Mid-term absorbable monofilament is safe and effective for gastrointestinal anastomosis - PROMEGAT - A single-arm prospective observational study.

INTRODUCTION: Various suture materials and suture techniques are used to perform gastrointestinal anastomosis after tumour resection, but the best combination is still a matter of debate. METHODS: This multi-centre, international, single-arm, prospective observational study aimed at demonstrating the non-inferiority of a mid-term absorbable monofilament in comparison to braided sutures in gastrointestinal anastomosis. Monosyn suture was used to create the gastrointestinal anastomosis and the frequency of anastomotic leakage until day of discharge was chosen as the primary parameter. The outcome was compared to the results published for braided sutures in the literature. Secondary parameters were the time to perform the anastomosis, length of hospital stay, costs, and postoperative complications. RESULTS: The anastomosis leakage rate was 2.91%, indicating that Monosyn suture was not inferior to braided sutures used in gastrointestinal anastomosis. Of the reported anastomotic suture techniques, the single layer continuous method was the fastest and most economical technique in the present observational study. CONCLUSION: Monosyn suture is safe and effective in gastrointestinal anastomosis and represents a good alternative to other sutures used for gastrointestinal anastomosis. With regard to safety, time and cost-efficiency, the single-layer continuous technique should be considered a preferred method. The transfer of results from clinical studies into daily practice with regard to surgical techniques for gastrointestinal anastomosis should be further evaluated in larger studies or in nationwide registries.

Correction: Use of Mesh in Laparoscopic Paraesophageal Hernia Repair: A Meta-Analysis and Risk-Benefit Analysis.

[This corrects the article DOI: 10.1371/journal.pone.0139547.].

Use of Mesh in Laparoscopic Paraesophageal Hernia Repair: A Meta-Analysis and Risk-Benefit Analysis.

INTRODUCTION: Mesh augmentation seems to reduce recurrences following laparoscopic paraesophageal hernia repair (LPHR). However, there is an uncertain risk of mesh-associated complications. Risk-benefit analysis might solve the dilemma. MATERIALS AND METHODS: A systematic literature search was performed to identify randomized controlled trials (RCTs) and observational clinical studies (OCSs) comparing laparoscopic mesh-augmented hiatoplasty (LMAH) with laparoscopic mesh-free hiatoplasty (LH) with regard to recurrences and complications. Random effects meta-analyses were performed to determine potential benefits of LMAH. All data regarding LMAH were used to estimate risk of mesh-associated complications. Risk-benefit analysis was performed using a Markov Monte Carlo decision-analytic model. RESULTS: Meta-analysis of 3 RCTs and 9 OCSs including 915 patients revealed a significantly lower recurrence rate for LMAH compared to LH (pooled proportions, 12.1% vs. 20.5%; odds ratio (OR), 0.55; 95% confidence interval (CI), 0.34 to 0.89; p = 0.04). Complication rates were comparable in both groups (pooled proportions, 15.3% vs. 14.2%; OR, 1.02; 95% CI, 0.63 to 1.65; p = 0.94). The systematic review of LMAH data yielded a mesh-associated complication rate of 1.9% (41/2121; 95% CI, 1.3% to 2.5%) for those series reporting at least one mesh-associated complication. The Markov Monte Carlo decision-analytic model revealed a procedure-related mortality rate of 1.6% for LMAH and 1.8% for LH. CONCLUSIONS: Mesh application should be considered for LPHR because it reduces recurrences at least in the mid-term. Overall procedure-related complications and mortality seem to not be increased despite of potential mesh-associated complications.

A-Part Gel, an adhesion prophylaxis for abdominal surgery: a randomized controlled phase I-II safety study [NCT00646412].

BACKGROUND: Intra-abdominal surgical intervention can cause the development of intra-peritoneal adhesions. To reduce this problem, different agents have been tested to minimize abdominal adhesions; however, the optimal adhesion prophylaxis has not been found so far. Therefore, the A-Part(®) Gel was developed as a barrier to diminish postsurgical adhesions; the aim of this randomized controlled study was a first evaluation of its safety and efficacy. METHODS: In this prospective, controlled, randomized, patient-blinded, monocenter phase I-II study, 62 patients received either the hydrogel A-Part-Gel(®) as an anti-adhesive barrier or were untreated after primary elective median laparotomy. Primary endpoint was the occurrence of peritonitis and/or wound healing impairment 28 ± 10 days postoperatively. As secondary endpoints anastomotic leakage until 28 days after surgery, adverse events and adhesions were assessed until 3 months postoperatively. RESULTS: A lower rate of wound healing impairment and/or peritonitis was observed in the A-Part Gel(®) group compared to the control group: (6.5 vs. 13.8 %). The difference between the two groups was -7.3%, 90 % confidence interval [-20.1, 5.4 %]. Both treatment groups showed similar frequency of anastomotic leakage but incidence of adverse events and serious adverse events were slightly lower in the A-Part Gel(®) group compared to the control. Adhesion rates were comparable in both groups. CONCLUSION: A-Part Gel(®) is safe as an adhesion prophylaxis after abdominal wall surgery but no reduction of postoperative peritoneal adhesion could be found in comparison to the control group. This may at least in part be due to the small sample size as well as to the incomplete coverage of the incision due to the used application. TRIAL REGISTRATION: NCT00646412.

The TICAP-Study (titanium clips for appendicular stump closure): A prospective multicentre observational study on appendicular stump closure with an innovative titanium clip.

BACKGROUND: To evaluate the effectiveness and safety of the DS Titanium Ligation Clip for appendicular stump closure in laparoscopic appendectomy. METHODS: Overall, 502 patients undergoing laparoscopic appendectomy were recruited for this observational multicentre study in nine study centres between October 2011 and July 2013. The clip was finally applied in 390 patients. Primary outcome variables were feasibility of the clip, intra-abdominal surgical site (abscesses, stump leakages) and superficial wound infections. Patients were followed 30 days after surgery. RESULTS: The clip was applicable in nearly 80 % of patients. Reasons for not applying the clip were mainly an inflamed caecum or a too large diameter of the appendix base. Superficial wound infections were found in nine (2.31 %), intra-abdominal abscesses in five (1.28 %), appendicular stump leak in one (0.26 %), and other adverse events in 22 (5.64 %) patients. In total, 12 (3.08 %) patients were re-admitted to hospital for treatment. Seven re-admissions were surgery-related; ten (2.56 %) patients had to be re-operated. One patient died during the course of the study due to persisting peritonitis (mortality 0.26 %). CONCLUSIONS: The results suggest that the DS Titanium Ligation Clip is a safe and effective option in securing the appendicular stump in laparoscopic appendectomy. The complication rates found with the use of the DS-Clip are comparable to the rates in the literature when other methods are used. TRIAL REGISTRATION: NCT01734837 .

Survival after renal cell carcinoma metastasis to the thyroid: single center experience and systematic review of the literature.

BACKGROUND: Renal cell carcinoma can metastasize to uncommon sites, for example, the thyroid gland where metastases are rarely found. To determine the patient survival and the time between cancer diagnosis and thyroid metastasis, we analyzed a large patient cohort from our hospital records and performed a systematic review. PATIENTS AND METHODS: Patients diagnosed between 1978 and 2007 with thyroid metastases from renal cell carcinoma were retrospectively identified from the hospital database. A systematic literature search was performed for publications describing at least three cases of thyroid metastasis from renal cell carcinoma. Case data from the identified studies were collected and used to determine the survival data. RESULTS: We identified 34 patients (19 females) from our hospital records with a mean age of 67 years (range, 33-79) when thyroid metastasis was diagnosed. Median time to primary metastasis after resection of renal cell carcinoma was 6.5 years (range, 0-25) with a single case of synchronous metastasis. Median survival after primary metastasis was 4.7 years (95% confidence interval [CI]: 1.8-7.6). The systematic review included 32 studies with 285 patients. Case data could be extracted for 202 patients. Median time to thyroid metastasis (without synchronous cases) was 8.8 years (95% CI: 7.5-10.1). Median actuarial survival after thyroid metastasis was 3.4 years (95% CI: 2.2-4.6). Total thyroidectomy was not associated with a better survival compared to partial thyroidectomies. CONCLUSIONS: Time to thyroid metastasis of renal cell carcinoma can be very long, and survival after thyroidectomy is favorable compared to metastasis to other sites.

Rationale, bench testing and in vivo evaluation of a novel 5 mm laparoscopic vessel sealing device with homogeneous pressure distribution in long instrument jaws.

BACKGROUND: In 1998, an electrothermal bipolar vessel sealing (EBVS) system was introduced and quickly became an integral component of the surgical armamentarium in various surgical specialties. Currently available EBVS instruments use a scissor-like jaw configuration and closing mechanism, which causes decreasing compression pressure from the proximal to the distal end of the jaws. A new EBVS system is described here which utilizes a different instrument jaw configuration and closing mechanism to enable a more homogeneous pressure distribution despite longer instrument jaws. METHODS: Results of jaw pressure distribution measurements as well as sealing experiments with subsequent burst pressure measurements ex vivo on bovine uterine arteries are demonstrated. Furthermore, an in vivo evaluation of the new EBVS system in a canine and porcine model including histological examination is presented. RESULTS: The device revealed an even pressure distribution throughout the whole jaw length. The ex vivo burst pressure measurements revealed high average burst pressures, above 300 mmHg, independent of the outer diameter (1 to 7 mm) of the tested vessels. Histological evaluation of sealed vessels 21 days postoperatively demonstrated sealed and fused vessels without adjacent tissue damage. CONCLUSIONS: The even pressure distribution leading to a sufficient tissue sealing in combination with the novel closing mechanism and extended jaw length differentiates the novel device from other available EBVS systems. This might offer a reduction of the overall procedure time, which should be further evaluated in a clinical study.

Fibrosis and pancreatic lesions: counterintuitive behavior of the diffusion imaging-derived structural diffusion coefficient d.

INTRODUCTION: Stroma reaction leading to fibrosis is the most characteristic histopathological feature of both pancreatic carcinoma and chronic pancreatitis with increased fibrosis compared with healthy pancreatic tissue and further increased fibrosis during radiochemotherapy. Recent studies using intravoxel incoherent motion-derived parameters did not show differences for structural diffusion constant D between these 2 diseases. The aim of this study was to verify the hypothesis that D correlates with the histopathological grade of fibrosis in pancreatic lesions. MATERIALS AND METHODS: We included 15 patients with histopathologically proven pancreatic carcinoma and 9 patients with histopathologically proven focal chronic pancreatitis. Diffusion-weighted magnetic resonance imaging was performed using 10 b values between 25 and 800 s/mm² before surgery. We calculated the apparent diffusion coefficient and the intravoxel incoherent motion-derived parameters D and f within tumors and focal chronic pancreatitis. The resected tissue was evaluated with regard to the grade of fibrosis. RESULTS: Fourteen patients were found to have moderate fibrosis and 10 patients had severe fibrosis. The difference between the D values for the moderate and severe fibrosis was significant with mean (SD) D value of 1.02 × 10⁻³ (0.48 × 10⁻³ mm/s) and mean (SD) D of 1.22 × 10⁻³ (0.76 × 10⁻³) mm²/s. There were no significant differences for the f and ADC values. CONCLUSIONS: Contrary to our hypothesis, D rises from moderate to severe fibrosis. It seems that cellular complexes surrounded by fibrosis provide more structural limitations than does fibrosis alone. Our data suggest that D is not intuitively related to the degree of fibrosis. Compared with healthy tissue, D is reduced in moderate fibrosis but increases when severe fibrosis is present.

Renal tumors and second primary pancreatic tumors: a relationship with clinical impact?

BACKGROUND: The occurrence of synchronous or metachronous renal cell carcinoma and pancreatic tumors has been described only in a few cases in the scientific literature. The study of double primary cancers is important because it might provide understanding of a shared genetic basis of different solid tumors and to detect patients at risk for secondary malignancy. METHODS: In a combined analysis of patient registries from University Departments of Urology and Visceral Surgery, 1178 patients with pancreatic tumors and 518 patients with renal cell carcinoma treated between 2001 and 2008 were evaluated, RESULTS: Overall 16 patients with renal cancer and synchronous (n = 6) or metachronous (n = 10) primary pancreatic tumors were detected. The median survival of all patients was 12.6 months, for the patients with synchronous resections 25.7 months and for the patients with metachronous resections 12.2 months, respectively. CONCLUSIONS: The association between these two etiologies of malignancy demands more detailed epidemiological and molecular investigation. Clinical outcomes would support a resection as a recommended clinically valid option.

[Barriers to clinical studies involving medical devices]. / Hürden bei Studien mit Medizinprodukten.

Clinical trials with medical devices need to be considered in terms of the complexity of surgical procedures. Creating the proper environment for the conduct of trials includes improved academic career opportunities in the field of clinical research, methodological competence, and established structures. The challenges and pitfalls in the design of clinical trials involving medical devices are based on aspects such as blinding, placebo, learning curves and surgeons' expertise. Surgical procedures should be standardised, and a study hypothesis needs to be established which is answerable by a relevant and feasible sample size. Besides the above-mentioned challenges, efficient interactions between authorities, universities, hospitals, and medical device manufacturers are mandatory to allow for quality and relevance of clinical studies in this field.

Expression of galectin-3 in pancreatic ductal adenocarcinoma.

Galectin-3 influences neoangiogenesis, tumor cell adhesion, and tumor-immune-escape mechanisms. Hence, the expression of galectin-3 in pancreatic ductal adenocarcinoma (PDAC) was evaluated. Galectin-3 expression in PDAC cell lines was proven by the presence of intracellular protein and by release into the supernatant. Furthermore, galectin-3 was found in the majority of human tissue samples. Serum concentrations of galectin-3 in PDAC patients did not differ significantly from healthy donors and did not correlate with established tumor markers. In conclusion, galectin-3 is expressed in PDAC tissues suggesting a role in tumor development; however, no relationship between expression and clinical findings could be established.

Galectin-3 inhibits the chemotaxis of human polymorphonuclear neutrophils in vitro.

In the recent years, the participation of the animal lectin galectin (gal)-3 in inflammation and in host defence mechanisms was extensively studied. In vivo studies implied - among others - a role of gal-3 in the recruitment of polymorphonuclear neutrophils (PMN) to sites of bacterial infection. In that context, we asked the question whether gal-3 was chemotactic for PMN. Functional assays revealed that gal-3 was not chemotactic for PMN, but that it inhibited the spontaneous migration and the chemotaxis of PMN towards complement C5a, interleukin (IL)-8, or ATP. Moreover, gal-3 inhibited the shape change and the actin polymerisation of PMN that occurs in response to C5a or IL-8. By use of FITC-labelled gal-3, we found that it attached rapidly to the PMN membrane in a lactose-sensitive manner. In response to gal-3 the MAP kinase p38 was phosphorylated. This kinase is crucial for the migration of PMN towards end-target chemokines, such as C5a, and is activated in response to C5a or IL-8. When PMN were preincubated with gal-3, the C5a-induced p38 phosphorylation was transiently enhanced, but eventually down-modulated. We conclude that by interfering with the chemokine-induced p38 phosphorylation gal-3 inhibits chemotaxis of PMN.

Down-regulation of CXCL1 inhibits tumor growth in colorectal liver metastasis.

As part of ongoing studies to obtain a global picture of invasion related events in colorectal liver metastases, here, we report our findings on gene expression of the pro-angiogenic subgroup of chemokines, the CXCL-ELR+ chemokines. Apart from their pro-angiogenic and chemoattractant function, these chemokines appear to also contribute to tumor cell transformation, growth and invasion. In our nude mouse model of colorectal liver metastases, we found CXCL1,2,3,5 and 8 (IL-8) to be up-regulated in the tumor cells of the invasion front as compared to the tumor cells in the inner parts of the tumor. ShRNA mediated down-regulation of the most prominently up-regulated group member, CXCL1/gro-alpha resulted in inhibition of cell viability, invasion and proliferation. In vivo, down-regulation of CXCL1 resulted in a nearly complete prevention of tumor growth in nude mice. Mechanistically, auto-regulatory mechanisms involving NF-kappaB and Akt appear to be involved in pro-tumorigenic functions of CXCL1.

Critical appraisal of the International Study Group of Pancreatic Surgery (ISGPS) consensus definition of postoperative hemorrhage after pancreatoduodenectomy.

PURPOSE: Postpancreatectomy hemorrhage (PPH) is one of the most serious complications after pancreatoduodenectomy (PD). This study analyzed and validated the International Study Group of Pancreatic Surgery (ISGPS) definition of PPH and aimed to identify risk factors for early (<24 h) and late PPH. METHODS: Patients who underwent PD for pancreatic head tumors between 2001 and 2008 were included and complications were prospectively recorded. Factors associated with PPH were assessed by uni- and multivariate analysis. RESULTS: Complete datasets were available for 796 patients. Classic and pylorus-preserving PD was performed in 13.8% and 86.2% of the patients, respectively. According to the ISGPS definition, PPH occurred in 29.1% of the cases (232 of 796 patients): 4.8% grade A, 15.2% grade B, and 9.2% grade C. The definition is based largely on surrogate markers (e.g., transfusion requirement) that are affected by other critical illnesses and more than 97% of patients with mild PPH had no clinical signs of bleeding. The need for postoperative intensive care as well as the incidence of pancreatic fistula, relaparotomy, and mortality rates significantly increased from grades A to C. Thirty-seven patients (4.6%) required interventional (endoscopy or angiography) and/or relaparotomy for PPH. Relaparotomy for PPH was performed in 3.1% of all patients. Independent risk factors for early PPH were preoperative anemia (hemoglobin, <11 mg/dl) and multivisceral resection while advanced age, chronic renal insufficiency, increased blood loss, and long operation time were associated with late PPH. CONCLUSIONS: The ISGPS definition of PPH is feasible and applicable but produces a high rate of false positive mild PPH cases. The different grades still significantly correlate with relevant outcome variables, thus the definition discriminates postoperative courses, but a minor modification of the definition of mild PPH is suggested. The new results further demonstrate the need to optimize preoperative anemia and chronic renal insufficiency.

Risk-benefit assessment of closed intra-abdominal drains after pancreatic surgery: a systematic review and meta-analysis assessing the current state of evidence.

BACKGROUND: This systematic review aims to analyse the risk-benefit association of (1) prophylactic drains and/or (2) the time of their removal after pancreatic resection. MATERIALS AND METHODS: A systematic literature search (Medline, Embase, Biosis, and The Cochrane Library) was performed to identify all types of controlled trials comparing the role of drainage or the time of their removal on postoperative complications following pancreatic surgery. Meta-analysis was performed using a random-effects model. RESULTS: Four studies, two randomised trials and two prospective cohort studies, were included in the systematic review and meta-analysis. Removal of drains at day 5 or later did not show an influence on mortality, morbidity, re-intervention or hospital stay compared to no insertion of drains. Early (day 3-4) compared to late (≥ day 5) drain removal significantly reduced pancreatic fistulas (odds ratio (OR) 0.13; 95% confidence interval (CI) 0.03-0.32; P = 0.0002), intra-abdominal collections (OR 0.08; 95% CI 0.01-0.67; P = 0.02) and abscesses (OR 0.26; 95% CI 0.07-1.00; P = 0.05). Moreover, hospital stay was significantly reduced after early drain removal (mean difference -2.60 days; 95% CI -4.74 to -0.46; P = 0.02) CONCLUSION: Further randomised controlled trials are warranted to clarify whether drains are of any use. In case of drain insertion, early removal seems to be superior to late removal.

A hydrogel for adhesion prevention: characterization and efficacy study in a rabbit uterus model.

OBJECTIVE: Postoperative peritoneal adhesions following gynaecological surgery remain a clinically relevant problem. One approach to prevent adhesion formation is to apply physical barriers such as hydrogels. STUDY DESIGN: A physically crosslinked polyvinyl alcohol and carboxymethylcellulose (PVA/CMC) hydrogel (A-Part) was characterized in vitro. Three different traumatization methods were evaluated in a rabbit uterine study. To determine its anti-adhesion efficacy, the hydrogel was first tested in an in vivo pilot study and then in a larger trial to compare it with icodextrin 4% solution (Adept) and controls. RESULTS: Rheological measurements showed an increased elasticity of the hydrogel after freezing. In vivo experiments revealed a clear reduction in incidence, extent and severity of adhesions compared to the icodextrin 4% solution and the untreated control group. CONCLUSIONS: These results warrant further investigation of the PVA/CMC A-Part hydrogel in clinical trials focused on gynaecological procedures.

Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial.

CONTEXT: Adjuvant fluorouracil has been shown to be of benefit for patients with resected pancreatic cancer. Gemcitabine is known to be the most effective agent in advanced disease as well as an effective agent in patients with resected pancreatic cancer. OBJECTIVE: To determine whether fluorouracil or gemcitabine is superior in terms of overall survival as adjuvant treatment following resection of pancreatic cancer. DESIGN, SETTING, AND PATIENTS: The European Study Group for Pancreatic Cancer (ESPAC)-3 trial, an open-label, phase 3, randomized controlled trial conducted in 159 pancreatic cancer centers in Europe, Australasia, Japan, and Canada. Included in ESPAC-3 version 2 were 1088 patients with pancreatic ductal adenocarcinoma who had undergone cancer resection; patients were randomized between July 2000 and January 2007 and underwent at least 2 years of follow-up. INTERVENTIONS: Patients received either fluorouracil plus folinic acid (folinic acid, 20 mg/m(2), intravenous bolus injection, followed by fluorouracil, 425 mg/m(2) intravenous bolus injection given 1-5 days every 28 days) (n = 551) or gemcitabine (1000 mg/m(2) intravenous infusion once a week for 3 of every 4 weeks) (n = 537) for 6 months. MAIN OUTCOME MEASURES: Primary outcome measure was overall survival; secondary measures were toxicity, progression-free survival, and quality of life. RESULTS: Final analysis was carried out on an intention-to-treat basis after a median of 34.2 (interquartile range, 27.1-43.4) months' follow-up after 753 deaths (69%). Median survival was 23.0 (95% confidence interval [CI], 21.1-25.0) months for patients treated with fluorouracil plus folinic acid and 23.6 (95% CI, 21.4-26.4) months for those treated with gemcitabine (chi(1)(2) = 0.7; P = .39; hazard ratio, 0.94 [95% CI, 0.81-1.08]). Seventy-seven patients (14%) receiving fluorouracil plus folinic acid had 97 treatment-related serious adverse events, compared with 40 patients (7.5%) receiving gemcitabine, who had 52 events (P < .001). There were no significant differences in either progression-free survival or global quality-of-life scores between the treatment groups. CONCLUSION: Compared with the use of fluorouracil plus folinic acid, gemcitabine did not result in improved overall survival in patients with completely resected pancreatic cancer. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00058201.

Expression of A disintegrin and metalloprotease 10 in pancreatic carcinoma.

The protease ADAM10 influences progression and metastasis of cancer cells and is overexpressed in various malignancies. Therefore, the aim of our study was to evaluate the expression and potential function of ADAM10 in the pathophysiology of pancreatic cancer (PDAC). ADAM10 expression in normal pancreatic (NP), chronic pancreatitis (CP), PDAC tissues, as well as PDAC cell lines was determined. To evaluate whether rhADAM10 or ADAM10 silencing influences cancer cell viability, MTT assay was used. Matrigel invasion and wound healing assays were performed to observe influence on invasion and migration. ADAM10 mRNA was expressed in all samples of NP, CP and PDAC tissue and cell lines. Western blotting and immunohistochemistry revealed stronger ADAM10 expression in PDAC than in NP. ADAM10 silencing or rhADAM10 had no effect on cell viability. ADAM10 silencing markedly reduced invasiveness and migration of cancer cells. These findings establish ADAM10 as a contributing factor in PDAC invasion and metastasis.

Soluble iC3b as an early marker for pancreatic adenocarcinoma is superior to CA19.9 and radiology.

Pancreatic adenocarcinoma as an aggressive tumor still lacks specific markers. Resection offers the only potential cure, and earlier diagnosis could benefit many patients. Here, we analyzed siC3b as a potential diagnostic marker. Soluble iC3b is generated in the fluid phase after binding of autoantibodies to tumor cells and subsequent inactivation of the complement cascade by interaction with complement regulatory proteins. Two hundred thirty-two plasma samples from patients with adjuvant treatment after resection, from healthy volunteers, and from vulnerable patients were collected prospectively and analyzed for siC3b. Every 3 months, the patients underwent imaging and the results from siC3b enzyme-linked immunosorbent assay were categorized according to radiologically defined recurrence within 4 months after blood withdrawal. Furthermore, the regulatory factors of the complement system were analyzed in tumor cells and in urine. The most important finding was that up to 4 months before radiologically defined recurrence, siC3b plasma level is increased with a sensitivity and specificity resulting in an area under the curve of 0.85, which could be further increased by combining it with CA19.9 (area under the curve=0.92). Complement regulatory proteins are highly expressed in pancreatic carcinoma cells and detectable in the patient's urine. In summary, screening for siC3b in patients with an increased risk for pancreatic ductal adenocarcinoma (patients with chronic pancreatitis, hereditary pancreatitis, after curative resection, and patients with a variety of familial cancer syndromes) allows for early detection with high sensitivity, as siC3b plasma levels are increased up to 4 months before radiologic evidence. Sensitivity could be further increased by combining this approach with CA19.9.