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Strategies for early detection of resectable pancreatic cancer
Keiichi Okano, Yasuyuki Suzuki
Keiichi Okano, Yasuyuki Suzuki, Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan
ORCID number: $[AuthorORCIDs]
Author contributions: Okano K drafted this manuscript, which was revised by Suzuki K.
Correspondence to: Keiichi Okano, MD, PhD, Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan. email@example.com
Telephone: +81-87-8912438 Fax: +81-87-8912439
Received: November 1, 2013 Revised: March 4, 2014 Accepted: April 15, 2014 Published online: August 28, 2014
Pancreatic cancer is difficult to diagnose at an early stage and generally has a poor prognosis. Surgical resection is the only potentially curative treatment for pancreatic carcinoma. To improve the prognosis of this disease, it is essential to detect tumors at early stages, when they are resectable. The optimal approach to screening for early pancreatic neoplasia has not been established. The International Cancer of the Pancreas Screening Consortium has recently finalized several recommendations regarding the management of patients who are at an increased risk of familial pancreatic cancer. In addition, there have been notable advances in research on serum markers, tissue markers, gene signatures, and genomic targets of pancreatic cancer. To date, however, no biomarkers have been established in the clinical setting. Advancements in imaging modalities touch all aspects of the clinical management of pancreatic diseases, including the early detection of pancreatic masses, their characterization, and evaluations of tumor resectability. This article reviews strategies for screening high-risk groups, biomarkers, and current advances in imaging modalities for the early detection of resectable pancreatic cancer.
Core tip: To improve the prognosis of patients with pancreatic cancer, it is essential to detect tumors at early stages, when they are resectable. The cancer of the pancreas screening program has reached several conclusions and recommendations for the management of patients who are at an increased risk of familial pancreatic cancer. Furthermore, genetic, epigenetic, and proteomics research have improved the understanding of the mechanisms of this disease, potentially offering biomarkers that could allow the cancer to be detected early. This article reviews strategies for the early detection of resectable pancreatic cancer.
Citation: Okano K, Suzuki Y. Strategies for early detection of resectable pancreatic cancer. World J Gastroenterol 2014; 20(32): 11230-11240
Pancreatic cancer is an especially lethal malignancy, with a mortality rate that almost equals its incidence. After pancreatic cancer is diagnosed, the 1-year relative survival rate is only 24%, and the 5-year overall survival rate is only 5%[1,2]. However, rates of overall survival have been improving over the past decades, for both resected and non-resected cases. These improvements are believed to have resulted from more optimal patient selection, refinements in surgical techniques, and better postoperative patient care, in addition to the development of effective adjuvant therapies. In cases of pancreatic carcinoma, complete surgical resection with adjuvant chemotherapy offers the best outcomes. However, over 80% of patients with pancreatic cancer present with an unresectable primary tumor and distant metastasis at the time of diagnosis. Of patients with resectable pancreatic cancers, only 15% have earliest-stage cancers (T1 or T2 tumors without lymph node metastases), which are associated with better survival[5,6]. Thus, only 2%-3% of all patients diagnosed with pancreatic cancer present with earliest-stage cancer. Among the patients with pancreatic cancer who undergo surgical resection, the 5-year survival rate is 15%-40%. In a study of operated pancreatic cancers from the Japanese Pancreatic Cancer Registry, it was observed that patients with stage I tumors < 2 cm in size had considerably better survival (58% alive at 5 years) than patients with stage IIb tumors (17% alive at 5 years). In another study, 100% 5-year survival was observed among 79 patients who had tumors < 1 cm and had undergone curative resection.
Recently, a valuable analysis about the timing of the genetic evolution of pancreatic cancer was reported. The authors indicated at least a decade between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell. Furthermore, at least five more years are required for the acquisition of metastatic ability and patients die an average of two years thereafter. These data provide novel insights into the genetic features underlying pancreatic cancer progression and define a broad time window of opportunity for early detection to prevent deaths from metastatic disease. For these reasons, significant efforts have been invested towards identifying high-risk groups, sensitive biomarkers, and accurate imaging modalities for pancreatic cancer. Each of these advancements can facilitate the early diagnosis of pancreatic cancer that is resectable or potentially resectable.
CURRENT CRITERIA FOR RESECTABILITY
In the absence of metastatic disease, pancreatic cancer cases are classified into three main categories: resectable, borderline resectable, and unresectable. Recent revisions of the National Comprehensive Cancer Network (NCCN) guidelines have attempted to distinguish tumors that are clearly resectable from those that are borderline resectable. Further, the NCCN guidelines provide a definition for radiographically resectable tumors. The specific NCCN guidelines have been quoted below.
Tumors considered “resectable” should demonstrate the following (1) No distant metastases; (2) No radiographic evidence of superior mesenteric vein (SMV) or portal vein (PV) distortion; and (3) Clear fat planes around the celiac axis, hepatic artery, and SMA.
Tumors considered “borderline resectable” include the following: (1) No distant metastases; (2) Venous involvement of the SMV or PV with distortion or narrowing of the vein or occlusion of the vein with suitable vessel proximal and distal, allowing safe resection and replacement; (3) Gastroduodenal artery encasement up to the hepatic artery with either short segment encasement or direct abutment of the hepatic artery, without extension to the celiac axis; and (4) Tumor abutment of the SMA not to exceed > 180° of the circumference of the vessel wall.
To improve the prognosis of patients with pancreatic cancer, it is essential to detect tumors at early stages, when they are more likely to be resectable.
SCREENING HIGH-RISK GROUPS TO FACILITATE EARLY DIAGNOSIS OF PANCREATIC CANCER
As presented in Table 1, previous studies have identified a variety of risk groups and factors for developing pancreatic cancer. An elevated risk of developing pancreatic cancer is associated with being a current smoker, African-American, over 55 years old, male, obese, previously diagnosed with intraductal papillary mucinous neoplasms (IPMNs), or previously diagnosed with diabetes[12,14]. Additionally, family history can be used to identify some individuals who have a high risk of developing pancreatic cancer. An increased risk of pancreatic cancer has been linked to family histories of pancreatic cancer[15,16], chronic pancreatitis[17,18], hereditary pancreatitis[19,20], Peutz-Jeghers syndrome[21,22], familial atypical multiple mole melanoma, cystic fibrosis, and familial cancer syndromes, which include Lynch syndromes[24,25], familial adenomatous polyposis pAPC mutation, and hereditary breast and ovarian cancer syndrome with BRCA1 and BRCA2 mutations[26,27]. This section of our review focuses on screening guidelines, the importance of new-onset diabetes, and the identification of precancerous lesions for the early detection of resectable pancreatic cancer.
An incidence ratio of 14-18 observed for the development of PC in CP cases, which is further increased by cigarette smoking
A 53-fold (95%CI: 23-105) increased risk for developing PC and a lifetime risk (age 70 yr) of PC of 30%-40% in comparison with normal. RR increases further in smokers
132-fold (95%CI: 44-261) increased risk of PC compared with the general population
8.6-fold (95%CI: 4.7-15.7) increased risk for developing PC compared with the general population. An estimated 3.68% (95%CI: 1.45%-45.88%) lifetime (age 70 yr) risk of PC
Hereditary breast and ovarian cancer
BRCA2 germline mutation carriers have a 5% lifetime risk of PC in comparison with 1.78% for controls. BRCA1 mutation is 2.26-times that of the normal population
PC: Pancreatic cancer.
The cancer of the pancreas screening (CAPS) program is one of largest pancreatic screening initiatives to date. Results from the CAPS 1 and CAPS 2 studies show that early pancreatic neoplasia can be detected by screening asymptomatic patients[28,29]. In the CAPS 1 study, the diagnostic yield of screening was 5.3%. Most encouragingly, the patient who was diagnosed with pancreatic cancer as a consequence of screening is still alive and disease free more than 5 years after surgery. CAPS 2 screening was performed using annual endoscopic ultrasound (EUS) and computed tomography (CT). Once an abnormality had been detected, endoscopic retrograde cholangiopancreatography (ERCP) was offered. Of the 72 high-risk patients, eight had pancreatic neoplasia confirmed by surgery or fine-needle aspiration biopsy (FNA), constituting a 10% yield of screening. The CAPS 3 study is an ongoing multicenter prospective controlled cohort study that involves annual screening using EUS and magnetic resonance cholangiopancreatography (MRCP). CAPS 3 is also investigating magnetic resonance imaging (MRI) with secretin and a panel of candidate DNA and protein markers (in serum and pancreatic juice) as indicators of pancreatic neoplasms. Carbohydrate antigen 19-9 (CA19-9), macrophage inhibitory cytokine-1 (MIC-1), DNA hypermethylation, and K-ras gene mutations are presently under investigation as potential markers. The CAPS consortium has reached several conclusions and recommendations for the management of patients who are at an increased risk of familial pancreatic cancer. The CAPS consortium specifically agreed that the following individuals were candidates for screening: first-degree relatives (FDRs) of patients with pancreatic cancer in a familial pancreatic cancer kindred with at least two affected FDRs; patients with Peutz-Jeghers syndrome; and carriers of p16, BRCA2, and hereditary non-polyposis colorectal cancer (HNPCC) mutations with at least one affected FDR. The consortium agreed that initial screening should include EUS, potentially with MRI or MRCP, but excluding CT and ERCP. The consortium did not agree on optimal screening modalities, intervals for follow-up imaging, or the use of EUS-FNA to evaluate cysts.
In general, screening was recommended for high-risk individuals. However, additional evidence is needed regarding the sensitivity and cost-effectiveness of screening, as well as the choice of management strategy for patients with lesions that are detected by screening.
The CAPS approach does not contribute to the early detection of pancreatic cancers that have completely sporadic onsets. To identify early pancreatic cancers in sporadic groups, it may be possible to screen patients at the onset of diabetes mellitus. The new onset of diabetes mellitus is occasionally associated with pancreatic carcinoma that is otherwise clinically silent and, indeed, is potentially resectable. A population-based cohort study of 2122 diabetic individuals identified 18 (0.8%) patients who developed diabetes at age 50 years or older and were diagnosed with pancreatic cancer in the next 3 years. In this cohort of individuals who were newly diagnosed with diabetes, the ratio of observed-to-expected pancreatic cancer incidence was 7.9 (95%CI: 4.7-12.5).
Diabetes is highly prevalent in cases of pancreatic cancer, even for early-stage pancreatic cancers[32-36]. Specifically, 50% of patients with stage I or II pancreatic cancer had diabetes. Tsuchiya et al observed abnormal glucose tolerance in 61% of patients with small pancreatic cancers (≤ 2 cm). A study of especially small pancreatic cancers (< 10 mm) noted a 33% prevalence of diabetes. Because diabetes arises in almost half of patients with pancreatic cancer, it is an attractive target for early pancreatic cancer screening.
Identification of precancerous lesions
Precancerous lesions are ideal targets for early identification because they can be treated before developing into invasive cancer. The majority of pancreatic masses treated by surgical resection are IPMNs, which have been increasingly recognized as precursors to pancreatic ductal adenocarcinoma. Post-resection cure rates are very high for IPMN that does not have an associated infiltrating ductal pancreatic adenocarcinoma[40,41]. Pancreatic intraepithelial neoplasias (PanINs) are small neoplasms (≤ 5 mm) that are mostly found in the head of the gland and are thought to be the most common precursor to invasive pancreatic ductal adenocarcinoma. Most precancerous lesions (and especially PanINs) can only be identified reliably after surgical resection. Because many healthy individuals have low-grade PanINs that will never progress to clinically important neoplasms, markers are needed to help differentiate between neoplastic and non-neoplastic pancreatic lesions, as well as to indicate the presence of microscopic high-grade PanINs that might be suggestive of future pancreatic cancer risk.
The most challenging aspect of screening and surveillance programs is the management of asymptomatic pancreatic lesions that are detected by imaging tests. It is essential to have individualized decision-making within multidisciplinary programs and prospective research studies.
BIOMARKERS THAT FACILITATE EARLY DIAGNOSIS OF PANCREATIC CANCER
Biomarker screening is one possible approach for identifying these early lesions. To date, over 2000 studies of possible biomarkers have been published. Yet, biomarkers for the detection of small pancreatic cancer have not been validated.
CA19-9 is a sialylated Lewis (a) antigen; it is a carbohydrate that is produced by exocrine epithelial cells and is normally absorbed onto erythrocyte surfaces. The measurement of CA19-9 levels has never been shown to be effective as a screening test for pancreatic cancer. In a study of 10162 asymptomatic individuals, abnormal CA19-9 levels were identified in only 18 (0.2%) persons. Although this study used a variety of screening tests, only four pancreatic cancers (0.04%) were detected. Pleskow et al performed one of the first studies that established CA19-9 as a promising biomarker in pancreatic cancer. In this study of 261 patients (including 54 with pancreatic cancer), the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of CA19-9 were 70%, 87%, 59%, 92% and 84%, respectively. In addition, preoperative CA19-9 test levels constitute false positives in the setting of biliary obstruction, which is present in the majority of patients with pancreatic cancer and various benign conditions related to the pancreas and biliary tract. There is some evidence that preoperative CA19-9 measurements can help determine whether a pancreatic cancer is resectable. Maithel et al reported a strong association between preoperative CA19-9 values and the identification of unresectable pancreatic cancer that could not be recognized on diagnostic imaging studies. They recommend staging laparoscopy for pancreatic cancers associated with CA19-9 levels that exceed 130 U/mL.
Carbohydrate antigens of mucin-1 (MUC-1) have been investigated as potential means of improving on the performance of CA19-9. Yet, none of the assays used to detect MUC-1 carbohydrate epitopes have proven to be superior to CA19-9 measurements. PAM-4 can be used to detect MUC-1 proteins expressed in pancreatic cancer with a greater specificity than MUC-1 proteins expressed in other cancers. Additionally, initial studies have shown that an enzyme-linked immunosorbent assay directed at detecting circulating MUC-1 epitopes is more sensitive and specific than CA19-9 for identifying patients with pancreatic cancer.
In a recent study, serum MIC-1 was determined to be more sensitive than CA19-9 as a marker of pancreatic cancer. MIC-1 belongs to the transforming growth factor-β superfamily, which was first identified in the context of macrophage activation. MIC-1 is overexpressed in pancreatic, colon, prostrate, breast, gastric, and several other types of cancers[53-55], and therefore, it may prove useful for diagnosing other cancers. In an investigation of pancreatic cancer and MIC-1 levels, 90% of patients with resectable pancreatic cancer had MIC-1 levels that were more than 2 standard deviations greater than those in age-matched controls. By comparison, only 62% of patients with resectable pancreatic cancer had elevated CA19-9. Elevated MIC-1 was observed to be independent of TNM stage. Further, elevated MIC-1 was observed in six of seven patients who had T1 or T2 cancers, but elevated CA19-9 was observed in only two of these seven patients. Based on these findings, serum MIC-1 may prove to be useful as a component of pancreatic screening protocols for detecting early stage pancreatic cancers in high-risk groups[28,58].
Proteomics approaches have also been employed in an attempt to identify protein markers of pancreatic cancer[59-62]. Several groups have identified protein fragments in serum using surface-enhanced laser desorption ionization, which appears to have found protein fragments that function as diagnostic makers at least as effectively as does serum CA19-9[63,64]. Pancreatic cancer proteins have also been identified in serum using matrix-associated laser desorption ionization, which is another mass spectrometry approach. Proteomics studies have identified several important proteins that are associated with pancreatic tumorigenesis, including galectin-1, gelsolin, lumican, 14-3-3 protein sigma, cathepsin D, cofilin, moesin, and plectin-1[60,66,67]. Gelsolin and lumican were later tested in plasma, showing an 80% sensitivity and a 95% specificity as a composite biomarker for separating early stage pancreatic cancer patients (stages I and II) from healthy controls and patients with chronic pancreatitis (via selected reaction-monitoring-based targeted proteomics assays). The application of proteomics to the study of pancreatic cancer is still in its early stages and remains challenging. Yet, despite being an emerging technology, proteomics has already provided fundamental information that has improved our understanding of this disease’s mechanisms. Further, proteomics potentially offers solutions for the early detection of this cancer.
Genetic and epigenetic markers
K-ras mutations are present in up to 90% of pancreatic ductal adenocarcinomas[69,70]. Accordingly, K-ras mutants have been thoroughly investigated as markers of pancreatic adenocarcinoma. In addition to invasive pancreatic cancers, K-ras mutations also occur in patients with chronic pancreatitis, persons who smoke, and PanINs in patients who do not have pancreatic cancer. Additionally, mutant K-ras is detected in the blood of patients with advanced-stage pancreatic cancers more commonly than it is detected in the blood of patients with less advanced pancreatic cancers[71,72].
TP53 mutations have been extensively investigated as possible diagnostic markers of a variety of cancers. In the case of invasive pancreatic cancer, however, such mutations do not normally occur until late in the neoplastic process. TP53 gene mutations are found in 70% of invasive pancreatic ductal adenocarcinomas. Mutations occur throughout the TP53 gene, although several nucleotide hot spots have been identified, at which mutations are especially common.
The strategy of combining markers can optimize the diagnosis of pancreatic cancer through molecular examination. In a study of a combined marker panel, the combination of methylated p16, mutant K-ras, and a functional yeast assay for TP53 mutations was investigated. The authors concluded that the presence of TP53 mutations was the most specific. With improvements in the technology for detecting mutations, TP53 mutations in pancreatic juice may underpin an effective diagnostic strategy.
Pancreatic cancer is both a genetic and an epigenetic disease[76,77]. Various genes are methylated as pancreatic cancer arises, and non-neoplastic pancreatic tissues rarely show methylation of these same genes. Genes that are methylated in the process of pancreatic cancer formation are p16, RELN, DAB1, ppENK, Cyclin D2, SOCS1, SPARC, TSLC1, and others[85,86]. Because the methylation of some of these genes can be detected through methylation-specific polymerase chain reaction, and because some of these genes are also highly expressed in pancreatic cancers, epigenetic markers may provide an opportunity for the early detection of pancreatic cancers.
Other potential markers
Promising biomarkers have also been established for predicting the effectiveness of chemotherapy and immune-based therapy. The human equilibrative nucleoside transporter (hENT1) protein transports gemcitabine into cells. In a prospective randomized trial (RTOG9704), hENT1 protein expression was associated with increased overall survival and disease-free survival in pancreatic cancer patients who received gemcitabine, but not in those who received fluorouracil. These findings are supported by preclinical data; the gemcitabine transporter hENT1 is therefore a molecular and mechanistically relevant predictive marker of benefit from gemcitabine in patients with resected pancreatic cancer. In addition to hENT1, key determinants of gemcitabine cytotoxicity include the activities of deoxycytidine kinase (dCK). Indeed, high levels of hENT1 and dCK predict longer survival times in patients with pancreatic cancer who are treated with adjuvant gemcitabine.
Mesothelin is a glycoprotein expressed on normal mesothelial cells. It is overexpressed in several histologic types of tumors, including pancreatic adenocarcinomas. A soluble form of mesothelin has been detected in patients with ovarian cancer and malignant mesothelioma, and has been found to have prognostic value. Circulating mesothelin is also a useful biomarker for pancreatic cancer. Furthermore, mesothelin-specific T cells can be induced in patients with pancreatic cancer. This suggests that mesothelin is a potential target for immune-based intervention strategies in pancreatic cancer. Although it is not yet clear how these markers specifically relate to the early diagnosis of pancreatic cancer, they may be clinically useful for treatment selection.
Investigations of pancreatic juice have involved both genetic and epigenetic markers for pancreatic cancer. To date, mutant K-ras, p53 mutations, DNA methylation alterations, mitochondrial DNA mutations, and other potential genetic and epigenetic markers have been investigated in pancreatic juice. The MitoChip allows investigations of the mitochondrial genome. Early studies using this novel technology suggest that it can be used to detect mitochondrial mutations in pancreatic juice samples that are taken from patients with pancreatic cancer.
Genetic, epigenetic, and proteomics research have improved the understanding of the mechanisms of pancreatic cancer, potentially offering biomarkers that could allow its early detection. It is critically important to validate the utility of these biomarkers in clinical setting as soon as possible.
IMAGING FOR THE EARLY DIAGNOSIS OF PANCREATIC CANCER
Every aspect of the clinical management of pancreatic diseases is influenced by imaging studies. Specific examples include the early detection and characterization of pancreatic masses, the identification of anatomical variants, investigations of local and vascular involvement, the determination of perineural and lymphatic invasion, margin assessments, the detection of distant metastases, and assessments of tumor resectabilty. Because effective screening markers remain elusive, imaging remains the primary form of screening for cases of familial pancreatic cancer, in addition to its more routine use in the staging and management of pancreatic cancer[28,29,92-94]. Recently, imaging accuracy has been improving as a result of technological improvements. However, imaging still fails to detect many lesions that are under a centimeter in size.
In comparison with other approaches to imaging, EUS has been growing in popularity. Indeed, EUS offers a large variety of benefits. First, it can detect pancreatic lesions and intraductal papillary mucinous neoplasms that are less than a centimeter in size with a greater sensitivity than is offered by abdominal ultrasonography, CT, or MRI. Second, EUS accurately judges deep tumors. Third, EUS-guided FNA enables lesion biopsies and has an excellent diagnostic accuracy (92%). Fourth, EUS detects lymph node metastasis and vascular infiltration with greater sensitivities than are offered by CT imaging. More specifically, advancements in contrast-enhanced EUS technology could improve the characterization of vessels in the desired lesions, the accuracy of tumor staging, the accuracy of tumor follow-up, and differential diagnosis. Additionally, improvements in EUS elastography could advance real-time evaluations of tissue stiffness. Finally, hybrid imaging (such as CT/ultrasonography or CT/ultrasonography/MRI) may offer an opportunity to improve the detection and characterization of focal lesions.
For lesions < 2 cm, EUS is associated with a sensitivity and accuracy that approach 100%, as well as a specificity > 95%[97-100]. In an analysis of EUS-FNA for pancreatic lesions < 3 cm, Tadic et al demonstrated a sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of 68%, 100%, 100%, 73%, and 83%, respectively. Based on these results, it appears that EUS has become quite capable of providing histological evidence, for which there is a great needed. Therefore, EUS should be performed wherever sufficient expertise is available.
The resolution and diagnostic capabilities of CT scanners have improved to remarkable extents. Currently, 64-section thin-cut intravenous contrast-enhanced multi-detector CT (MDCT) is the tool of choice for radiological investigations. Scanning occurs in a sequence of phases: non-contrast, arterial, pancreatic parenchymal, and portal venous. Key features of MDCT are its rapid anatomic coverage and excellent spatial resolution. When employed for the detection of pancreatic cancers, the sensitivity of CT ranges from 75% to 100%, and its specificity ranges from 70% to 100%[97,99,102-105]. Yet, for lesions ≤ 2 cm in size, this sensitivity diminishes to 68%-77%[97,103], with an accuracy of 77%.
The diagnosis of small pancreatic carcinoma is aided by findings of dilatation of the main pancreatic duct (MPD) and associated pancreatitis. In the case of associated pancreatitis, a contrasting effect is evident between the areas of the pancreatic parenchyma proximal and distal to the site of the MPD obstruction[107,108].
CT and MRI/MRCP are the primary investigations that are most commonly performed for the diagnosis and staging of pancreatic cancers. The choice between CT and MRI/MRCP is generally determined by the availability these individual modalities at medical centers, as well as the availability of the technical expertise that is necessary for interpreting and reporting their results. Fusari et al found that, for the diagnosis of pancreatic cancer, MRCP offered a sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of 100%, 88%, 98%, 97%, and 100%, respectively. They also found that MRCP, when evaluating the resectability of pancreatic carcinomas, offered a sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of 88%, 100%, 90%, 100%, and 70%, respectively. As outlined by Miller et al, the addition of MRCP to CT can offer substantial benefits to tumor diagnosis and staging in several contexts. MRI’s excellent contrast resolution is beneficial for detecting small tumors on gadolinium-enhanced fat-suppressed images.
PET is a functional imaging modality that can detect metabolic alterations in tumors, which may precede notable morphological alterations. The radioactive tracer 18F-fluorodeoxyglucose (FDG) has been used extensively in the PET imaging of malignant tumors. PET/CT can accurately detect small primary pancreatic lesions, distant metastases, and post-surgery recurrences. As a result of these capabilities, PET/CT has become increasingly important in the diagnosis and management of pancreatic cancer[110-112]. Elevated glucose metabolism has been found in the precursor lesions of pancreatic cancer, which suggests that there may be an opportunity to detect these changes using PET/CT, and thereby improve the timeliness of diagnosis and patient outcomes.
We have previously investigated the role of FDG-PET with dual-time point evaluation in cases of small pancreatic cancer. When investigated using FDG-PET with dual-time point evaluation, all TS1 tumors (< 20 mm) had higher standardized uptake values in the delayed phase than in the early phase, which suggested that the lesions were malignant tumors. These results indicate that FDG-PET with dual-time point evaluation is a useful modality for diagnosing small pancreatic cancers.
A recent meta-analysis regarding the detection of pancreatic carcinoma found a pooled sensitivity of 90.1% for PET-CT, which was substantially better than the 81.2% pooled sensitivity of EUS. However, PET-CT was also associated with a pooled specificity of 80.1%, while EUS had a pooled specificity of 92.3%. These results are similar to the findings of two previously published reviews of the literature on the same topic[116,117]. The role of FDG-PET in the early detection and accurate staging of pancreatic cancer is controversial. We suggest that future research should definitely focus on the development of more specific PET tracers for pancreatic ductal adenocarcinoma.
Despite advancements in surgical techniques and adjuvant treatment, the prognosis of pancreatic cancer has only improved marginally over the past years. Future research should continue and expand recent investigations of screening for high-risk groups, sensitive biomarkers, and imaging modalities for the early diagnosis of resectable pancreatic cancer. Recent studies have successfully identified pre-invasive neoplasms using accurate pancreatic imaging tests. These advancements are encouraging. They attest to the importance of additional studies that are aimed at identifying individuals at a substantially increased risk of developing pancreatic neoplasia.
P- Reviewer: Martignoni ME, Pazienza V S- Editor: Zhai HH L- Editor: A E- Editor: Wang CH
Egawa S, Toma H, Ohigashi H, Okusaka T, Nakao A, Hatori T, Maguchi H, Yanagisawa A, Tanaka M. Japan Pancreatic Cancer Registry; 30th year anniversary: Japan Pancreas Society.Pancreas. 2012;41:985-992.
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010.CA Cancer J Clin. 2010;60:277-300.
Páez D, Labonte MJ, Lenz HJ. Pancreatic cancer: medical management (novel chemotherapeutics).Gastroenterol Clin North Am. 2012;41:189-209.
Howlader NNA, Krapcho M. SEER Cancer Statistics Review 1975-2009. USA: National Cancer institute 2012; .
Tascilar M, Skinner HG, Rosty C, Sohn T, Wilentz RE, Offerhaus GJ, Adsay V, Abrams RA, Cameron JL, Kern SE. The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma.Clin Cancer Res. 2001;7:4115-4121.
Yeo CJ, Cameron JL, Lillemoe KD, Sitzmann JV, Hruban RH, Goodman SN, Dooley WC, Coleman J, Pitt HA. Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients.Ann Surg. 1995;221:721-31; discussion 731-3.
Ariyama J, Suyama M, Ogawa K, Ikari T. [Screening of pancreatic neoplasms and the diagnostic rate of small pancreatic neoplasms].Nihon Rinsho. 1986;44:1729-1734.
Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B, Kamiyama M, Hruban RH, Eshleman JR, Nowak MA. Distant metastasis occurs late during the genetic evolution of pancreatic cancer.Nature. 2010;467:1114-1117.
Lynch SM, Vrieling A, Lubin JH, Kraft P, Mendelsohn JB, Hartge P, Canzian F, Steplowski E, Arslan AA, Gross M. Cigarette smoking and pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium.Am J Epidemiol. 2009;170:403-413.
Magruder JT, Elahi D, Andersen DK. Diabetes and pancreatic cancer: chicken or egg?Pancreas. 2011;40:339-351.
Tanno S, Nakano Y, Koizumi K, Sugiyama Y, Nakamura K, Sasajima J, Nishikawa T, Mizukami Y, Yanagawa N, Fujii T. Pancreatic ductal adenocarcinomas in long-term follow-up patients with branch duct intraductal papillary mucinous neoplasms.Pancreas. 2010;39:36-40.
Ben Q, Xu M, Ning X, Liu J, Hong S, Huang W, Zhang H, Li Z. Diabetes mellitus and risk of pancreatic cancer: A meta-analysis of cohort studies.Eur J Cancer. 2011;47:1928-1937.
Klein AP, Brune KA, Petersen GM, Goggins M, Tersmette AC, Offerhaus GJ, Griffin C, Cameron JL, Yeo CJ, Kern S. Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds.Cancer Res. 2004;64:2634-2638.
Canto MI, Harinck F, Hruban RH, Offerhaus GJ, Poley JW, Kamel I, Nio Y, Schulick RS, Bassi C, Kluijt I. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer.Gut. 2013;62:339-347.
McKay CJ, Glen P, McMillan DC. Chronic inflammation and pancreatic cancer.Best Pract Res Clin Gastroenterol. 2008;22:65-73.
Raimondi S, Lowenfels AB, Morselli-Labate AM, Maisonneuve P, Pezzilli R. Pancreatic cancer in chronic pancreatitis; aetiology, incidence, and early detection.Best Pract Res Clin Gastroenterol. 2010;24:349-358.
Lowenfels AB, Maisonneuve P, DiMagno EP, Elitsur Y, Gates LK, Perrault J, Whitcomb DC. Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group.J Natl Cancer Inst. 1997;89:442-446.
Klein AP. Genetic susceptibility to pancreatic cancer.Mol Carcinog. 2012;51:14-24.
van Lier MG, Wagner A, Mathus-Vliegen EM, Kuipers EJ, Steyerberg EW, van Leerdam ME. High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations.Am J Gastroenterol. 2010;105:1258-164; author reply 1265.
Matsubayashi H, Fukushima N, Sato N, Brune K, Canto M, Yeo CJ, Hruban RH, Kern SE, Goggins M. Polymorphisms of SPINK1 N34S and CFTR in patients with sporadic and familial pancreatic cancer.Cancer Biol Ther. 2003;2:652-655.
Kastrinos F, Mukherjee B, Tayob N, Wang F, Sparr J, Raymond VM, Bandipalliam P, Stoffel EM, Gruber SB, Syngal S. Risk of pancreatic cancer in families with Lynch syndrome.JAMA. 2009;302:1790-1795.
Geary J, Sasieni P, Houlston R, Izatt L, Eeles R, Payne SJ, Fisher S, Hodgson SV. Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC).Fam Cancer. 2008;7:163-172.
van Asperen CJ, Brohet RM, Meijers-Heijboer EJ, Hoogerbrugge N, Verhoef S, Vasen HF, Ausems MG, Menko FH, Gomez Garcia EB, Klijn JG. Cancer risks in BRCA2 families: estimates for sites other than breast and ovary.J Med Genet. 2005;42:711-719.
Thompson D, Easton DF. Cancer Incidence in BRCA1 mutation carriers.J Natl Cancer Inst. 2002;94:1358-1365.
Canto MI, Goggins M, Yeo CJ, Griffin C, Axilbund JE, Brune K, Ali SZ, Jagannath S, Petersen GM, Fishman EK. Screening for pancreatic neoplasia in high-risk individuals: an EUS-based approach.Clin Gastroenterol Hepatol. 2004;2:606-621.
Canto MI, Goggins M, Hruban RH, Petersen GM, Giardiello FM, Yeo C, Fishman EK, Brune K, Axilbund J, Griffin C. Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study.Clin Gastroenterol Hepatol. 2006;4:766-81; quiz 665.
Pannala R, Basu A, Petersen GM, Chari ST. New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer.Lancet Oncol. 2009;10:88-95.
Chari ST, Leibson CL, Rabe KG, Ransom J, de Andrade M, Petersen GM. Probability of pancreatic cancer following diabetes: a population-based study.Gastroenterology. 2005;129:504-511.
Permert J, Ihse I, Jorfeldt L, von Schenck H, Arnqvist HJ, Larsson J. Pancreatic cancer is associated with impaired glucose metabolism.Eur J Surg. 1993;159:101-107.
Cersosimo E, Pisters PW, Pesola G, McDermott K, Bajorunas D, Brennan MF. Insulin secretion and action in patients with pancreatic cancer.Cancer. 1991;67:486-493.
Chari ST, Klee GG, Miller LJ, Raimondo M, DiMagno EP. Islet amyloid polypeptide is not a satisfactory marker for detecting pancreatic cancer.Gastroenterology. 2001;121:640-645.
Permert J, Ihse I, Jorfeldt L, von Schenck H, Arnquist HJ, Larsson J. Improved glucose metabolism after subtotal pancreatectomy for pancreatic cancer.Br J Surg. 1993;80:1047-1050.
Tsuchiya R, Noda T, Harada N, Miyamoto T, Tomioka T, Yamamoto K, Yamaguchi T, Izawa K, Tsunoda T, Yoshino R. Collective review of small carcinomas of the pancreas.Ann Surg. 1986;203:77-81.
Pannala R, Leirness JB, Bamlet WR, Basu A, Petersen GM, Chari ST. Prevalence and clinical profile of pancreatic cancer-associated diabetes mellitus.Gastroenterology. 2008;134:981-987.
Ishikawa O, Ohigashi H, Imaoka S, Nakaizumi A, Uehara H, Kitamura T, Kuroda C. Minute carcinoma of the pancreas measuring 1 cm or less in diameter--collective review of Japanese case reports.Hepatogastroenterology. 1999;46:8-15.
Hruban RH, Takaori K, Klimstra DS, Adsay NV, Albores-Saavedra J, Biankin AV, Biankin SA, Compton C, Fukushima N, Furukawa T. An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms.Am J Surg Pathol. 2004;28:977-987.
Tollefson MK, Libsch KD, Sarr MG, Chari ST, DiMagno EP, Urrutia R, Smyrk TC. Intraductal papillary mucinous neoplasm: did it exist prior to 1980?Pancreas. 2003;26:e55-e58.
Sohn TA, Yeo CJ, Cameron JL, Iacobuzio-Donahue CA, Hruban RH, Lillemoe KD. Intraductal papillary mucinous neoplasms of the pancreas: an increasingly recognized clinicopathologic entity.Ann Surg. 2001;234:313-21; discussion 321-2.
Hruban RH, Adsay NV, Albores-Saavedra J, Compton C, Garrett ES, Goodman SN, Kern SE, Klimstra DS, Klöppel G, Longnecker DS. Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions.Am J Surg Pathol. 2001;25:579-586.
Homma T, Tsuchiya R. The study of the mass screening of persons without symptoms and of the screening of outpatients with gastrointestinal complaints or icterus for pancreatic cancer in Japan, using CA19-9 and elastase-1 or ultrasonography.Int J Pancreatol. 1991;9:119-124.
Pleskow DK, Berger HJ, Gyves J, Allen E, McLean A, Podolsky DK. Evaluation of a serologic marker, CA19-9, in the diagnosis of pancreatic cancer.Ann Intern Med. 1989;110:704-709.
Marrelli D, Caruso S, Pedrazzani C, Neri A, Fernandes E, Marini M, Pinto E, Roviello F. CA19-9 serum levels in obstructive jaundice: clinical value in benign and malignant conditions.Am J Surg. 2009;198:333-339.
Glenn J, Steinberg WM, Kurtzman SH, Steinberg SM, Sindelar WF. Evaluation of the utility of a radioimmunoassay for serum CA 19-9 levels in patients before and after treatment of carcinoma of the pancreas.J Clin Oncol. 1988;6:462-468.
Maithel SK, Maloney S, Winston C, Gönen M, D’Angelica MI, Dematteo RP, Jarnagin WR, Brennan MF, Allen PJ. Preoperative CA 19-9 and the yield of staging laparoscopy in patients with radiographically resectable pancreatic adenocarcinoma.Ann Surg Oncol. 2008;15:3512-3520.
Koprowski H, Steplewski Z, Mitchell K, Herlyn M, Herlyn D, Fuhrer P. Colorectal carcinoma antigens detected by hybridoma antibodies.Somatic Cell Genet. 1979;5:957-971.
Gold DV, Modrak DE, Ying Z, Cardillo TM, Sharkey RM, Goldenberg DM. New MUC1 serum immunoassay differentiates pancreatic cancer from pancreatitis.J Clin Oncol. 2006;24:252-258.
Koopmann J, Buckhaults P, Brown DA, Zahurak ML, Sato N, Fukushima N, Sokoll LJ, Chan DW, Yeo CJ, Hruban RH. Serum macrophage inhibitory cytokine 1 as a marker of pancreatic and other periampullary cancers.Clin Cancer Res. 2004;10:2386-2392.
Bootcov MR, Bauskin AR, Valenzuela SM, Moore AG, Bansal M, He XY, Zhang HP, Donnellan M, Mahler S, Pryor K. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily.Proc Natl Acad Sci USA. 1997;94:11514-11519.
Buckhaults P, Rago C, St Croix B, Romans KE, Saha S, Zhang L, Vogelstein B, Kinzler KW. Secreted and cell surface genes expressed in benign and malignant colorectal tumors.Cancer Res. 2001;61:6996-7001.
Welsh JB, Sapinoso LM, Su AI, Kern SG, Wang-Rodriguez J, Moskaluk CA, Frierson HF, Hampton GM. Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancer.Cancer Res. 2001;61:5974-5978.
Lee DH, Yang Y, Lee SJ, Kim KY, Koo TH, Shin SM, Song KS, Lee YH, Kim YJ, Lee JJ. Macrophage inhibitory cytokine-1 induces the invasiveness of gastric cancer cells by up-regulating the urokinase-type plasminogen activator system.Cancer Res. 2003;63:4648-4655.
Brown DA, Stephan C, Ward RL, Law M, Hunter M, Bauskin AR, Amin J, Jung K, Diamandis EP, Hampton GM. Measurement of serum levels of macrophage inhibitory cytokine 1 combined with prostate-specific antigen improves prostate cancer diagnosis.Clin Cancer Res. 2006;12:89-96.
Koopmann J, Rosenzweig CN, Zhang Z, Canto MI, Brown DA, Hunter M, Yeo C, Chan DW, Breit SN, Goggins M. Serum markers in patients with resectable pancreatic adenocarcinoma: macrophage inhibitory cytokine 1 versus CA19-9.Clin Cancer Res. 2006;12:442-446.
Brentnall TA, Bronner MP, Byrd DR, Haggitt RC, Kimmey MB. Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancer.Ann Intern Med. 1999;131:247-255.
Crnogorac-Jurcevic T, Gangeswaran R, Bhakta V, Capurso G, Lattimore S, Akada M, Sunamura M, Prime W, Campbell F, Brentnall TA. Proteomic analysis of chronic pancreatitis and pancreatic adenocarcinoma.Gastroenterology. 2005;129:1454-1463.
Chen R, Yi EC, Donohoe S, Pan S, Eng J, Cooke K, Crispin DA, Lane Z, Goodlett DR, Bronner MP. Pancreatic cancer proteome: the proteins that underlie invasion, metastasis, and immunologic escape.Gastroenterology. 2005;129:1187-1197.
Grønborg M, Kristiansen TZ, Iwahori A, Chang R, Reddy R, Sato N, Molina H, Jensen ON, Hruban RH, Goggins MG, Maitra A, Pandey A. Biomarker discovery from pancreatic cancer secretome using a differential proteomic approach.Mol Cell Proteomics. 2006;5:157-171.
Yu KH, Rustgi AK, Blair IA. Characterization of proteins in human pancreatic cancer serum using differential gel electrophoresis and tandem mass spectrometry.J Proteome Res. 2005;4:1742-1751.
Koopmann J, Zhang Z, White N, Rosenzweig J, Fedarko N, Jagannath S, Canto MI, Yeo CJ, Chan DW, Goggins M. Serum diagnosis of pancreatic adenocarcinoma using surface-enhanced laser desorption and ionization mass spectrometry.Clin Cancer Res. 2004;10:860-868.
Bhattacharyya S, Siegel ER, Petersen GM, Chari ST, Suva LJ, Haun RS. Diagnosis of pancreatic cancer using serum proteomic profiling.Neoplasia. 2004;6:674-686.
Koomen JM, Shih LN, Coombes KR, Li D, Xiao LC, Fidler IJ, Abbruzzese JL, Kobayashi R. Plasma protein profiling for diagnosis of pancreatic cancer reveals the presence of host response proteins.Clin Cancer Res. 2005;11:1110-1118.
Lu Z, Hu L, Evers S, Chen J, Shen Y. Differential expression profiling of human pancreatic adenocarcinoma and healthy pancreatic tissue.Proteomics. 2004;4:3975-3988.
Shen J, Person MD, Zhu J, Abbruzzese JL, Li D. Protein expression profiles in pancreatic adenocarcinoma compared with normal pancreatic tissue and tissue affected by pancreatitis as detected by two-dimensional gel electrophoresis and mass spectrometry.Cancer Res. 2004;64:9018-9026.
Pan S, Chen R, Brand RE, Hawley S, Tamura Y, Gafken PR, Milless BP, Goodlett DR, Rush J, Brentnall TA. Multiplex targeted proteomic assay for biomarker detection in plasma: a pancreatic cancer biomarker case study.J Proteome Res. 2012;11:1937-1948.
Berger DH, Chang H, Wood M, Huang L, Heath CW, Lehman T, Ruggeri BA. Mutational activation of K-ras in nonneoplastic exocrine pancreatic lesions in relation to cigarette smoking status.Cancer. 1999;85:326-332.
Tada M, Komatsu Y, Kawabe T, Sasahira N, Isayama H, Toda N, Shiratori Y, Omata M. Quantitative analysis of K-ras gene mutation in pancreatic tissue obtained by endoscopic ultrasonography-guided fine needle aspiration: clinical utility for diagnosis of pancreatic tumor.Am J Gastroenterol. 2002;97:2263-2270.
Yamada T, Nakamori S, Ohzato H, Oshima S, Aoki T, Higaki N, Sugimoto K, Akagi K, Fujiwara Y, Nishisho I. Detection of K-ras gene mutations in plasma DNA of patients with pancreatic adenocarcinoma: correlation with clinicopathological features.Clin Cancer Res. 1998;4:1527-1532.
Mulcahy HE, Lyautey J, Lederrey C, qi Chen X, Anker P, Alstead EM, Ballinger A, Farthing MJ, Stroun M. A prospective study of K-ras mutations in the plasma of pancreatic cancer patients.Clin Cancer Res. 1998;4:271-275.
Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CJ, Kern SE. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma.Nat Genet. 1994;8:27-32.
Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers.Science. 1991;253:49-53.
Yan L, McFaul C, Howes N, Leslie J, Lancaster G, Wong T, Threadgold J, Evans J, Gilmore I, Smart H. Molecular analysis to detect pancreatic ductal adenocarcinoma in high-risk groups.Gastroenterology. 2005;128:2124-2130.
Ueki T, Toyota M, Sohn T, Yeo CJ, Issa JP, Hruban RH, Goggins M. Hypermethylation of multiple genes in pancreatic adenocarcinoma.Cancer Res. 2000;60:1835-1839.
Sato N, Goggins M. The role of epigenetic alterations in pancreatic cancer.J Hepatobiliary Pancreat Surg. 2006;13:286-295.
Fukushima N, Sato N, Ueki T, Rosty C, Walter KM, Wilentz RE, Yeo CJ, Hruban RH, Goggins M. Aberrant methylation of preproenkephalin and p16 genes in pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma.Am J Pathol. 2002;160:1573-1581.
Sato N, Fukushima N, Chang R, Matsubayashi H, Goggins M. Differential and epigenetic gene expression profiling identifies frequent disruption of the RELN pathway in pancreatic cancers.Gastroenterology. 2006;130:548-565.
Fukushima N, Walter KM, Uek T, Sato N, Matsubayashi H, Cameron JL, Hruban RH, Canto M, Yeo CJ, Goggins M. Diagnosing pancreatic cancer using methylation specific PCR analysis of pancreatic juice.Cancer Biol Ther. 2003;2:78-83.
Matsubayashi H, Sato N, Fukushima N, Yeo CJ, Walter KM, Brune K, Sahin F, Hruban RH, Goggins M. Methylation of cyclin D2 is observed frequently in pancreatic cancer but is also an age-related phenomenon in gastrointestinal tissues.Clin Cancer Res. 2003;9:1446-1452.
Fukushima N, Sato N, Sahin F, Su GH, Hruban RH, Goggins M. Aberrant methylation of suppressor of cytokine signalling-1 (SOCS-1) gene in pancreatic ductal neoplasms.Br J Cancer. 2003;89:338-343.
Sato N, Fukushima N, Maehara N, Matsubayashi H, Koopmann J, Su GH, Hruban RH, Goggins M. SPARC/osteonectin is a frequent target for aberrant methylation in pancreatic adenocarcinoma and a mediator of tumor-stromal interactions.Oncogene. 2003;22:5021-5030.
Jansen M, Fukushima N, Rosty C, Walter K, Altink R, Heek TV, Hruban R, Offerhaus JG, Goggins M. Aberrant methylation of the 5’ CpG island of TSLC1 is common in pancreatic ductal adenocarcinoma and is first manifest in high-grade PanlNs.Cancer Biol Ther. 2002;1:293-296.
Ueki T, Walter KM, Skinner H, Jaffee E, Hruban RH, Goggins M. Aberrant CpG island methylation in cancer cell lines arises in the primary cancers from which they were derived.Oncogene. 2002;21:2114-2117.
Sato N, Fukushima N, Maitra A, Matsubayashi H, Yeo CJ, Cameron JL, Hruban RH, Goggins M. Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarrays.Cancer Res. 2003;63:3735-3742.
Farrell JJ, Elsaleh H, Garcia M, Lai R, Ammar A, Regine WF, Abrams R, Benson AB, Macdonald J, Cass CE. Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer.Gastroenterology. 2009;136:187-195.
Maréchal R, Bachet JB, Mackey JR, Dalban C, Demetter P, Graham K, Couvelard A, Svrcek M, Bardier-Dupas A, Hammel P. Levels of gemcitabine transport and metabolism proteins predict survival times of patients treated with gemcitabine for pancreatic adenocarcinoma.Gastroenterology. 2012;143:664-74.e1-6.
Johnston FM, Tan MC, Tan BR, Porembka MR, Brunt EM, Linehan DC, Simon PO, Plambeck-Suess S, Eberlein TJ, Hellstrom KE. Circulating mesothelin protein and cellular antimesothelin immunity in patients with pancreatic cancer.Clin Cancer Res. 2009;15:6511-6518.
Maitra A, Cohen Y, Gillespie SE, Mambo E, Fukushima N, Hoque MO, Shah N, Goggins M, Califano J, Sidransky D. The Human MitoChip: a high-throughput sequencing microarray for mitochondrial mutation detection.Genome Res. 2004;14:812-819.
Langer P, Kann PH, Fendrich V, Habbe N, Schneider M, Sina M, Slater EP, Heverhagen JT, Gress TM, Rothmund M. Five years of prospective screening of high-risk individuals from families with familial pancreatic cancer.Gut. 2009;58:1410-1418.
Poley JW, Kluijt I, Gouma DJ, Harinck F, Wagner A, Aalfs C, van Eijck CH, Cats A, Kuipers EJ, Nio Y. The yield of first-time endoscopic ultrasonography in screening individuals at a high risk of developing pancreatic cancer.Am J Gastroenterol. 2009;104:2175-2181.
Vasen HF, Wasser M, van Mil A, Tollenaar RA, Konstantinovski M, Gruis NA, Bergman W, Hes FJ, Hommes DW, Offerhaus GJ. Magnetic resonance imaging surveillance detects early-stage pancreatic cancer in carriers of a p16-Leiden mutation.Gastroenterology. 2011;140:850-856.
Raut CP, Grau AM, Staerkel GA, Kaw M, Tamm EP, Wolff RA, Vauthey JN, Lee JE, Pisters PW, Evans DB. Diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration in patients with presumed pancreatic cancer.J Gastrointest Surg. 2003;7:118-26; discussion 127-8.
Gheonea DI, Săftoiu A. Beyond conventional endoscopic ultrasound: elastography, contrast enhancement and hybrid techniques.Curr Opin Gastroenterol. 2011;27:423-429.
Kitano M, Kudo M, Maekawa K, Suetomi Y, Sakamoto H, Fukuta N, Nakaoka R, Kawasaki T. Dynamic imaging of pancreatic diseases by contrast enhanced coded phase inversion harmonic ultrasonography.Gut. 2004;53:854-859.
DeWitt J, Devereaux B, Chriswell M, McGreevy K, Howard T, Imperiale TF, Ciaccia D, Lane KA, Maglinte D, Kopecky K. Comparison of endoscopic ultrasonography and multidetector computed tomography for detecting and staging pancreatic cancer.Ann Intern Med. 2004;141:753-763.
Legmann P, Vignaux O, Dousset B, Baraza AJ, Palazzo L, Dumontier I, Coste J, Louvel A, Roseau G, Couturier D. Pancreatic tumors: comparison of dual-phase helical CT and endoscopic sonography.AJR Am J Roentgenol. 1998;170:1315-1322.
Miller FH, Rini NJ, Keppke AL. MRI of adenocarcinoma of the pancreas.AJR Am J Roentgenol. 2006;187:W365-W374.
Tadic M, Kujundzic M, Stoos-Veic T, Kaic G, Vukelic-Markovic M. Role of repeated endoscopic ultrasound-guided fine needle aspiration in small solid pancreatic masses with previous indeterminate and negative cytological findings.Dig Dis. 2008;26:377-382.
Bronstein YL, Loyer EM, Kaur H, Choi H, David C, DuBrow RA, Broemeling LD, Cleary KR, Charnsangavej C. Detection of small pancreatic tumors with multiphasic helical CT.AJR Am J Roentgenol. 2004;182:619-623.
Diehl SJ, Lehmann KJ, Sadick M, Lachmann R, Georgi M. Pancreatic cancer: value of dual-phase helical CT in assessing resectability.Radiology. 1998;206:373-378.
Agarwal B, Abu-Hamda E, Molke KL, Correa AM, Ho L. Endoscopic ultrasound-guided fine needle aspiration and multidetector spiral CT in the diagnosis of pancreatic cancer.Am J Gastroenterol. 2004;99:844-850.
Shimizu Y, Yasui K, Matsueda K, Yanagisawa A, Yamao K. Small carcinoma of the pancreas is curable: new computed tomography finding, pathological study and postoperative results from a single institute.J Gastroenterol Hepatol. 2005;20:1591-1594.
Takeshita K, Furui S, Yamauchi T, Harasawa A, Kohtake H, Sasaki Y, Suzuki S, Tanaka H, Takeshita T. [Minimum intensity projection image and curved reformation image of the main pancreatic duct obtained by helical CT in patients with main pancreatic duct dilation].Nihon Igaku Hoshasen Gakkai Zasshi. 1999;59:146-148.
Nino-Murcia M, Jeffrey RB, Beaulieu CF, Li KC, Rubin GD. Multidetector CT of the pancreas and bile duct system: value of curved planar reformations.AJR Am J Roentgenol. 2001;176:689-693.
Fusari M, Maurea S, Imbriaco M, Mollica C, Avitabile G, Soscia F, Camera L, Salvatore M. Comparison between multislice CT and MR imaging in the diagnostic evaluation of patients with pancreatic masses.Radiol Med. 2010;115:453-466.
Casneuf V, Delrue L, Kelles A, Van Damme N, Van Huysse J, Berrevoet F, De Vos M, Duyck P, Peeters M. Is combined 18F-fluorodeoxyglucose-positron emission tomography/computed tomography superior to positron emission tomography or computed tomography alone for diagnosis, staging and restaging of pancreatic lesions?Acta Gastroenterol Belg. 2007;70:331-338.
Lee JK, Kim AY, Kim PN, Lee MG, Ha HK. Prediction of vascular involvement and resectability by multidetector-row CT versus MR imaging with MR angiography in patients who underwent surgery for resection of pancreatic ductal adenocarcinoma.Eur J Radiol. 2010;73:310-316.
Park HS, Lee JM, Choi HK, Hong SH, Han JK, Choi BI. Preoperative evaluation of pancreatic cancer: comparison of gadolinium-enhanced dynamic MRI with MR cholangiopancreatography versus MDCT.J Magn Reson Imaging. 2009;30:586-595.
Farma JM, Santillan AA, Melis M, Walters J, Belinc D, Chen DT, Eikman EA, Malafa M. PET/CT fusion scan enhances CT staging in patients with pancreatic neoplasms.Ann Surg Oncol. 2008;15:2465-2471.
Okano K, Kakinoki K, Akamoto S, Hagiike M, Usuki H, Yamamoto Y, Nishiyama Y, Suzuki Y. 18F-fluorodeoxyglucose positron emission tomography in the diagnosis of small pancreatic cancer.World J Gastroenterol. 2011;17:231-235.
Tang S, Huang G, Liu J, Liu T, Treven L, Song S, Zhang C, Pan L, Zhang T. Usefulness of 18F-FDG PET, combined FDG-PET/CT and EUS in diagnosing primary pancreatic carcinoma: a meta-analysis.Eur J Radiol. 2011;78:142-150.
Gambhir SS, Czernin J, Schwimmer J, Silverman DH, Coleman RE, Phelps ME. A tabulated summary of the FDG PET literature.J Nucl Med. 2001;42:1S-93S.
Pakzad F, Groves AM, Ell PJ. The role of positron emission tomography in the management of pancreatic cancer.Semin Nucl Med. 2006;36:248-256.