Current Trends in Endoscopic Diagnosis and Treatment of Early Esophageal Cancer.

Diagnosis of esophageal adenocarcinoma mostly occurs in the context of reflux disease or surveillance of Barrett's metaplasia. Optimal detection rates are obtained with high definition and virtual or dye chromoendoscopy. Smaller lesions can be treated with endoscopic mucosal resection. Endoscopic submucosal dissection (ESD) is an option for larger lesions. Endoscopic resection is considered curative (i.e., without significant risk of lymph node metastasis) if histopathology confirms en bloc and R0 resection of a well-differentiated (G1/2) tumor without infiltration of lymphatic or blood vessels and the maximal submucosal infiltration depth is 500µm. Ablation of remaining Barrett's metaplasia is important, to reduce the risk of metachronous cancer. Esophageal squamous cell cancer is associated with different risk factors, and most of the detected lesions are diagnosed during upper gastrointestinal endoscopy for other indications. Virtual high definition and dye chromoendoscopy with Lugol's solution are used for screening and evaluation. ESD is the preferred resection technique. The criteria for curative resection are similar to Barrett's cancer, but the maximum infiltration depth must not exceed lamina propria mucosae. Although a submucosal infiltration depth of up to 200 µm carries a substantial risk of lymph node metastasis, ESD combined with adjuvant chemo-radiotherapy gives excellent results. The complication rates of endoscopic resection are low, and the functional outcomes are favorable compared to surgery.

Endoscopic full-thickness resection using an over-the-scope device for treatment of recurrent / residual colorectal neoplasia: a single-center case series.

BACKGROUND: Endoscopic mucosal resection (EMR) in piecemeal technique is the treatment standard for larger flat or sessile colorectal lesions. The method is burdened by a high recurrence rate mostly presenting as difficult to resect lesions. In these situations, endoscopic full thickness resection (EFTR) with an over-the-scope device offers the option of complete resection despite scar formation. METHODS: We conducted a retrospective case review of 30 consecutive EFTR interventions on small (< 20 mm), difficult to resect recurrent / residual colorectal neoplastic lesions treated by EFTR. RESULTS: EFTR was technically feasible in 28/30 (93,3%) of the cases with an R0 resection in 24/30 (80%) and a median procedure time (marking to full thickness resection) of 34,5 min (11-120). After the first 15 procedures, the per-protocol rate increased from 13/15 to 15/15 and the R0 resection rate increased from 9/15 (69,2%) to 15/15 (100,0%; p < 0.01). One patient suffered from a delayed perforation the day after the procedure and needed emergency surgery (3,6%). Minor bleeding occurred in 3/28 patients (10,7%) and post-interventional fever in one patient (3,6%). The 30-day mortality rate was 0%. CONCLUSIONS: EFTR with an over-the-scope device is a useful method for endoscopic resection of difficult to treat recurrent or residual colorectal neoplasia after previous endoscopic therapy. High R0 resection rates were observed after a relatively short learning curve. The complication rate in this series seems acceptable given the complexity of the resected lesions.

Implementation of endoscopic submucosal dissection for early upper gastrointestinal tract cancer after primary experience in colorectal endoscopic submucosal dissection.

Background Current guidelines recommend endoscopic submucosal dissection (ESD) as a treatment option for early cancers of the upper gastrointestinal tract with absent or minimal risk of lymph node metastasis. However, due to the low prevalence of these entities, it is difficult to achieve a competence level for ESD of upper gastrointestinal tract cancers in the Western World. Here, we present single-center data on the implementation of upper gastrointestinal ESD after previous experience with 89 colorectal ESD cases. Methods Retrospective case series of 39 consecutive patients with early cancers of the esophagus (n = 13) or cardia and stomach (n = 26) treated with ESD over a 4-year period. Results ESD was technically feasible in all cases with en bloc, R0, and curative resection rates of 100 %, 76.9 %, and 71.8 %, respectively, and a mean procedure time of 100 minutes (30 - 360 minutes). After an initial 20 procedures, the R0 and curative resection rates increased from 65.0 % to 89.5 %, and from 60.0 % to 84.2 %, respectively. Complications were observed in four patients (10.3 %): three perforations, one case of delayed bleeding, and one esophageal stricture. No case required emergency surgery; the 30-day mortality rate was 0 %. Conclusion In this modest case series from Europe, we observed an effectiveness and complication rate for ESD for early esophageal and gastric cancer that are comparable to other series from Europe but also to more abundant data from Asia. The results indicate that even small numbers of upper gastrointestinal cancers can be managed adequately in centers with expertise in colorectal ESD.

Endoscopic resection techniques for colorectal neoplasia: Current developments.

Endoscopic polypectomy and endoscopic mucosal resection (EMR) are the established treatment standards for colorectal polyps. Current research aims at the reduction of both complication and recurrence rates as well as on shortening procedure times. Cold snare resection is the emerging standard for the treatment of smaller (< 5mm) polyps and is possibly also suitable for the removal of non-cancerous polyps up to 9 mm. The method avoids thermal damage, has reduced procedure times and probably also a lower risk for delayed bleeding. On the other end of the treatment spectrum, endoscopic submucosal dissection (ESD) offers en bloc resection of larger flat or sessile lesions. The technique has obvious advantages in the treatment of high-grade dysplasia and early cancer. Due to its minimal recurrence rate, it may also be an alternative to fractionated EMR of larger flat or sessile lesions. However, ESD is technically demanding and burdened by longer procedure times and higher costs. It should therefore be restricted to lesions suspicious for high-grade dysplasia or early invasive cancer. The latest addition to endoscopic resection techniques is endoscopic full-thickness resection with specifically developed devices for flexible endoscopy. This method is very useful for the treatment of smaller difficult-to-resect lesions, e.g., recurrence with scar formation after previous endoscopic resections.

Full-thickness resection with an over-the-scope device: possible translocation of adenoma tissue in a case of an incomplete resection at the appendix.

Background and study aims Clip-assisted endoscopic full-thickness resection has great potential for treatment of difficult-to-resect colorectal neoplasia. Here, we report on endoscopic full-thickness resection at the appendiceal orifice with the appendix in situ requiring emergency surgery due to acute appendicitis. Final histopathology showed appendicitis and residual serrated adenoma within the appendiceal stump, but unexpectedly, also a displaced adenoma fragment at the serosal surface of the cecum. Given the transmural placement of the clip prior to snare resection, translocation of neoplastic tissue to the extra luminal site in cases of incomplete adenoma/carcinoma resection could be a concern.

Endoscopic submucosal dissection for flat or sessile colorectal neoplasia > 20 mm: A European single-center series of 182 cases.

BACKGROUND AND STUDY AIMS: Colorectal endoscopic submucosal dissection (ESD) is an attractive method for en bloc resection of larger flat neoplastic lesions. Experience with this method is limited in the Western World. PATIENTS AND METHODS: A total of 182 consecutive flat or sessile colorectal lesions (cecum n = 43; right-sided colon n = 65; left-sided colon n = 11, rectum: n = 63) with a size > 20 mm (mean 41.0 ±â€Š17.4 mm) were resected in 178 patients. The data were recorded prospectively. RESULTS: ESD was technically feasible in 85.2 % of patients with a mean procedure time of 127.5 min (±â€Š99.8) min and a complication rate of 11.5 % (microperforation 9.3 %, delayed bleeding 2.7 %, no case of emergency surgery, 30-day mortality rate 0 %). For 155 successfully completed procedures the en bloc and R0 resection rates were 88.4 and 62.6 %. Efficacy was better for smaller lesions (20 mm to 49 mm; n = 131) than for larger lesions (50 mm to 140 mm; n = 51) with R0 rates of 70.8 vs. 40.5 % (P < 0.001) and procedure times of 92.7 ±â€Š62.4 minutes vs. 217.0 ±â€Š120.9 minutes (P < 0,001). CONCLUSIONS: This series confirms the efficacy of ESD for en bloc resection of colorectal lesions > 20 mm. RESULTS are satisfactory for lesions up to 50 mm. ESD for larger lesions was associated with low R0 resection rates and very long procedure times. The clinical consequences of microperforations were minor and do not argue against the spread of ESD in the West. Meeting presentations: The data were presented in part at DDW 2014, Chicago IL, USA (Gastrointest Endosc 2014; 79: AB536).

Outpatient Intraperitoneal Catumaxomab Therapy for Malignant Ascites Related to Advanced Gynecologic Neoplasms.

BACKGROUND: Catumaxomab (CATU) is a trifunctional antibody approved for intraperitoneal (i.p.) treatment of malignant ascites (MA) related to carcinomas expressing the epithelial cell-adhesion molecule (EpCAM). CATU is mostly given to hospitalized patients, although outpatient treatment seems appropriate in selected individuals. This observational trial sought to obtain more detailed information regarding the feasibility of CATU in outpatients with MA related to various gynecologic tumors, including epithelial ovarian (EOC) and metastatic breast cancer (MBC). MATERIALS AND METHODS: A total of 30 patients were included, 17 with EOC, 7 with MBC, and 6 with other malignancies. The patients had failed a median of 5 (range 1-12) previous systemic treatments. CATU was administered via an indwelling i.p. catheter at four increasing doses (i.e., 10, 20, 50, and 150 µg) given at 4-day intervals over 2 weeks. Toxicities were scored according to the Common Terminology Criteria for Adverse Events, version 4.03. Puncture-free survival (PuFS) was calculated from the start of CATU until the next puncture for MA, death, or loss to follow-up. Overall survival (OS) was calculated from the start of CATU to death from any reason or loss to follow-up. We also investigated various clinical parameters to predict PuFS and OS. These included age, tumor type, performance status, intensity of pretreatment, presence of extraperitoneal metastases, relative lymphocyte count at baseline, patient adherence to therapy, and the patients' ability to undergo systemic treatment after CATU. RESULTS: CATU was exclusively given on an outpatient basis, and 19 patients (63.3%) received all four planned i.p. instillations. Toxicity was the reason for discontinuation in only 2 patients. Toxicity was generally manageable, with abdominal pain, nausea/vomiting, fatigue, and fever the predominant adverse effects. Secondary hospitalization was necessary for 7 patients (23.3%), with a general deteriorated condition in 5 and fever/infection or abdominal pain in 1 patient each. Subsequent systemic treatment was possible in 11 patients (36.7%). Only 5 patients (16.7%) required a second puncture after i.p. CATU. The median PuFS was 56 days, and the median OS was 79.5 days. Positive predictors of both PuFS and OS were performance status, absence of extraperitoneal tumor, the capability to receive all four CATU infusions, and the ability to undergo subsequent systemic treatment. CONCLUSION: Outpatient i.p. CATU therapy for MA related to various gynecologic carcinomas is safe and effective in producing good ascites control in most individuals, allowing for subsequent systemic therapy in a substantial proportion of patients. IMPLICATIONS FOR PRACTICE: Intraperitoneal treatment with the trifunctional antibody catumaxomab (CATU) was possible in a selected population of 30 outpatients with malignant ascites due to epithelial female genital tract or breast carcinoma. Toxicity was largely manageable. Patients in good condition at baseline, without extraperitoneal tumor and/or liver metastases, and with the ability to complete all four planned CATU instillations and the capability of undergoing subsequent systemic therapy benefited the most in terms of both puncture-free and overall survival. Outpatient i.p. CATU is safe and effective in a selected group of patients with malignant ascites due to various gynecologic malignancies and could be cost-saving compared with an inpatient approach.

Modulators of the urokinase-type plasminogen activation system for cancer.

IMPORTANCE OF THE FIELD: The serine protease urokinase-type plasminogen activator (uPA) and its receptor uPAR as well as two specific inhibitors, the plasminogen activator inhibitor type-1 (PAI-1) and type-2 (PAI-2), are involved in the control of extracellular matrix turnover and tumor growth. Data accumulating over the past 20 years have made increasingly clear that the uPA system has a multifunctional role in neoplastic evolution, affecting cancer cell proliferation, tumor angiogenesis, adhesion and migration. AREAS COVERED IN THIS REVIEW: Several therapeutic strategies inhibiting the uPA system have been or are currently being developed for suppression of tumor growth. This review examines the role of the uPA system in tumor progression and assesses the various therapeutic strategies developed to selectively exploit this system. WHAT WILL THE READER GAIN: We focus on the therapeutic developments of the last 15 years. In addition to antibodies and recombinant uPA- or uPAR-derived proteins, various antagonistic peptides as well as small molecules have been designed and synthesized that inhibit the uPA system, leading to reduced tumor progression. TAKE HOME MESSAGE: The multifunctional potential of the uPA system in cancer has rendered this system an attractive novel target for anticancer therapy. A few novel tumor biology-based therapeutic strategies reported here, opening new ways for patient-optimized and individualized cancer therapy. It may be the right time to evaluate the hypothesis that the uPA system plays a pivotal role in cancer progression and that targeting this system will lead to clinical benefit in cancer patients.

Tumor stroma is the predominant uPA-, uPAR-, PAI-1-expressing tissue in human breast cancer: prognostic impact.

UNLABELLED: Urokinase-type plasminogen activator (uPA), its receptor (uPAR) and its inhibitor PAI-1, play a key role in tumor invasion and metastasis. uPA and PAI-1 were the first novel tumor biological factors to be validated at the highest level of evidence regarding their clinical utility in breast cancer. Their antigens are determined in tumor tissue extracts by standardized, quality-assured immunometric assays (ELISA). Since the late 1980s, numerous independent studies have demonstrated that patients with low levels of uPA- and PAI-1 in their primary tumor tissue have significantly better survival than patients with high levels of either factor. However, it is unclear whether it is their (relative) levels in the tumor stroma or in the tumor cells themselves that is most relevant to patient outcome. This missing knowledge leads to an uncertainty concerning the management of breast cancer tissue specimens. It is unclear how much tumor stroma is allowed in one tumor tissue specimen for an adequate assessment of the patients' outcome. This is the first study in which tumor cells and stromal tissue of invasive breast carcinomas (n=60) were separated by laser capture microdissection followed by ELISA-based determination of the uPA-, uPAR- and PAI-1-levels. In addition, we have assessed uPA-, uPAR- and PAI-1 distribution in formalin-fixed, paraffin-embedded breast cancer specimens (n=60) by immunohistochemistry. The uPA-, uPAR- and PAI-1 in tumor stroma only, tumor cells only and not separated tumor tissue did not show any significant differences in protein-levels determined by ELISA. Cox regression analysis showed that patients with high uPA-, high uPAR-, and/or high PAI-1-levels, as compared to patients with low levels of either factor, showed a significantly shorter relapse-free survival and overall survival (p=0.000001). These results suggest that a strong expression of uPA, uPAR and PAI-1 in the tumor stroma, as well as in tumor cells, have the same impact on the clinical behaviour of breast cancer. CONCLUSION: When using uPA- and PAI-1 levels as prognostic and predictive factors in breast cancer the quantity of tumor stroma in the tumor tissue specimen is not relevant for the assessment of the patients' outcome.

Amplification of the urokinase-type plasminogen activator receptor (uPAR) gene in ductal pancreatic carcinomas identifies a clinically high-risk group.

The serine protease urokinase-type plasminogen activator (uPA) and its receptor (uPAR) are known to be involved in the invasion and metastasis of many solid tumors. In this study, we analyzed the role of the uPAR/uPA system in both the development and progression of pancreatic cancer in invasive ductal adenocarcinomas of the pancreas (PDA) and their premalignant precursors (PanIN lesions) in 50 patients with long-term clinical follow-up. We found overexpression of the uPAR in 48 of 50 invasive carcinomas as well as in a large proportion of high-grade PanIN lesions by immunohistochemistry and in situ hybridization. Fluorescence in situ hybridization analysis showed both high- and low-level amplification of the uPAR gene in approximately 50% of cases with strictly identical patterns between invasive cancers and their accompanying precursor lesions. These results suggest that PDA may develop from PanIN lesions along an alternative rather than a sequential molecular pathway. The detection of the gene amplification of uPAR was a highly significant, adverse prognostic parameter (P < 0.001) because it likely renders the tumors more sensitive to uPA and its proproliferative and anti-apoptotic signals. We conclude that the activation of the uPAR/uPA system is an early event in the development of PDA and that uPAR gene amplifications identify a subgroup of particularly aggressive tumors, making the uPAR/uPA system a critical and highly promising target for therapeutic interventions.

A 7.5-year prospective study of longer than 18 months type-specific human papillomavirus persistence in a routine cytology-based cervical screening population of about 31,000 women in West Germany.

The objective of this study was to analyse the prevalence, infection pattern, duration and outcome of long-term, type-specific, persistent human papillomavirus (HPV) infections in a routine cytology-based cervical screening population of West German women followed up for 7.5 years. From a screening population of 31,000 women, a strictly selected cohort of 100 patients with > or =18-month persistent, type-specific HPV infection were prospectively followed up for a mean of 35.52 months (+/-13.0). HPV type prevalence and odds ratios for regression, progression and steady state were analysed, as well as the influence of age and HPV coinfection on outcome. Altogether, 21 different genotypes were detected. Seventy-two percent of women were infected with high-risk HPVs, 24% with low-risk and 4% with unknown risk HPV types; 44% of cases had coinfections with multiple HPV types. The risk of progression in low-grade squamous intraepithelial lesions and high-grade squamous intraepithelial lesions was the highest for infections with high-risk HPVs [odds ratio: 2.2 (0.79-6.11, 95% confidence interval)], whereas cases with low-risk and unknown risk HPVs tended to regress or remained unchanged during follow-up. The mean duration of infections showed considerable variation among the different HPV types and risk groups detected and ranged between 19.7 and 54.3 months. Age was not significantly associated with disease progression and infection duration, and histology had a poor sensitivity for detecting high-grade dysplasia. In conclusion, detecting long-term persistent HPV infections by genotyping may help to identify women with cervical intraepithelial lesions who are at lower and higher risk of developing high-grade precancer and cancer. This may influence future screening strategies and therapy decisions.

The prevalence and distribution of human papillomavirus genotypes in oral epithelial hyperplasia: proposal of a concept.

BACKGROUND: Evidence is accumulating for the aetiological role of human papillomavirus (HPV) in the pathogenesis of potentially malignant oral mucosal lesions and squamous cell carcinomas. METHODS: Paraffin tissue sections from 49 patients with 'white patches' of the oral mucosa were investigated histologically, by broad-spectrum PCR followed by genotyping and chromogenic in situ hybridisation (CISH). RESULTS: Histologically, 33 flat hyperplasias and 16 papillary hyperplasias were diagnosed. Twenty-two of 28 samples studied (78.6%) were positive for HPV DNA by PCR and six were negative. The following HPV types were detected in decreasing order of prevalence: HPV 35, HPV 6, HPV16, HPV 53, HPV 18, HPV 51 and HPV 55. Seventeen samples (60.7%) contained high-risk HPV DNA. Using CISH, >or= 1 HPV signals were detected at least in a few epithelial cells in 95% of cases studied. All but one case were positive with the high-risk HPV probe and all HPV infections contained low viral load. Concordant positive results both by PCR and CISH were detected in 14 of 19 cases (73.7%) analysed. CONCLUSIONS: The high prevalence of HPV infection in hyperplastic 'white patches' of the oral mucosa supports the putative role of HPV at an early stage of oral carcinogenesis. These results further indicate that the majority of white oral mucosal lesions - flat, exophytic, wart-like or papillary proliferations - could be considered as the clinical manifestations of oral HPV infection. This finding has clinical relevance regarding therapy and patient management and may help in elucidating the role of HPV infection in oral carcinogenesis.

Quantitative molecular grading of bladder tumours: a tool for objective assessment of the biological potential of urothelial neoplasias.

The present study aimed to assess whether patients with bladder urothelial tumours can be more objectively stratified into low- and high-risk groups for recurrence and progression using a 2-tired molecular grading scheme, than by subjective histopathological grading alone. Biopsy material from 45 consecutive patients with urothelial bladder neoplasias (2 papillary urothelial neoplasm of low malignant potentials, 18 pTa, 1 pTis, 19 pT1 and 5 pT2) was analysed for immunohistochemical Ki-67 and p53 expression. Labelling indices were assessed by automated cellular image analysis. UroVysion FISH test results were evaluated by automated signal counting, and DNA ploidy of single nuclei preparations were measured by image cytometry. Sixty-nine percent of cases showed >10% Ki-67 LI, 64% had >10% p53 LI, 53% revealed DNA aneuploidy and 56% expressed a high-risk FISH pattern. Based on a combination of single molecular markers, 75% of neoplasias were classified as high molecular grade. Tumour stage and histopathological grade were significantly associated with FISH pattern, DNA ploidy and MIB1 LI. Stage was also related with molecular grade. Clinical outcome showed a significant correlation with MIB1 LI and molecular grade. P53 had neither diagnostic nor prognostic relevance, nor was there any correlation between histological and molecular grade. Our preliminary data strongly suggest that the combination of quantitative biomarkers provides superior and objective prognostic tools in bladder urothelial neoplasias compared to classic clinicopathological features and indices.

The urokinase-system in tumor tissue stroma of the breast and breast cancer cell invasion.

The urokinase-system has been implicated in tumor spread. The serine protease urokinase-type plasminogen activator (uPA), its receptor (uPAR) and its inhibitor (PAI-1) are involved in the control of extracellular turnover, cell migration, invasion, cell signalling, proliferation, apoptosis and angiogenesis leading to a variety of different responses, under both physiological and pathological conditions. uPA and PAI-1 were the first novel tumor biological factors to be validated at the highest level of evidence regarding their clinical utility in breast cancer. However, it is unclear whether it is their (relative) levels in the tumor stroma or in the tumor cells themselves that is the most relevant to patients outcome. This is the first study in which tumor cells and stromal tissue of invasive breast carcinomas were separated by laser capture microdissection followed by ELISA-based determination of the uPA, uPAR and PAI-1 levels. In addition, we localized uPA, uPAR and PAI-1 distribution in invasive breast cancer (n=30) and in ductal carcinoma in situ (DCIS, n=30) by immunohistochemistry and in situ hybridization. We have demonstrated that no significant differences between uPA, uPAR and PAI-1 levels in tumor stroma only, tumor cells only and not separated breast cancer tissue exist (p>0.05). Our results suggest that similar expression levels of these factors in both compartments and in not separated breast cancer tissue may have the same impact on the clinical behavior of breast cancer. These results are an important issue for practical use of tissue sampling. For using uPA and PAI-1 levels as prognostic and predictive factors in breast cancer the quantity of tumor stroma in the tumor tissue specimen is not relevant for assessment patients outcome. Our results were confirmed by immunohistochemistry and in situ hybridization analysis showing that in nearly all cases of invasive carcinomas and DCIS fibroblasts as well as macrophages strongly express uPA, uPAR and PAI-1. Prompted by our immunohistological results that nearly all myoepithelial cells of DCIS exhibit uPA, uPAR and PAI-1, we investigated these important host cells in detail. We have demonstrated by multimodal methods that uPAR and PAI-1 protein and mRNA is expressed in most myoepithelial cells of DCIS. Additionally, we furnish evidence that uPAR expression of myoepithelial cells are important for uPAR Vitronectin-associated cell-matrix interaction, which regulates cell adhesion and detachment. We speculate that the loss of the anti-invasive myoepithelial cell layer in DCIS may be triggered by PAI-1 and could be an early sign of subsequent tumor cell invasion.

Outcome of invasive and noninvasive intraductal papillary-mucinous neoplasms of the pancreas (IPMN): a 10-year experience.

BACKGROUND: Intraductal papillary-mucinous neoplasms (IPMN) were officially introduced into the TNM classification in 1996. Based on a two-center database, we reevaluated histopathological findings, clinicopathological pattern, predictive markers for malignancy, and outcome. METHODS: Between 1996 and 2006, a total of 1424 pancreatic resections were performed in the University Hospitals Dresden and Mannheim. Pathologists of both institutions reviewed the IPMN diagnoses and other with cystic or solid tumor diagnoses. All possible markers, such as diabetes, jaundice, etc., were analyzed for prediction of malignancy. We performed a survival analysis based on the morphologic classification to determine the prognosis of IPMN. RESULTS: There were 43 patients of primarily diagnosed IPMN along with 1174 patients with diagnoses, such as ductal adenocarcinoma. In 207 patients, the diagnoses revealed other cystic or small solid tumors. A histopathological review of the latter patients revealed 54 IPMNs, resulting in a total of 97 IPMN patients (29 noninvasive, 68 invasive). All IPMN patients had a median survival of 36 months. Recurrence occurred more frequently in invasive IPMN. Predictive markers of malignancy were pain, preoperative weight loss, jaundice, and elevated CA 19.9. The strongest independent prognostic factor was invasive growth. The survival analysis revealed excellent prognosis for noninvasive IPMN. CONCLUSIONS: Since the introduction of IPMN in 1996, even specialized centers have had to deal with a learning curve. By reevaluating all cystic or small solid tumors, centers can improve and their patients' treatment can be optimized. Because the preoperative diagnostic methods are not sensitive enough to differentiate between benign and malignant lesions, surgery is advocated for all main duct IPMN, because they have a high malignant potential. For branch duct IPMN, surgery is advocated if the lesion is symptomatic, >3 cm, or has enlarged nodules.

The urokinase-system--role of cell proliferation and apoptosis.

The serine protease urokinase-type plasminogen activator (uPA) and its receptor (uPAR) are involved in the control of extracellular matrix turnover, cell migration, invasion and cell signalling leading to a variety of different responses, under both physiological and pathological conditions. The urokinase receptor, binding to the growth factor-like domain of uPA, directs membrane-associated extracellular proteolysis and signals through transmembrane proteins, thus regulating tissue regeneration, angiogenesis, cancer growth and metastasis. Since these physiological and patho-physiological processes of the uPA-system are known, less informations concerning uPA-induced cell proliferation and anti-apoptotic effects of the uPA-system are available. Recent studies show a close relationship of the uPA-system and cell proliferation/ apoptosis. uPA is responsible for the activation and release of different growth factors and modulates the cell proliferation/apoptosis ratio through the dynamic control of cell-matrix interactions. This article focuses on the important role of the uPA/uPAR-system for cell proliferation and apoptosis.