Frank Dobrowolski

A randomized multi-center phase II trial of the angiogenesis inhibitor Cilengitide (EMD 121974) and gemcitabine compared with gemcitabine alone in advanced unresectable pancreatic cancer

BackgroundAnti-angiogenic treatment is believed to have at least cystostatic effects in highly vascularized tumours like pancreatic cancer. In this study, the treatment effects of the angiogenesis inhibitor Cilengitide and gemcitabine were compared with gemcitabine alone in patients with advanced unresectable pancreatic cancer.MethodsA multi-national, open-label, controlled, randomized, parallel-group, phase II pilot study was conducted in 20 centers in 7 countries. Cilengitide was administered at 600 mg/m2 twice weekly for 4 weeks per cycle and gemcitabine at 1000 mg/m2 for 3 weeks followed by a week of rest per cycle. The planned treatment period was 6 four-week cycles. The primary endpoint of the study was overall survival and the secondary endpoints were progression-free survival (PFS), response rate, quality of life (QoL), effects on biological markers of disease (CA 19.9) and angiogenesis (vascular endothelial growth factor and basic fibroblast growth factor), and safety. An ancillary study investigated the pharmacokinetics of both drugs in a subset of patients.ResultsEighty-nine patients were randomized. The median overall survival was 6.7 months for Cilengitide and gemcitabine and 7.7 months for gemcitabine alone. The median PFS times were 3.6 months and 3.8 months, respectively. The overall response rates were 17% and 14%, and the tumor growth control rates were 54% and 56%, respectively. Changes in the levels of CA 19.9 went in line with the clinical course of the disease, but no apparent relationships were seen with the biological markers of angiogenesis. QoL and safety evaluations were comparable between treatment groups. Pharmacokinetic studies showed no influence of gemcitabine on the pharmacokinetic parameters of Cilengitide and vice versa.ConclusionThere were no clinically important differences observed regarding efficacy, safety and QoL between the groups. The observations lay in the range of other clinical studies in this setting. The combination regimen was well tolerated with no adverse effects on the safety, tolerability and pharmacokinetics of either agent.

Prevalence and treatment of bleeding complications in chronic pancreatitis

ObjectivesAs spontaneous major haemorrhage in patients with chronic pancreatitis is rare, limited data have been reported, and no evidence-based guidelines are currently available regarding the optimal treatment modality.Patients and methodsWe report our experience with 36 patients with severe bleeding complications from a series of 541 patients presenting with chronic pancreatitis (representing a prevalence of 6.7% of admitted patients), treated in one surgical department over a period of 9.5 years, with a median follow-up of 4.1 years.ResultsHaemorrhage was indirectly related to chronic pancreatitis in eight patients (22.2%) with ulcer or variceal bleeding. Three patients (8.4%) demonstrated spleen infarction or rupture. The most common causes of major haemorrhage were pseudoaneurysms in 25 patients (69.4%). Nine of them were treated with primary embolization. Sixteen patients with pseudoaneurysms underwent surgery. The only mortalities (8.3%) observed were from bleeding-associated complications of pseudoaneurysms. Two patients died after surgery, and one after primary embolization. We observed a higher re-bleeding rate after surgery (25% vs 11% after embolization). The presence of haemorrhagic shock, and the amount of blood transfused, were significant determinants of hospital mortality. Patient age, pseudoaneurysm location, and treatment modality had no significant influence on mortality.ConclusionsAny haemodynamically stable patient with haemorrhage due to arterial pseudoaneurysms should undergo angiography with embolization when technically possible. If there are no other pancreas-related indications for surgery, embolization remains the definitive treatment. If embolization is not available or has failed, surgery is indicated, although perioperative morbidity will be higher.

Curative resection of a primarily unresectable acinar cell carcinoma of the pancreas after chemotherapy

BackgroundAcinar cell carcinoma (ACC) represents only 1–2% of pancreatic cancers and is a very rare malignancy. At the time of diagnosis only 50% of the tumors appear to be resectable. Reliable data for an effective adjuvant or neoadjuvant treatment are not available.Case presentationA 65-year old male presented with obstructive jaundice and non-specific upper abdominal pain. MRI-imaging showed a tumor within the head of the pancreas concomitant with Serum-Lipase and CA19-9. During ERCP, a stent was placed. Endosonographic fine needle biopsy confirmed an acinar cell carcinoma. Laparotomy presented an locally advanced tumor with venous infiltration that was consequently deemed unresectable. The patient was treated with five cycles of 5-FU monotherapy with palliative intention. Chemotherapy was well tolerated, and no severe complications were observed. Twelve months later, the patient was in stable condition, and CT-scanning showed an obvious reduction in the size of the tumor. During further operative exploration, a PPPD with resection of the portal vein was performed. Histopathological examination gave evidence of a diffuse necrotic ACC-tumor, all resection margins were found to be negative. Eighteen months later, the patient showed no signs of recurrent disease.ConclusionACC responded well to 5-FU monochemotherapy. Therefore, neoadjuvant chemotherapy could be an option to reduce a primarily unresectable ACC to a point where curative resection can be achieved.

Prognostic significance of immunohistochemical RhoA expression on survival in pancreatic ductal adenocarcinoma: a high-throughput analysis

Among all human carcinomas, pancreatic cancer has one of the worst survival rates. Most patients will die of this cancer shortly after diagnosis, and currently, surgery is the only potential cure. Ductal adenocarcinoma is the most common histologic type. The search for prognostic parameters has progressed from mere physical or histomorphological tumor properties to molecular parameters. These, in turn, might point toward new therapeutic strategies. The K-ras oncogene is known to play a role in early stages of ductal adenocarcinoma carcinogenesis, and ras homologues are differentially expressed in cancerous versus normal ductal cells. RhoA belongs to a family of ras homologues comprising RhoA, RhoB, and RhoC. It is a guanosine triphosphatase associated with the cytoskeleton that seems to be involved in epithelial mesenchymal transition, a process of dedifferentiation. Immunohistologic RhoA expression was studied in a tissue microarray of 94 pancreatic ductal adenocarcinomas and correlated with clinicopathologic parameters and follow-up. RhoA protein expression, measured as labeling intensity or evaluated as percentage of reactive tumor cells, correlated with overall survival. A multivariate analysis demonstrated that RhoA protein expression is independent from other known prognostic parameters such as tumor size or grade. Moreover, a score combining RhoA expression with tumor size and grade resulted in a highly significant increase in the prognostic value for the overall survival of patients with pancreatic ductal adenocarcinoma.

Chronic pancreatitis: early results of pancreatoduodenectomy and analysis of risk factors.

Objectives: Although mortality after pancreatoduodenectomy for chronic pancreatitis has declined, the complication rate remains high. Today, there is an increasing need to base clinical decisions on the available scientific evidence to provide the best available treatment for the patients. Therefore, we retrospectively analyzed comprehensive preoperative and postoperative characteristics of patients undergoing pancreatic head resection for chronic pancreatitis and performed an outcome analysis to provide prospective selection or managing criteria that could improve the early surgical results. Methods: Data from 168 patients who underwent pancreatic head resection for chronic pancreatitis between October 1993 and November 2008 in our center were retrospectively analyzed. Risk factors for surgical complications were evaluated by multivariate analysis. Results: Perioperative mortality was 0.6%, and surgical morbidity was 14.3%. Multivariate analysis identified hypertension as significant independent risk factor for surgical complications with an odds ratio (OR) of 3.24. We also found protective factors, namely, preoperative exocrine insufficiency (OR, 0.33) and preoperative diabetes (OR, 0.18). Both protective factors might indicate an advanced chronic pancreatitis. Conclusions: As patients undergoing pancreatic head resection are highly selected, the identified risk factors should only individually be considered in the decision to operate.

Surgical Therapy of Intrapancreatic Metastasis from Renal Cell Carcinoma

Background: Pancreatic metastases from renal cell carcinoma (RCC) are clinically rare but highly resectable. The aim of this article is to identify patients who profit from pancreatic resection of RCC despite the invasiveness of the surgery. Methods: Between January 1996 and December 2007, data from 744 patients were collected in a prospective pancreatic surgery database, and patients with metastasis into the pancreas from RCC were identified. Results: Resective surgery was performed in 14 patients with metastasis to the pancreas from RCC. Most patients were clinically asymptomatic. The median interval between primary treatment of RCC and occurrence of pancreatic metastasis was 94 months (range 32–158). The morbidity rate was 42.8%. Patients with a metastasis size <2.5 cm had a much better survival after resection (100 months) than those with a metastasis size >2.5 cm (44 months). Moreover, the number of metastases predicts the survival after resection. Conclusions: In patients with pancreatic metastases from RCC who have only limited disease, complete resection of all lesions can be successfully performed with a low rate of complications. Thus, patients with a history of RCC should be monitored for more than 10 years after nephrectomy to detect recurrence.

Color Doppler imaging predicts portal invasion by pancreatic adenocarcinoma.

AbstractBackgroundTumor infiltration of the intima of the portal vein (PV) and superior mesenteric vein (SMV) by pancreatic adenocarcinoma is classically considered a criterion for unsuitability for resection and poor prognosis. This study was performed to evaluate modern color duplex imaging (CDI) for the assessment of PV/SMV infiltration by pancreatic adenocarcinomas.MethodFrom 1994 to 2005, Whipple’s procedure or pylorus-preserving pancreato-duodenectomy (PPPD) was performed in 303 patients with pancreatic adenocarcinoma; 35 of these underwent partial PV/SMV resection. Applying a previously reported CDI score, we evaluated the integrity of the echogenic border layer between the vein and tumor (mural demarcation) and maximum blood flow velocity (Vmax) in the PV segment in contact with the tumor. The results were compared to the final histological findings in the resected venous walls.ResultsCDI findings correlated well with the histological invasion grades. By measuring Vmax and evaluating mural demarcation, we observed a sensitivity of 66.7% and 100% and a specificity of 98.3% and 93.9%, respectively, in predicting full thickness vein invasion, including the intima. Vmax above 80 cm/s and lack of mural demarcation were predictors of PV/SMV invasion. The postoperative survival rates depended on the depth of tumor infiltration into the PV/SMV.ConclusionsModern CDI is a reliable and valid technique for evaluation of morphological and hemodynamic parameters in the portal vein segment adjacent to pancreatic adenocarcinoma. Maximal blood-flow velocity in the portal segment in contact with the tumor and absence of the echogenic vessel-parenchymal sonographic interface are parameters predictive of tumor infiltration of the portal intima.

IAP Society News

Abstracts of the Joint Meeting of the European Pancreatic Club (EPC) and the International Association of Pancreatology (IAP) Lodz, June 25–28, 2008 www.pancreasweb.com/abstracts/abstracts.asps of the Joint Meeting of the European Pancreatic Club (EPC) and the International Association of Pancreatology (IAP) Lodz, June 25–28, 2008 www.pancreasweb.com/abstracts/abstracts.asp

Das seröse Cystadenom des Pankreas

Abstract.Introduction: Serous cystadenomas of the pancreas are rare tumors and thought to be almost always benign. Methods: We report our experience in the diagnosis and surgical treatment of 12 patients with these tumors. Results: Between October 1993 and December 1998, 41 patients with cystic tumors of the pancreas underwent surgical resection; in 12 cases (11 women, 1 man) a serous cystadenoma (10 micrcocystic, 2 oligomacrocystic) was found. Only 6 (50 %) patients had symptoms. The mean tumor size was 4.8 (2.7–10) cm. Ultrasound, CT and MRT usually could detect the mass, but differentiation with other cystic lesions was not reliable. All tumors were resected: 4 Whipple procedures, 7 distal pancreatectomies and 1 segmental resection were performed. No patient died after surgery and none had to be reoperated on. Conclusions: Because of the difficulty in reliably differentiating benign and malignant lesions of the pancreas, we believe that cystic tumors of the pancreas should be resected.Zusammenfassung.Einleitung: Seröse Cystadenome des Pankreas sind seltene Tumoren und gelten in der Regel als benigne. Methoden: In einer retrospektiven Auswertung werden die Daten zur Diagnostik und die Ergebnisse der chirurgischen Therapie analysiert. Ergebnisse: Im Zeitraum von Oktober 1993 bis Dezember 1998 wurden 41 Patienten mit einer cystischen Neoplasie des Pankreas operiert, bei 12 Patienten (11 Frauen, 1 Mann) fand sich histologisch ein seröses Cystadenom (10mal mikrocystisch; 2mal oligomakrocystisch). Nur 6 Patienten (50 %) waren symptomatisch, die Größe der Tumoren betrug im Mittel 4,8 (2,7–10) cm. Sonographie, CT und MRT erwiesen sich als zuverlässigste Untersuchungsverfahren zum Nachweis der neoplastischen Raumforderung, wobei jedoch eine differentialdiagnostische Zuordnung meist nicht möglich war. Alle Patienten wurden reseziert, dabei wurden 4 Whipple-Operationen, 7 Pankreaslinksresektionen und eine Segmentresektion durchgeführt. Kein Patient verstarb nach dem Eingriff, relaparotomiepflichtige Komplikationen traten ebenfalls nicht auf. Schlußfolgerungen: Angesichts der problematischen Abgrenzung benigner und maligner Raumforderungen des Pankreas stellt auch bei den cystischen Tumoren die Resektion die Therapie der Wahl dar.

W1675 Palliative Treatment of Obstructive Jaundice in Patients With Carcinoma of the Pancreatic Head or Distal Biliary Tree: Endoscopic Stent Placement vs. Hepaticojejunostomy

CONTEXT Palliative procedures play an important role in the treatment of malignancies of the pancreatic head/distal biliary tree, as only 20-30% can be cured by surgical resection. OBJECTIVE We sought to determine if surgical or non-surgical management was the most appropriate therapy for the treatment of obstructive jaundice in the palliative setting. SETTING High volume center for pancreatic surgery. PATIENTS Analysis of 342 palliatively-treated patients with adenocarcinoma of the pancreatic head or the distal biliary tree. MAIN OUTCOME MEASURES We studied the outcomes with regard to treatment, complications and survival times. DESIGN The patients were divided into three groups. Group 1: endoscopic bile duct endoprosthesis (no. 138, 56%); Group 2: preoperative stenting followed by laparotomy (if patients were found to be unresectable, palliative hepaticojejunostomy was performed) (no. 68, 28%); Group 3: hepaticojejunostomy without preoperative stenting (no. 41, 16%). We also determined the frequency of re-hospitalization for recurrent jaundice. RESULTS Two hundred and sixty-one (76%) patients showed obstructive jaundice. Mortality in Groups 1, 2, and 3 was 2.2%, 0%, and 2.4%, respectively and morbidity was 5.1%, 17.6%, and 14.6%, respectively. The mean interval between stent exchanges was 70.8 days. Median survival for patients treated only with an endoscopic stent (Group 1) was significantly shorter than that of patients who were first stented and subsequently treated with hepaticojejunostomy (Group 2) (5.1 vs. 9.4 months; P<0.001). CONCLUSIONS Hepaticojejunostomy can be performed with satisfactory operative results and acceptable morbidity. Considering that biliary stents can occlude, a hepaticojejunostomy may be superior to endoscopic stenting; hepaticojejunostomy should be especially favored in patients whose disease is first found to be unresectable intraoperatively.