approach shows low hospital mortality (<1%) and favorable long-term outcomes when complete tumor removal is achieved. Careful intraoperative evaluation is key to optimizing results.

Pancreatic Cancer – Low Survival Rates

Pancreatic cancer remains highly lethal, with over 95% of patients facing incurable outcomes. Risk factors such as smoking and chronic alcohol consumption account for 30% of cases. Only patients in TNM stages I and II benefit from oncologic tumor resection, achieving modest survival rates with adjuvant chemotherapy (3-year: ~30%, 5-year: <15%). Median survival post-R0 resection is 17–28 months. Prevention strategies focus on reducing smoking and alcohol use and early surgical removal of cystic neoplasms. Screening protocols are suggested for high-risk patients.

Pancreatic head resection: the risk for local and systemic complications in 1315 patients - a monoinstitutional experience

Pancreatic head resection, while complex, has achieved low complication rates in high-volume centers, with hospital mortality dropping to 2.05%. Analyzing 1,315 cases, pancreatic fistula occurred in 6.8% of patients but was largely managed non-surgically without affecting mortality. However, the breakdown of pancreaticojejunostomosis—occurring in 2.5%—posed a life-threatening risk, with hospital mortality rising to 34.5% due to abdominal sepsis. High-volume centers ensure safer outcomes, but vigilant management of severe complications remains crucial.

Systemic immune dysfunction in pancreatic cancer patients

Pancreatic cancer patients exhibit systemic immune dysfunction, characterized by elevated levels of immune-suppressive cytokines such as TNF-alpha, TGF-beta1, and IL-10, and reduced IL-2 levels. Despite normal immune cell distribution, their lymphocytes show impaired responsiveness to mitogenic stimulation. These findings highlight a shift towards a T helper cell type 2 cytokine profile and immune suppression, suggesting potential targets for immunomodulatory therapies in pancreatic cancer.

The clinical efficacy of adjuvant systemic chemotherapy with gemcitabine and NSC-631570 in advanced pancreatic cancer

A combination of Gemcitabine and NSC-631570 appears to be a promising adjuvant therapy for advanced resected pancreatic cancer. In a study involving 30 patients, the regimen was well-tolerated with no severe toxicities and achieved a median survival of 33.8 months, with 5-year survival rates at 23.3%. Despite an 80% recurrence rate, the treatment significantly extended relapse-free survival to 21.7 months. These findings suggest potential for improved outcomes, warranting further clinical investigation.

Increased Etheno-DNA Adducts in Affected Tissues of Patients Suffering from Crohn’s Disease, Ulcerative Colitis, and Chronic Pancreatitis

Chronic inflammation contributes to cancer risk by inducing oxidative stress and lipid peroxidation, generating DNA-reactive aldehydes like HNE. This study found significantly elevated etheno-DNA adducts, particularly epsilondC, in inflamed pancreatic tissue and colonic mucosa of patients with inflammatory diseases, suggesting impaired DNA repair. These findings highlight the role of inflammation-driven DNA damage, such as K-ras and p53 mutations, in promoting malignancy in cancer-prone conditions.

Antibiotic Prophylaxis in Severe Acute Pancreatitis

Severe acute pancreatitis (SAP) often involves bacterial infection of necrotic tissue, significantly increasing mortality rates from 5–25% in sterile necrosis to 15–28% with infection. Although prophylactic antibiotics have shown potential in reducing infections and mortality in earlier studies, recent large, placebo-controlled trials using ciprofloxacin and metronidazole found no overall benefit. These findings suggest antibiotic prophylaxis should be reserved for specific high-risk subgroups rather than all patients with necrotizing pancreatitis.

Influence of PMN Leukocyte-Mediated Pancreatic Damage on the Systemic Immune Response in Severe Acute Pancreatitis in Rats

The progression of severe acute pancreatitis is driven by systemic inflammatory responses and subsequent organ dysfunction. Using a rat model, researchers observed that PMN leukocyte activity increased in early tissue damage but was mitigated by anti-ICAM-1 antibodies and oxygen radical scavengers. Helper T cell shifts, including a rise in CD45RC(high)/CD45RC(low) ratios, were linked to increased lymphocyte homing. These findings suggest that PMN-mediated damage only partially explains the immunological changes, highlighting anti-ICAM-1 as a potential therapeutic target.

Comparative Analysis of Extracellular Matrix Proteins in Chronic Pancreatitis: Differences Between Pancreatic Head and Tail

In chronic pancreatitis (cP) with an inflammatory mass in the pancreatic head, fibrosis is significantly more pronounced in the pancreatic head compared to the resection margin, particularly in alcohol-induced cases. Collagen type IV and laminin showed higher expression in the head, suggesting their role in disease progression. These findings support the hypothesis that the pancreatic head acts as a 'pacemaker' in cP, with specific extracellular matrix proteins contributing to its pathology.

Pancreatic Cancer: Significance of Neoadjuvant Therapy

Neoadjuvant radiochemotherapy for pancreatic cancer is not yet standardized but shows promise in improving outcomes. Administered over 5–8 weeks with radiotherapy doses of 50–54 Gy and 5FU as a radiosensitizer, it extends median survival to 15–30 months in resectable cases, particularly UICC stage II. Approximately 15% of patients (UICC I–III) experience tumor downstaging, improving the success of R0 resections and reducing local recurrence. Controlled clinical trials are needed to confirm its efficacy and establish guidelines.

Treatment of pancreatic cancer patients with Ukrain: Four case reports

A small case series explored the combination of Ukrain and gemcitabine in four advanced pancreatic cancer patients who had no remaining standard treatment options. All patients showed clinical improvement and signs of partial remission, with no severe side effects reported. While promising, these findings require validation in larger, controlled studies to confirm efficacy and safety.

Cyclooxygenase-2 is Overexpressed in Chronic Pancreatitis

A study analyzing COX-2 expression in pancreatic tissues found significant overexpression in chronic pancreatitis and pancreatic cancer patients, but not in normal tissues. COX-2 levels in chronic pancreatitis correlated with the frequency of acute attacks, particularly in atrophic acinar cells. This suggests COX-2 plays a role in inflammatory responses and may contribute to disease progression. No links were found with factors like disease duration, diabetes, or alcohol use. These findings highlight COX-2 as a potential target in managing chronic pancreatitis.

NSC-631570 (Ukrain) in the palliative treatment of pancreatic cancer. Results of a phase II trial

A study on NSC-631570 (Ukrain), a semisynthetic compound derived from *Chelidonium majus*, evaluated its efficacy in unresectable pancreatic cancer. Patients receiving Ukrain alone or combined with gemcitabine had significantly better outcomes than those treated with gemcitabine alone. Median survival was 5.2 months with gemcitabine, 7.9 months with Ukrain, and 10.4 months with the combination. Survival rates after 6 months were also higher in combination therapy. Ukrain demonstrated potential to nearly double survival in advanced pancreatic cancer.

Low Serum Levels of CD44, CD44v6, and Neopterin Indicate Immune Dysfunction in Chronic Pancreatitis

Chronic pancreatitis is linked to reduced immune activity, as shown by significantly lower serum levels of CD44, CD44v6, and neopterin compared to healthy controls. Although IL-2 receptor levels were also lower, the difference was not significant. These reductions in immune markers are attributed to decreased T-lymphocyte and macrophage activation caused by the inflammatory process itself, rather than external immunosuppressive factors. Surgical resection may help restore immune function in these patients.

Epidermal Growth Factor Induces Cyclin D1 in Human Pancreatic Carcinoma: Evidence for a Cyclin D1–Dependent Cell Cycle Progression

Cyclin D1 overexpression in pancreatic carcinoma correlates with poor prognosis and is influenced by epidermal growth factor (EGF) signaling via the EGF receptor (EGFR). In cell line studies, EGF stimulation increased cyclin D1 mRNA and protein levels, promoting cell cycle progression. Immunohistochemical analysis of tumor tissues revealed overexpression of EGF, EGFR, and cyclin D1 in 51%, 54%, and 62.3% of cases, respectively, with significant correlations. These findings highlight the role of EGF-EGFR signaling in driving cyclin D1-mediated tumor progression.

Overexpression of Caspase-1 in Pancreatic Disorders: Implications for a Function Besides Apoptosis

Caspase-1, known for its role in apoptosis, is significantly overexpressed in pancreatic cancer and chronic pancreatitis, but with distinct patterns. In cancer tissues, 71% showed cytoplasmic overexpression of caspase-1, correlating with prognostic markers like cyclin D1 and EGFR, hinting at a role in cell proliferation. Chronic pancreatitis showed nuclear expression in atrophic cells and cytoplasmic expression in hyperplastic ducts and dedifferentiating acinar cells. These findings suggest caspase-1’s dual role in apoptosis and tumor-related proliferation.

Reduced membranous and ectopic cytoplasmic expression of ? -catenin correlate with cyclin D1 overexpression and poor prognosis in pancreatic cancer

?-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 ?-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 ?-catenin expression (25 of 43, 58.1%) and accumulation of ?-catenin in the cytoplasm (28 of 43, 65.1%) correlated significantly with cyclin D1 overexpression (both p < 0.0005). Furthermore, we could show a clear correlation between reduced membranous expression and ectopic cytoplasmic expression of ?-catenin (p < 0.0005). 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 (p < 0.01). Co-precipitation experiments revealed reduced ?-catenin bound to the E-cadherin–catenin complex in pancreatic tumor tissues compared with normal pancreatic tissues. These results suggest that ?-catenin may be involved in the tumorigenesis of pancreatic cancer and exhibited its effects mainly by the transactivation of cyclin D1. © 2001 Wiley-Liss, Inc.

Reduced membranous and ectopic cytoplasmic expression of beta -catenin correlate with cyclin D1 overexpression and poor prognosis 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 p < 0.0005). Furthermore, we could show a clear correlation between reduced membranous expression and ectopic cytoplasmic expression of beta-catenin (p < 0.0005). 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 (p < 0.01). 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.

Distributional and Functional Alterations of Immunocompetent Peripheral Blood Lymphocytes in Patients with Chronic Pancreatitis

To investigate whether the chronic inflammatory process in patients with chronic pancreatitis affects their immune function. Chronic pancreatitis is a chronic inflammatory disease of the exocrine pancreas. In approximately 30% of patients, an inflammatory mass of the pancreatic head is found, representing an indication for surgery. This study comprised 28 patients with chronic pancreatitis. Sixteen patients were also reevaluated 1 year after resection of the pancreatic head for chronic pancreatitis. Compared with an age- and gender-matched control group, the number of CD3(+) cells was significantly increased in patients with chronic pancreatitis, with an increase of both CD3(+)CD4(+) and CD3(+)CD8(+) cells. The number of natural killer cells or B lymphocytes did not differ between the patients and the control group. After stimulation with phytohemagglutinin or anti-CD3 antibodies, the blastogenic response was significantly attenuated in the patients with chronic pancreatitis. One year after resection of the pancreatic head for chronic pancreatitis, the distribution and the blastogenic response to phytohemagglutinin and anti-CD3 antibodies had returned to normal compared with preoperative values. The chronic inflammatory process in chronic pancreatitis markedly affects the distribution and function of peripheral immunocompetent blood cells, and elimination of the chronic inflammatory focus by pancreatic head resection restores the suppressed immune function in these patients.

Expression of facilitative glucose transporters in pancreatic cancer. Prognostic relevance of Glut4

Ectopic cytoplasmic expression of ?-catenin carrelates with cyclin D1 overexpression in pancreatic cancer

Cytotoxic effects of the alkaloid chelidonine from Chelidonium majus on pancreatic cancer cells. An old and highly potent anticancer drug.

Inhibition of caspase-1 induces cell death in pancreatic carcinoma cells and potentially modulates expression levels of bcl-2 family proteins

Caspase-1 (interleukin-1beta-converting enzyme) is reported to play an important role in the regulation of apoptosis. We investigated the inhibition of caspase-1 by the cell permeable caspase-1 inhibitor Ac-AAVALLPAVLLALLAP-YVAD.CHO in pancreatic carcinoma cells. Inhibition of caspase-1 induced a non-apoptotic/'necrotic-like' cell death in AsPC-1, BxPC-3, MiaPaCa-2 and Panc-1 cells. Expression levels of bcl-2 and bax were up-regulated in caspase-1 inhibitor-treated cells while that of bcl-x(L) remained unaltered. Our observations support our previous findings that caspase-1 is potentially involved in anti-apoptotic processes in pancreatic carcinoma.

Modulation of Endogenous Nitric Oxide Synthase in Experimental Acute Pancreatitis: Role of Anti-ICAM-1 and Oxygen Free Radical Scavengers

To evaluate, in an experimental model of acute pancreatitis, the impact of nitric oxide on the disease process and the interaction between nitric oxide and oxygen free radicals. Nitric oxide and oxygen free radicals are involved in the pathophysiology of acute pancreatitis. It is well established that oxygen free radicals play an important role in the development of pancreatic cell damage and remote organ failure, but the impact of nitric oxide on the disease process and the interactions between the two radical species remain controversial. Necrotizing pancreatitis (NP) was induced in Wistar rats by intraductal sodium taurocholate infusion after pretreatment with isotonic saline (NP-S), superoxide dismutase/catalase (NP-SOD/CAT), or an anti-ICAM-1 antibody (aICAM-1). Sham-operated rats received isotonic saline (SHX). After an observation period of 5 minutes and 24 hours, the pancreas was removed for microscopy, glutathione, and myeloperoxidase (MPO) analysis. The inducible NO synthase (NOS-2) was detected by Western blotting or RT-PCR. Serum was analyzed for nitrite/nitrate (NO2-/NO3-) and S-nitrosothioles (RSNO), while plasma was used to assay for trypsinogen activation peptides (TAP). NP-S animals showed a significant decrease in GSH levels after NP-induction as compared with animals under therapy. Increased MPO levels in the NP-S group were significantly reduced by aICAM-1 while SOD/CAT injection showed no changes. Serum NO-derivatives peaked at 12 hours while TAP levels had a maximum at 6 hours after NP induction, and were lower after aICAM-1 application SOD/CAT treatment increased both parameters. Extended acinar cell damage and inflammatory infiltrate developed in NP-S animals and was significantly improved by SOD/CAT and aICAM-1 treatment. RT-PCR and Western-blot analysis revealed NOS-2 expression in the NP-S group, which was reduced by radical scavengers and aICAM-1. Enhanced nitric oxide synthase expression and increased nitric oxide derivatives are found during severe acute pancreatitis. Oxygen free radicals and neutrophils seem to be potent and important regulation mechanisms for nitric oxide synthase activity and nitric oxide-mediated toxicity but imply only a secondary role for nitric oxide in the local pathologic mechanism of this disease.

CD44v6 cell surface expression is a common feature of macrophages and macrophage-like cells - Implication for a natural macrophage extravasation mechanism mimicked by tumor cells

Soluble CD44standard (sCD44s) and CD44v6 (sCD44v6) cannot only be detected in sera of patients with pancreatic carcinoma but also of healthy blood donors. To investigate whether sCD44s and sCD44v6 are derived from white blood cells, we stimulated whole blood with phytohemagglutinin and interleukin-2, which induced expression of CD44v6 only on monocytes. For further investigations, we used the promyelocytic leukemia cell line Hl-60. Only Hl-60 cells differentiating along the macrophage pathway showed increased expression of CD44s and CD44v6. Furthermore, only macrophages showed increased secretion of sCD44s and sCD44v6. Our data suggest that CD44s and CD44v6 are common adhesion molecules on macrophages and macrophage-like cells.

Serum amyloid A versus C-reactive protein in acute pancreatitis: Clinical value of an alternative acute-phase reactant

The acute-phase reactant C-reactive protein (CRP) is currently the serum variable of choice for an early, accurate, and cost-effective severity assessment of acute pancreatitis in the daily clinical routine. Serum amyloid A (SAA) proteins comprise a family of apolipoproteins that constitute another major acute-phase reactant and thus could be a potential alternative to CRP assessment. In the present study we investigated the clinical usefulness of SAA determinations in acute pancreatitis using an automated immunoassay technique. Cohort study, comparing patients with complicated and mild acute pancreatitis; control groups included individuals with further abdominal disorders and healthy volunteers. A collaborative study between the department of general surgery and the routine laboratory of the department of clinical chemistry/pathobiochemistry. We enrolled 66 patients with acute pancreatitis in the present study. Control groups consisted of healthy subjects (n = 30), patients with chronic pancreatitis (n = 20), patients with pancreatic carcinoma (n = 20), and patients with acute appendicitis (n = 20). Blood samples were collected during 14 consecutive days in patients with acute pancreatitis. A single blood specimen was taken in all control groups after the diagnosis was established. SAA concentrations were 3 mg/L (median; range, 3-93) in healthy subjects. Although SAA and CRP both reached their maximum within 4 days after onset of symptoms in patients with acute pancreatitis, SAA concentrations rose faster above normal ranges and reached 676 mg/L (median; range, 12-1880), higher than CRP, which reached 313 mg/L (median; range, 29-613). As observed for CRP, SAA was significantly higher in patients who developed complications such as necrosis, infection of necrosis, or multiple organ dysfunction syndrome or in patients who died. SAA achieved best results in discriminating between necrotizing pancreatitis and interstitial edematous pancreatitis. However, CRP provided an earlier differentiation between both entities and a significantly better overall accuracy, as shown by receiver operating characteristics analysis. SAA concentrations in patients with chronic pancreatitis were 6 mg/L (median; range, 3-756). In patients with pancreatic carcinoma, SAA concentrations were 7 mg/L (median; range, 3-492), and in patients with acute appendicitis, they were 50 mg/L (median; range, 3-2140). SAA is a nonspecific and rapidly produced variable in inflammatory abdominal disorders with a wider dynamic range than CRP. The current assay technique renders SAA an applicable and readily available variable under clinical routine conditions. In cases of acute pancreatitis, however, CRP is still superior to SAA for early and accurate stratification of patients with a complicated course.

Pathophysiologic Role of Oxygen Free Radicals in Acute Pancreatitis

Oxidative stress is an important factor in the pathogenesis of acute pancreatitis, as shown in vivo by the beneficial effects of scavenger treatment and in vitro by the potential of free radicals to induce acinar cell damage. However, it is still unclear whether oxygen free radicals (OFR) act only as mediators of tissue damage or represent the initiating event in acute pancreatitis in vivo as well. In the present study the authors aimed to address this issue in an experimental set-up. Two hundred male Wistar rats were randomly assigned to one of the following experimental groups. In two groups, acute necrotizing pancreatitis was induced by retrograde intraductal infusion of 3% sodium taurocholate. Through the abdominal aorta, a catheter was advanced to the origin of the celiac artery for continuous regional arterial (CRA) pretreatment with isotonic saline (NP-S group) or superoxide dismutase/catalase (NP-SOD/CAT group). In another group, oxidative stress was generated by CRA administration of xanthine oxidase and intravenous administration of hypoxanthine (HX/XOD group). Sham-operated rats received isotonic saline both arterially and intraductally. After observation periods of 5 and 30 minutes and 3 and 6 hours, the pancreas was removed for light microscopy and determination of reduced glutathione (GSH), oxidized glutathione (GSSG), conjugated dienes (CD), and malondialdehyde as a marker for OFR-induced lipid peroxidation as well as myeloperoxidase as a parameter for polymorphonuclear leukocyte accumulation. A significant decrease of GSH was paralleled by an increased ratio of GSSG per total glutathione and elevated CD levels after 5 minutes in the NP-S group versus the sham-operated group. Thereafter, the percentage of GSSG and GSH returned to normal levels until the 6-hour time point. After a temporary decrease after 30 minutes, CD levels increased again at 3 hours and were significantly higher at 6 hours in contrast to sham-operated rats. Myeloperoxidase levels were significantly elevated at 3 and 6 hours after pancreatitis induction. In contrast to NP-S rats, treatment with SOD/CAT significantly attenuated the changes in glutathione metabolism within the first 30 minutes and the increase of CDs after 6 hours. HX/XOD administration lead to changes in levels of GSH, GSSG, and CDs at 5 minutes as well as to increased myeloperoxidase levels at 3 hours; these changes were similar to those observed in NP-S rats. Acinar cell damage including necrosis was present after 5 minutes in both NP groups, but did not develop in HX/XOD rats. In addition, serum amylase and lipase levels did not increase in the latter group. SOD/CAT treatment significantly attenuated acinar cell damage and inflammatory infiltrate compared with NP-S animals during the later time intervals. OFRs are important mediators of tissue damage. However, extracellular OFR generation alone does not induce the typical enzymatic and morphologic changes of acute pancreatitis. Factors other than OFRs must be involved for triggering acute pancreatitis in vivo.

The role of immunocytes in acute and chronic pancreatitis: When friends turn into enemies

Caspase 1 overexpression in chronic pancreatitis due to ductular proliferation

Biglycan induced growth inhibition in pancreatic cancer cell lines is caused by cell cycle arrest in G1

Lymphocyte depletion has a protective effect on local andsystemic complications in experimental acute pancreatitis

Rapamycin inhibits the constitutively active FRAP-p40(s6k) pathway and autonomous cell growth in human pancreatic cancer cells.

Inhibition of epidermal growth factor-induced interleukin-1beta-converting enzyme expression reduces proliferation in the pancreatic carcinoma cell line AsPC-1

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.

Intraarterial Adjuvant Chemotherapy after Pancreaticoduodenectomy for Pancreatic Cancer: Significant Reduction in Occurrence of Liver Metastasis

The clinical benefit of adjuvant chemotherapy in pancreatic cancer patients is still questionable. Phase II studies using radiochemotherapy based on 5-fluorouracil (5-FU) provided evidence of an increase in median survival times. Because palliative chemotherapy by celiac artery infusion (CAI) led to an increase in survival in pancreatic cancer, we treated 24 patients with adjuvant CAI following resection of the head of the pancreas for pancreatic cancer (21 patients with Union Internationale contre le Cancer (UICC) stage III, 2 with UICC stage II, 1 with UICC stage I). Catheters were placed angiographically into the celiac artery and remained there for 5 consecutive days. One cycle of chemotherapy consisted of mitoxantrone, 5-FU, folinic acid, and cisplatinum. This treatment was repeated five times at monthly intervals. CAI was well tolerated, and World Health Organization (WHO) grade III toxicities were observed in 8%; WHO grade IV was seen in none of the treatment cycles. Furthermore, we observed pain reduction in nearly all patients under CAI. Median survival times in patients who received CAI were 23 months for all patients, whereas in patients who did not receive adjuvant treatment the median survival was 10.5 months. With Kaplan-Meier regression analysis of the patients who were curatively resected (R0 resection) and received CAI, the overall 4-year survival was 54%, whereas in patients without CAI the 4-year survival was 9.5%. The occurrence of liver metastases in the CAI group went down to 17%. These results demonstrate that CAI is well tolerated, reduces the risk of liver metastasis, and increases the survival time of pancreatic cancer patients.

Regulation of cell growth and cyclin D1 expression by the constitutively active FRAP-p70s6K pathway in human pancreatic cancer 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.

Effect of therapy on survival of patients with pancreatic carcinoma

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 (p < 0.002). 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.

p53 in Relation to Therapeutic Outcome of Locoregional Chemotherapy in Pancreatic Cancer

Since celiac artery infusion (CAI) led to an increase in survival in palliative chemotherapy in pancreatic cancer, we treated 26 patients with adjuvant CAI following resection for advanced pancreatic cancer. Catheters were placed angiographically into the celiac artery and remained there for five consecutive days. One cycle of chemotherapy consisted of mitoxantrone, 5-fluorouracil (5-FU), folinic acid, and cis-platinum. This treatment was repeated five times in monthly intervals. Median survival times in patients who received CAI are 21 months for all patients, whereas in patients who did not receive adjuvant treatment median survival is 10.5 months. In all patients p53 expression of the carcinomas was determined by immunohistochemistry. In 11/26 patients a p53 overexpression was observed. Although p53 overexpression turned out to be associated with poor prognosis in the patients who underwent adjuvant regional cancer treatment, p53 is not a sufficient prognostic parameter in pancreatic carcinoma, since p53 overexpression was more frequent in undifferentiated tumors and in palliative resected tumors.

Serum and Correspondent Tissue Measurements of Epidermal Growth Factor (EGF) and Epidermal Growth Factor Receptor (EGF-R): Clinical Relevance in Pancreatic Cancer and Chronic Pancreatitis

The results of this study show that routine measurements of epidermal growth factor (EGF) and epidermal growth factor receptor (EGF-R) cannot improve screening for pancreatic cancer despite the frequently present tissue overexpression. Both values fail to reveal this malignancy in a serum test. Patients with chronic pancreatitis exhibit no or very low concentrations of EGF. In cases where preoperative diagnosis is difficult the noninvasive EGF and EGF-R serum measurements may be helpful in discriminating between pancreatic cancer and chronic pancreatitis. EGF and EGF-R are frequently overexpressed in the tissue of patients suffering from ductal pancreatic cancer and to lesser degree in patients with chronic pancreatitis. The aim of this study was to determine the value of serum measurements in these patients to detect malignant pancreatic disease. In cases of pancreatic cancer, the tissue expression of EGF and EGF-R was evaluated by immunohistochemistry. Thirty-five patients with chronic pancreatitis and 31 patients with pancreatic cancer were evaluated; 71 patients admitted for routine surgery (hernia repair, cholecystectomy, goiter surgery) served as controls. EGF and EGF-R values were not significantly different in pancreatic cancer as compared to controls and did not correlate with other tumor markers (CA 19-9, carcinoembryonic antigen [CEA], tumor polypeptide antigen [TPA]) or with the stage of the disease. Fourteen patients (67%) with pancreatic cancer displayed tissue overexpression for EGF and 11 patients for EGF-R (52%). These patients, however, also failed to exhibit any significant pathological changes in serum concentration. In chronic pancreatitis, EGF and EGF-R were significantly decreased as compared to pancreatic cancer and controls. This was an unexpected finding. There was a positive correlation to clinical exocrine insufficiency.

Increased Angiogenin Expression in Obstructive Chronic Pancreatitis Surrounding Pancreatic Cancer But Not in Pure Chronic Pancreatitis

We previously demonstrated the increased expression of angiogenin (ANG) in pancreatic cancer and its relation to cancer aggressiveness; however, the expression patterns and the roles of angiogenin in chronic pancreatitis are still unknown. We investigated the expression of ANG both in the tissues and in the sera of chronic pancreatitis patients (pure chronic pancreatitis) by using in situ hybridization, Western blot analysis, and enzyme-linked immunosorbent assay. In situ hybridization revealed no detectable ANG messenger RNA (mRNA) signals in all tissues of pure chronic pancreatitis and normal pancreas. Only a small amount of protein band expression was obtained in all of the protein lysates of pure chronic pancreatitis and normal pancreas. Accordingly, there was no significant difference between the mean serum ANG concentration of chronic pancreatitis patients (352.1+/-72.5 ng/ml) and that of healthy volunteers (357.6+/-45.2 ng/ml). By contrast, acinar cells and interstitial fibroblasts in the tissues surrounding pancreatic cancer showed increased ANG mRNA expression. Strong protein band expression was obtained in the protein lysates of pancreatic cancer surrounding tissue, and mean serum ANG concentration was increased in pancreatic cancer patients. These findings suggest that ANG expression is increased in pancreatic cancer surrounding tissue but is not increased in pure chronic pancreatitis, and that ANG is potentially involved in the pancreatic cancer microenvironment rather than the establishment of pure chronic pancreatitis.

Shimoyama S, Gansauge F, Gansauge S, Kaminishi M, Beger HGBasal expression and cytokine induction of intercellular adhesion molecule-1 in human pancreatic cancer cell lines. J Exp Clin Cancer Res 18: 107-110

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.

Levels of serum neopterin are increased in pancreatic cancer patients and correlate with the prognosis

Neopterin has been recognized as a valid marker for cellular immune activation. Raised neopterin levels indicate the stimulation of macrophages and indirectly T-cell activation. So far no data is available on serum neopterin in pancreatic cancer patients. In this prospective clinical study serum neopterin values were evaluated in 83 patients with adenocarcinoma of the pancreas (PC), 47 patients with chronic pancreatitis (CP), 8 patients with cystadenocarcinoma (CA) of the pancreas and 24 healthy controls (HC). Serum neopterin was significantly elevated in PC (p < 0. 05) and CA (p < 0.04) as compared to HC. There was no difference found between CP and HC. Pancreatic cancer patients with neopterin levels above 2 pmol/ml had a significantly better survival (p < 0. 05) regardless of stage. In stage III and IV (UICC) this difference was highly significant (p < 0.001). Serum levels of neopterin in resectable patients were also significantly correlated with increased survival and in multivariate analysis proved to be an independent prognostic factor. Neopterin in PC was neither correlated with sex, resectability nor with CA 19/9 and CEA. Patients suffering from PC who did show activated cellular immune response reflected in elevated neopterin levels above 2 pmol/ml had a significantly better prognosis regardless of tumor stage. In advanced stages elevated neopterin concentrations were significantly associated with increased survival. Cellular immune response seems to influence survival in these advanced stages to a higher degree as expected. These findings underline the possibility for supportive immunotherapy in this patient group.

Increased oxidative stress in the RAW 264.7 macrophage cell line is partially mediated via the S-nitrosothiol-induced inhibition of glutathione reductase

We investigated whether endogenously or exogenously produced nitric oxide (NO) can inhibit cellular glutathione reductase (GR) via the formation of S-nitrosothiols to decrease cellular glutathione (GSH) and increase oxidative stress in RAW 264.7 cells. The specificity of this inhibition was demonstrated by addition of a NO-synthase inhibitor, and met- or oxyhemoglobin. Using isolated GR we found that only certain NO donors inhibit this enzyme via S-nitrosothiol. Furthermore, we found that cellular GSH decrease is paralleled by an increase of superoxide anion production. Our results show that the GR enzyme is a potential target of S-nitrosothiols to decrease cellular GSH levels and to induce oxidative stress in macrophages.

Basal expression and cytokine induction of intercellular adhesion molecule-1 in human pancreatic cancer cell lines

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 a 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-I 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.

Non-operative management of arterial liver hemorrhages

A retrospective evaluation of embolotherapy in patients with arterial liver hemorrhages was carried out. Twenty-six patients, ranging in age from 10 days to 77 years with active arterial liver hemorrhages, underwent non-surgical embolotherapy. Bleeding was attributed to trauma (n = 21), tumor (n = 3), pancreatitis (n = 1), or unknown cause (n = 1). Twenty-nine embolizations were performed via a transfemoral (n = 26) or biliary (n = 2) approach. One bare Wallstent was placed into the common hepatic artery via to an axillary route to cover a false aneurysm due to pancreatitis. Treatment was controlled in 4 patients by cholangioscopy (n = 2) or by intravascular ultrasound (n = 2). Prior surgery had failed in 3 patients. Intervention controlled the hemorrhage in 24 of 26 (92%) patients within 24 h. Embolotherapy failed in 1 patient with pancreatic carcinoma and occlusion of the portal vein. In 1 patient with an aneurysm of the hepatic artery treated by Wallstent insertion, total occlusion was not achieved in the following days, as demonstrated by CT and angiography. However, colour Doppler flow examination showed no flow in the aneurysm 6 months later. Complications were one liver abscess, treated successfully by percutaneous drainage for 10 days, and one gallbladder necrosis after superselective embolization of the cystic artery. Embolization is a effective tool with a low complication rate in the treatment of liver artery hemorrhage, even in patients in whom surgery has failed.

Controversies in clinical pancreatology. Workup of a patient with familiar pancreatic cancer

Multimodal Therapies for Pancreatic Ductal Adenocarcinoma

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).

Prognostic significance of soluble interleukin-2 receptor- ?? in adenocarcinoma of the pancreas

Soluble interleukin-2-receptor-? (sIL-2R?) serum concentrations were examined in chronic pancreatitis patients, patients with cystadenocarcinoma of the pancreas, patients with adenocarcinoma of the pancreas and healthy blood donors. sIL-2R? serum concentrations in pancreatic cancer patients were significantly higher than those of normal control subjects or chronic pancreatitis patients. In patients with adenocarcinoma of the pancreas no significant differences were found between sIL-2R? and tumor size, grading, resectability and lymph node involvement. In Kaplan–Meier regression analysis patients with adenocarcinoma of the pancreas with low sIL-2R? levels (

Diagnosis of gallstone ileus

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.

The splice-pattern of CD44 is altered in chronic pancreatitis exhibiting dysplastic changes

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-induced Apoptosis in Human Pancreatic Carcinoma Cell Lines Is Associated with a G1Arrest and an Increase of the Cyclin-dependent Kinase Inhibitor p21WAFI/CIPI I

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.

Imaging of gallstone ileus

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.

Adjuvant regional chemotherapy in advanced pancreatic cancer: Results of a prospective study

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 (p < 0.0006). Hepatic disease progression seemed to be suppressed. In conclusion regional chemotherapy seems to be effective for adjuvant treatment in resected pancreatic cancer.

Gansauge F, Gansauge S, Schmidt E, M??ller J, Beger HGPrognostic significance of molecular alterations in human pancreatic carcinoma - an immunohistological study. Langenbecks Arch Surg 383: 152-155

During the last decade, many molecular alterations have been described for pancreatic carcinomas. However, the clinical and prognostic value of these alterations has been discussed and is controversial. An immunohistochemical study was performed in 82 cases of adenocarcinoma of the pancreas. Using specific antibodies, expression of EGF, EGF-receptor, cERB-B2, p53, p21CIP1, cyclin-D1, BCL-2, CD95 and KI67 was evaluated. Overexpression of the different molecules was found in 44-69% of the pancreatic carcinomas. With regard to clinico-pathological features, p53 positivity was more frequently found in advanced and undifferentiated tumours (P<0.05), EGF overexpression was significantly more frequent in advanced tumours (P<0.05) and CD95 overexpression was observed to a greater extent in undifferentiated tumours (P<0.05). Besides cyclin-D1, none of the molecules tested was of prognostic significance. Patients whose tumours expressed cyclin-DI lived significantly shorter than patients with cyclin-D1-negative tumours. However, in subgroup analyses of patients with the same tumour stage or tumour grade, even cyclin-D1. expression had no prognostic significance. These results demonstrate that the prognostic significance of the molecules tested here is low. Nevertheless, with regard to tumorigenesis and tumour biology of pancreatic carcinoma, determination of molecular alterations could provide important information about pancreatic cancer.

Carcinoma of the head of the pancreas arising from the uncinate process

Carcinoma located in the uncinate process (CUP) of the pancreatic head is considered to be rare. Exact epidemiological data, however, are not available because the series published so far consist of fewer than ten patients. The purpose of this prospective study was to evaluate the clinical appearance of CUP and to compare findings with those of patients with carcinoma in the ventral aspect of the pancreatic head (VPC), which represents the most frequent localization. Some 39 (8 per cent) of 506 evaluated patients suffered from CUP. Mean age was 63.3 years. The most frequent complaints were upper abdominal pain (n = 32) and weight loss (n = 35). Jaundice was seen in only five patients and was never an early symptom. The level of CA19-9 was raised in 33 patients. The best diagnostic procedure to detect CUP was computed tomography (CT) (sensitivity 93 per cent), whereas endoscopic retrograde cholangiopancreatography was not useful (sensitivity 21 per cent). Vascular involvement was significantly (P < 0.01) more common in CUP (n = 19) than in VPC (48 versus 19 per cent). This finding and the fact that most patients with CUP were diagnosed at a late stage with distant metastasis or severe vascular involvement present (n = 21) are responsible for the significantly lower rate of operation (n = 25) (64 versus 92 per cent, P < 0.05) and the significantly shorter median survival time (5 versus 11 months, P < 0.05). Patients with CUP have a poor prognosis as a result of the lack of early symptoms (jaundice) and early vascular involvement due to the proximity of the uncinate process to the mesenteric root. A raised level of CA19-9, together with weight loss and/or upper abdominal pain, should prompt CT.

p53 genetic alterations, protein expression and autoantibodies in human colorectal carcinoma: A comparative study

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.

Prognostic value of molecular biologogy and immunologic parameters in human pancreatic carcinoma

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.

Nitrogen monoxide and oxygen radicals work contrarily on proliferation behaviour of human fibroblasts

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.

Pylorus-preserving partial duodenopancreatectomy for ductal pancreatic carcinoma

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.

Nitric Oxide and oxygen radicals contrary influence the proliferation of human fibroblasts

Palliative, adjuvant therapeutic options in pancreatic cancer with special regard to regional chemotherapeutic options

Nuclear accumulation of p53 correlates significantly with clinical features and inversely with the expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) in pancreatic cancer

Recent studies have suggested a p53-independent expression of p21(WAF1/CIP1). We investigated the correlation between p53 overexpression and the expression of p21(WAF1/CIP1) in 57 patients with pancreatic adenocarcinoma. By means of reverse transcription and polymerase chain reaction (RT-PCR), we examined the mRNA levels of WAF1/CIP1 and compared them with the p53 status in 20 patients and in a further six pancreatic tumour cell lines. In pancreatic cancer tissues, immunohistological evaluation revealed a significant correlation between active p53 and p21(WAF1/CIP1) (P < 0.005) as well as WAF1/CIP1 mRNA expression (P < 0.005). This coherence was also evident in human pancreatic carcinoma cell lines. The analysis of p53 and p21(WAF1/CIP1) expression in relation to clinicopathological features revealed a significant correlation between p53 overexpression and tumour stage, tumour size, grading and lymph node metastases, whereas p21(WAF1/CIP1) expression correlated only with tumour size. We conclude that the expression of p21(WAF1/CIP1) normally depends on active p53, but that there may also exist p53-independent pathways of induction that reduce the correlation of p21(WAF1/CIP1) to clinicopathological features. Images Figure 1Figure 2Figure 4Figure 5Figure 6

Gansauge S, Gansauge F, Ramadani M, Stobbe H, Rau B, Harada N, Beger HGOverexpression of cyclin D1 in human pancreatic carcinoma is associated with poor prognosis. Cancer Res 57: 1634-1637

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; P < 0.01 (chi2 test)].

The induction of apoptosis in proliferating human fibroblasts by oxygen radicals is associated with a p53- and p21(WAF1CIP1) induction

The role of reactive oxygen species (ROS) generated by hypoxanthine/xanthine oxidase (HX/XO) in the induction of apoptosis was studied in the human fibroblast cell line WI38. Apoptosis but not necrosis was observed in proliferating fibroblasts after 48 h incubation with 1 mM HX and 0.05 U/ml XO. Induction of apoptosis was hindered by catalase. Cell-cycle analysis revealed a reduction of cells in the S/G2 phase 24 and 48 h after stimulation, suggesting that ROS induce a G1 arrest in proliferating fibroblasts. This was supported by an accumulation of p53 and the cdk inhibitor p21WAF1/CIP1. Since apoptosis was not inducible in senescent fibroblasts our data indicate that ROS mainly induces apoptosis in proliferating cells.

Multimodal therapies in ductal pancreatic cancer. The future

Conclusions: Intra-arterial infusion chemotherapy via the celiac axis combined with external beam radiotherapy might be an effective method for palliative and perioperative multimodal treatment in pancreatic cancer. To improve the dismal prognosis in resectable and nonresectable pancreatic cancer, the results of multimodal palliative, adjuvant, and neoadjuvant therapies were reviewed and put into perspective with the results of two intra-arterial palliative and adjuvant treatment studies conducted at our department. The benefits and pitfalls of each method were outweighed, resulting in a concept for performing intra-arterial chemotherapy with radiotherapy in nonresectable stage UICC-III pancreatic cancer that eventually will be developed as a combined neoadjuvant/adjuvant treatment of all potentially resectable ductal pancreatic carcinomas.

Intravenous immunoglobulins inhibit LPS-induced TNFa release from human monocytic cells

Celiac artery adjuvant chemotherapy. Results of a prospective trial

Celiac artery infusion (CAI) seems to be a qualified and successful method for adjuvant treatment of pancreatic cancer. To improve the dismal prognosis of resected pancreatic cancer patients, we performed postoperative regional chemotherapy via the celiac axis. From 1994-1995, 20 patients with pancreatic cancer (18 ductal adenocarcinoma, 2 cystadenocarcinoma) received adjuvant celiac axis intra-arterial infusions (CAI) after resection of their tumors. Sixteen patients had macroscopically complete tumor removal (R0/R1 resection, 80% of the patients), whereas four patients had gross residual disease remaining after resection (R2 resection, 20% of the patients). Postoperative tumor stages were UICC I in 1 patient, UICC II in 3 patients, and UICC III in 16 patients. CAI was performed for six postoperative cycles via catheters placed into the celiac artery using Seldinger's technique. The chemotherapeutic protocol consisted of mitoxantrone (Novantron), Wyeth-Lederle (Münster, Germany) 10 mg/m2 (d 1), folinic acid (Leucovorin, Wyeth-Lederle, or Rescuvolin, Medac, Hamburg, Germany) 170 mg/m2 for 10 min, followed by 5-FU (Fluoroblastin, Farmitalia, Freiburg, Germany) 600 mg/m2 for 120 min (d 2-4), and Cisplatin (Cisplatin-medac, Medac) 60 mg/m2 (d 5). The cycles were repeated after a rest period of 4 wk. Cisplatin infusions were accompanied by supportive antiemetic (8 mg Tropisetrone i.v. [Navoban, Sandoz, Nürnberg, Germany] and 8 mg Dexametason i.v.) and diuretic measures. Toxicity WHO III occurred in 8% of 100 cycles, and no toxic side effects WHO IV were encountered. The median survival of 21 mo in the treated group was nearly twice as long as the 9.3 mo of a historical matched control group (p < 0.0003). CAI seems to be a qualified and successful method for adjuvant treatment of pancreatic cancer.

Synthesis and In Vitro Antitumor Activity of 2?-deoxy-5-fluorouridylyl-(3??5?)-2?-deoxy-5-fluoro-N4-octadecylcytidine: A New Amphiphilic Dinucleoside Phosphate

The new amphiphilic dinucleoside phosphate, 2?-deoxy-5-fluorouridylyl-(3??5?)-2?-deoxy-5-fluoro-N4-octadecylcytidine (4) was synthesized on a gram scale, using the phosphotriester method, starting from the cytostatic drug 2?-deoxy-5-fluorouridine (5FdU) and 2?-deoxy-5-fluoro-N4-octadecylcytidine (1d). In in vitro clonogenic growth assays using the human pancreatic adenocarcinoma cell line MIA PaCa 2, the amphiphilic dimer was significantly more effective than the parent monomeric 5FdU. The IC50 of the dimer was 10 ?g/ml when applied as an aqueous solution and 12 ?g/ml when given as a liposome dispersion, whereas with 5FdU the IC50 concentration was not reached within the concentration range used.

Adjuvant therapy in pancreatic cancer

Cancer of the pancreas still has a very poor prognosis. Even in the rare cases which can be resected under curative aspects, 5-year survival is seldomly higher than 10%. Most adjuvant chemotherapeutic trials using 5-FU as chemotherapeutic agent did not strongly increase median survival times. Adjuvant radiochemotherapy in pancreatic cancer is under investigation in recent multinational prospective trials (e.g. ESPAC-1). Adjuvant regional chemotherapy is an interesting new approach to adjuvant treatment and recent studies suggest that this treatment is highly effective in pancreatic cancer.

The potential role of procalcitonin and interleukin-8 in the prediction of infected necrosis in acute pancreatitis

CAM 17.1-A new diagnostic marker in pancreatic cancer

CAM 17.1-Ab is a recently described monoclonal antibody that detects a mucus glycoprotein with high specificity for intestinal mucus, particularly in the colon, small intestine, biliary tract and pancreas. We investigated the expression and release of CAM 17.1 in pancreatic carcinoma cell lines and tissue specimens of normal pancreas, chronic pancreatitis and pancreatic cancer. CAM 17.1 was weakly expressed on normal ductal cells and chronic pancreatitis, whereas it was overexpressed in pancreatic cancer. Serum analysis using a new enzyme-linked antibody sandwich assay (CAM 17.1/WGA) of patients with chronic pancreatitis, pancreatic cancer or other gastrointestinal cancer and of healthy blood donors revealed a high sensitivity (67%) and excellent specificity (90%) of CAM 17.1/WGA assay in pancreatic cancer. In comparison with the tumour marker CA19-9, the sensitivity of the CAM 17.1/WGA assay was similar to the sensitivity of CA 19-9 (67% and 76%, P = 0.22), whereas the specificity of CAM 17.1/WGA assay was higher than in CA 19-9 (90% compared with 78% in chronic pancreatitis, P > 0.05). Images Figure 2

Regional Chemotherapy Directed by Individual Chemosensitivity Testing in Vitro: A Prospective Decision-aiding Trial

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%; P < 0.05). 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.

Release of histamine in whole blood by oxygen radicals: Division between specific and unspecific processes

Oxygen derived free radicals are involved in many pathological processes such as postischemic reperfusion injuries, hepatotoxicity of drugs and inflammatory processes. Thereby these oxygen radicals induce lipid peroxidation and perturbation of cellular membranes. The aim of our present study was to determine whether oxygen radicals generated by the xanthine oxidase/ hypoxanthine system cause a release of histamine in human blood cell cultures. Stimulation of blood cell cultures with oxygen radicals induced a histamine liberation which was mainly due to calcium independent processes during the first 30 min, whereas then calcium requiring processes took part in the release of histamine. The regulation of the leukocyte selection LECAM-1 was altered by oxygen radicals whereas histamine, which is known to modulate vascular selectin expression, did not affect the expression of LECAM-1. Our data indicate that oxygen radicals induce a direct calcium independent release of histamine which is due to membrane pertubating processes during the first phase but also induce a specific reaction leading to a further indirect histamine liberation which is probably mediated by PAF.

Molecular oncology in pancreatic cancer

Cancer of the pancreas still has a very poor prognosis despite improved diagnostic methods and therapeutic regimens. The reasons for the aggressiveness of this cancer are not known, and the molecular mechanisms that govern the growth of pancreatic cancer cells are still not clearly defined. During the past two decades the development of new molecular biological techniques has offered new perspectives for a better understanding of pancreatic cancer. Tumor markers such as CA19-9 and CEA are used for diagnosis and for following the postoperative course of cancer patients. Characterization of pancreatic cancer cells using several molecular biological techniques has revealed overexpression or altered expression of growth factors and adhesion molecules, implying altered cell-cell and growth-regulatory interactions. In pancreatic cancer mutations in oncogenes and tumor suppressor genes are frequently detected in p53 and K-ras. This article reviews the possible molecular approaches for diagnosis, prognosis, or even therapy of pancreatic cancer.

The role of Anti-p53-autoantibodies in pancreatic disorders

Conclusion: Anti-p53-autoantibodies (a-p53-aabs) may suppress the development of distant metastases, but not lymph node metastases. This could explain the significantly prolonged survival of patients with UICC stage III tumors who have a-p53-aabs compared to those without a-p53-aabs. Background: Mutation within the tumor suppressor gene p53 leads to increased intracellular p53 protein levels and an increased antibody formation against this molecule. Altered p53 has been proposed to be associated with poor prognosis, and the present study investigated whether the detection of a humoral response to p53 gives evidence for a prognostic or diagnostic parameter in pancreatic disorders. Methods: We screened 145 patients with pancreatic cancer and 95 patients with chronic pancreatitis for the development of a-p53-aab via ELISA and Western-blotting. p53 expression was examined by immunohistochemistry. Results: We found that 41% of the tissues of patients suffering from pancreatic carcinoma overexpressed p53, and 15.9% of the patients suffering from pancreatic cancer developed a-p53-aab. In pancreatic cancer, we could exhibit a significant correlation between grading, p53-overexpression, survival, and antibody response against p53. A-p53-aabs were significantly more frequent in patients with stage III tumors (tumors with lymph node metastases, but not distant metastases, p < 0.02).

Pancreatic carcinoma in chronic pancreatitis with inflammatory tumor of the head of the pancreas

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 (p < 0.001). 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.

Overexpression of endothelium derived nitric oxide synthase (NOS III) in the vasculature of human pancreatic tumor: Differences with regard to pancreatic cell lines. Proceedings of the 1st international Conference on Gastroenterological Carcinogenesis

Overexpression of endothelium derived nitric oxide synthase (NOS III) in the vasculature of human pancreatic tumor: Differences with regard to pancreatic human tumor cell lines

Expression of C-erbB receptors (EGF-R, C-erbB2), TGF alpha and P53 in experimental hepatocarcinogenesis

The experimental hepatocarcinogenesis was studied using the syrian hamster model where tumors are induced by application of nitrosamines. The concentration of EGF-R, C-erbB2, TGF alpha and P53 (wildtype) was measured and correlated with the histological findings. It was shown that in a very early stage where preneoplastic changes are subtle already a highly significant overexpression of TGF alpha EGF-R and P53 occurs, while concentrations of C-erbB2 remain low. It is therefore concluded that the receptor-ligand complex of TGF alpha and EGF-R may represent an important pathway by which early tumor initiation functions. These findings are supported by the fact that the C-erbB2 receptor which is not capable of binding TGF alpha is not overexpressed. The high concentrations of P53 could represent the activation of a cellular defense mechanism against the neoplastic changes occuring.

Anti-oxidative therapy before exhaustive exercise - A clinical and experimental trial

Nowadays the toxicity of oxygen radicals (OR) is uncontested. In spite of a lot of in vitro and of animal experiments it is still difficult to transform the results into the clinical routine. This is caused by the complex clinical situation. Therefore we tried to establish a human, reproducable and standardized model, allowing to study clinically the effects of OR and specific therapies. It is supposed by indirect measurements, that exhaustive exercise generates OR. Direct measurements of OR are missed. To evaluate the clinical meaning of this model for OR-research and therapy human subjects were asked to run on a treadmill until exhaustion and blood samples were taken before, 15' and 24 h after the run. Malondialdehyde (MDA) a marker of lipid peroxidation was measured in the serum of probands in tests with and without vitamin supplementation for 14 days. Intake of vitamin E for 14 days led to a clear increase in vitamin E serum concentrations. MDA concentrations were significantly decreased following vitamin E supplementatioon but not significantly changed 15 min and 24 h after a run. OR in the serum were measured directly by spin trapping. It could be shown that radical activity increases significantly while exhaustive exercise. This can partly be pervented by vitamin E treatment. The single cell gel test (SCG test) was used to study DNA damage in peripheral white blood cells (WBC). A clear increase in DNA strang breakage was observed in the 24 h sample of all probands. When the volunteers were given a supplement of vitamin E (12000) mg daily for 14 days prior to a run exercise induced DNA damage was clearly reduced in all probands. Our results demonstrate that vitamin E prevents exercise induced DNA damage and indicate that DNA breakage occurs in WBC after exhaustive exercise as a consequence of oxidative stress. These results prove the clinical valence of exhaustive exercise for OR research.

Soluble CD44v6 - A prognostic parameter in pancreatic cancer

Variant CD44 splice products, especially CD44v6, are expressed on activated lymphocytes and tumour cells. The soluble forms of CD44s and CD44v6 are present in the serum of normal individuals. We investigated sera from patients with pancreatic cancer for the concentration of CD44v6 by using Western blots and ELISA. CD44v6 was significantly reduced in patients with pancreatic cancer (120 ng/ml, p<0.00005). Survival analysis of pancreatic cancer patients revealed that median survival in the group with CD44v6 serum concentrations below 120 ng/ml was significantly decreased compared to the group with serum concentrations higher than 120 ng/ml (6.7 vs. 15.1 months; p<0.0005) suggesting that CD44v6 is a good prognostic marker in pancreatic cancer.

Increased toxicity and specificity of cytosinarabinosid by liposomal encapsulation in immunoliposomas

Cytosinarabinosid was encapsulated in liposomes. These liposomes were bound to a monoclonal antibody, which detects a tumorassociated antigen. In-vitro tumorcelltoxicity of the immunoliposomes was enhanced one hundred fold as compared to uncoupled liposomes. In mixtures of cell lines immunoliposomes showed a selective targeting of the cells which expressed the antigen that is detected by the monoclonal antibody. Bone marrow toxicity of the immunoliposomes was moderate since pluripotent stem cells do not express the antigen recognized by the monoclonal antibody.

Serum-CD44v6 — A Prognostic Marker in Pancreatic Cancer

Various gastrointestinal tumors, such as colorectal, gastric, and pancreatic cancers, express splice variants of the CD44 glycoprotein (CD44v), which differ from the standard form (CD44s) by including additional extracellular peptide domains encoded by exons v2–v10. While CD44s is ubiquitously expressed, CD44v isoforms are limited to specific cells, including keratinocytes, epithelial cells, activated lymphocytes, and macrophages. CD44v6-containing isoforms are implicated in tumor metastasis and lymphocyte activation. Soluble forms of CD44 (sCD44s and sCD44v6) can be detected in serum using ELISA or Western blotting. Given the parallels between tumor metastasis and lymphocyte migration, this study explores whether sCD44v6 could serve as a prognostic marker in pancreatic cancer.

Altered expression of extracellular matrix molecules and their receptors in chronic pancreatitis and pancreatic adenocarcinoma in comparison with normal pancreas

The aim of this study was to elucidate the expression and distribution patterns of both integrins and extracellular matrix (ECM) molecules in chronic pancreatitis (CP) and pancreatic adenocarcinoma (PC) compared with normal pancreas (NP). Expression of nine ?-subunits (?2-?6, ?v, ?l, ?m, and ?x), four ?-subunits (?1, ?3-?5), and four ECM molecules (type IV collagen, laminin, fibronectin, and vitronectin) was investigated immunohistochemically. In CP, all integrins except ?v showed nearly the same staining patterns compared with NP. Some acinar cells in CP expressed ?v. Whereas ?2, ?3, and ?6 expression was stronger and diffuse, no ?5 expression was seen in PC. Basement membrane (BM) showed continuous staining in CP, whereas it showed discontinuous/absent staining in PC with antitype IV collagen, laminin, and vitronectin antibodies. Some carcinoma cells showed reverse correlation between ?2, ?3, and ?6 expression and type IV collagen and laminin expression. Fibronectin showed diffuse stromal expression in CP and PC. Some acinar cells or duct cells in CP carcinoma cells in PC showed intracellular VN expression. These results suggest that these integrins and ECM molecules are involved in inflammatory and malignant processes in pancreas.

Response prediction in hepatic artery infusion with fluoropyrimidines using cell culture and thymidylate synthase quantitation

Since non-responders to chemotherapy should be withheld from therapy, while treatment should be administered to all responders, our aim was to predict individual response (CR + PR) and resistance (NC + PD) of patients with isolated non resectable liver metastases treated regionally with fluoropyrimidines via an intraarterial (i.a.) access device using the combination of the human tumor colony-forming assay (HTCA) and the quantitation of thymidylate synthase gene expression (TSGE). This treatment and selection strategy might save unnecessary toxicity and resources and increase response rates in the treated group. Biopsies of 15 patients (pts) with liver metastases of colorectal cancer (CRC) and 1 pt with liver metastases of an unknown primary tumor were tested in the HTCA for 5- fluorouracil (FU)/folinic acid (FA) sensitivity and/or were quantitated for TSGE. The HTCA was performed in soft agar culture with continuous 5-FU/FA exposure, the TSGE by using the polymerase chain reaction with ?-actin expression as an internal standard. Nine pts received 5-FU/FA via ports and 7 pts 5-fluoro-2'-deoxyuridine (FUDR) via totally implantable pumps. Response was evaluated after 2 or 3 therapy cycles according to WHO criteria. One out of 16 pts achieved a CR and 5/16 PR (CR + PR: 6/16, 37.5%), while 6/16 pts showed NC and 4/16 PD. In 9 pts the combination of the HTCA and TSGE was used for correlative clinical response prediction, while in 7 pts only TSGE data were available, since no HTCA result could be obtained. If in vitro resistance was defined as TSGE > 8 x 10-3 and reduction of colony growth < 50% in the HTCA, all pts classified in vitro resistant (6/16) showed clinical resistance (NC + PD) to fluoropyrimidine treatment. There was no pt resistant in vitro, who responded clinically. With the definition of in vitro sensitivity as TSGE ? 8 x 10-3 and reduction of colony growth ? 50% in the HTCA 6/10 in vitro sensitive pts showed clinical response (1 CR, 5 PR) and 4/10 did not respond (2 NC, 2 PD). Using the test combination 100% (6/6, test sensitivity) of the responders and 60% (6/10, test specificity) of the non-responders were predicted correctly. In vitro sensitivity corresponded in 60% (6/10) with clinical outcome, in vitro resistance in 100% (6/6). In view of these results, the HTCA and TSGE in combination might be valuable in vitro techniques for prediction of clinical resistance and response to fluoropyrimidines administered regionally to the liver.

Pancreas

Therapeutic approaches for acute necrotizing pancreatitis with organ failure have undergone significant changes over the past two decades. Neither immediate radical necrosectomy nor strictly conservative treatment is now universally recommended as a sole approach. Instead, a better understanding of the disease's pathophysiological processes at different stages has enabled a more nuanced strategy, incorporating new treatment modalities.

Regional Treatment of Advanced Nonresectable and of Resected Pancreatic Cancer via Celiac Axis Infusion

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.

Individual chemosensitivity testing for regional chemotherapy in a prospective correlative and a prospective decision aiding test

Chemosensitivity testing for regional chemotherapy mainly of liver tumors was performed in two trials to find out whether individual drug selection is possible with the Human Tumor Colony Assay (HTCA). In a first step, the drugs used in treatment protocols were tested and the HTCA results 'in vitro sensitive' and 'in vitro resistent' were correlated to the clinical treatment results 'response' or 'resistance' (N = 37 patients and 39 correlations). In this prospective correlative trial (PCT), the HTCA-result had no impact on drug choice. In the subsequent study, the prospective decision aiding trial (PDAT), the drug(s) most active in the HTCA were chosen for hepatic artery infusion (N = 22 patients) or intraperitoneal regional chemotherapy (N = 1 patient). The patients had metastatases of various histological origins. The HTCA results of the PDAT were correlated to the clinical responses determined according to WHO-criteria. In the PCT, the HTCA sensitivity and clinical response correlated correctly in 100%, the HTCA- and clinical resistances in 93%. In the PDAT, the HTCA sensitivity was correctly associated with clinical response in 63% or 89%, if CR+PR or CR+PR+NC were validated as response; for HTCA resistance the correlation to clinical PD was correct in 75%. The overall predictive accuracies of the HTCA were 97% in the PCT and 65%-87% in the PDAT. The clinical response rates in the PDAT were 56% (CR+PR) or 78% (CR+PR+NC). In conclusion, individual chemosensitivity testing with the HTCA is useful for drug selection in regional chemotherapy.

Nitric oxide-induced apoptosis in human pancreatic carcinoma cell lines is associated with a G1-arrest and an increase of the cyclin-dependent kinase inhibitor p21WAF1/CIP1

Endogenously produced NO induced apoptosis in all of the tested pancreatic carcinoma cell lines and endogenous production of NO revealed a G1-arrest in all the tested cell lines.

The induction of apoptosis in proliferating human fibroblasts by oxygen radicals is associated with a p53- and p21WAF1CIP1 induction

It is suggested that the use of nanofiltration membranes for the recovery of phosphorous with a second type of technology is to be considered as a viable process for recovery of nitrogen in the short term.

Pancreatic head resection: the risk for local and systemic complications in 1315 patients—a monoinstitutional experience

In high-volume centers, morbidity and mortality after pancreatic head resection decreased to below 5% and risk factors with significant relation to outcome criteria on nonsurvival are the breakdown of pancreaticojejunostomosis, severe intra-ABdominal bleeding, intra-abdominal abscess, and postoperative multiorgan dysfunction syndrome.

Synthesis and In Vitro Antitumor Activity of 2?-Deoxy-5-fluorouridylyl-(3?5?)-2?-deoxy-5-fluoro-N4-octadecylcytidine: A New Amphiphilic Dinucleoside Phosphate

In in vitro clonogenic growth assays using the human pancreatic adenocarcinoma cell line MIA PaCa 2, the amphiphilic dimer was significantly more effective than the parent monomeric 5FdU.

Pankreaskarzinom: Stellenwert der neoadjuvanten Therapie

In patients with resectable pancreatic cancer, particularly in UICC-stage II neoadjuvant radiochemotherapy, this results in an improvement in survival: the median survival is between 15 and 30 months.

Prognostic significance of soluble interleukin-2 receptor-? in adenocarcinoma of the pancreas

Soluble interleukin-2-receptor-alpha (sIL-2Ralpha) serum concentrations were examined in chronic pancreatitis patients, patients with cystadenocarcinoma of the pancreas, patients of normal control subjects or chronic Pancreas patients and healthy blood donors, suggesting that determination of sIL- 2Ralpha serum concentrations could provide additional important information about prognosis.

Effectivity of Long Antigen Exposition Dendritic Cell Therapy (LANEXDC ® ) in the Palliative Treatment of Pancreatic Cancer

It is demonstrated 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, and median survival can be increased by early beginning and repetition of LANEX- DC(®) treatment.

Rapamycin inhibits the constitutively active Frap-p70S6K pathway and autonomous cell growth in human pancreatic cancer cells

Inhibition of Epidermal Growth Factor-induced Interleukin-1?-converting Enzyme Expression Reduces Proliferation in the Pancreatic Carcinoma Cell Line AsPC-1

It is suggested that interleukin-1beta-converting enzyme (ICE) and ICE-related proteases play an important role in programmed cell death (apoptosis) and a time-dependent expression of active ICE induced by epidermal growth factor is found in the human pancreatic carcinoma cell line AsPC-1.

Prognostic value of molecular biologogy and immunologic parameters in human pancreatic carcinoma

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.

Effect of therapy on survival of patients with pancreatic carcinoma

Among with surgery, biologically effective dose strongly influences overall survival in patients treated for pancreatic carcinoma and treatment volume should be kept as small as possible and all efforts should be made to avoid treatment splits in radiation therapy.

Cytotoxic effects of the alkaloid chelidonine from chelidonium majus on pancreatic cancer cells. An old and highly potent anticancer drug