Biomarker Commons

Enhanced discrimination of malignant from benign pancreatic disease by measuring the CA 19-9 antigen on specific protein carriers.

PLoS One. 2011;6(12):e29180

Authors: Yue T, Maupin KA, Fallon B, Li L, Partyka K, Anderson MA, Brenner DE, Kaul K, Zeh H, Moser AJ, Simeone DM, Feng Z, Brand RE, Haab BB

Abstract
The CA 19-9 assay detects a carbohydrate antigen on multiple protein carriers, some of which may be preferential carriers of the antigen in cancer. We tested the hypothesis that the measurement of the CA 19-9 antigen on individual proteins could improve performance over the standard CA 19-9 assay. We used antibody arrays to measure the levels of the CA 19-9 antigen on multiple proteins in serum or plasma samples from patients with pancreatic adenocarcinoma or pancreatitis. Sample sets from three different institutions were examined, comprising 531 individual samples. The measurement of the CA 19-9 antigen on any individual protein did not improve upon the performance of the standard CA 19-9 assay (82% sensitivity at 75% specificity for early-stage cancer), owing to diversity among patients in their CA 19-9 protein carriers. However, a subset of cancer patients with no elevation in the standard CA 19-9 assay showed elevations of the CA 19-9 antigen specifically on the proteins MUC5AC or MUC16 in all sample sets. By combining measurements of the standard CA 19-9 assay with detection of CA 19-9 on MUC5AC and MUC16, the sensitivity of cancer detection was improved relative to CA 19-9 alone in each sample set, achieving 67-80% sensitivity at 98% specificity. This finding demonstrates the value of measuring glycans on specific proteins for improving biomarker performance. Diagnostic tests with improved sensitivity for detecting pancreatic cancer could have important applications for improving the treatment and management of patients suffering from this disease.

PMID: 22220206 [PubMed - indexed for MEDLINE]

The MethDet: a technology for biomarker development.

Expert Rev Mol Diagn. 2011 Nov;11(8):807-12

Authors: Levenson VV, Melnikov AA

Abstract
Early detection and diagnosis of a disease in its presymptomatic form has to rely on biomarkers, and multiple laboratories are involved in their development and validation. In this article, we describe our work on a platform technology for a genome-wide analysis of DNA methylation while still using a small amount of sample - a biopsy, a section from a formalin-fixed paraffin-embedded tissue or a small volume (0.4 ml) of plasma from blood. This technology (methylation detection or MethDet) allows genome-wide association studies similar to the analysis of single-nucleotide polymorphisms. Instead of mostly static genetic differences, the MethDet technology tests disease-dependent changes of epigenetic makeup, which is closely related to the gene expression pattern of a disease. The MethDet assay has the capacity to utilize highly fragmented DNA (e.g., cell-free circulating DNA from plasma) to identify disease-specific changes, effects of treatment or changes in the disease activity.

PMID: 22022943 [PubMed - indexed for MEDLINE]

Subject review: pancreatic ductal adenocarcinoma in the setting of mutations in the cystic fibrosis transmembrane conductance regulator gene: case report and review of the literature.

J Gastrointest Surg. 2011 Dec;15(12):2284-90

Authors: Rittenhouse DW, Talbott VA, Anklesaria Z, Brody JR, Witkiewicz AK, Yeo CJ

Abstract
BACKGROUND: Cystic fibrosis (CF) is the most commonly inherited lethal autosomal recessive genetic disease amongst Caucasians. CF results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Patients with homozygous or compound heterozygous CFTR mutations have a risk of pancreatitis, but typically do not live long enough to develop pancreatic ductal adenocarcinoma (PDA), a disease that has an average age at diagnosis of 65 years. Little is known about the risk of the development of PDA in people who are heterozygous for mutations in the CFTR gene.
PATIENTS AND METHODS: We report a case of a patient with PDA who underwent resection, who is a carrier for the W1282X nonsense mutation in the CFTR gene. The patient is of Ashkenazi Jewish ethnicity and has a family history of CF, but no family history of PDA. We reviewed the English language literature for the prevalence of PDA in CF patients (and CFTR mutations in the setting of PDA) and their significance in terms of screening, and the use of this mutation as a biomarker for an increased risk of the development of PDA.
CONCLUSION: We conclude that patients with CFTR mutations, who also have other risks for the development of PDA such as a family history of the disease, should undergo screening and be educated about their risks.

PMID: 21809164 [PubMed - indexed for MEDLINE]

A pilot study to explore circulating tumour cells in pancreatic cancer as a novel biomarker.

Br J Cancer. 2012 Jan 31;106(3):508-16

Authors: Khoja L, Backen A, Sloane R, Menasce L, Ryder D, Krebs M, Board R, Clack G, Hughes A, Blackhall F, Valle JW, Dive C

Abstract
BACKGROUND: Obtaining tissue for pancreatic carcinoma diagnosis and biomarker assessment to aid drug development is challenging. Circulating tumour cells (CTCs) may represent a potential biomarker to address these unmet needs. We compared prospectively the utility of two platforms for CTC enumeration and characterisation in pancreatic cancer patients in a pilot exploratory study.
PATIENTS AND METHODS: Blood samples were obtained prospectively from 54 consenting patients and analysed by CellSearch and isolation by size of epithelial tumour cells (ISET). CellSearch exploits immunomagnetic capture of CTCs-expressing epithelial markers, whereas ISET is a marker independent, blood filtration device. Circulating tumour cell expression of epithelial and mesenchymal markers was assessed to explore any discrepancy in CTC number between the two platforms.
RESULTS: ISET detected CTCs in more patients than CellSearch (93% vs 40%) and in higher numbers (median CTCs/7.5 ml, 9 (range 0-240) vs 0 (range 0-144)). Heterogeneity observed for epithelial cell adhesion molecule, pan-cytokeratin (CK), E-Cadherin, Vimentin and CK 7 expression in CTCs may account for discrepancy in CTC number between platforms.
CONCLUSION: ISET detects more CTCs than CellSearch and offers flexible CTC characterisation with potential to investigate CTC biology and develop biomarkers for pancreatic cancer patient management.

PMID: 22187035 [PubMed - indexed for MEDLINE]

Novel diagnostic value of circulating miR-18a in plasma of patients with pancreatic cancer.

Br J Cancer. 2011 Nov 22;105(11):1733-40

Authors: Morimura R, Komatsu S, Ichikawa D, Takeshita H, Tsujiura M, Nagata H, Konishi H, Shiozaki A, Ikoma H, Okamoto K, Ochiai T, Taniguchi H, Otsuji E

Abstract
BACKGROUND: Several recent studies have demonstrated that microRNAs (miRNAs) are stably detectable in the plasma/serum. We hypothesised that miR-18a in the plasma is a potential biomarker in patients with pancreatic cancer.
METHODS: miR-18a is located in the miR-17-92 cluster and reported to be highly expressed in pancreatic cancer tissues. This study was divided into three parts: (1) Confirmation of higher miR-18a levels in primary pancreatic cancer tissues and cell lines than in normal pancreatic tissues and a human fibroblast cell line. (2) Evaluation of the plasma miR-18a assay using quantitative RT-PCR by comparing plasma results obtained from 36 patients with pancreatic cancer and from 30 healthy volunteers. (3) Evaluation of the assay for monitoring tumour dynamics in patients with pancreatic cancer.
RESULTS: (1) The expression of miR-18a was significantly higher in pancreatic cancer tissues (P=0.012) and pancreatic cancer cell lines (P=0.015) than in normal tissues and fibroblasts. (2) Plasma concentrations of miR-18a were significantly higher in pancreatic cancer patients than in controls (P<0.0001). The value of the area under the receiver-operating characteristic curve (AUC) was 0.9369. (3) Plasma levels of miR-18a were significantly lower in postoperative samples than in preoperative samples (P=0.0077).
CONCLUSION: Circulating miR-18a might provide new complementary tumour markers for pancreatic cancer.

PMID: 22045190 [PubMed - indexed for MEDLINE]

Pilot trial of sunitinib therapy in patients with von Hippel-Lindau disease.

Ann Oncol. 2011 Dec;22(12):2661-6

Authors: Jonasch E, McCutcheon IE, Waguespack SG, Wen S, Davis DW, Smith LA, Tannir NM, Gombos DS, Fuller GN, Matin SF

Abstract
BACKGROUND: Von Hippel-Lindau (VHL) disease induces vascular neoplasms in multiple organs. We evaluated the safety and efficacy of sunitinib in VHL patients and examined the expression of candidate receptors in archived tissue.
METHODS: Patients with VHL were given four cycles of 50 mg sunitinib daily for 28 days, followed by 14 days off. Primary end point was toxicity. Modified RECIST were used for efficacy assessment. We evaluated 20 archival renal cell carcinomas (RCCs) and 20 hemangioblastomas (HBs) for biomarker expression levels using laser-scanning cytometry (LSC).
RESULTS: Fifteen patients were treated. Grade 3 toxicity included fatigue in five patients. Dose reductions were needed in 10 patients. Eighteen RCC and 21 HB lesions were evaluable. Six of the RCCs (33%) responded partially, versus none of the HBs (P = 0.014). LSC revealed that mean levels of phosphorylated vascular endothelial growth factor receptor-2 were lower in HB than in RCC endothelium (P = 0.003) and mean phosphorylated fibroblast growth factor receptor substrate-2 (pFRS2) levels were higher in HB (P = 0.003).
CONCLUSIONS: Sunitinib treatment in VHL patients showed acceptable toxicity. Significant response was observed in RCC but not in HB. Greater expression of pFRS2 in HB tissue than in RCC raises the hypothesis that treatment with fibroblast growth factor pathway-blocking agents may benefit patients with HB.

PMID: 22105611 [PubMed - indexed for MEDLINE]

Plasma concentrations of angiogenesis-related molecules in patients with pancreatic cancer.

Jpn J Clin Oncol. 2012 Feb;42(2):105-12

Authors: Sakamoto H, Kimura H, Sekijima M, Matsumoto K, Arao T, Chikugo T, Yamada Y, Kitano M, Ito A, Takeyama Y, Kudo M, Nishio K

Abstract
BACKGROUND: Anti-angiogenic agents are now being clinically evaluated for the treatment of pancreatic cancer and a detailed investigation of the angiogenic profile of pancreatic cancer is needed. The aim of this study was to evaluate the plasma concentrations of angiogenesis-related molecules in patients with pancreatic cancer, compared with those with other diseases.
METHODS: Plasma samples obtained from 45 patients with pancreatic cancer were analyzed and compared with those from 9 patients with pancreatitis, 16 patients with benign hepatobiliary diseases and 58 patients with colorectal cancers. The plasma levels of angiogenesis-related molecules including angiopoietin-2, follistatin, granulocyte-colony stimulating factor, hepatocyte growth factor, interleukin-8, leptin, platelet-derived growth factor beta polypeptide, platelet endothelial cell adhesion molecule-1 and vascular endothelial growth factor were determined using an antibody suspension bead arrays system.
RESULTS: The plasma levels of all the angiogenesis-related molecules were not increased in patients with pancreatic cancer, compared with those with pancreatitis and benign hepatobiliary diseases, whereas the levels of those with colorectal cancer were markedly increased. The plasma interleukin-8 concentration was significantly elevated in patients with distant metastases and was associated with a poor treatment outcome of chemotherapy in patients with pancreatic cancer.
CONCLUSIONS: The plasma levels of angiogenesis-related molecules were not elevated in patients with pancreatic cancer, compared with those with benign diseases or colorectal cancer. The plasma interleukin-8 level may be a novel biomarker for the response to chemotherapy in patients with pancreatic cancer and warrants further prospective study.

PMID: 22167663 [PubMed - indexed for MEDLINE]

Boswellic acid suppresses growth and metastasis of human pancreatic tumors in an orthotopic nude mouse model through modulation of multiple targets.

PLoS One. 2011;6(10):e26943

Authors: Park B, Prasad S, Yadav V, Sung B, Aggarwal BB

Abstract
Pancreatic cancer (PaCa) is one of the most lethal cancers, with an estimated 5-year survival of <5% even when patients are given the best treatment available. In addition, these treatments are often toxic and expensive, thus new agents which are safe, affordable and effective are urgently needed. We describe here the results of our study with acetyl-11-keto-β-boswellic acid (AKBA), an agent obtained from an Ayurvedic medicine, gum resin of Boswellia serrata. Whether AKBA has an activity against human PaCa, was examined in in vitro models and in an orthotopic nude mouse model of PaCa. We found that AKBA inhibited the proliferation of four different PaCa cell lines (AsPC-1, PANC-28, and MIA PaCa-2 with K-Ras and p53 mutations, and BxPC-3 with wild-type K-Ras and p53 mutation). These effects correlated with an inhibition of constitutively active NF-κB and suppression of NF-κB regulating gene expression. AKBA also induced apoptosis, and sensitized the cells to apoptotic effects of gemcitabine. In the orthotopic nude mouse model of PaCa, p.o. administration of AKBA alone (100 mg/kg) significantly inhibited the tumor growth; this activity was enhanced by gemcitabine. In addition, AKBA inhibited the metastasis of the PaCa to spleen, liver, and lungs. This correlated with decreases in Ki-67, a biomarker of proliferation, and CD31, a biomarker of microvessel density, in the tumor tissue. AKBA produced significant decreases in the expression of NF-κB regulating genes in the tissues. Immunohistochemical analysis also showed AKBA downregulated the expression of COX-2, MMP-9, CXCR4, and VEGF in the tissues. Overall these results demonstrate that AKBA can suppress the growth and metastasis of human pancreatic tumors in an orthotopic nude mouse model that correlates with modulation of multiple targets.

PMID: 22066019 [PubMed - indexed for MEDLINE]

Pathobiological implications of MUC16 expression in pancreatic cancer.

PLoS One. 2011;6(10):e26839

Authors: Haridas D, Chakraborty S, Ponnusamy MP, Lakshmanan I, Rachagani S, Cruz E, Kumar S, Das S, Lele SM, Anderson JM, Wittel UA, Hollingsworth MA, Batra SK

Abstract
MUC16 (CA125) belongs to a family of high-molecular weight O-glycosylated proteins known as mucins. While MUC16 is well known as a biomarker in ovarian cancer, its expression pattern in pancreatic cancer (PC), the fourth leading cause of cancer related deaths in the United States, remains unknown. The aim of our study was to analyze the expression of MUC16 during the initiation, progression and metastasis of PC for possible implication in PC diagnosis, prognosis and therapy. In this study, a microarray containing tissues from healthy and PC patients was used to investigate the differential protein expression of MUC16 in PC. MUC16 mRNA levels were also measured by RT-PCR in the normal human pancreatic, pancreatitis, and PC tissues. To investigate its expression pattern during PC metastasis, tissue samples from the primary pancreatic tumor and metastases (from the same patient) in the lymph nodes, liver, lung and omentum from Stage IV PC patients were analyzed. To determine its association in the initiation of PC, tissues from PC patients containing pre-neoplastic lesions of varying grades were stained for MUC16. Finally, MUC16 expression was analyzed in 18 human PC cell lines. MUC16 is not expressed in the normal pancreatic ducts and is strongly upregulated in PC and detected in pancreatitis tissue. It is first detected in the high-grade pre-neoplastic lesions preceding invasive adenocarcinoma, suggesting that its upregulation is a late event during the initiation of this disease. MUC16 expression appears to be stronger in metastatic lesions when compared to the primary tumor, suggesting a role in PC metastasis. We have also identified PC cell lines that express MUC16, which can be used in future studies to elucidate its functional role in PC. Altogether, our results reveal that MUC16 expression is significantly increased in PC and could play a potential role in the progression of this disease.

PMID: 22066010 [PubMed - indexed for MEDLINE]

Biomarkers and molecular imaging in gastroenteropancreatic neuroendocrine tumors.

Horm Metab Res. 2011 Nov;43(12):832-7

Authors: Lindholm DP, Oberg K

Abstract
Neuroendocrine gastrointestinal and pancreatic tumors (GEP-NETs) are a heterogenous group of cancers with various clinical expressions. All tumors produce and secret various amines and peptides, which can be used as tissue and circulating markers. Chromogranin A (CgA) is a general tumor marker stored in secretory granules within the tumor cell and released upon stimulation. CgA is the best general tumor marker at the moment, expressed in 80-90% in all patients with GEP-NETs. CgA and NSE are used as tissue markers for the delineation of the neuroendocrine features of the tumors, but recently also the proliferation marker Ki-67 has been included in the standard procedure for evaluation of the proliferation. GEP-NETs are classified into well differentiated neuroendocrine tumors (Ki-67<2%), well-differentiated neuroendocrine carcinoma (Ki-67 2-20%), poorly differentiated neuroendocrine carcinoma (Ki-67>20%). The molecular imaging of NETs is based on the ability of these tumor cells to express somatostatin receptors as well as the APUD features. Octreoscan has been applied for imaging and staging of the disease for more than 2 decades and will nowadays be replaced by 68Ga-DOTA-Octreotate, with higher specificity and sensitivity. 18Fluoro-DOPA and 11C-5HTP are specific tracers for NETs with high specificity and selectivity. A new potential biomarker is auto-antibodies to paraneoplastic antigen MA2, which might indicate early recurrence of carcinoids after surgery with a curative intent. Circulating tumor cells (CTC) have been applied in GEP-NETs quite recently. There is still an unmet need for new markers.

PMID: 22009449 [PubMed - indexed for MEDLINE]

Use of a mouse model of pancreatic neuroendocrine tumors to find pericyte biomarkers of resistance to anti-angiogenic therapy.

Horm Metab Res. 2011 Nov;43(12):884-9

Authors: Franco M, Pàez-Ribes M, Cortez E, Casanovas O, Pietras K

Abstract
The successful introduction of rationally targeted agents into standard cancer care is a testimony of the vast knowledge base in tumor biology. However, in order to provide individually tailored therapy to patients and to identify small subsets of patients with a high likelihood to benefit from treatment, the identification of biomarkers for response or resistance to a particular therapeutic regimen is imperative. Herein, by the use of a genetically engineered mouse model of pancreatic neuroendocrine tumors, we have assessed the utility of pericyte characteristics in terms of differential marker expression to serve as surrogate markers for response or evasive resistance to anti-angiogenic therapy. We found that tumors refractory to therapy following long-term treatment with a vascular endothelial growth factor receptor-2 blocking antibody contained blood vessels with a prolific investment of pericytes expressing α-smooth muscle actin. Further analysis by simultaneous immunostaining for different pericyte markers led to the conclusion that the increased abundance of this particular subtype of blood vessels most likely occurred by co-option of vessels from the surrounding exocrine pancreas. Our findings may form the basis for retrospective analysis of pancreatic neuroendocrine tumors from patients having undergone treatment with anti-angiogenic agents in order to validate the occurrence of pericytes expressing α-smooth muscle actin as a biomarker for tumors refractory to therapy.

PMID: 21960459 [PubMed - indexed for MEDLINE]

Mitochondrial DNA copy number and pancreatic cancer in the alpha-tocopherol beta-carotene cancer prevention study.

Cancer Prev Res (Phila). 2011 Nov;4(11):1912-9

Authors: Lynch SM, Weinstein SJ, Virtamo J, Lan Q, Liu CS, Cheng WL, Rothman N, Albanes D, Stolzenberg-Solomon RZ

Abstract
Diabetes, obesity, and cigarette smoke, consistent risk factors for pancreatic cancer, are sources of oxidative stress in humans that could cause mitochondrial DNA (mtDNA) damage and increase mtDNA copy number. To test whether higher mtDNA copy number is associated with increased incident pancreatic cancer, we conducted a nested case-control study in the Alpha-Tocopherol Beta Carotene Cancer Prevention (ATBC) Study cohort of male smokers, aged 50 to 69 years at baseline. Between 1992 and 2004, 203 incident cases of pancreatic adenocarcinoma occurred (follow-up: 12 years) among participants, with whole blood samples used for mtDNA extraction. For these cases and 656 controls, we calculated ORs and 95% CIs using unconditional logistic regression, adjusting for age, smoking, and diabetes history. All statistical tests were two sided. Higher mtDNA copy number was significantly associated with increased pancreatic cancer risk (highest vs. lowest mtDNA copy number quintile, OR = 1.64, 95% CI = 1.01-2.67, continuous OR = 1.14, 95% CI 1.06-1.23), particularly for cases diagnosed during the first 7 years of follow-up (OR = 2.14, 95% CI = 1.16-3.96, P(trend) = 0.01, continuous OR = 1.21, 95% CI = 1.10-1.33), but not for cases occurring during follow-up of 7 years or greater (OR = 1.14, 95% CI = 0.53-2.45, continuous OR = 1.05, 95% CI = 0.93-1.18). Our results support the hypothesis that mtDNA copy number is associated with pancreatic cancer and could possibly serve as a biomarker for pancreatic cancer development.

PMID: 21859925 [PubMed - indexed for MEDLINE]

Mining the malignant ascites proteome for pancreatic cancer biomarkers.

Proteomics. 2011 Dec;11(23):4551-8

Authors: Kosanam H, Makawita S, Judd B, Newman A, Diamandis EP

Abstract
Pancreatic cancer (PC) is one of the most lethal malignancies and disease-specific biomarkers are desperately needed for better diagnosis, prognosis, monitoring treatment efficacy and for accelerating the development of novel targeted therapeutics. Being an advanced stage manifestation and a proximal fluid in contact with cancer tissues, the ascitic fluid presents itself as a promising rich source of biomarkers. Herein, we present a comprehensive proteomic analysis of pancreatic ascitic fluid. To fractionate the complex ascites proteome, we adopted a multi-dimensional chromatographic approach that included size-exclusion, ion-exchange and lectin-affinity chromatographic techniques. Our detailed proteomic analysis with high-resolution Orbitrap(®) mass spectrometer resulted in the identification of 816 proteins. We followed rigorous filtering criteria that consisted of PC-specific information obtained from three publicly available databases (Oncomine, Protein Atlas and Unigene) to segregate 20 putative biomarker candidates for future validation. Since these proteins are of membranous and extra-cellular origin, most are glycosylated, and many of them are over-expressed in cancer tissues, the probability of these proteins entering the peripheral blood circulation is high. Their validation as serological PC biomarkers in the future is highly warranted.

PMID: 21932441 [PubMed - indexed for MEDLINE]

MicroRNA-10b expression correlates with response to neoadjuvant therapy and survival in pancreatic ductal adenocarcinoma.

Clin Cancer Res. 2011 Sep 1;17(17):5812-21

Authors: Preis M, Gardner TB, Gordon SR, Pipas JM, Mackenzie TA, Klein EE, Longnecker DS, Gutmann EJ, Sempere LF, Korc M

Abstract
INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Diagnosis and management of PDAC are hampered by the absence of sensitive and specific disease biomarkers. MicroRNAs (miRNA) are noncoding regulatory RNAs involved in initiation and progression of human cancers. In this study, we sought to determine whether miR-10b could serve as a biomarker for PDAC.
EXPERIMENTAL DESIGN: miRNA expression was characterized by fluorescence-based in situ hybridization using locked nucleic acid-modified DNA probes against miR-10b, miR-21, miR-155, miR-196a, and miR-210, followed by codetection of proteins by immunohistochemistry on the same tissue sections. miRNA expression in surgically resected PDAC tissues and in endoscopic ultrasonography (EUS)-guided fine-needle aspirate (EUS-FNA) samples was analyzed in cytokeratin 19 (CK19)-positive epithelial cells using optical intensity analysis.
RESULTS: In 10 resected PDAC samples, miR-10b was the most frequently and consistently overexpressed miRNA among characterized miRNAs, exhibiting a four-fold increase in the cancer cells (P = 0.012). Given this preferential overexpression of miR-10b, we sought to determine whether miR-10b expression was clinically relevant. Accordingly, miR-10b expression was examined in 106 EUS-FNA samples obtained from pancreatic lesions. miR-10b expression was increased in cancer cells compared with CK19-positive epithelial cells in benign lesions (P = 0.0001). In patients with PDACs, lower levels of miR-10b were associated with improved response to multimodality neoadjuvant therapy, likelihood of surgical resection, delayed time to metastasis, and increased survival.
CONCLUSION: miR-10b is a novel diagnostic biomarker for PDACs when assessing pancreatic lesions. Expression of miR-10b is predictive of response to neoadjuvant therapy and outcome in this disease.

PMID: 21652542 [PubMed - indexed for MEDLINE]

Serum APRIL, a potential tumor marker in pancreatic cancer.

Clin Chem Lab Med. 2011 Oct;49(10):1715-9

Authors: Wang F, Chen L, Ding W, Wang G, Wu Y, Wang J, Luo L, Cong H, Wang Y, Ju S, Shao J, Wang H

Abstract
BACKGROUND: A proliferation-inducing ligand (APRIL) is a newly-found member in the tumor necrosis factor (TNF) superfamily. Our previous studies have already confirmed that APRIL is overexpressed in pancreatic cancer tumors, however, it is not expressed or has a weak expression in normal pancreatic gland tissues. Furthermore, there is no report on serum APRIL in patients with pancreatic diseases. Herein, in order to explore the clinical implication of serum APRIL in patients with pancreatic cancer, serum APRIL, together with carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)19-9, was examined.
METHODS: Serum APRIL was tested by ELISA in patients with pancreatic cancer. Meanwhile, two other conventional serum tumor markers, CEA and CA19-9, were measured by Elecsys 2010 Chemistry Analyzer.
RESULTS: Serum APRIL increased in patients with pancreatic cancer, which proved a positive correlation with CEA and CA19-9. When the diagnosis of benign or malignant condition was examined by one tumor marker, the sensitivity of APRIL alone (70.1%) was greater than that of CEA alone (56.7%), and the specificity of APRIL alone (85.5%) was higher than that of CA19-9 alone (83.6%). When examined by a combination of two markers, the sensitivity of the combination of APRIL and CA19-9 was the highest (88.1%), as it was compared with that of APRIL alone, CEA alone and APRIL+CEA, p<0.05. In addition, serum APRIL also correlated with the tumor stage and postoperative survival in patients with pancreatic cancer.
CONCLUSIONS: Our results indicate that serum APRIL, as a potential biomarker, has a positive diagnosis and prognosis value for pancreatic cancer. Moreover, the combination assay of APRIL and CA19-9 is highly sensitive to pancreatic cancer.

PMID: 21612541 [PubMed - indexed for MEDLINE]

Chromogranin A and neuron-specific enolase as prognostic markers in patients with advanced pNET treated with everolimus.

J Clin Endocrinol Metab. 2011 Dec;96(12):3741-9

Authors: Yao JC, Pavel M, Phan AT, Kulke MH, Hoosen S, St Peter J, Cherfi A, Öberg KE

Abstract
CONTEXT: Everolimus, an oral inhibitor of mammalian target of rapamycin, significantly prolongs progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumors (pNET). Chromogranin A (CgA) and neuron-specific enolase (NSE) are considered general biomarkers of these tumors.
OBJECTIVE: The objective of the study was to evaluate the prognostic value of CgA and NSE in patients with pNET treated with everolimus.
PATIENTS AND METHODS: Patients with low- to intermediate-grade advanced pNET enrolled in two phase 2 studies [RAD001 in Advanced Neuroendocrine Tumors (RADIANT-1) and single institution phase II study at The University of Texas M. D. Anderson Cancer Center] received everolimus. Blood samples were collected and analyzed by a central laboratory at baseline and monthly thereafter. PFS and overall survival (OS) were evaluated in patients with elevated and nonelevated baseline CgA/NSE levels.
RESULTS: In RADIANT-1, elevated vs. nonelevated baseline CgA was associated with shorter median PFS (8.34 vs. 15.64 months; P = 0.03) and OS (16.95 months vs. not reached; P < 0.001). Elevated vs. nonelevated baseline NSE resulted in shorter median PFS (7.75 vs. 12.29 months; P = 0.01) and OS (13.96 vs. 24.90 months; P = 0.005). Median PFS was prolonged in patients with early CgA or NSE response (11.0 vs. 5.0 months) compared with those without early biomarker response. More patients with CgA (87 vs. 50%) or NSE (81 vs. 14%) response experienced tumor shrinkage compared with those without response. CgA response data from the single-institution phase II study at The University of Texas M. D. Anderson Cancer Center study are consistent with data from the RADIANT-1 study.
CONCLUSIONS: Elevated baseline CgA/NSE provided prognostic information on PFS and survival; early CgA/NSE responses are potential prognostic markers for treatment outcomes in patients with advanced pNET.

PMID: 21994954 [PubMed - indexed for MEDLINE]

Toll-like receptor 9 agonist IMO cooperates with cetuximab in K-ras mutant colorectal and pancreatic cancers.

Clin Cancer Res. 2011 Oct 15;17(20):6531-41

Authors: Rosa R, Melisi D, Damiano V, Bianco R, Garofalo S, Gelardi T, Agrawal S, Di Nicolantonio F, Scarpa A, Bardelli A, Tortora G

Abstract
PURPOSE: K-Ras somatic mutations are a strong predictive biomarker for resistance to epidermal growth factor receptor (EGFR) inhibitors in patients with colorectal and pancreatic cancer. We previously showed that the novel Toll-like receptor 9 (TLR9) agonist immunomodulatory oligonucleotide (IMO) has a strong in vivo activity in colorectal cancer models by interfering with EGFR-related signaling and synergizing with the anti-EGFR monoclonal antibody cetuximab.
EXPERIMENTAL DESIGN: In the present study, we investigated, both in vitro and in vivo, the antitumor effect of IMO alone or in combination with cetuximab in subcutaneous colon and orthotopic pancreatic cancer models harboring K-Ras mutations and resistance to EGFR inhibitors.
RESULTS: We showed that IMO was able to significantly restore the sensitivity of K-Ras mutant cancer cells to cetuximab, producing a marked inhibition of cell survival and a complete suppression of mitogen-activated protein kinase phosphorylation, when used in combination with cetuximab. IMO interfered with EGFR-dependent signaling, modulating the functional interaction between TLR9 and EGFR. In vivo, IMO plus cetuximab combination caused a potent and long-lasting cooperative antitumor activity in LS174T colorectal cancer and in orthotopic AsPC1 pancreatic cancer. The capability of IMO to restore cetuximab sensitivity was further confirmed by using K-Ras mutant colorectal cancer cell models obtained through homologous recombination technology.
CONCLUSIONS: We showed that IMO markedly inhibits growth of K-Ras mutant colon and pancreatic cancers in vitro and in nude mice and cooperates with cetuximab via multiple mechanisms of action. Therefore, we propose IMO plus cetuximab as a therapeutic strategy for K-Ras wild-type as well for K-Ras mutant, cetuximab-resistant colorectal and pancreatic cancers.

PMID: 21890455 [PubMed - indexed for MEDLINE]

Reduced expression of desmocollin 2 is an independent prognostic biomarker for shorter patients survival in pancreatic ductal adenocarcinoma.

J Clin Pathol. 2011 Nov;64(11):990-4

Authors: Hamidov Z, Altendorf-Hofmann A, Chen Y, Settmacher U, Petersen I, Knösel T

Abstract
BACKGROUND: Cell--cell adhesion molecules such as desmosomes and cytokeratins may play a major role in epithelial--mesenchymal transition and have been suggested to have a relevant impact on tumour progression. This study investigated 15 biomarkers in pancreatic ductal adenocarcinoma (PDAC) and correlated the results with clinicopathological parameters.
METHODS: Tissue microarrays of 115 R0-resected PDAC were constructed to evaluate the protein expression of 15 in genome-wide expression profiling differentially expressed biomarkers.
RESULTS: At the protein level a high expression of desmocollin 2 (DSC2) was observed in 90.4%, DSC1 (67.6%), DSC3 (0.9%), MDM2 (16.2%), CEA (64.8%), CK7 (85.2%), CK8 (96.5%), CK18 (96.5%), CK19 (93.9%), CK20 (11.5%), CA19-9 (86.6%), TLE1 (8.7%), PITX1 (91.2%), factor H (95.7%) and mesothelin (9.6%). Reduced expression of DSC2 was statistically correlated with shorter patient survival, higher tumour grading and positive lymph node status (p=0.008, p=0.029, p=0.011, respectively). In multivariable analysis reduced expression of DSC2, higher tumour grading and positive lymph node status were independently correlated with shorter patient survival.
CONCLUSIONS: Reduced expression of DSC2 is independently correlated with shorter patient survival, higher tumour grading and positive lymph node status in PDAC and could serve as a prognostic marker.

PMID: 21725043 [PubMed - indexed for MEDLINE]