Outcome Determining Factors of Intraductal Papillary Neoplasm of the Biliary Tract (IPNB)-a Single Center Survey and Analysis of Current Literature.

PURPOSE: Intraductal papillary neoplasms of the biliary tract (IPNB) are rare tumors originating from the bile duct epithelium. Metastatic disease of IPNB is extremely rare and only reported in a small number of cases worldwide. Due to this limitation in number, the treatment of IPNB mainly relies on retrospective case series. PATIENTS AND METHODS: We reported three cases of IPNB, one benign, one carcinoma with lymph node metastasis, and one case with histologically proven metachronous pulmonary metastasis. We correlated our findings with the existing data found in the literature. All patients underwent hemihepatectomy and complete tumor resection was achieved. RESULTS: Diagnosis of IPNB can be challenging due to varying presentation. The treatment of choice is surgical oncological resection in an early tumor stage. Long-term outcome highly depends on the underlying grade of dysplasia, multiplicity, and tumor-free margins. Aggressive tumor invasion is reported in up to 72% of cases in IPNB. Furthermore, the recurrence rate of IPNB is high with up to 22%. Further factors associated with an impaired survival are incomplete resection, lymph node involvement, and MUC1 expression. CONCLUSION: High potential for dysplasia and proof of invasive carcinoma upon diagnosis are hallmarks of IPNB. Metastatic disease in IPNB is reported only in small numbers. IPNB is an aggressive tumor entity with impaired long-term outcomes. A drawback for interpretation of current data is the fact that they rely on case series and reports and are not validated through more powerful randomized multicentric trials.

Clinical Impact of Iatrogenic Small Bowel Perforation Secondary to Laparoscopic Cholecystectomy: A Single-center Experience.

OBJECTIVE: Bowel, vascular, and biliary injuries during laparoscopic cholecystectomy (LC) have to be addressed with high priority. The focus of this study was on small bowel injury (SBI) and its impact on clinical management. METHODS: We report 5 cases of SBI in a retrospective database of 2062 consecutive LC between January 2004 and December 2017. RESULTS: We report isolated iatrogenic SBI in 0.24% (5 of 2062) after LC. We identified 3 cases with SBI associated with the technique of Hasson or related problems with intraoperative relaxation toward the end of the LC. All 5 patients needed at least 1 reoperation. There was no mortality in this series and all patients with iatrogenic SBI got discharged from the clinic in good health. Nevertheless, 3 of 5 patients (60%) with SBI filed a law suit. CONCLUSIONS: Isolated iatrogenic SBI is a rare but dreaded complication after LC with high impact on patient's health and prone for medicolegal claims. Strict precaution on thorough relaxation throughout the operation, meticulous handling of closing technique of the fascial layer and "eternal vigilance" are mandatory to reduce risks of SBI after LC.

Liver resections can be performed safely without Pringle maneuver: A prospective study.

AIM: To evaluate liver resections without Pringle maneuver, i.e., clamping of the portal triad. METHODS: Between 9/2002 and 7/2013, 175 consecutive liver resections (n = 101 major anatomical and n = 74 large atypical > 5 cm) without Pringle maneuver were performed in 127 patients (143 surgeries). Accompanying, 37 wedge resections (specimens < 5 cm) and 43 radiofrequency ablations were performed. Preoperative volumetric calculation of the liver remnant preceeded all anatomical resections. The liver parenchyma was dissected by water-jet. The median central venous pressure was 4 mmHg (range: 5-14). Data was collected prospectively. RESULTS: The median age of patients was 60 years (range: 16-85). Preoperative chemotherapy was used in 70 cases (49.0%). Liver cirrhosis was present in 6.3%, and liver steatosis of ≥ 10% in 28.0%. Blood loss was median 400 mL (range 50-5000 mL). Perioperative blood transfusions were given in 22/143 procedures (15%). The median weight of anatomically resected liver specimens was 525 g (range: 51-1850 g). One patient died postoperatively. Biliary leakages (n = 5) were treated conservatively. Temporary liver failure occurred in two patients. CONCLUSION: Major liver resections without Pringle maneuver are feasible and safe. The avoidance of liver inflow clamping might reduce liver damage and failure, and shorten the hospital stay.

Impact of preoperative local water-filtered infrared A irradiation on postoperative wound healing: a randomized patient- and observer-blinded controlled clinical trial.

OBJECTIVE: In addition to a preoperative antibiotic single-shot prophylaxis, we tested the impact of a one-time preoperative water-filtered infrared A irradiation (wIRA) on postoperative wound healing of patients. BACKGROUND: wIRA improves wound healing in postoperative settings. METHODS: A total of 400 consecutive patients undergoing gastrointestinal surgery were randomly assigned to the treatment group (A) or placebo group (B). We applied wIRA for 20 minutes while patients were prepared for surgery. Patients and observer were blinded to group assignment. Primary endpoints were surgical site infections (SSIs), wound healing, and rate and level of pain within 30 days after surgery. Primary efficacy analysis was carried out on the basis of an intention-to-treat (ITT) population and a full-analysis set (FAS). Missing values of primary outcome variables were considered as SSIs and maximum pain levels in the ITT analysis, respectively. RESULTS FAS: The incidence of SSI was 9 of 178 patients (5.1%) within group A compared with 22 of 182 (12.1%) within group B [P = 0.018; relative risk (RR) = 0.42; 95% CI: 0.18-0.93]. ITT: 32 of 200 (16%) SSIs occurred within group A and 39 of 200 (20%) within group B (P = 0.248) with an RR of 0.74 (95% CI: 0.43-1.28). The wIRA group showed lower postoperative pain at both the ITT (P = 0.092) and the FAS analysis (P = 0.045). CONCLUSIONS: This trial indicates a clinically relevant benefit of one-time application of preoperative wIRA as a supportive addition to prophylactic antibiotics. wIRA contributes to both reduced SSI rates and postoperative pain but also effectively decreases morbidity and related expenses in the health care system.

Heme oxygenase 1-generated carbon monoxide and biliverdin attenuate the course of experimental necrotizing pancreatitis.

OBJECTIVE: The cytoprotective enzyme heme oxygenase 1 (HO-1) is highly up-regulated in acute pancreatitis (AP). In this study, we tested its metabolites as potential therapeutic agents for AP in rats. METHODS: Acute necrotizing pancreatitis was induced by retrograde intraductal injection of sodium taurocholate in rats. Biliverdin hydrochloride (BV HCl) (50 µmol/kg subcutaneously), the carbon monoxide, donor methylene chloride (MC) (500 mg/kg orally), or iron-chelating desferrioxamine (DFO) (125 mg/kg subcutaneously) were administered in a therapeutic manner starting with the first dose 4 hours after taurocholate injection to mimic the effects of HO-1 metabolites. RESULTS: Administration of BV HCl, MC, or DFO showed significant reduction of inflammatory activity in comparison to controls leading to lower myeloperoxidase activity in the pancreas, less edema, lower ascites volumes, and preservation of tissue integrity (P < 0.05). Administration of either BV HCl or MC markedly increased 5-day survival rate (70% and 75% vs 40%; P < 0.05), whereas DFO had no significant effect on survival (60%). When given in therapeutic manner, all 3 substances led to diminished nuclear factor κB activity in the pancreas (P < 0.05). CONCLUSIONS: Therapeutic use of BV HCl and MC led to marked reduction of mortality in experimental pancreatitis. Thus, HO-1 metabolites may present a novel therapeutic approach in AP treatment.

Impact of CD39 and purinergic signalling on the growth and metastasis of colorectal cancer.

Despite improvements in prevention and management of colorectal cancer (CRC), uncontrolled tumor growth with metastatic spread to distant organs remains an important clinical concern. Genetic deletion of CD39, the dominant vascular and immune cell ectonucleotidase, has been shown to delay tumor growth and blunt angiogenesis in mouse models of melanoma, lung and colonic malignancy. Here, we tested the influence of CD39 on CRC tumor progression and metastasis by investigating orthotopic transplanted and metastatic cancer models in wild-type BALB/c, human CD39 transgenic and CD39 deficient mice. We also investigated CD39 and P2 receptor expression patterns in human CRC biopsies. Murine CD39 was expressed by endothelium, stromal and mononuclear cells infiltrating the experimental MC-26 tumors. In the primary CRC model, volumes of tumors in the subserosa of the colon and/or rectum did not differ amongst the treatment groups at day 10, albeit these tumors rarely metastasized to the liver. In the dissemination model, MC-26 cell line-derived hepatic metastases grew significantly faster in CD39 over-expressing transgenics, when compared to CD39 deficient mice. Murine P2Y2 was significantly elevated at both mRNA and protein levels, within the larger liver metastases obtained from CD39 transgenic mice where changes in P2X7 levels were also noted. In clinical samples, lower levels of CD39 mRNA in malignant CRC tissues appeared associated with longer duration of survival and could be linked to less invasive tumors. The modulatory effects of CD39 on tumor dissemination and differential levels of CD39, P2Y2 and P2X7 expression in tumors suggest involvement of purinergic signalling in these processes. Our studies also suggest potential roles for purinergic-based therapies in clinical CRC.

Radiofrequency ablation of liver tumors: Actual limitations and potential solutions in the future.

Over the past decade, radiofrequency ablation (RFA) has evolved into an important therapeutical tool for the treatment of non resectable primary and secondary liver tumors. The clinical benefit of RFA is represented in several clinical studies. They underline the safety and feasibility of this new and modern concept in treating liver tumors. RFA has proven its clinical impact not only in hepatocellular carcinoma (HCC) but also in metastatic disease such as colorectal cancer (CRC). Due to the increasing number of HCC and CRC, RFA might play an even more important role in the future. Therefore, the refinement of RFA technology is as important as the evaluation of data of prospective randomized trials that will help define guidelines for good clinical practice in RFA application in the future. The combination of hepatic resection and RFA extends the feasibility of open surgical procedures in patients with extensive tumors. Adverse effects of RFA such as biliary tract damage, liver failure and local recurrence remain an important task today but overall the long term results of RFA application in treating liver tumors are promising. Incomplete ablation of liver tumors due to insufficient technology of ablation needles, tissue cooling by the neighbouring blood vessels, large tumor masses and ablation of tumors in close vicinity to heat sensitive organs remain difficult tasks for RFA. Future solutions to overcome these limitations of RFA will include refinement of ultrasonographic guidance (accuracy of probe placement), improvements in needle technology (e.g. needles preventing charring) and intraductal cooling techniques.

Variable impact of CD39 in experimental murine colitis.

BACKGROUND: Dysregulation of immune responses in inflammatory bowel diseases (IBD) results in intestinal inflammation and vascular injury while exacerbating systemic disease. CD39 is an ectonucleotidase, expressed by T regulatory cells and dendritic cells, that hydrolyzes extracellular nucleotides to modify those cellular immune responses implicated in IBD. Genetic polymorphisms of CD39 have been linked to Crohn's disease while gene deletion in mice exacerbates dextran sodium sulphate-induced colitis. AIM: The aim of this study was to test how global deletion of CD39 in mice impacts other models of experimental colitis. METHODS: Colitis was induced in CD39-null and -wt mice, using trinitrobenzene sulfonic acid (TNBS, 125 mg/kg) administered intrarectally. Oxazolone colitis (1.5% oxazolone in 50% alcohol) was induced in comparable groups. Morphology, clinical and molecular parameters, and FACS analyses of lamina propria mononuclear cells (LPMC) were examined in CD39-null mice. CD39 expression was analyzed in human IBD biopsies. RESULTS: Paradoxically, TNBS colitis in CD39-null mice was characterized by improved survival, favorable clinical scores, and decreased MPO activity, when compared to wt mice (P < 0.05). LPMC from TNBS colitis contained significantly increased amounts of T-cells (CD3(+) and CD4(+)) and TNF-α mRNA expression were increased over those in CD39 null mice (P < 0.05). In contrast, oxazolone treated CD39-null and wt mice had comparable outcomes. In both ulcerative colitis and Crohn's disease, CD39 is present at high levels in intestinal tissue biopsies. CONCLUSIONS: TNBS colitis was attenuated in CD39-null mice whereas oxazolone-induced colitis was not impacted. Impaired adaptive cellular immune reactivity in the CD39-null environment appears protective in hapten-mediated Th1-type colitis. CD39 is expressed at high levels in clinical IBD tissues.

Is laparoscopic colorectal cancer surgery equal to open surgery? An evidence based perspective.

Laparoscopic colorectal surgery (LCS) is an evolving subject. Recent studies show that LCS can not only offer safe surgery but evidence is growing that this new technique can be superior to classical open procedures. Fewer perioperative complications and faster postoperative recovery are regularly mentioned when studies of LCS are presented. Even though the learning curve of LCS is frequently debated when limitations of laparoscopic surgeries are reviewed, studies show that in experienced hands LCS can be a safe procedure for colorectal cancer treatment. The learning curve however, is associated with high conversion rates and economical aspects such as higher costs and prolonged hospital stay. Nevertheless, laparoscopic colorectal cancer surgery (LCCR) offers several advantages such as less co-morbidity and less postoperative pain in comparison with open procedures. Furthermore, the good exposure of the pelvic cavity by laparoscopy and the magnification of anatomical structures seem to facilitate pelvic dissection laparoscopically. Moreover, recent studies describe no difference in safety and oncological radicalness in LCCR compared to the open total mesorectal excision (TME). The oncological adequacy of LCCR still remains unproven today, because long-term results do not yet exist. To date, only a few studies have described the results of laparoscopic TME combined with preoperative adjuvant treatment for colorectal cancer. The aim of this review is to examine the various areas of development andcontroversy of LCCR in comparison to the conventional open approach.

Identification of the ectonucleotidases expressed in mouse, rat, and human Langerhans islets: potential role of NTPDase3 in insulin secretion.

Extracellular nucleotides and adenosine regulate endocrine pancreatic functions such as insulin secretion by Langerhans islet ß-cells via the activation of specific P2 and P1 receptors. Membrane-bound ectonucleotidases regulate the local concentration of these ligands and consequently control the activation of their receptors. The objective of this study was to identify and localize the major ectonucleotidases, namely NTPDases and ecto-5'-nucleotidase, present in the endocrine pancreas. In addition, the potential implication of ecto-ATPase activity on insulin secretion was investigated in the rat ß-cell line INS-1 (832/13). The localization of ectonucleotidase activity and protein was carried out in situ by enzyme histochemistry and immunolocalization in mouse, rat, and human pancreas sections. NTPDase1 was localized in all blood vessels and acini, and NTPDase2 was localized in capillaries of Langerhans islets and in peripheral conjunctive tissue, whereas NTPDase3 was detected in all Langerhans islet cell types. Interestingly, among the mammalian species tested, ecto-5'-nucleotidase was present only in rat Langerhans islet cells, where it was coexpressed with NTPDase3. Notably, the inhibition of NTPDase3 activity by BG0136 and NF279 facilitated insulin release from INS-1 (832/13) cells under conditions of low glycemia, probably by affecting P2 receptor activation. NTPDase3 activity also regulated the inhibitory effect of exogenous ATP in the presence of a high glucose concentration most likely by controlling adenosine production. In conclusion, all pancreatic endocrine cells express NTPDase3 that was shown to modulate insulin secretion in rat INS-1 (832/13) ß-cells. Ecto-5'-nucleotidase is expressed in rat Langerhans islet cells but absent in human and mouse endocrine cells.

From the Cover: CD39 deletion exacerbates experimental murine colitis and human polymorphisms increase susceptibility to inflammatory bowel disease.

CD39/ENTPD1 hydrolyzes proinflammatory nucleotides to generate adenosine. As purinergic mediators have been implicated in intestinal inflammation, we hypothesized that CD39 might protect against inflammatory bowel disease. We studied these possibilities in a mouse model of colitis using mice with global CD39 deletion. We then tested whether human genetic polymorphisms in the CD39 gene might influence susceptibility to Crohn's disease. We induced colitis in mice using Dextran Sodium Sulfate (DSS). Readouts included disease activity scores, histological evidence of injury, and markers of inflammatory activity. We used HapMap cell lines to find SNPs that tag for CD39 expression, and then compared the frequency of subjects with high vs. low CD39-expression genotypes in a case-control cohort for Crohn's disease. Mice null for CD39 were highly susceptible to DSS injury, with heterozygote mice showing an intermediate phenotype compared to wild type (WT). We identified a common SNP that tags CD39 mRNA expression levels in man. The SNP tagging low levels of CD39 expression was associated with increased susceptibility to Crohn's disease in a case-control cohort comprised of 1,748 Crohn's patients and 2,936 controls (P = 0.005-0.0006). Our data indicate that CD39 deficiency exacerbates murine colitis and suggest that CD39 polymorphisms are associated with inflammatory bowel disease in humans.

Heme oxygenase-1 and its metabolites affect pancreatic tumor growth in vivo.

BACKGROUND: Pancreatic cancer (PaCa) is a fatal human cancer due to its exceptional resistance to all current anticancer therapies. The cytoprotective enzyme heme oxygenase-1 (HO-1) is significantly overexpressed in PaCa and seems to play an important role in cancer resistance to anticancer treatment. The inhibition of HO-1 sensitized PaCa cells to chemo- and radiotherapy in vitro. Therefore, we investigated the effects of HO-1 and its metabolites biliverdin, carbon monoxide and iron on PaCa cells. PaCa cell lines with divergent HO-1 expression patterns were used in a murine orthotopic cancer model. HO-1 expression and activity was regulated by zinc (inhibition) and cobalt (induction) protoporphyrin. Furthermore, the influence of cellular HO-1 levels and its metabolites on effects of standard chemotherapy with gemcitabine was tested in vivo and in vitro. RESULTS: High HO-1 expression in PaCa cell lines was associated with increased chemoresistance in vitro. Chemoresistance to gemcitabine was increased during HO-1 induction in PaCa cells expressing low levels of HO-1. The inhibition of HO-1 activity in pancreatic tumors with high HO-1 boosted chemotherapeutic effects in vivo significantly. Furthermore, biliverdin and iron promoted PaCa resistance to chemotherapy. Consequently, specific iron chelation by desferrioxamine revealed profound anticancerous effects. CONCLUSION: In summary, the inhibition of HO-1 and the chelation of iron in PaCa cells were associated with increased sensitivity and susceptibility of pancreatic tumors to chemotherapy in vivo. The metabolites biliverdin and iron seem to be involved in HO-1-mediated resistance to anticancer treatment. Therefore, HO-1 inhibition or direct interference with its metabolites may evolve new PaCa treatment strategies.

Disordered pancreatic inflammatory responses and inhibition of fibrosis in CD39-null mice.

BACKGROUND & AIMS: Extracellular nucleotides are released from injured cells and bind purinergic-type 2 receptors (P2-Rs) that modulate inflammatory responses. Ectonucleotidases, such as CD39/nucleoside triphosphate diphosphohydrolase-1, hydrolyze extracellular nucleotides to integrate purinergic signaling responses. Because the role of extracellular nucleotides and CD39 in mediating inflammation and fibrosis are understood poorly, we studied the impact of CD39 gene deletion in a model of pancreatic disease. METHODS: Pancreatitis was induced by cyclosporine pretreatment, followed by cerulein injections (50 mug/kg, 6 intraperitoneal injections/day, 3 times/wk); mice were killed at day 2, week 3, and week 6. Experimental parameters were correlated with cytokine levels in blood, RNA, and protein expression of purinergic and fibrosis markers in tissues. Immunohistochemistry and pancreatic morphometry of fibrosis were performed in wild-type and CD39-null mice. Effects of CD39 deletion on proliferation of primary pancreatic stellate cells (PSCs) were investigated in vitro. RESULTS: Wild-type mice developed morphologic features of pancreatitis with the anticipated development of parenchymal atrophy and fibrosis. CD39 and P2-R became overexpressed in vascular and adventitious wild-type tissues. In contrast, CD39-null mice had inflammatory reactions but developed only minor pancreatic atrophy and limited fibrosis. Interferon-gamma became significantly increased in tissues and plasma of CD39-null mice. Wild-type PSCs expressed high levels of CD39 and P2-R. CD39-null PSCs showed decreased rates of proliferation and the expression of procollagen-alpha1 was inhibited significantly in vitro (P < .03). CONCLUSIONS: CD39 deletion decreases fibrogenesis in experimental pancreatitis. Our data implicate extracellular nucleotides as modulators of PSC proliferation and collagen production in pancreatitis.

Upregulation of CD39/NTPDases and P2 receptors in human pancreatic disease.

Chronic inflammation, fibrosis, atrophy, malignant transformation, and thromboembolic events are hallmarks of chronic pancreatic disease. Extracellular nucleotides have been implicated as inflammatory mediators in many pathological situations. However, there are minimal data detailing expression of ectonucleotidases and type-2 purinergic receptors (P2R) in chronic pancreatitis and pancreatic cancer. We have therefore defined tissue distribution and localization of the CD39 family of ectonucleotidases and associated P2R in human disease. Transcripts of ectonucleotidases (CD39 and CD39L1) together with P2R (P2X7, P2Y2, and P2Y6) are significantly increased in both chronic pancreatitis and pancreatic cancer. CD39 and CD39L1 are preferentially associated with the vasculature and stromal elements in pathological tissues. P2X7 mRNA upregulation was associated with chronic pancreatitis, and heightened protein expression was found to be localized to infiltrating cells. P2Y2 was markedly upregulated in biopsies of pancreatic cancer tissues and expressed by fibroblasts adjacent to tumors. High-tissue mRNA levels of CD39 significantly correlated with better long-term survival after tumor resection in patients with pancreatic cancer. Heightened expression patterns and localization patterns of CD39, P2X7, and P2Y2 infer associations with chronic inflammation and neoplasia of the pancreas. Our data suggest distinct roles for CD39 and P2-purinergic signaling in both tissue remodeling and fibrogenesis with respect to human pancreatic diseases.

Epstein-Barr virus-associated lymphoepithelial carcinoma in the pancreas.

Lymphoepithelial carcinoma is a relatively common malignancy in the nasopharyngeal region, but it rarely occurs at other sites. We report a lymphoepithelial carcinoma in the pancreas of a 65-year-old male patient operated on for a gastric stump carcinoma 7 years previously. The solitary tumor in the pancreas presented as a circumscribed lesion and measured 5.5 cm in diameter. The tumor was densely infiltrated by lymphocytes, and the neoplastic cells fulfilled all criteria for a lymphoepithelial carcinoma. Several peripancreatic lymph node metastases were observed. Marked reactivity for Epstein-Barr virus (EBV) early RNA (EBER) was detected in the majority of tumor cells using in situ hybridization. Nuclear EBER signals were also detected in the previously operated gastric stump adenocarcinoma, which also exhibited focal lymphocytic infiltration but otherwise displayed a histology different from lymphoepithelial carcinoma and did not show local recurrence. Even though an unusually late metastasis of the gastric carcinoma cannot be ruled out, we favor the hypothesis that this patient developed an EBV-related pancreatic lymphoepithelial carcinoma as a second primary tumor, based on the considerable delay of this tumor manifestation, the unusual site, the pathologic presentation, the exclusively peripancreatic nodal spread, and the different histology of the lesion.

Influences of the lysosomal associated membrane proteins (Lamp-1, Lamp-2) and Mac-2 binding protein (Mac-2-BP) on the prognosis of pancreatic carcinoma.

BACKGROUND: Lamps and Mac-2-BP are ligands of galectin-3, and they were suggested to influence tumor proliferation and metastasis formation. The authors studied the expression of Lamp-1, Lamp-2, and Mac-2-BP in pancreatic carcinoma and evaluated their influence on patient prognosis. METHODS: Northern blot analysis, in situ hybridization, and immunohistochemistry were performed in 12 normal and 28 pancreatic carcinoma tissue samples and in pancreatic carcinoma cell lines. The molecular findings in the tumor samples were correlated with the prognosis and histopathologic tumor characteristics. In addition, in Lamp-1 transfected CAPAN-1 pancreatic carcinoma cells, cell proliferation was analyzed. RESULTS: Lamp-1, Lamp-2, and Mac-2-BP were overexpressed in 61% (1.6-fold increase, not significant), 71% (3.0-fold increase, P < 0.01), and 93% (5.6-fold increase, P < 0.01) of the pancreatic carcinoma samples. Lamp-1 and Lamp-2 immunoreactivity was present at the luminal side of the ductal carcinoma cells whereas Mac-2-BP immunoreactivity was diffusely spread over the whole cytoplasm and the nucleolus of ductal carcinoma cells. Correlation of the molecular data with clinical patient parameters revealed that patients whose tumors exhibited high Lamp-1 mRNA expression lived significantly longer (median, 17 months) after tumor resection than patients whose tumors exhibited low to moderate Lamp-1 mRNA levels (median, 8 months; P < 0.02). No relation between Lamp-2 and Mac-2-BP mRNA expression and any of the histopathologic parameters was found. Lamp-1 transfected CAPAN-1 cells showed decreased cell growth compared with the nontransfected cells. CONCLUSIONS: Lamp-1 might influence local tumor progression rather than the formation of tumor metastasis in pancreatic carcinoma, whereas Mac-2-BP and Lamp-2 seem to have little influence on these parameters in pancreatic carcinoma.