JOP. J Pancreas (Online) 2005; 6(4):410-416.
PANCREAS ALERTS
Ann Surg 2005; 241(6):948-57. (PMID: 15912044)
Surgical management of complications associated with percutaneous and/or endoscopic management of pseudocyst of the pancreas.
Nealon WH, Walser E.
Department of Surgery, Division of General Surgery, University of Texas Medical Branch. Galveston, TX, USA.
The authors aimed to study the magnitude of complications associated with the nonoperative management of peripancreatic fluid collections and pseudocysts and to assess the surgical management of these complications. These are compared with complications associated with operative management. Pancreatic pseudocysts and peripancreatic fluid collections associated with acute pancreatitis have been managed with success using nonoperative techniques for more than a decade. When successful, these techniques have clear advantages compared with operative management. There has, however, been little focus on the magnitude and outcomes after complications sustained by nonoperative management. This report focuses on these complications and pseudocysts and on the surgical management. The authors have been struck by the high percentage of patients who sustain significant and at times life-threatening complications related to the nonoperative management of fluid collections. They further define an association between the main pancreatic ductal anatomy and the likelihood of major complications after nonoperative management. Between 1992 and 2003, all patients admitted to with peripancreatic fluid collections or pseudocysts were monitored. The authors evaluated complications patients managed with percutaneous (PD) or endoscopic drainage (E). Data were collected regarding patient characteristics, need for intensive care unit (ICU) stays, hemorrhage, hypotension, renal failure, and ventilator support. The authors further focused on the duration of fistula drainage from patients who have had a percutaneous drainage, and they assessed the necessity for urgent or emergent operation. By protocol, all patients had pancreatic ductal anatomy evaluated by means of endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP). Patients with complications of E and PD were compared with 100 consecutive patients who underwent operative management of pseudocyst and fluid collections as their sole mode of intervention. A total of 79 patients with complications of PD, E, or both were studied. There were 41 males and 38 females in the group of patients who sustained complications (mean age 49 years). Sixty-six of the 79 subsequently required operation to manage their peripancreatic fluid collection, 37 urgent or emergent. The mean elapsed time from diagnosis to nonoperative intervention was 18.1 days. This group of 79 patients had mean 3.1±0.7 hospitalization (range, 1-7) and length-of-stay 42.7±4.1 days. ICU stays were required in 36 of the 79 (46%). A defined episode of clinical sepsis was identified in 72 of 79 (91%) and was by far the most common complication. Hemorrhage requiring transfusion was identified in 16 of the 79 (20%), clinical shock 51 of the 79 (65%), renal failure 16 of the 79 (20%), ventilator support for longer than 24 hours 19 of the 79 (24%). A persistent pancreatic fistula occurred in 66 of the 79 patients (84%); mean duration was 61.4±9.6 days. Sixty-three of the 79 patients with complications of E or PD had ductal anatomy (ERCP/MRCP) which predicted failure because of significant disruption or stenosis of the main pancreatic duct. Among the 100 operated patients, 69 complications occurred in 6 of the 100 (6%). Operation was initiated electively a mean interval of 42.7 days after diagnosis of pseudocyst. Hemorrhage, hypotension, renal failure, sepsis, persistent fistula, or urgent operation all were not seen in the complications associated with operated patients. CT imaging obtained at least 6 months after intervention documented complete resolution after surgery alone in 91 and 9 with cystic structures less than 2 cm. In patients with operation after failed nonoperative therapy, 6 patients had persistent cystic lesions less than 2 cm in diameter. These data support the premise that a choice between operative and nonoperative management for peripancreatic fluid collections and pseudocysts should be made with careful assessment of the pancreatic ductal anatomy, with a clear recognition of the magnitude of complications which are likely to occur should nonoperative measures be used in patients most likely to sustain complications. It is vital to recognize the magnitude and severity of complications of nonoperative measures as one chooses a modality. Ductal anatomy predicts patients who will have complications or failure of management of their peripancreatic fluid collection.
Biochem Pharmacol 2005; 69(9):1325-31. (PMID: 15826603)
Severity of pancreatitis-associated gut barrier dysfunction is reduced following treatment with the PAF inhibitor lexipafant.
Leveau P, Wang X, Sun Z, Borjesson A, Andersson E, Andersson R.
Department of Surgery, Lund University Hospital. Lund, Sweden.
The aim of the present study was to investigate the potential effect of treatment with a platelet-activating factor (PAF) antagonist, lexipafant (BB-882), on gut endothelial and epithelial barrier dysfunction and leukocyte recruitment in rats with acute pancreatitis. Severe acute pancreatitis was induced by the intraductal administration of 5% sodium taurodeoxycholate and pancreatitis-associated gut barrier dysfunction was characterized by increased exudation of radiolabelled albumin into the interstitium and alterations in bidirectional (over both the endothelial and epithelial barrier components) permeability of the intestine at the early stage of bile salt-induced acute pancreatitis. Levels of interleukin 1beta and 6, ileal and colonic myeloperoxidase (MPO) content, clearance of radiolabelled albumin from blood to the gut lumen or gut lumen to blood, and leakage of radiolabelled albumin to the ileum or colon were measured 3 and 12 h after induction of acute pancreatitis. Treatment with lexipafant 30 min and 6 h after pancreatitis reduced severity of pancreatitis-associated intestinal dysfunction, associated with a diminish in systemic concentrations of IL-1 and local leukocyte recruitment. The findings imply that PAF plays a critical role in the development of pancreatitis-associated gut barrier dysfunction and that PAF antagonist in some forms may represent potential candidates for future therapeutic intervention.
Lancet Oncol 2005; 6(6):369-76. (PMID: 15925814)
Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial.
Reni M, Cordio S, Milandri C, Passoni P, Bonetto E, Oliani C, et al.
Department of Radiochemotherapy, S. Raffaele H Scientific Institute. Milan, Italy.
Patients with advanced pancreatic adenocarcinoma have a poor response, progression-free survival, and overall survival with standard treatment. The authors aimed to assess whether a four-drug regimen could improve 4 month progression-free survival compared with gemcitabine alone. In a randomised multicentre phase III trial, 52 patients were randomly assigned to 40 mg/m2 cisplatin and 40 mg/m2 epirubicin both given on day 1,600 mg/m2 gemcitabine given intravenously over 1 h on days 1 and 8, and 200 mg/m2 fluorouracil a day given by continuous infusion on days 1-28 of a 4-week cycle (PEFG regimen), and 47 were assigned to 1,000 mg/m2 gemcitabine given intravenously over 30 min once a week for 7 of 8 consecutive weeks in cycle 1 and for 3 of 4 weeks thereafter. The primary endpoint was 4-month progression-free survival. Secondary endpoints were overall survival, objective response, safety, and quality of life. Analyses were by intention to treat. Fifty-one patients assigned PEFG and 46 assigned gemcitabine alone had disease progression. 49 patients in the PEFG group and 46 in the gemcitabine group died from progressive disease. More patients allocated PEFG (60%; 95% CI: 46-72%) than gemcitabine alone (28%; 95% CI: 17-42%); were alive without progressive disease at 4 months (hazard ratio, HR=0.46; 95% CI: 0.26-0.79). One-year overall survival in the PEFG group was 38.5% (95% CI: 25.3-51.7%) and in the gemcitabine group was 21.3% (95% CI: 9.6-33.0%) (HR=0.68; 95% CI: 0.42-1.09). More patients assigned PEFG showed disease response than did those assigned gemcitabine (38.5%; 95% CI: 25.3-51.7%) vs. 8.5% (95% CI: 0.5-16.5%); odds ratio 6.60 (95% CI: 2.11-20.60; P=0.0008). More patients in the PEFG group had grade 3-4 neutropenia and thrombocytopenia than in the gemcitabine group (P<0.0001). The authors concluded that the PEFG regimen could be considered for treatment of advanced pancreatic adenocarcinoma.
J Clin Oncol 2005; 23(15):3509-16. (PMID: 15908661)
Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial.
Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, Andre T, et al.
Service d'Oncologie, Hopital Saint Antoine. Paris, France.
Gemcitabine (Gem) is the standard treatment for advanced pancreatic cancer. Given the promising phase II results obtained with the Gem-oxaliplatin (GemOx) combination, the authors conducted a phase III study comparing GemOx with Gem alone in advanced pancreatic cancer. Patients with advanced pancreatic cancer were stratified according to center, performance status, and type of disease (locally advanced vs. metastatic) and randomly assigned to either GemOx (gemcitabine 1 g/m2 as a 100-minute infusion on day 1 and oxaliplatin 100 mg/m2 as a 2-hour infusion on day 2 every 2 weeks) or Gem (gemcitabine 1 g/m2 as a weekly 30-minute infusion). Three hundred twenty-six patients were enrolled; 313 were eligible, and 157 and 156 were allocated to the GemOx and Gem arms, respectively. GemOx was superior to Gem in terms of response rate (26.8% vs. 17.3%, respectively; P=0.04), progression-free survival (5.8 vs. 3.7 months, respectively; P=0.04), and clinical benefit (38.2% vs. 26.9%, respectively; P=0.03). Median overall survival (OS) for GemOx and Gem was 9.0 and 7.1 months, respectively (P=0.13). GemOx was well tolerated overall, although a higher incidence of National Cancer Institute Common Toxicity Criteria grade 3 and 4 toxicity per patient was observed for platelets (14.0% for GemOx vs. 3.2% for Gem), vomiting (8.9% for GemOx vs. 3.2% for Gem), and neurosensory symptoms (19.1% for GemOx vs. 0% for Gem). These results confirm the efficacy and safety of GemOx, but this study failed to demonstrate a statistically significant advantage in terms of OS compared with Gem. Because GemOx is the first combined treatment to be superior to Gem alone in terms of clinical benefit, this promising regimen deserves further development.
Cancer Res 2005; 65(9):3664-70. (PMID: 15867361)
Neuropilin-1 suppresses tumorigenic properties in a human pancreatic adenocarcinoma cell line lacking neuropilin-1 coreceptors.
Gray MJ, Wey JS, Belcheva A, McCarty MF, Trevino JG, Evans DB, et al.
Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center. Houston, TX, USA.
Neuropilin-1 (NRP-1) was first described as a coreceptor implicated in neuronal guidance that bound members of the semaphorin/collapsin family. NRP-1 is also expressed in endothelial cells and is believed to promote angiogenesis by acting as a coreceptor with vascular endothelial growth factor (VEGF) receptor 2. Recent studies suggest that NRP-1 can function through both a VEGF-dependent and VEGF-independent fashion. Expression of NRP-1 has been shown in many human tumors, including pancreatic adenocarcinomas. The exact role of NRP-1 in tumor cells is unknown, particularly in cells that lack the NRP-1 coreceptors VEGF receptor 2 and Plexin-A1. To discern the regulatory role(s) of NRP-1 in pancreatic adenocarcinoma that lack these coreceptors, the authors overexpressed both full-length NRP-1 and a deletion form of NRP-1 that does not interact with semaphorin or VEGF. Overexpression of either isoform reduced several key tumorigenic properties, including anchorage-independent cell growth and migration in vitro, and resulted in reduced tumor incidence and tumor volume in vivo. Conversely, reduction of NRP-1 expression by small interfering RNA targeting led to enhanced tumor growth. Thus, NRP-1 may play distinct growth regulatory roles in different tumor types, and altering NRP-1 expression or function may be a means of influencing the growth of pancreatic cancers.
Am J Surg 2005; 189(5):632-6. (PMID: 15862510)
Outcomes following resection of invasive and noninvasive intraductal papillary mucinous neoplasms of the pancreas.
Wada K, Kozarek RA, Traverso WL.
Department of General Surgery, Virginia Mason Medical Center. Seattle, WA, USA.
Since any intraductal papillary mucinous neoplasm (IPMN) is at least premalignant, avoiding conversion to invasion by pancreatic resection should provide a survival advantage-but how much? The authors reviewed 100 cases of IPMN that were resected. Survival was compared between 3 groups: noninvasive IPMN (n=75), invasive IPMN (n=25), and invasive ductal adenocarcinoma (n=24), the latter matched by tumor-node-metastasis (TNM) stage to the IPMN invasive group. The 5-year disease-specific survival was significantly better for the noninvasive IPMN group (100%) than the invasive IPMN group (46%). Tumor recurrence was infrequent with noninvasive IPMNs (1.3% benign IPMN). Recurrence was common in the invasive IPMN group (46%). Even the subgroup with stage 1 disease had a 25% recurrence of malignancy. Survival curves were not different (P=0.11) between the cases matched by stage for those with invasive IPMN cases versus cases with ductal adenocarcinoma. Patients with the invasive form of IPMN will have a similarly poor survival as those with ductal adenocarcinoma. In patients thought to have a benign IPMN, these lesions should be removed to avoid conversion to invasive cancer and to preserve the opportunity for the more favorable prognosis observed in this study.
Cancer Genet Cytogenet 2005; 159(1):10-7. (PMID: 15860351)
AURKA amplification, chromosome instability, and centrosome abnormality in human pancreatic carcinoma cells.
Zhu J, Abbruzzese JL, Izzo J, Hittelman WN, Li D.
Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center. Houston, TX, USA.
To test the hypothesis that AURKA amplification contributes to pancreatic tumorigenesis by increasing centrosome abnormality and chromosome instability, the current study explored the associations between AURKA amplification, chromosome instability, centrosome abnormality, and the expression of several important proteins that are involved in cell proliferation (Ki-67), cell cycle regulation (p53, p16), and apoptosis (survivin) in 12 human pancreatic carcinoma cell lines. Using fluorescence in situ hybridization (FISH), the authors observed that 5 of the 12 cell lines had an AURKA amplification index (AI) (percentage of cells with more than three signals) greater than 60%. Both the AURKA AI and the average number of signals per cell (ANSPC) were significantly associated with the copy number of chromosome 9 but not chromosome 17. The AURKA ANSPC was positively associated with the percentage of cells with the centrosome abnormality. Furthermore, centrosome abnormality was significantly associated with the frequency of cells with abnormal nuclei and abnormal mitotic figures, but no direct association was detected between the frequency of centrosome abnormalities and chromosome instabilities. The AURKA AI was also associated with a lower expression of Ki-67, a higher expression of survivin, and the lack of expression of p16. These associations support the hypothesis that AURKA amplification contributes to pancreatic carcinogenesis by increasing chromosome instability and centrosome abnormality.
Am J Pathol 2005; 166(5):1379-92. (PMID: 15855639)
SCF(beta-TrCP1) controls Smad4 protein stability in pancreatic cancer cells.
Wan M, Huang J, Jhala NC, Tytler EM, Yang L, Vickers SM, et al.
Department of Pathology, School of Medicine, University of Alabama at Birmingham. Birmingham, AL, USA.
Smad4, also known as deleted in pancreatic carcinoma locus 4 (DPC4), is a critical co-factor in signal transduction pathways activated by transforming growth factor (TGF)-beta-related ligands that regulate cell growth and differentiation. Mutations in Smad4/DPC4 have been identified in approximately 50% of pancreatic adenocarcinomas. Here the authors report that SCF(beta-TrCP1), a ubiquitin (E3) ligase, is a critical determinant for Smad4 protein degradation in pancreatic cancer cells. The authors found that F-box protein beta-TrCP1 in this E3 ligase interacted with Smad4 and that SCF(beta-TrCP1) inhibited TGF-beta biological activity in pancreatic cancer cells by decreasing Smad4 stability. Very low Smad4 protein levels in human pancreatic ductal adenocarcinoma cells were observed by immunohistochemistry. By analyzing pancreatic tumor-derived Smad4 mutants, the authors found that most point-mutated Smad4 proteins, except those within or very close to a mutation cluster region, exhibited higher interaction affinity with beta-TrCP1 and significantly elevated protein ubiquitination by SCF(beta-TrCP1). Furthermore, AsPC-1 and Caco-2, two cancer cell lines harboring Smad4 point mutations, exhibited rapid Smad4 protein degradation due to the effect of SCF(beta-TrCP1). Both Smad4 levels and TGF-beta signaling were elevated by retrovirus-delivered beta-TrCP1 siRNA in pancreatic cancer cells. Therefore, inhibition of Smad4-specific E3 ligase might be a target for therapeutic intervention in pancreatic cancer.
Ann Surg 2005; 241(5):776-83. (PMID: 15849513)
Neuroendocrine hepatic metastases: does aggressive management improve survival?
Touzios JG, Kiely JM, Pitt SC, Rilling WS, Quebbeman EJ, Wilson SD, Pitt HA.
Departments of Surgery, Medical College of Wisconsin. Milwaukee, WI, USA.
The aim of this study was to determine whether aggressive management of neuroendocrine hepatic metastases improves survival. Survival in patients with carcinoid and pancreatic neuroendocrine tumors is significantly better than adenocarcinomas arising from the same organs. However, survival and quality of life are diminished in patients with neuroendocrine hepatic metastases. In recent years, aggressive treatment of hepatic neuroendocrine tumors has been shown to relieve symptoms. Minimal data are available, however, to document improved survival with this approach. The records of patients with carcinoid (n=84) and pancreatic neuroendocrine tumors (n=69) managed from January 1990 through July 2004 were reviewed. Eighty-four patients had malignant tumors, and hepatic metastases were present in 60 of these patients. Of these 60 patients, 23 received no aggressive treatment of their liver metastases, 19 were treated with hepatic resection and/or ablation, and 18 were managed with transarterial chemoembolization (TACE) frequently (n=11) in addition to resection and/or ablation. These groups did not differ with respect to age, gender, tumor type, or extent of liver involvement. Median and 5-year survival were 20 months and 25% for the nonaggressive group, more than 96 months and 72% for the resection/ablation group, and 50 months and 50% for the TACE group. The survival for the resection/ablation and the TACE groups was significantly better (P<0.05) when compared with the nonaggressive group. Patients with more than 50% liver involvement had a poor outcome (P<0.001). These data suggest that aggressive management of neuroendocrine hepatic metastases does improve survival, that chemoembolization increases the patient population eligible for this strategy, and that patients with more than 50% liver involvement may not benefit from an aggressive approach.
Ann R Coll Surg Engl 2005; 87(3):163-6. (PMID: 15901374)
Pancreatic cancer: is an aggressive approach justified?
Krysa J, Miller M, Kukreja N, Steger A.
Department of Surgery, University Hospital Lewisham. London, United Kingdom.
Surgery is the only curative treatment for carcinoma of the pancreas. Resection rates can be low (4.5%), figures of 30% have also been suggested as possible. The approach undertaken in this unit is to consider all patients as potentially resectable unless otherwise proven. One-hundred and forty patients were studied over 6-year period; 113 underwent palliative treatment (48% distant metastases, 40% local spread, 11% high operative risk); 14 had a triple bypass (14/113; 12%), 99 were managed conservatively, 43 received palliative chemotherapy. Twenty-three out of 140 (16%) underwent Whipple's procedure (n=23; 12 females, 11 males; mean age, 60 years); 4/23 had chronic pancreatitis. Distal pancreatectomy was undertaken in 4 patients. Median survival time for patients undergoing a triple bypass was 5 months (range, 0.1-20 months), 3 months for patients treated conservatively (range, 0.1-30 months) and 5 months for patients undergoing palliative chemotherapy (range, 1-30 months). 30-day mortality for Whipple's procedure was 4% (1/23) with median survival rate for patients with carcinoma of 13 months (range, 5-66 months); 31 months for patients with clear resection margins and negative nodes (n=5). This policy allows a resection rate of 19% with increased median survival rate for patients with cancer by 8 months more than those who where not resected. Aggressive staging and pancreatic biopsies allow patients to be entered into chemotherapy trials with improvement in survival and potential future benefits.
Biochem Biophys Res Commun 2005; 330(2):526-32. (PMID: 15796914)
Proteomics-based identification of DEAD-box protein 48 as a novel autoantigen, a prospective serum marker for pancreatic cancer.
Xia Q, Kong XT, Zhang GA, Hou XJ, Qiang H, Zhong RQ.
Department of Molecular Immunology, Institute of Basic Medical Science. Beijing, PR China.
Patients with cancer frequently develop autoantibodies, and the identification of panels of tumor autoantigens may have utility in early cancer diagnosis and immunotherapy. This study aims to exploit the autoantibody repertoire in pancreatic cancer and identify the possible serum marker for pancreatic cancer. Sera from 55 newly diagnosed patients with pancreatic cancer and 52 healthy controls were analyzed for antibody-based reactivity against Hep-2, a human larynx epithelioma cancer cell line, with one-dimensional immunoblot assay. From this analysis, the authors observed a prominent band with a molecular weight of 47 kDa in 63.6% (35/55) patients, while in only 1.9% normal group (1/52). Using immunoblot analysis after two-dimensional electrophoresis combined with liquid chromatography-electrospray ionization tandem mass spectrometry, this target antigen was identified as DEAD-box protein 48 (DDX48). BLAST analysis showed that it was highly similar to eukaryotic initiation factor 4A and might play a role in pre-mRNA processing. An enzyme-linked immunosorbent assay was performed using recombinant, purified DDX48 as an antigen to detect anti-DDX48 autoantibodies in sera. Reactivity was observed in 20 of 60 (33.3%) pancreatic cancer patients, 3 of 30 (10.0%) colorectal cancer patients, 2 of 30 (6.7%) gastric cancer patients, 2 of 30 (6.7%) hepatocellular cancer patients, while none of the 20 chronic pancreatitis patients, 30 lung cancer patients, and 60 normal individuals. Together, these results demonstrate that the detection of autoantibodies to DDX48 may have clinical utility for the improved diagnosis of pancreatic cancer.