Cancer of the Pancreas
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Pancreatic cancer is a disease in which the cells of the pancreas become malignant. The pancreas has two main functions; (i) it makes juices that help digest food and (ii) produces hormones (including insulin) that conrol how food is used and stored in the body. The vast majority of pancreatic cancers are associated with the part of the pancreas that makes digestive juices - these are known as "exocrine" pancreatic cancers. Only about 1/20 pancreatic cancers start in the hormone producing part of the pancreas ; these are known as "endocrine" pancreatic cancer or "islet cell cancer". There are several types of exocrine pancreatic cancers (based on how the cells appear under the microsope), most are classed as "ductal adenocarcinomas". Pancreatic cancer is rare before the age of 40 years, incidence increases sharply with increasing age.

Menu: Cancer of the Pancreas

Information for Patients and the Public
Information for Health Professionals / Researchers
Latest Research Publications
Pancreatic Neuroendocrine Tumours (Islet Cell Tumours)
Familial Pancreatic Cancer

Information Patients and the Public (16 links)


Information for Health Professionals / Researchers (8 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Son J, Lyssiotis CA, Ying H, et al.
Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway.
Nature. 2013; 496(7443):101-5 [PubMed] Article available free on PMC after 04/10/2013
Cancer cells have metabolic dependencies that distinguish them from their normal counterparts. Among these dependencies is an increased use of the amino acid glutamine to fuel anabolic processes. Indeed, the spectrum of glutamine-dependent tumours and the mechanisms whereby glutamine supports cancer metabolism remain areas of active investigation. Here we report the identification of a non-canonical pathway of glutamine use in human pancreatic ductal adenocarcinoma (PDAC) cells that is required for tumour growth. Whereas most cells use glutamate dehydrogenase (GLUD1) to convert glutamine-derived glutamate into α-ketoglutarate in the mitochondria to fuel the tricarboxylic acid cycle, PDAC relies on a distinct pathway in which glutamine-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate by aspartate transaminase (GOT1). Subsequently, this oxaloacetate is converted into malate and then pyruvate, ostensibly increasing the NADPH/NADP(+) ratio which can potentially maintain the cellular redox state. Importantly, PDAC cells are strongly dependent on this series of reactions, as glutamine deprivation or genetic inhibition of any enzyme in this pathway leads to an increase in reactive oxygen species and a reduction in reduced glutathione. Moreover, knockdown of any component enzyme in this series of reactions also results in a pronounced suppression of PDAC growth in vitro and in vivo. Furthermore, we establish that the reprogramming of glutamine metabolism is mediated by oncogenic KRAS, the signature genetic alteration in PDAC, through the transcriptional upregulation and repression of key metabolic enzymes in this pathway. The essentiality of this pathway in PDAC and the fact that it is dispensable in normal cells may provide novel therapeutic approaches to treat these refractory tumours.


Bertsch T, Aschenneller C, Bewarder N, et al.
European proficiency study with control serum for the tumor marker CA 19-9 measured on different test systems.
Clin Lab. 2013; 59(1-2):185-92 [PubMed]
BACKGROUND: Reliable and precise CA 19-9 testing is required for the long-term follow-up of patients with pancreatic carcinoma during therapy. The aim of this longitudinal proficiency study was to evaluate the comparability, linearity, and precision of CA 19-9 determinations performed in different laboratories using currently available test systems under routine conditions.
METHODS: During the one year study period, 15 laboratories applied 7 different tests and included a liquid BIOREF control serum with pancreatic carcinoma derived CA 19-9 in their routine testing and quality control procedures. The results were collected centrally and evaluated statistically.
RESULTS: The comparability of CA 19-9 results is limited especially when different tests are used, albeit, some tests show a good correlation: The CA 19-9 values obtained by different laboratories using different test systems vary up to a factor of 2. The precision of CA 19-9 determinations was acceptable in most laboratories with coefficients of variation ranging between very low 3.2% and high 17.8%. The imprecision was slightly increased when automatic dilution procedures of the analysers were used.
CONCLUSIONS: The comparability of CA 19-9 test results must be improved. The precision is acceptable in most cases. In order to monitor key performance parameters, every laboratory should participate in external quality assessment schemes and should perform a routine internal quality control with a control serum independent from the test kit manufacturer.


Yin Q, Wang C, Wu Z, et al.
Adenosquamous carcinoma of the pancreas: multidetector-row computed tomographic manifestations and tumor characteristics.
J Comput Assist Tomogr. 2013 Mar-Apr; 37(2):125-33 [PubMed]
OBJECTIVE: The purpose of this article was to present the adenosquamous carcinoma (ASqC) of the pancreas: multidetector-row computed tomographic (CT) features and tumor characteristics.
MATERIALS AND METHODS: The clinical data and CT studies of 12 patients with pathologically proven ASqC of the pancreas between the dates February 2001 and February 2010 were retrospectively analyzed.
RESULTS: The presenting symptoms of ASqC of the pancreas were nonspecific. Elevated serum levels of carbohydrate antigen 19-9, carbohydrate antigen 12-5, and carcinoembryonic antigen were noted. The tumor was most commonly involved in the pancreatic head in 6 patients, with the dilation of the common bile duct and the upstream main pancreatic duct. All ASqCs exhibited invasive growth. No calcification and intratumoral hemorrhage were noted in ASqCs. Ten tumors showed enhancement in the early arterial phase and persistent enhancement in the portal vein phase.
CONCLUSION: The typical CT appearance of ASqC was solitary oval or round without any capsule and a defined margin. The dilation of the main pancreatic duct and/or the common bile duct was always discovered. The huge infiltrative lesion outside the pancreas was detected in the tail and/or the body of the pancreas. Not only the elevation of carbohydrate antigen 19-9 is common, but also Ca12-5 and CEA, whereas human alpha fetoprotein elevation is not observed. The enhancement pattern of tumor showed persistence in the portal vein phase.


Jarry J, Bodin R, Peycru T, et al.
Role of laparoscopic distal pancreatectomy for solid pseudopapillary tumor.
JSLS. 2012 Oct-Dec; 16(4):552-8 [PubMed] Article available free on PMC after 04/10/2013
BACKGROUND: Since the first case report regarding laparoscopic distal pancreatectomy (DP) for solid pseudopapillary tumor (SPT), few additional articles have been published. The objective of this study was to evaluate the feasibility, safety, and long-term outcome of the laparoscopic DP based on a series of adult SPT patients.
METHODS: In a single-center study, we screened all adult patients undergoing a laparoscopic DP for SPT. Preoperative, operative, and postoperative data were retrospectively analysed and compared to the results of open DP for SPT published in the medical literature.
RESULTS: From April 2000 to June 2010, 5 adult female patients (median age 34 y) underwent a laparoscopic DP for an SPT. No conversion to open surgery was required. The median size of the tumor was 45 mm. The postoperative mortality rate was 0%, and serious complications (Dindo IV) occurred in 2 patients. The postoperative quality of life was not significantly altered by the laparoscopic procedure. At a median follow-up of 60 mo, all patients were alive and without evidence of local recurrence, distant metastasis, diabetes, or exocrine insufficiency.
CONCLUSION: Laparoscopy may offer an alternative to open surgery in the treatment of SPT of the distal pancreas in adult female patients. The laparoscopic procedure impacts neither the oncologic outcome nor the quality of life. However, due to the risk of postoperative complications, this procedure should be reserved for specialized centers.


Sherwinter DA, Lewis J, Hidalgo JE, Arad J
Laparoscopic distal pancreatectomy.
JSLS. 2012 Oct-Dec; 16(4):549-51 [PubMed] Article available free on PMC after 04/10/2013
BACKGROUND: Laparoscopic management of distal pancreatic malignancies has been slow to gain a foothold in all but high-volume tertiary referral centers. The aim of this study was to assess the safety and outcomes of laparoscopic distal pancreatectomy (LDP) performed in a low-volume community hospital by a diverse group of surgeons, none of whom have a specialized laparoscopic background.
METHODS: We conducted a retrospective review of all patients who underwent open distal pancreatectomies (ODPs) and LDPs between August 2001 and June 2008. Data included type of surgery, open versus laparoscopy, demographics, operative time, blood loss, length of hospital stay, histopathologic diagnosis, postoperative complications, American Society of Anesthesiologists score, and mortality.
RESULTS: Twenty-seven patients with pancreatic masses underwent distal pancreatic resection during the study period. Fifty-nine percent (n = 16) underwent LDP, and 41% (n = 11) underwent ODP. Mean patient age was 66 y (range, 40 to 86) for the LDP group and 62 (range, 40 to 84) for the ODP group. Mean operative time was 231 min (range, 195 to 305) for LDP and 240 (range, 150 to 210) for the ODP technique. Mean length of stay for LDP and ODP was 8 (range, 3 to 22) and 12 d (range, 5 to 2), respectively. Morbidity was 25% (n = 4) in the LDP group and 36% (n = 4) in the ODP group. None of the differences between the LDP and ODP groups were statistically significant. No mortalities occurred in either group.
CONCLUSION: This study supports the idea that LDP can be safely and effectively performed by any surgeon comfortable with basic laparoscopy and may not require specialized training or a specialized center. Further data are required to make more definitive conclusions.


Skelton WP, Skelton M, Vesely DL
Inhibition of AKT in human pancreatic, renal and colorectal cancer cells by four cardiac hormones.
Anticancer Res. 2013; 33(3):785-90 [PubMed]
BACKGROUND: Protein kinase-B (AKT) is a serine/threonine protein kinase that has a key role in cell proliferation and cancer cell invasiveness. Four cardiac peptide hormones, namely vessel dilator, atrial natriuretic peptide (ANP), kaliuretic peptide, and long-acting natriuretic peptide (LANP) have anticancer effects both in vitro and in vivo.
MATERIALS AND METHODS: Four cardiac hormones were examined for their ability to inhibit AKT, measured with a solid-phase enzyme-linked immunosorbent assay (ELISA) in human colorectal, pancreatic, and renal cancer cells.
RESULTS: Vessel dilator, kaliuretic peptide, ANP, and LANP maximally reduced the concentration of AKT by 47%, 45%, 52%, and 46% in human colorectal cancer cells (p<0.0001), by 60%, 61%, 64%, and 59% in human pancreatic carcinoma cells (p<0.0001), and by 31%, 32%, 31%, and 31% in renal adenocarcinoma cells (p<0.001).
CONCLUSION: These four cardiac hormones are significant inhibitors of AKT in human cancer cells, as part of their anticancer mechanism(s) of action.


Pointer DT, Slakey LM, Slakey DP
Safety and effectiveness of vessel sealing for dissection during pancreaticoduodenectomy.
Am Surg. 2013; 79(3):290-5 [PubMed]
Traditional pancreaticoduodenectomy dissection techniques are tedious and time-consuming. The LigaSure(®) Vessel Sealing System is an alternative to standard dissection methods. LigaSure(®) can be used in replace of ligatures, clips, and sutures in most of the pancreaticoduodenectomy procedure. The objective of this study was to examine our experience with LigaSure(®) in pancreaticoduodenectomies and to show the safety and time-effectiveness. Forty-three pancreaticoduodenectomies were performed by a single surgeon using the LigaSure(®) device in place of traditional dissection techniques. A retrospective chart review was conducted to evaluate patient management and outcome. Demographics, preoperative, intraoperative, and postoperative data were analyzed. The average patient age was 61 years. Primary pathologic diagnoses were: periampullary carcinoma (56%), chronic pancreatitis (5%), cystic lesion (26%), neuroendocrine tumor (7%), and other (5%). Our patient population demonstrated American Society of Anesthesiologists Class I (2%), Class II (14%), III (75%), and IV (9%). Average operative time was 4:11 hours. The study group required an average of 0.49 ± 1.35 units of blood. Eight patients (19%) received blood transfusion, receiving an average of 2.63 ± 2.13 units. Patients had a median hospital stay of 10 days (range, 5 to 41 days). An oral diet was ordered for most patients by Day 4. Fourteen patients (32.5%) had a complication, including two patients requiring additional surgery for drainage of abscess. There were no postoperative deaths. The use of LigaSure(®) is a practical and safe alternative to standard dissection techniques. Operative time, blood loss, and complication rate are favorable compared with published series.


Kawamoto S, Johnson PT, Shi C, et al.
Pancreatic neuroendocrine tumor with cystlike changes: evaluation with MDCT.
AJR Am J Roentgenol. 2013; 200(3):W283-90 [PubMed]
OBJECTIVE: The objective of our study was to determine the prevalence and CT appearance of cystlike changes of pancreatic neuroendocrine tumor (NET), particularly of small (≤ 3 cm) tumors.
MATERIALS AND METHODS: The clinical records, images, and pathologic reports of 74 consecutive patients (average age, 55.5 years) with surgically resected pancreatic NETs who underwent preoperative CT were retrospectively reviewed. The size and location of the pancreatic NETs were recorded. The tumors were classified on the basis of CT appearance as small (≤ 3 cm) or large (> 3 cm) and as solid, partially (≤ 50% or > 50%) cystic, or purely (≈ 100%) cystic. Peripheral contrast enhancement on CT was characterized, and lymph node and liver metastases found by pathologic examination were recorded.
RESULTS: A total of 78 pancreatic NETs were reviewed. Five were not visualized on CT, leaving 73 pancreatic NETs in 69 patients (multiple tumors were visualized on CT of three patients) for analysis. The mean size of the 73 tumors was 3.0 ± 2.6 (SD) cm (range, 0.7-13.1 cm); 52 tumors were 3 cm or smaller and 21 tumors were larger than 3 cm. Gross pathologic results confirmed that 13 of the 73 (17.8%) tumors were predominantly (> 50% or ≈ 100%) cystic: 10 of the 52 (19.2%) tumors 3 cm or smaller and three of the 21 (14.3%) tumors larger than 3 cm. Peripheral contrast enhancement was seen in 11 of the 13 (85%) predominantly cystic pancreatic NETs. Compared with solid pancreatic NETs, predominantly cystic pancreatic NETs were less commonly associated with lymph node and liver metastases.
CONCLUSION: Cystic pancreatic NETs are not rare and should be included in the differential diagnosis of a cystic pancreatic mass, particularly if the cystic mass is associated with peripheral contrast enhancement. A minority of cystic pancreatic NETs can present with no peripheral enhancement.


Raman SP, Kawamoto S, Blackford A, et al.
Histopathologic findings of multifocal pancreatic intraductal papillary mucinous neoplasms on CT.
AJR Am J Roentgenol. 2013; 200(3):563-9 [PubMed]
OBJECTIVE: The criteria for resection of solitary pancreatic side-branch intraductal papillary mucinous neoplasm (IPMN) have been well described by the Sendai consensus statement. However, the management of multiple pancreatic cystic lesions is less certain, with no clear guidelines in the literature to date. The purpose of this study was to evaluate the histopathologic findings in pancreatic IPMNs in patients with multiple (≥ 4) pancreatic cysts.
MATERIALS AND METHODS: The CT scans of all patients with a pathologically proven IPMN at our institution were reviewed, and a total of 52 patients with four or more pancreatic cysts were found. Each case was reviewed for the number of cysts and the presence of signs of invasive malignancy including a coexistent solid pancreatic mass, pancreatic ductal dilatation, and mural nodularity.
RESULTS: A total of 52 patients (19 men, 33 women; mean age, 71.8 years) were found to have multifocal IPMNs, defined as four or more cysts, on CT. Of these 52 patients, nine also had evidence of a solid pancreatic mass on CT. Retrospective review of the pathologic results for the remaining 43 patients (17 men, 26 women; mean age, 71.76 years) showed 18 cases of an IPMN with either high-grade dysplasia or a coexistent invasive carcinoma. Most important, 37% (7/19 patients) had no CT findings of an invasive malignancy according to the Sendai criteria (i.e., cysts ≥ 3 cm in the axial plane, main pancreatic ductal dilatation ≥ 6 mm, or mural nodularity within a cyst) but were found to have an IPMN with either high-grade dysplasia or invasive carcinoma. When the pancreas contained 10 or more cysts, high-grade dysplasia or invasive carcinoma tended to be more likely than low- or intermediate-grade dysplasia (odds ratio, 3.83; 95% CI, 0.87-16.8; p = 0.075).
CONCLUSION: The presence of multiple pancreatic cysts should be looked on with suspicion, particularly when there are a large number of cysts, even when none of the cysts individually meet the imaging criteria for resection according to the Sendai consensus recommendations. At the very least, these patients need to be followed very closely.


Yao JC, Phan AT, Jehl V, et al.
Everolimus in advanced pancreatic neuroendocrine tumors: the clinical experience.
Cancer Res. 2013; 73(5):1449-53 [PubMed]
The incidence of neuroendocrine tumors (NET) has increased dramatically in the past 30 years. This information has revitalized basic and clinical research into the molecular biology of NET and has resulted in the recent approval of new therapies for pancreatic NET (pNET), including the oral inhibitor of the mTOR everolimus. Everolimus significantly improved progression-free survival among patients with pNET in the phase III RADIANT-3 study. Here, we review the clinical studies showing the efficacy of everolimus in pNET and summarize the translational science from these studies. To understand the mechanisms of resistance and cause of treatment failure, we compared the type of progression events observed in the everolimus and placebo arms of the RADIANT-3 study. Comparison of the everolimus arm to the placebo arm indicated the fractions of progression events due to new metastasis only (21% vs. 22%), growth of preexisting lesions only (54% vs. 49%), and new metastasis along with growth of preexisting lesions (24% vs. 27%) were similar. These results suggest that although everolimus delays disease progression in patients with pNET, patients who experience disease progression while on everolimus do not appear to have a more aggressive metastatic phenotype than those whose disease progresses while on placebo.


Heinemann V, Ebert MP, Laubender RP, et al.
Phase II randomised proof-of-concept study of the urokinase inhibitor upamostat (WX-671) in combination with gemcitabine compared with gemcitabine alone in patients with non-resectable, locally advanced pancreatic cancer.
Br J Cancer. 2013; 108(4):766-70 [PubMed] Article available free on PMC after 05/03/2014
Background:To evaluate the efficacy and tolerability of the urokinase plasminogen activator (uPA) inhibitor upamostat in combination with gemcitabine in locally advanced pancreatic adenocarcinoma (LAPC).Methods:Within a prospective multicenter study, LAPC patients were randomly assigned to receive 1000 mg m(-2) of gemcitabine IV weekly either alone (arm A) or in combination with 200 mg (arm B) or 400 mg (arm C) oral upamostat daily. Efficacy endpoints of this proof-of-concept study included response rate, time to first metastasis, progression-free and overall survival (OS).Results:Of the 95 enroled patients, 85 were evaluable for response and 93 for safety. Median OS was 12.5 months (95% CI 8.2-18.2) in arm C, 9.7 months (95% CI 8.4-17.1) in arm B and 9.9 months (95% CI 7.4-12.1) in arm A; corresponding 1-year survival rates were 50.6%, 40.7% and 33.9%, respectively. More patients achieved a partial remission (confirmed responses by RECIST) with upamostat combination therapy (arm C: 12.9%; arm B: 7.1%; arm A: 3.8%). Overall, only 12 patients progressed by developing detectable distant metastasis (arm A: 4, arm B: 6, arm C: 2). The most common adverse events considered to be related to upamostat were asthenia, fever and nausea.Conclusion:In this proof-of-concept study targeting the uPA system in LAPC, the addition of upamostat to gemcitabine was tolerated well; similar survival results were observed for the three treatment arms.


Guillaumond F, Leca J, Olivares O, et al.
Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma.
Proc Natl Acad Sci U S A. 2013; 110(10):3919-24 [PubMed] Article available free on PMC after 05/03/2014
Pancreatic ductal adenocarcinoma is one of the most intractable and fatal cancer. The decreased blood vessel density displayed by this tumor not only favors its resistance to chemotherapy but also participates in its aggressiveness due to the consequent high degree of hypoxia. It is indeed clear that hypoxia promotes selective pressure on malignant cells that must develop adaptive metabolic responses to reach their energetic and biosynthetic demands. Here, using a well-defined mouse model of pancreatic cancer, we report that hypoxic areas from pancreatic ductal adenocarcinoma are mainly composed of epithelial cells harboring epithelial-mesenchymal transition features and expressing glycolytic markers, two characteristics associated with tumor aggressiveness. We also show that hypoxia increases the "glycolytic" switch of pancreatic cancer cells from oxydative phosphorylation to lactate production and we demonstrate that increased lactate efflux from hypoxic cancer cells favors the growth of normoxic cancer cells. In addition, we show that glutamine metabolization by hypoxic pancreatic tumor cells is necessary for their survival. Metabolized glucose and glutamine converge toward a common pathway, termed hexosamine biosynthetic pathway, which allows O-linked N-acetylglucosamine modifications of proteins. Here, we report that hypoxia increases transcription of hexosamine biosynthetic pathway genes as well as levels of O-glycosylated proteins and that O-linked N-acetylglucosaminylation of proteins is a process required for hypoxic pancreatic cancer cell survival. Our results demonstrate that hypoxia-driven metabolic adaptive processes, such as high glycolytic rate and hexosamine biosynthetic pathway activation, favor hypoxic and normoxic cancer cell survival and correlate with pancreatic ductal adenocarcinoma aggressiveness.


He J, Cameron JL, Ahuja N, et al.
Is it necessary to follow patients after resection of a benign pancreatic intraductal papillary mucinous neoplasm?
J Am Coll Surg. 2013; 216(4):657-65; discussion 665-7 [PubMed]
BACKGROUND: Little is known about the risk of subsequently developing a new or progressive intraductal papillary mucinous neoplasm (IPMN) after partial pancreatic resection of a noninvasive IPMN.
STUDY DESIGN: One hundred thirty patients with more than 1 year of follow-up after resection were included in this analysis.
RESULTS: At a median follow-up of 38 months, 22 (17%) developed imaging evidence of a new or progressive IPMN. Eleven (8%) underwent completion resection. Three of the 11 patients had invasive adenocarcinoma. Two other patients developed metastatic pancreatic adenocarcinoma and did not undergo resection. All 5 patients (4%) with cancer had negative margins at initial operation. Sixteen of 100 patients (16%) with negative margins for IPMN at the initial operation developed a new IPMN vs 6 of 30 patients (20%) with margins positive for IPMN (p = ns). Five of 22 patients (23%) with a new IPMN had a family history of pancreatic cancer, while 8 of 108 patients (7%) without a new IPMN had a family history (p < 0.05). Overall, the chances of developing a new IPMN at 1, 5, and 10 years after the initial surgery were 4%, 25%, and 62%, respectively, and of requiring surgery were 1.6%, 14%, and 18%, respectively. The estimated chances of developing invasive pancreatic cancer were 0%, 7%, and 38% at 1, 5, and 10 years, respectively.
CONCLUSIONS: Patients who have undergone resection for noninvasive IPMN require indefinite close surveillance because of the risks of developing a new IPMN, of requiring surgery, and of developing cancer. A family history of pancreatic cancer, but not margin status or degree of dysplasia, is associated with a risk of development of a new or progressive IPMN.


Morrison M
Pancreatic cancer and diabetes.
Adv Exp Med Biol. 2012; 771:229-39 [PubMed]
Diabetes studies have increasingly been associated with several types of cancer. Diabetes and pancreatic cancer have a unique relationship. Genetic mutations, such as activation of the KRAS2 oncogene, inactivation of the tumor-suppressor gene CDKN2A, inactivation of the tumor-suppressor gene TP53 and deleted in pancreatic cancer 4 (DPC4) gene defects are seen in those with pancreatic cancer. Approximately 80% of those patients, diagnosed with pancreatic cancer, are identified as having concomitant diabetes with a poor prognostic factor. Damaged pancreatic tissue, secondary to pancreatic cancer, leads to diabetes as islet cells and beta cells are taken over by malignancy. Additionally, those on certain anti-diabetic regimens are shown to be at a higher risk of developing pancreatic cancer due to the effect of stimulation on the pancreatic beta and islet cells. Therefore, diabetes is thought to be both a potential cause and effect of pancreatic cancer. Diabetes has become a pandemic, and pancreatic cancer is one of the most lethal forms of malignancy known. In order to better understand these diseases and how they are associated, more research needs to be done. Particularly, research focusing on different types of diabetes in the setting of pancreatic cancer will be an important issue for further understanding of the link between diabetes and pancreatic cancer.


López R, Méndez CM, Fernández MJ, et al.
Phase II trial of erlotinib plus capecitabine as first-line treatment for metastatic pancreatic cancer (XELTA study).
Anticancer Res. 2013; 33(2):717-23 [PubMed]
AIM: To evaluate the efficacy and safety of erlotinib plus capecitabine for metastatic pancreatic cancer.
PATIENTS AND METHODS: This was a multicenter, uncontrolled, phase II trial. Patients with untreated metastatic pancreatic cancer received oral capecitabine at 1,000 mg/m(2) twice daily on days 1-14, of a 21-day treatment cycle; and oral erlotinib at 150 mg daily.
RESULTS: Thirty-two patients were enrolled. The overall response rate (ORR) was 6%, with a median time to treatment failure of 2.1 months. The median follow-up was 7.6 months. The median progression-free survival was 2.1 months and median overall survival was 4.3 months. The one-year survival rate was 22%. Major grade 1 and 2 non-hematological toxicities were skin rash (34%), asthenia (31%) and diarrhea (31%). Grade 3 hematological toxicity was <13%. No grade 4 toxicities were detected. None of the patients died due to treatment toxicity.
CONCLUSION: The combination of capecitabine with erlotinib is an active regimen with a favorable safety profile for patients with metastatic pancreatic cancer.


Sugimoto M, Gotohda N, Kato Y, et al.
Pancreatic resection for metastatic melanoma originating from the nasal cavity: a case report and literature review.
Anticancer Res. 2013; 33(2):567-73 [PubMed]
Metastatic pancreatic malignant melanoma is considered to be a highly aggressive neoplasm, and only few metastasectomies for lesions originating from the skin or the ocular region have been reported. We report a case of resection of pancreatic metastasis of malignant melanoma originating from the nasal cavity. An isolated pancreatic tumor was detected in a 46-year-old man who had undergone proton-beam therapy for nasal melanoma 12 months earlier. He underwent distal pancreatectomy with splenectomy and the pathological diagnosis was metastatic malignant melanoma. We review cases of malignant melanoma metastatic to the pancreas and further discuss their incidence, therapeutic strategy, and outcome of mucosal melanoma of the head and neck.


Shi Y, Tong M, Wu Y, et al.
VEGF-C ShRNA inhibits pancreatic cancer growth and lymphangiogenesis in an orthotopic fluorescent nude mouse model.
Anticancer Res. 2013; 33(2):409-17 [PubMed]
The aim of this study was to assess the inhibitory efficacy of short hairpin RNA (ShRNA) targeting vascular endothelial growth factor C (VEGF-C) in an orthotopic pancreatic cancer mouse model. BxPC-3 human pancreatic cancer cells expressing green fluorescent protein (GFP) were orthotopically implanted onto the pancreas of nude mice. All mice were randomly divided into four groups when the average tumor size had reached 100 mm(3) and were treated with either vehicle or gemcitabine at 150 mg/kg; or intravenous VEGF-C ShRNA at 150 mg/kg; or intratumoral VEGF-C ShRNA at 150 μg/kg. In vivo fluorescence imaging was performed to monitor tumor growth and metastasis during the study. Real-time quantitative polymerase chain reaction (RT-qPCR) and an enzyme-linked immunosorbent assay (ELISA) were performed to determine the mRNA and protein level of VEGF-C in tumor tissues. Lymphatic vessel marker D2-40, blood vessel marker CD31 and proliferation marker Ki67 expression of the tumor tissues were analyzed by immunohistochemistry staining. Intravenous and intratumoral VEGF-C ShRNA treatment significantly inhibited tumor growth, downregulated the expression of VEGF-C mRNA, reduced tumor microlymphatic vessel density (MLVD), and inhibited cancer cell proliferation. Gemcitabine, as the standard treatment for pancreatic cancer, demonstrated a stronger inhibitory effect on tumor growth, with less inhibition of MLVD and more inhibition of microvessel density (MVD) and proliferation than VEGF-C ShRNA. These results indicate that different mechanisms are associated with the efficacy of gemcitabine and VEGF-C ShRNA.


Kulke MH
Systemic therapy for advanced pancreatic neuroendocrine tumors.
Semin Oncol. 2013; 40(1):75-83 [PubMed]
Neuroendocrine tumors (NETs) occur throughout the body, and share similar histologic characteristics. However, it has become increasingly evident that pancreatic NETs tend to respond differently to therapeutic agents than do other NET subtypes. In most cases, systemic therapy has been more effective in NETs of pancreatic origin than in NETs arising from other locations. Traditional systemic treatment options for pancreatic NETs include somatostatin analogs or cytotoxic chemotherapy. Recently, the biologically targeted agents everolimus and sunitinib were approved for use in patients with metastatic disease. Novel agents, as well as novel drug combinations, are currently under investigation.


Toumpanakis C, Caplin ME
Update on the role of somatostatin analogs for the treatment of patients with gastroenteropancreatic neuroendocrine tumors.
Semin Oncol. 2013; 40(1):56-68 [PubMed]
Somatostatin analogs (SA) are the standard of care for controlling symptoms of patients with functional gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). SA control symptoms in more than 70% of patients with carcinoid syndrome. Similar results are obtained in patients with functional, hormone-secreting, pancreatic NETs. The use of SA as antiproliferative agents has been established only recently. Retrospective studies have shown stabilization of tumor growth in >50% of patients with progressive disease. The results of a recent randomized phase III trial (PROMID) demonstrated that the median time to progression in patients with midgut carcinoid tumors treated with octreotide LAR (Long-Acting-Repeatable, Novartis, Basel, Switzerland) was more than twice as long compared to that of patients treated with placebo. The results of a phase III study of lanreotide versus placebo in nonfunctional NETs are not yet available. More studies are needed to determine whether combining SA with novel targeted treatments will result in enhanced antiproliferative activity compared to treatment with a SA alone. Studies are ongoing using pan-receptor agonists (eg, pasireotide) and chimeric dimers, which possess features of somatostatin and dopamine agonists (dopastatins) and are thought to enhance symptom control by binding multiple receptors (somatostatin and dopamine receptors). Somatostatin receptor antagonists are also currently being developed for clinical use. Peptide receptor radionuclide therapy (PRRT), consisting of yttrium-90 and lutetium-177 isotopes conjugated with SA appear to be efficacious in advanced NETs. Randomized studies are needed to definitively establish the safety and efficacy of this strategy compared to other available treatments, and to determine which radiolabeled isotopes or combinations are most effective.


Zhang Z, Wang Z, Liu X, et al.
Up-regulation of p21WAF1/CIP1 by small activating RNA inhibits the in vitro and in vivo growth of pancreatic cancer cells.
Tumori. 2012; 98(6):804-11 [PubMed]
AIMS AND BACKGROUND: To study the inhibitory effect of p21WAF1/CIP1 activation by saRNA on the growth of human pancreatic cancer cells PANC-1 in vitro and in vivo.
METHODS AND STUDY DESIGN: A dsRNA (dsP21) targeting the p21WAF1/CIP1 gene promoter at position-322 relative to the transcription start site was transfected into PANC-1 cells. Expression of mRNA and protein was evaluated by semiquantitative RT-PCR and Western blotting. Proliferation of PANC-1 cells was measured by the MTT method, and the apoptosis rate was detected by flow cytometry. PANC-1 cells were transplanted subcutaneously in nude mice, and the inhibitory effect of dsP21 on tumor growth was observed.
RESULTS: The introduction of dsP21 was shown to efficiently up-regulate expression of the p21WAF1/CIP1 gene in PANC-1 cells according to the results of RT-PCR and Western blotting (P <0.01, compared with controls). The inhibitory effect on cell proliferation was confirmed by the MTT test (P <0.05, compared with controls). The apoptosis rate of PANC-1 cells treated with dsP21 was significantly higher than that of the control cells (P <0.01). Our experimental data showed that dsP21-mediated up-regulation of p21 expression exerted an apparent growth inhibitory effect on PANC-1 cells in vivo.
CONCLUSIONS: dsP21 targeting the p21WAF1/CIP1 gene promoter can specifically up-regulate expression of the p21WAF1/CIP1 gene in PANC-1 cells. It therefore has a substantially inhibitory effect on cell proliferation in vitro and in vivo and can be used as a new method and material for the gene therapy of pancreatic cancer.


Lewis GH, Wang H, Bellizzi AM, et al.
Prognosis of minimally invasive carcinoma arising in mucinous cystic neoplasms of the pancreas.
Am J Surg Pathol. 2013; 37(4):601-5 [PubMed] Article available free on PMC after 01/04/2014
Although patients with surgically resected noninvasive mucinous cystic neoplasms (MCNs) of the pancreas are cured, the behavior of surgically resected minimally invasive adenocarcinomas arising in MCN has not been well established. We report 16 surgically resected MCNs with minimal invasion defined as unifocal or multifocal microscopic invasive adenocarcinoma confined to the ovarian stroma of the MCN without capsular or pancreatic parenchymal invasion. Pathologic findings were correlated with patient demographics, type of surgery, and long-term follow-up. Our study included 15 women and 1 man ranging in age from 25 to 66 years. The patients were followed up for a mean of 48.6 months (range, 12 to 148 mo). The MCNs ranged in size from 3.5 to 25 cm and were all located in the body/tail of the gland. Lymphovascular invasion was not identified in any of the cases, and all lymph nodes were negative for tumor. Ten neoplasms had unifocal invasion, whereas 6 had multifocal invasion. Twelve of the neoplasms were partially submitted for microscopic examination, whereas 4 were submitted entirely. Only 1 of the 16 minimally invasive MCNs recurred, and that tumor had been lighlty sampled pathologically. Our study demonstrates that the majority of patients with minimally invasive adenocarcinoma arising in MCNs are cured by surgery, particularly if the neoplasms are completely examined histologically.


Ino Y, Yamazaki-Itoh R, Shimada K, et al.
Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer.
Br J Cancer. 2013; 108(4):914-23 [PubMed] Article available free on PMC after 05/03/2014
Background:The host immune reaction is represented by immune/inflammatory cell infiltrates. Here we systematically analysed tumour-infiltrating immune/inflammatory cells in pancreatic ductal carcinoma (PDC) and evaluated their clinicopathological impact.Methods:Using immunohistochemistry, we examined tumour-infiltrating CD68(+) pan-macrophages, HLA-DR(+)CD68(+) M1 macrophages (M1), CD163(+) or CD204(+) M2 macrophages (M2), CD66b(+) neutrophils (Neu), CD4(+) T cells (CD4(+)T), CD8(+) T cells (CD8(+)T), and FOXP3(+)CD4(+) regulatory T cells (Treg) in 212 cases of PDC, and conducted correlation and survival analyses using the Kaplan-Meier method and Cox proportional hazards model.Results:Higher levels of tumour-infiltrating pan-macrophages, M2, Neu, or the ratio of Tregs to CD4(+)T (%Treg) were significantly associated with shorter survival, whereas higher levels of tumour-infiltrating CD4(+)T, CD8(+)T, or the ratio of M1 to pan-macrophages (%M1) were significantly associated with longer survival. Survival analysis of pairs of these variables revealed that some of the resulting patient groups had exclusively longer survival. We then connected the apparently related factors, and two significant variables emerged: tumour-infiltrating CD4(+)T(high)/CD8(+)T(high)/%Treg(low) and tumour-infiltrating %M1(high)/M2(low). Multivariate survival analysis revealed that these variables were significantly correlated with longer survival and had a higher hazard ratio.Conclusion:Tumour-infiltrating CD4(+)T(high)/CD8(+)T(high)/%Treg(low) and %M1(high)/M2(low) are independent prognosticators useful for evaluating the immune microenvironment of PDC.


Welsh JL, Wagner BA, van't Erve TJ, et al.
Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial.
Cancer Chemother Pharmacol. 2013; 71(3):765-75 [PubMed] Article available free on PMC after 01/03/2014
BACKGROUND: Treatment for pancreatic cancer with pharmacological ascorbate (ascorbic acid, vitamin C) decreases tumor progression in preclinical models. A phase I clinical trial was performed to establish safety and tolerability of pharmacological ascorbate combined with gemcitabine in patients with biopsy-proven stage IV pancreatic adenocarcinoma.
DESIGN: Nine subjects received twice-weekly intravenous ascorbate (15-125 g) employing Simon's accelerated titration design to achieve a targeted post-infusion plasma level of ≥350 mg/dL (≥20 mM). Subjects received concurrent gemcitabine. Disease burden, weight, performance status, hematologic and metabolic laboratories, time to progression and overall survival were monitored.
RESULTS: Mean plasma ascorbate trough levels were significantly higher than baseline (1.46 ± 0.02 vs. 0.78 ± 0.09 mg/dL, i.e., 83 vs. 44 μM, p < 0.001). Adverse events attributable to the drug combination were rare and included diarrhea (n = 4) and dry mouth (n = 6). Dose-limiting criteria were not met for this study. Mean survival of subjects completing at least two cycles (8 weeks) of therapy was 13 ± 2 months.
CONCLUSIONS: Data suggest pharmacologic ascorbate administered concurrently with gemcitabine is well tolerated. Initial data from this small sampling suggest some efficacy. Further studies powered to determine efficacy should be conducted.


Huang SC, Wu TH, Chen CC, Chen TC
Spontaneous rupture of solid pseudopapillary neoplasm of the pancreas during pregnancy.
Obstet Gynecol. 2013; 121(2 Pt 2 Suppl 1):486-8 [PubMed]
BACKGROUND: Spontaneous rupture of solid pseudopapillary neoplasm of the pancreas is an unusual complication during pregnancy.
CASE: At 19 weeks of gestation, a 29-year-old woman presented with a pancreatic mass and upper abdominal pain radiating to the back. On the third day of admission, shock and peritoneal signs developed. Exploratory laparotomy and subsequent subtotal pancreatectomy were performed for a bleeding tumor. Solid pseudopapillary neoplasm was confirmed by pathological examination. The patient delivered a healthy full-term girl vaginally. Eight months postoperatively, the clinical courses of both mother and infant have been uneventful.
CONCLUSION: Ruptured solid pseudopapillary neoplasms can cause an acute abdomen during pregnancy. The expression of progesterone receptors in solid pseudopapillary neoplasm is a possible cause of this potentially devastating event.


Graham RP, Shrestha B, Caron BL, et al.
Islet-1 is a sensitive but not entirely specific marker for pancreatic neuroendocrine neoplasms and their metastases.
Am J Surg Pathol. 2013; 37(3):399-405 [PubMed]
Islet-1 (Isl1) is a transcription factor involved in the embryogenesis of islets of Langerhans. Immunohistochemically, Isl1 is a sensitive lineage-specific marker for pancreatic neuroendocrine neoplasms (NENs) and their metastases. Its specificity has not been documented, nor have large numbers of NENs from other parts of the gut or other organs been studied. We examined Isl1 expression in 203 primary NENs (gastroenteropancreatic, lung, breast, and ovarian neoplasms) and 40 hepatic NEN metastases (enteropancreatic and lung neoplasms) from known primaries. The correlation between Isl1 and CDX2 expression was studied using a tissue microarray containing 46 pancreatic NENs. Immunostaining for Isl1 and CDX2 was also performed in selected NENs from other sites. Isl1 was positive in 90% of pancreatic, 89% of duodenal, 100% of rectal, 38% of colonic, 14% of appendiceal, and 6% of ileal primaries. Isl1 was negative in all other NENs. Among metastatic neoplasms, 76% of pancreatic and 2 of 2 rectal NEN metastases were Isl1 positive, whereas all other tested metastases were negative. The overall sensitivity and specificity of Isl1 in identifying primary pancreatic NENs was 88% and 80%, respectively. Thirty-six of 46 pancreatic NENs in the tissue microarray were Isl1 positive; 4 were Isl1 negative but CDX2 positive. Our findings confirm that Isl1 is a sensitive marker of pancreatic origin in cases of metastatic NEN. However, Isl1 does not distinguish pancreatic NEN from duodenal and colorectal NEN, even when used in association with CDX2.


Gallotti A, Johnston RP, Bonaffini PA, et al.
Incidental neuroendocrine tumors of the pancreas: MDCT findings and features of malignancy.
AJR Am J Roentgenol. 2013; 200(2):355-62 [PubMed]
OBJECTIVE: The objective of our study was to evaluate the MDCT features of incidentally detected neuroendocrine tumors (NETs) of the pancreas, identify features that can predict tumor biology or aggressiveness and long-term outcome, and determine the incidence of "nonbenign" behavior.
MATERIALS AND METHODS: In this retrospective study, 60 histologically verified pancreatic NETs incidentally detected with contrast-enhanced MDCT were included. Various MDCT features such as size, morphology, enhancement, and presence of calcifications were evaluated and were correlated with tumor biology on histopathology. The sensitivity, specificity, predictive values, and accuracy were calculated for MDCT features in predicting nonbenign biology and risk of recurrence.
RESULTS: A total of 32 of 60 (53%) NETs were nonbenign: most were large (mean, 29.1 mm) with a solid or complex pattern. NET size of 3 cm or larger yielded a positive predictive value of 61% for nonbenign tumors and 100% when calcification was present. In 12 patients with recurrence, 92% of NETs were nonbenign. The presence of calcification, local invasion, main pancreatic duct dilatation, vascular invasion, and lymph node enlargement along with angioinvasion and a Ki-67 index greater than 2% on histology were associated with a nonbenign diagnosis and a higher risk of recurrence.
CONCLUSION: Approximately 50% of incidental NETs show uncertain or malignant behavior. Solid tumors 3 cm or larger are commonly nonbenign; however, about 30% of tumors smaller than that size cutoff can be malignant. Nonbenign tumors and those with invasive features on MDCT have a higher incidence of recurrence.


Sahani DV, Kambadakone A, Macari M, et al.
Diagnosis and management of cystic pancreatic lesions.
AJR Am J Roentgenol. 2013; 200(2):343-54 [PubMed]
OBJECTIVE: The purpose of this review is to outline the management guidelines for the care of patients with cystic pancreatic lesions.
CONCLUSION: The guidelines are as follows: Annual imaging surveillance is generally sufficient for benign serous cystadenomas smaller than 4 cm and for asymptomatic lesions. Asymptomatic thin-walled unilocular cystic lesions smaller than 3 cm or side-branch intraductal papillary mucinous neoplasms should be followed up with CT or MRI at 6 and 12 months interval after detection. Cystic lesions with more complex features or with growth rates greater than 1 cm/year should be followed more closely or recommended for resection if the patient's condition allows surgery. Symptomatic cystic lesions, neoplasms with high malignant potential, and lesions larger than 3 cm should be referred for surgical evaluation. Endoscopic ultrasound with fine-needle aspiration (FNA) biopsy can be used preoperatively to assess the risk of malignancy.


Herman JM, Wild AT, Wang H, et al.
Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results.
J Clin Oncol. 2013; 31(7):886-94 [PubMed]
PURPOSE: TNFerade biologic is a novel means of delivering tumor necrosis factor alpha to tumor cells by gene transfer. We herein report final results of the largest randomized phase III trial performed to date among patients with locally advanced pancreatic cancer (LAPC) and the first to test gene transfer against this malignancy.
PATIENTS AND METHODS: In all, 304 patients were randomly assigned 2:1 to standard of care plus TNFerade (SOC + TNFerade) versus standard of care alone (SOC). SOC consisted of 50.4 Gy in 28 fractions with concurrent fluorouracil (200 mg/m(2) per day continuous infusion). TNFerade was injected intratumorally before the first fraction of radiotherapy each week at a dose of 4 × 10(11) particle units by using either a percutaneous transabdominal or an endoscopic ultrasound approach. Four weeks after chemoradiotherapy, patients began gemcitabine (1,000 mg/m(2) intravenously) with or without erlotinib (100 to 150 mg per day orally) until progression or toxicity.
RESULTS: The analysis included 187 patients randomly assigned to SOC + TNFerade and 90 to SOC by using a modified intention-to-treat approach. Median follow-up was 9.1 months (range, 0.1 to 50.5 months). Median survival was 10.0 months for patients in both the SOC + TNFerade and SOC arms (hazard ratio [HR], 0.90; 95% CI, 0.66 to 1.22; P = .26). Median progression-free survival (PFS) was 6.8 months for SOC + TNFerade versus 7.0 months for SOC (HR, 0.96; 95% CI, 0.69 to 1.32; P = .51). Among patients treated on the SOC + TNFerade arm, multivariate analysis showed that TNFerade injection by an endoscopic ultrasound-guided transgastric/transduodenal approach rather than a percutaneous transabdominal approach was a risk factor for inferior PFS (HR, 2.08; 95% CI, 1.06 to 4.06; P = .032). The patients in the SOC + TNFerade arm experienced more grade 1 to 2 fever and chills than those in the SOC arm (P < .001) but both arms had similar rates of grade 3 to 4 toxicities (all P > .05).
CONCLUSION: SOC + TNFerade is safe but not effective for prolonging survival in patients with LAPC.


Yun SM, Jung KH, Lee H, et al.
Synergistic anticancer activity of HS-173, a novel PI3K inhibitor in combination with Sorafenib against pancreatic cancer cells.
Cancer Lett. 2013; 331(2):250-61 [PubMed]
The RAF/MEK/ERK and PI3K/AKT pathways are highly implicated in the development of pancreatic cancer. The principal objective of this study was to assess the synergic effect between Sorafenib (a RAF inhibitor) and HS-173 (a novel PI3K inhibitor) to gain insight into novel therapeutic strategies for treating pancreatic cancer. We first investigated the cytotoxic effect of co-treatment with Sorafenib and HS-173 using the Calcusyn program. Combined treatment of the two drugs synergistically inhibited the viability of Panc-1 cells (combination index<1). Concomitantly, the co-treatment induced G2/M arrest and increased apoptosis with the loss of mitochondrial membrane potential. Apoptosis resulting from the co-treatment was accompanied by increased levels of cleaved caspase-3 and PARP as well as greater numbers of TUNEL-positive apoptotic cells compared to treatment with either drug alone. Furthermore, combined treatment with these drugs decreased the expression of HIF-1α and VEGF which play an important role in angiogenesis. This anti-angiogenic effect was confirmed by the suppressed tube formation of VEGF-induced human umbilical vein endothelial cells and inhibition of blood vessel formation in a Matrigel plug assay in mice. Taken together, our study demonstrates that combined treatment with Sorafenib and HS-173 has a synergistic anti-cancer effect on pancreatic cancer cells, indicating that simultaneously targeting the RAF/MEK and PI3K/AKT pathways can induce a synergistic inhibitory effect on pancreatic cancers in which both pathways are activated. Based on the observations from our study, we suggest that the combined administration of these two drugs may be considered to be a new therapeutic regimen for treating pancreatic cancer.


Baehner T, Guetgemann I, Heinze I, et al.
A rare case of direct tumor extension to the right ventricle.
Ann Thorac Surg. 2013; 95(2):706-7 [PubMed]
We report the case of a 72-year-old woman with signs of pulmonary embolism and right heart failure. Echocardiographic imaging and computed tomography revealed a mass within the inferior vena cava reaching from the head of the pancreas to the right ventricle. From standard imaging procedures and clinical findings alone, differentiation of a cardiac thrombus from a metastatic tumor mass was difficult. After resection of the intravascular tumor, histopathologic analysis confirmed a metastasis of primary ductal pancreatic adenocarcinoma. This is a report of a case of mucinous adenocarcinoma of the pancreas reaching the heart by continuous intravascular spreading.


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