Piotr Hogendorf

Prostaglandin E2 (PGE2) in Portal Blood in Patients with Pancreatic Tumor—A Single Institution Series

ABSTRACT Background: Cyclooxygenase-2 (COX-2) may play a significant role in the development of pancreatic cancer. One of COX-2 main metabolites is prostaglandin E2 (PGE2), which is involved both in inflammation and carcinogenesis. As PGE2 is inactivated in the lungs and the liver we assumed that the best medium to assess the level of PGE2 is not peripheral but portal blood. Patients and methods: Fifty-seven patients with pathologically verified diagnosis of pancreatic ductal adenocarcinoma (PDAC group, n = 38) and chronic pancreatitis (CP group, n = 19) were enrolled in this study. Sample of blood from central line was collected before surgery. Intraoperatively portal vein was identified and sampled. PGE2 levels were determined using ELISA test. All the patients were followed-up for 1–35 months. Results: PGE2 portal blood levels in patients with PDAC were higher than in patients with CP (190.55 ± 149.86 versus 120.23 ± 132.60; p = .04). PGE2 concentration at a cut-off value of 94.46 pg/ml had a sensitivity of 91.67%, specificity of 50%, AUC = 0.631 (95% CI, 0.489–0.758). Conclusion: The PGE2 portal blood levels in PDAC patients are higher than in those with CP. The PGE2 portal concentration cannot be a single marker in diagnosing PDAC due to low specificity.

Preoperative high level of D-dimers predicts unresectability of pancreatic head cancer.

AIM To assess the value of D-dimer level in determining resectability of pancreatic cancer. METHODS Preoperative prediction of pancreatic head cancer resectability remains inaccurate. The use of hemostatic factors may be of potential help, since D-dimers correlate with tumor stage. Single center clinical trial study comprised patients with potentially resectable pancreatic head tumor and without detectable venous thrombosis (n = 64). Resectability was defined as no evidence of nodal involvement, distant spread and no invasion of mesenteric vessels. Final decision of resectability was confirmed intraoperatively. Experienced pancreatic surgeon performed all surgeries. Following the dissection of hepatoduodenal ligament, samples of portal blood and bile were taken. Peripheral blood via central line and urine via Foley catheter were sampled. D-dimer levels were further measured. RESULTS At laparotomy only 29 (45.3%) tumors were found to be resectable. Our analysis showed higher by 57.5% (P < 0.001) mean D-dimer values in peripheral and 43.7% (P = 0.035) in portal blood of patients with unresectable pancreatic cancer. Significant differences were not observed when analyzing D-dimer levels in bile and urine. Peripheral D-dimer level correlated with pancreatic cancer resectability. When cut-off D-dimer value of 570.6 μg/L was used, the sensitivity for assessment of tumor unresectability was 82.8%. Furthermore, D-dimer level in peripheral blood of metastatic disease (n = 15) was significantly higher when compared to locally advanced (n = 20) pancreatic cancer (2470 vs 1168, P = 0.029). The area under ROC curve for this subgroup of patients was 0.87; for determination of unresectable disease when threshold of 769.8 μg/L was used, sensitivity and specificity was 86.6% and 80%, respectively. CONCLUSION Patients with resectable pancreatic head cancer based on preoperative imaging studies and high D-dimer level may be considered unresectable due to occult hepatic metastases. These patients may benefit from diagnostic laparoscopy to avoid exploratory laparotomy.

Very high concentration of D-dimers in portal blood in patients with pancreatic cancer.

UNLABELLED Nowadays, increasing attention has been focused on relation between increased D-dimer levels and cancer among patients without detectable thrombosis. The aim of the study was to measure plasma D-dimer levels in portal and peripheral blood in pancreatic cancer patients with absence of venous thromboembolism. MATERIAL AND METHODS Fifteen consecutive patients hospitalized in the Department of General and Transplant Surgery of Medical University in Łódź, from January to March 2012 who underwent surgery due to a pancreatic cancer were enrolled. At laparotomy, portal and peripheral blood were sampled concurrently. D-dimer and fibrinogen levels were measured. Moreover, to investigate overall coagulation function prothrombin time (PT), prothrombin index (PI), international normalized ratio (INR), thrombin time (TT), activated partial thromboplastin time (APTT), TT and APTT index were evaluated. RESULTS Peripheral plasma D-dimmer levels above normal range were found in 10/15 patients (66,67%), whereas D-dimer above normal values were confirmed in all portal blood samples. Mean D-dimer values were higher in portal than in peripheral blood (3279.37 vs 824.64, by 297%, p=0,025). These discrepancies were accompanied by normal limits of portal and peripheral levels of fibrinogen and comparable coagulation function indexes. CONCLUSION Our preliminary study showed the close relation between activation of hemostasis, reflected by elevated D-dimers in portal blood and presence of pancreatic cancer. These data suggest that measurement of portal blood D-dimer levels may be a potentially useful technique for screening the pancreatic cancer.

Neutrophil Gelatinase-Associated Lipocalin (NGAL) concentration in urine is superior to CA19-9 and Ca 125 in differentiation of pancreatic mass: Preliminary report.

BACKGROUND Currently pancreatic cancer is the fourth leading cause of cancer-related death worldwide. Because of its late manifestation and consequent dismal prognosis, there is an urgent need to develop highly sensitive and specific marker. Neutrophil Gelatinase-Associated Lipocalin (NGAL) recently emerged as a protein playing an important role in carcinogenesis of various neoplasms. OBJECTIVE Our aim was to assess the potential of urine and bile concentration of NGAL in differentiating pancreatic adenocarcinoma from chronic pancreatitis. METHODS Forty-two patients operated on due to pancreatobiliary lesions were enrolled in this study. All enrolled patients had eGFR within reference range. Levels of CEA, CA 125 and Ca19-9 were assessed using standard laboratory protocols. A sample of urine was collected prior to the surgery. Intraoperatively a 5 ml sample of bile was collected directly from the common bile duct. Bile and urine levels of NGAL were measured using a ELISA kit. After standard pathological examination of specimens obtained during surgery, patients were divided into 2 groups: 21 patients with pancreatic adenocarcinoma and 15 patients with focal chronic pancreatitis. RESULTS NGAL concentration in bile in patients with PDAC vs CP was 75.72 ± 16.05 ng/mL vs 62.62 ± 18.6 ng/mL respectively (p= 0,011). NGAL concentration in urine was 43.26 ± 21.21 ng/mL vs 17.96 ± 14.58 ng/mL (p= 0.002) respectively. In order to compare these markers with routinely used ones, ROC curve was built for Ca125 to establish cutoff point and in case of CA19-9 clinically used cutoff (≥ 37U/mL) was applied. Sensitivity and specificity for NGALurine with cutoff value of 27 ng/mL was 80.95% and 80% respectively, while these values for NGALbile were 71.43% and 80% respectively. Ca19-9 measured in plasma with clinically used cutoff value had sensitivity of 71.43% and specificity of 73.33%. Sensitivity and specificity for Ca 125 measured in plasma with cutoff value of 13 U/mL were 85.71% and 66.67% respectively. CONCLUSIONS In conclusion, NGAL in urine and bile are remarkably accurate in differentiating pancreatic mass due to chronic pancreatitis from pancreatic adenocarcinoma. Therefore, NGAL concentrations in bile and urine should be further investigated in order to assess their usefulness in early pancreatic adenocarcinoma diagnosis.

D-dimers revisited: a new marker of pancreatic cancer.

To the Editor: The excellent article of Sun et al elucidated the clinical and prognostic significance of coagulation assays in pancreatic cancer (PC) patients with absence of venous thromboembolism. The manuscript, with a review of the literature, comes to the conclusion that the pretreatment level of plasma D-dimers (DD) was a potential predictor of prognosis in PC patients without venous thromboembolism. Various solid tumors including lung, prostate, cervical, and colorectal cancer are found to have elevated DD levels in the peripheral plasma. However, we found a very high concentration in portal blood, but only a moderately elevated value of DD in peripheral blood of patients with PC and without detectable DVT (n = 89, 3738.4 ± 3999.8 vs. 1217.7 ± 1718.9, respectively, P < 0.001). On this basis, we hypothesized that the site of blood sampling for DD assessment influences the laboratory results and may be of great clinical importance. Portal, but not peripheral blood DD level may help to better differentiate malignant from benign pancreatic tumors. We confirmed this hypothesis in another analysis comparing the DD level in portal and peripheral blood of patients with PC (n = 89) and chronic pancreatitis (ChP, n = 28) (in peripheral blood, the DD levels were 1100.4 ± 1856.9 for the PC group and 1217.7 ± 1718.9 for the ChP group, P = 0.504; in portal blood the DD levels were 3738.4 ± 3999.8 vs. 1141.2 ± 1847.5, for the PC and ChP groups, respectively, P < 0.001). High DD are associated with a poor prognosis in cancer patients; therefore, we have carried out another study on DD portal and peripheral blood levels in patients with metastatic pancreatic cancer (mPC, n = 19) and nonmetastatic pancreatic cancer (nmPC, n = 70). The results of the study showed that the mean DD value in peripheral blood was higher in mPC when compared with nmPC patients (2139.3 ± 2752.5 vs. 963.9 ± 1213.2, P < 0.001). Portal blood DD concentration in both the groups studied (mPC and nmPC) remained at a very high level (3128.2 ± 3565.1 vs. 3908.9 ± 4121.4, respectively, P = 0.573). Therefore, we hypothesized that the liver might contribute toward elimination of DD from portal blood. To determine whether the liver acts as a “levee” for this marker, we attempted a study to elucidate DD in bile of patients with PC. Our analysis found a higher DD level in bile of patients with PC (n = 52) when compared with the control group of ChP (n = 29) (2583.3 ± 3455.2 vs. 654.5 ± 1054.5, respectively, P = 0.006). From the above study, we concluded that the hepatic barrier for DD may be responsible for only moderately elevated values of this marker in patients with nonmetastatic pancreatic adenocarcinoma. In contrast, in metastatic disease DD by-pass hepatic sieve and its concentration becomes very high in the general circulation of blood. Therefore, peripheral blood DD might be a novel marker in the diagnostic algorithm for the exclusion of occult hepatic metastases before surgery of patients with PC. All our studies were approved by the local Ethics Committee and written informed consents were obtained from all patients. After the dissection of the hepatoduodenal ligament, samples of portal blood and bile were taken, as described earlier. Peripheral blood from the central line was sampled. Portal, peripheral plasma, and bile DD levels were measured using commercial kits (VIDAS D-Dimer Exclusion II, bioMérieux, France). All statistical calculations were carried out using the SigmaPlot version 12.0 (Systat Software Inc., San Jose, CA) with the level of statistical significance at P < 0.05. As described by Sun et al plasma coagulation parameters including DD may be associated with tumor progression, metastasis, and prognosis. However, measurement of plasma DDs has limited specificity in cancer diagnosis as many conditions are associated with fibrin formation. Nonetheless, to date, only peripheral blood has been investigated in cancer patients. Our analyses on various novel sites of assessing DD levels indicate that it may help overcome the limitations of this assay. Further multicenter studies to assess clinical applicability of portal blood, bile, and urine DD levels for the diagnosis of PC are definitely needed. Adam Durczynski, MD, PhD* Anna Kumor, MD, PhDw Piotr Hogendorf, MD, PhD* Dariusz Szymanski, MD, PhD* Grazyna Poznanska, MDz Piotr Grzelak, MD, PhDy Janusz Strzelczyk, MD, PhD* Departments of *General and Transplant Surgery wAllergology and Pulmonary Diseases yRadiology and Diagnostic Imaging, Medical University of Lodz zDepartment of Anesthesiology and Intensive Care, Barlicki Teaching Hospital, Lodz, Poland

Pancreatic head carcinoma and vascular endothelial growth factor (VEGF-A) concentration in portal blood: its association with cancer grade, tumor size and probably poor prognosis.

Introduction Vascular endothelial growth factor (VEGF) is overexpressed in pancreatic cancer. Although VEGF has been shown to be a probable marker for poor prognosis, the VEGF concentration in portal blood has not yet been clinically reported in pancreatic ductal adenocarcinoma (PDAC). The aim of the study was to measure VEGF-A portal blood concentration in patients with PDAC and to evaluate its performance as a prognostic marker. Material and methods Thirty-six consecutive patients out of 57 operated on for pancreatic head lesion with pathologically verified diagnosis of PDAC were enrolled in this study. We evaluated the VEGF concentration in portal blood samples obtained intraoperatively and associated their values with tumor size, stage, grade and survival. Results The portal VEGF-A concentration was associated with tumor grade (G1: 80.52 ±43.05 vs. G2: 185.39 ±134.98, p = 0.006, G2: 185.39 ±134.98 vs. G3: 356.46 ±229.12, p = 0.08), and there was a positive correlation with tumor size (r = 0.42, p < 0.05). In the multivariate regression analysis high levels of VEGF-A were not correlated with poor survival (HR = 5.22, 95% CI = –0.6457 to 3.9513, p = 0.19). Conclusions The portal VEGF-A concentration is associated with tumor grade and size. The correlation of portal VEGF-A with poor survival is not clear and needs further investigation.

Expression and Clinical Significance of Cancer Stem Cell Markers CD24, CD44, and CD133 in Pancreatic Ductal Adenocarcinoma and Chronic Pancreatitis

Cancer stem cells (CSC) play an important role in pancreatic carcinogenesis and prognosis. The study aimed at examining the expression of CD24, CD44, and CD133 in human PDAC and CP in order to evaluate its clinicopathological correlations and the clinical significance. Surgical specimens from 23 patients with PDAC and 15 patients with chronic pancreatitis after pancreatic resection were stained with CD24, CD44, and CD133 antibodies. The intensity of staining was scored from 0 (negative) to 3 (strongly positive). Results. Mean CD24 staining score in PDAC was 1.38 ± 0.76 and was significantly higher than that in CP: 0.70 ± 0.53 (p < 0.01); CD44 score in PDAC was 2.23 ± 0.42 and was significantly higher than that in CP: 1.87 ± 0.55 (p < 0.05); CD133 score 0.93 ± 0.58 was not different from CP: 0.71 ± 0.43 (p > 0.05). CD44 immunoreactivity was significantly higher (p < 0.05) in pT1 and pT2 patients together as regards pT3: 2.45 ± 0.37 versus 2.06 ± 0.38 as well as in N0 patients compared to N1 patients: 2.5 ± 0.38 versus 2.04 ± 0.34. Conclusions. CD24 and CD44 are upregulated in human pancreatic cancer compared to chronic pancreatitis. CD44 immunoreactivity decreases with the tumor advancement and may represent the negative PDAC prognostic factor. Each CSC marker was differently related to PDAC advancement. CD133 may lack clinical significance in PDAC.

Synchronous occurrence of multiple focal nodular hyperplasia and huge hepatic Perivascular epithelioid cells tumor (PEComa) in young woman after oral contraceptive use – is there a common pathogenesis?

The association of focal nodular hyperplasia (FNH) and various neoplasms was described, but coincidence of multiple FNH and hepatic perivascular epithelioid cells tumor (PEComa) has not been reported. The clinical debate of oral contraceptive (OC) influence on FNH growth is ongoing, but no evidence exists about association of hepatic PEComa with OC use. Herein, we report a case of two FNH lesions and huge (150x100x80 mm) left hepatic lobe PEComa that occurred simultaneously in 18-year-old female with previous two year history of OC use, who underwent left hemihepatectomy and right hepatic FNH enucleation. Up to date, the patient has been followed-up for 65 months and remained disease-free. FNH and PEComa have a common vascular cytogenetic denominator. Our case raising a question of a causal relationship of FNH and PEComa with OC use that might be attributed to vascular changes. Future researches of larger sample sizes should further address this issue.

A Panel of CA19-9, Ca125, and Ca15-3 as the Enhanced Test for the Differential Diagnosis of the Pancreatic Lesion

Background. Proper diagnosis of pancreatic lesion etiology is a challenging clinical dilemma. Studies suggest that surgery for suspected pancreatic ductal adenocarcinoma (PDAC) reveals a benign lesion in 5% to 13% of cases. The aim of our study was to assess whether routinely used biomarkers such as CA19-9, Ca125, Ca15-3, and CEA, when combined, can potentially yield an accurate test predicting pancreatic lesion etiology. Methods. We retrospectively analyzed data of 326 patients who underwent a diagnostic process due to pancreatic lesions of unknown etiology. Results. We found statistically significant differences in mean levels of all biomarkers. In logistic regression model, we applied levels CA19-9, Ca125, and Ca15-3 as variables. Two validation methods were used, namely, random data split into training and validation groups and bootstrapping. Afterward, we built ROC curve using the model that we had created, reaching AUC = 0,801. With an optimal cut-off point, it achieved specificity of 81,2% and sensitivity of 63,10%. Our proposed model has superior diagnostic accuracy to both CA19-9 (p = 0,0194) and CA125 (p = 0,0026). Conclusion. We propose a test that is superior to CA19-9 in a differential diagnosis of pancreatic lesion etiology. Although our test fails to reach exceptionally high accuracy, its feasibility and cost-effectiveness make it clinically useful.

Sentinel lymph node mapping in tumors of the pancreatic body: preliminary report

Aim of the study Actual lymphatic drainage of pancreatic body neoplasms and the proper extent of lymphadenectomy remain unknown. The aim of the study was to define the exact lymphatic draining pattern using the dye mapping method. Material and methods The study enrolled patients who were operated on for tumor of the pancreatic body in the Department of General and Transplant Surgery of the Medical University of Lodz during 2010, with injection of 1 ml of blue dye (Patent Blue, Guerbet) in the centre of the neoplasm and sentinel node identification. Radical surgical management included distal pancreatectomy, whereas gastrojejunal or triple bypass anastomoses were performed in irresectable cases. Results The study group consisted of 13 patients with locally advanced tumors of the pancreatic body (T3 and T4, mean tumor size 4.9 cm). Lymphatic mapping was able to identify sentinel nodes in 5 of 13 cases (38.46%). A sentinel node was found in station 11p (3 cases) and 9 (1 case). Skip metastasis to the left gastric artery node (group 7) was noted. All identified sentinel nodes were metastatic; tumor deposits were confirmed in non-sentinel nodes as well. Conclusions In advanced pancreatic body tumors feasibility of sentinel node navigation is considerably restricted. Further studies in smaller tumors using optimized newer markers may define the exact lymphatic draining pattern.