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.

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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 (15 links)

Information for Health Professionals / Researchers (8 links)

Latest Research Publications

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

Liu Y, Sadowski SM, Weisbrod AB, et al.
Multimodal image driven patient specific tumor growth modeling.
Med Image Comput Comput Assist Interv. 2013; 16(Pt 3):283-90 [PubMed] Related Publications
Personalized tumor growth model using clinical imaging data is valuable in tumor staging and therapy planning. In this paper, we build a patient specific tumor growth model based on longitudinal dual phase CT and FDG-PET. We propose a reaction-advection-diffusion model integrating cancerous cell proliferation, infiltration, metabolic rate and extracellular matrix biomechanical response. We then develop a scheme to bridge our model with multimodal radiologic images through intracellular volume fraction (ICVF) and Standardized Uptake Value (SUV). The model was evaluated by comparing the predicted tumors with the observed tumors in terms of average surface distance (ASD), root mean square difference (RMSD) of the ICVF map, the average ICVF difference (AICVFD) of tumor surface and the tumor relative volume difference (RVD) on six patients with pathologically confirmed pancreatic neuroendocrine tumors. The ASD between the predicted tumor and the reference tumor was 2.5 +/- 0.7 mm, the RMSD was 4.3 +/- 0.6%, the AICVFD was 2.6 +/- 0.8%, and the RVD was 7.7 +/- 1.9%.

Xing F, Su H, Yang L
An integrated framework for automatic Ki-67 scoring in pancreatic neuroendocrine tumor.
Med Image Comput Comput Assist Interv. 2013; 16(Pt 1):436-43 [PubMed] Related Publications
The Ki-67 labeling index is a valid and important biomarker to gauge neuroendocrine tumor cell progression. Automatic Ki-67 assessment is very challenging due to complex variations of cell characteristics. In this paper, we propose an integrated learning-based framework for accurate Ki-67 scoring in pancreatic neuroendocrine tumor. The main contributions of our method are: a novel and robust cell detection algorithm is designed to localize both tumor and non-tumor cells; a repulsive deformable model is applied to correct touching cell segmentation; a two stage learning-based scheme combining cellular features and regional structure information is proposed to differentiate tumor from non-tumor cells (such as lymphocytes); an integrated automatic framework is developed to accurately assess the Ki-67 labeling index. The proposed method has been extensively evaluated on 101 tissue microarray (TMA) whole discs, and the cell detection performance is comparable to manual annotations. The automatic Ki-67 score is very accurate compared with pathologists' estimation.

Schultz NA, Dehlendorff C, Jensen BV, et al.
MicroRNA biomarkers in whole blood for detection of pancreatic cancer.
JAMA. 2014 Jan 22-29; 311(4):392-404 [PubMed] Related Publications
IMPORTANCE: Biomarkers for the early diagnosis of patients with pancreatic cancer are needed to improve prognosis.
OBJECTIVES: To describe differences in microRNA expression in whole blood between patients with pancreatic cancer, chronic pancreatitis, and healthy participants and to identify panels of microRNAs for use in diagnosis of pancreatic cancer compared with the cancer antigen 19-9 (CA19-9).
DESIGN, SETTING, AND PARTICIPANTS: A case-control study that included 409 patients with pancreatic cancer and 25 with chronic pancreatitis who had been included prospectively in the Danish BIOPAC (Biomarkers in Patients with Pancreatic Cancer) study (July 2008-October 2012) plus 312 blood donors as healthy participants. The microRNA expressions in pretreatment whole blood RNA samples were collected and analyzed in 3 randomly determined subcohorts: discovery cohort (143 patients with pancreatic cancer, 18 patients with chronic pancreatitis, and 69 healthy participants), training cohort (180 patients with pancreatic cancer, 1 patient with chronic pancreatitis, and 199 healthy participants), and validation cohort (86 patients with pancreatic cancer, 7 patients with chronic pancreatitis, and 44 healthy participants); 754 microRNAs were screened in the discovery cohort and 38 microRNAs in the training cohort and 13 microRNAs in the validation cohort.
MAIN OUTCOMES AND MEASURES: Identification of microRNA panels (classifiers) for diagnosing pancreatic cancer.
RESULTS: The discovery cohort demonstrated that 38 microRNAs in whole blood were significantly dysregulated in patients with pancreatic cancer compared with controls. These microRNAs were tested in the training cohort and 2 diagnostic panels were constructed comprising 4 microRNAs in index I (miR-145, miR-150, miR-223, miR-636) and 10 in index II (miR-26b, miR-34a, miR-122, miR-126*, miR-145, miR-150, miR-223, miR-505, miR-636, miR-885.5p). The test characteristics for the training cohort were index I area under the curve (AUC) of 0.86 (95% CI, 0.82-0.90), sensitivity of 0.85 (95% CI, 0.79-0.90), and specificity of 0.64 (95% CI, 0.57-0.71); index II AUC of 0.93 (95% CI, 0.90-0.96), sensitivity of 0.85 (95% CI, 0.79-0.90), and specificity of 0.85 (95% CI, 0.80-0.85); and CA19-9 AUC of 0.90 (95% CI, 0.87-0.94), sensitivity of 0.86 (95% CI, 0.80-0.90), and specificity of 0.99 (95% CI, 0.96-1.00). Performances were strengthened in the validation cohort by combining panels and CA19-9 (index I AUC of 0.94 [95% CI, 0.90-0.98] and index II AUC of 0.93 [95% CI, 0.89-0.97]). Compared with CA19-9 alone, the AUC for the combination of index I and CA19-9 was significantly higher (P = .01). The performance of the panels in patients with stage IA-IIB pancreatic cancer was index I AUC of 0.80 (95% CI, 0.73-0.87); index I and CA19-9 AUC of 0.83 (95% CI, 0.76-0.90); index II AUC of 0.91 (95% CI, 0.87-0.94); and index II and CA19-9 AUC of 0.91 (95% CI, 0.86-0.95).
CONCLUSIONS AND RELEVANCE: This study identified 2 diagnostic panels based on microRNA expression in whole blood with the potential to distinguish patients with pancreatic cancer from healthy controls. Further research is necessary to understand whether these have clinical implications for early detection of pancreatic cancer and how much this information adds to serum CA19-9.

Lok T, Chen L, Lin F, Wang HL
Immunohistochemical distinction between intrahepatic cholangiocarcinoma and pancreatic ductal adenocarcinoma.
Hum Pathol. 2014; 45(2):394-400 [PubMed] Related Publications
Distinction between primary intrahepatic cholangiocarcinoma (ICC) and metastatic pancreatic ductal adenocarcinoma (PDA) on a liver biopsy is essentially impossible histologically but has important clinical implications. In this study, 41 ICCs and 60 PDAs were immunohistochemically evaluated for the expression of S100P, pVHL, IMP3, maspin, MUC5AC, and CK17 proteins. The results showed pVHL expression in 29 (71%) ICCs but in only 3 (5%) PDAs. S100P, MUC5AC, and CK17 were frequently expressed in PDAs, seen in 57 (95%), 40 (67%), and 36 (60%) cases, respectively. In contrast, only 11 (27%), 5 (12%), and 5 (12%) ICC cases expressed these proteins. IMP3 was expressed in 37 (90%) ICC and 54 (90%) PDA cases with equal frequency. All 60 (100%) PDA and 30 (73%) ICC cases showed positive maspin immunoreactivity. A S100P-/pVHL+/MUC5AC-/CK17- staining pattern was essentially indicative of ICC, whereas the S100P+/pVHL-/MUC5AC+/CK17+ and S100P+/pVHL-/MUC5AC-/CK17+ staining patterns were suggestive of PDA. These observations demonstrate that S100P, pVHL, MUC5AC, and CK17 are a useful immunohistochemical panel that may help distinguish primary ICC from metastatic PDA.

Related: Liver Cancer

Reid MD, Saka B, Balci S, et al.
Molecular genetics of pancreatic neoplasms and their morphologic correlates: an update on recent advances and potential diagnostic applications.
Am J Clin Pathol. 2014; 141(2):168-80 [PubMed] Related Publications
OBJECTIVES: To summarize the most clinically and biologically relevant advances in molecular/genetic characteristics of various pancreatic neoplasms, with morphologic correlation.
METHODS: Whole-exome sequencing of numerous benign and malignant pancreatic tumors, along with the plethora of highly sensitive molecular studies now available for analyzing these tumors, provide mounting evidence to support the long-held belief that cancer is essentially a genetic disease. These genetic discoveries have not only helped to confirm the age-old, morphology-based classifications of pancreatic neoplasia but have shed new light on their mechanisms. Many of these molecular discoveries are currently being used in preoperative diagnosis.
RESULTS: Mutations in KRAS, P16/CDKN2A, TP53, and SMAD4/DPC4 are commonly seen in ductal neoplasia but not in nonductal tumors; ductal adenocarcinomas with SMAD4/DPC4 loss are associated with widespread metastasis and poor prognosis. GNAS and RNF43 mutations have been discovered in most intraductal pancreatic mucinous neoplasms, providing critical molecular fingerprints for their diagnosis. Mutation in DAXX/ATRX is only seen in pancreatic neuroendocrine tumors, making it a useful potential marker in distinguishing these tumors from mimics.
CONCLUSIONS: When combined with morphologic observations, molecular studies will increase our understanding of the pathogenesis and morphomolecular signatures associated with specific neoplasms and provide new horizons for precision medicine and targeted therapies.

Estrella JS, Li L, Rashid A, et al.
Solid pseudopapillary neoplasm of the pancreas: clinicopathologic and survival analyses of 64 cases from a single institution.
Am J Surg Pathol. 2014; 38(2):147-57 [PubMed] Related Publications
Although solid pseudopapillary neoplasms (SPNs) are considered tumors of low malignant potential, patients may present with aggressive disease (ie, liver metastasis/invasion into adjacent organs) and, rarely, die from disease. Although the clinicopathologic features associated with aggressive SPNs have been reported, important prognostic factors of survival remain unclear. We systematically reviewed 64 cases of SPN resected at our institution for tumor size, extent of invasion, margin status, presence of lymphovascular, muscular vessel, and perineural invasion, and lymph node and distant metastases. Clinicopathologic characteristics were correlated with the presence of metastasis/recurrence and disease-specific survival. Five (8%) patients presented with stage IV disease. During follow-up, 5 (13%) of 39 patients with stage I-II disease had recurrences. Patients with metastatic/recurrent SPNs had significantly larger tumor size (P<0.001) and more frequent tumor invasion into muscular vessels (P=0.02). In a median follow-up of 76 months, only 2 died of disease (1 who presented with extensive peritoneal tumor involvement who died 2.5 mo after surgery, and 1 unusual case who presented with multiple liver metastasis and peritoneal seeding who died 19 mo after surgery), and 5 were alive with disease. The 10-year disease-specific survival rate was 96%. Muscular vessel invasion (P=0.001), tumor (T) stage by European Neuroendocrine Tumors Society (ENETS) classification (P<0.001), ENETS stage grouping (P<0.001), and stage grouping by the American Joint Committee on Cancer (AJCC stage, P<0.001) were important predictors of disease-specific survival in patients with SPN. Our study highlights the importance of pathologic evaluation in risk assessment in patients with SPNs.

Rustgi AK
Familial pancreatic cancer: genetic advances.
Genes Dev. 2014; 28(1):1-7 [PubMed] Article available free on PMC after 01/07/2014 Related Publications
Beset by poor prognosis, pancreatic ductal adenocarcinoma is classified as familial or sporadic. This review elaborates on the known genetic syndromes that underlie familial pancreatic cancer, where there are opportunities for genetic counseling and testing as well as clinical monitoring of at-risk patients. Such subsets of familial pancreatic cancer involve germline cationic trypsinogen or PRSS1 mutations (hereditary pancreatitis), BRCA2 mutations (usually in association with hereditary breast-ovarian cancer syndrome), CDKN2 mutations (familial atypical mole and multiple melanoma), or DNA repair gene mutations (e.g., ATM and PALB2, apart from those in BRCA2). However, the vast majority of familial pancreatic cancer cases have yet to have their genetic underpinnings elucidated, waiting in part for the results of deep sequencing efforts.

Related: Melanoma

Scarpa MG, Norbedo S, Murru F, et al.
Abdominal asymmetry in a 17 year old girl.
Pediatr Med Chir. 2012 Nov-Dec; 34(6):297-8 [PubMed] Related Publications
The pseudopapillary pancreatic solid tumor (TPSP) is a rare malignancy typical of young adult women (only 12 pediatric cases from 2000 to 2009), it can recur and metastasize. The prognosis is usually good after radical surgical removal. We emphasize the importance of TPSP in differential diagnosis of retrogastric, peripancreatic masses especially in puberal females. We describe the case of an adolescent girl with an abdominal mass revealed as a rare pancreatic neoplasia.

Al-Hawary MM, Francis IR, Chari ST, et al.
Pancreatic ductal adenocarcinoma radiology reporting template: consensus statement of the society of abdominal radiology and the american pancreatic association.
Gastroenterology. 2014; 146(1):291-304.e1 [PubMed] Related Publications
Pancreatic ductal adenocarcinoma is an aggressive malignancy with a high mortality rate. Proper determination of the extent of disease on imaging studies at the time of staging is one of the most important steps in optimal patient management. Given the variability in expertise and definition of disease extent among different practitioners as well as frequent lack of complete reporting of pertinent imaging findings at radiologic examinations, adoption of a standardized template for radiology reporting, using universally accepted and agreed on terminology for solid pancreatic neoplasms, is needed. A consensus statement describing a standardized reporting template authored by a multi-institutional group of experts in pancreatic ductal adenocarcinoma that included radiologists, gastroenterologists, and hepatopancreatobiliary surgeons was developed under the joint sponsorship of the Society of Abdominal Radiologists and the American Pancreatic Association. Adoption of this standardized imaging reporting template should improve the decision-making process for the management of patients with pancreatic ductal adenocarcinoma by providing a complete, pertinent, and accurate reporting of disease staging to optimize treatment recommendations that can be offered to the patient. Standardization can also help to facilitate research and clinical trial design by using appropriate and consistent staging by means of resectability status, thus allowing for comparison of results among different institutions.

Al-Hawary MM, Francis IR, Chari ST, et al.
Pancreatic ductal adenocarcinoma radiology reporting template: consensus statement of the Society of Abdominal Radiology and the American Pancreatic Association.
Radiology. 2014; 270(1):248-60 [PubMed] Related Publications
Pancreatic ductal adenocarcinoma is an aggressive malignancy with a high mortality rate. Proper determination of the extent of disease on imaging studies at the time of staging is one of the most important steps in optimal patient management. Given the variability in expertise and definition of disease extent among different practitioners as well as frequent lack of complete reporting of pertinent imaging findings at radiologic examinations, adoption of a standardized template for radiology reporting, using universally accepted and agreed on terminology for solid pancreatic neoplasms, is needed. A consensus statement describing a standardized reporting template authored by a multi-institutional group of experts in pancreatic ductal adenocarcinoma that included radiologists, gastroenterologists, and hepatopancreatobiliary surgeons was developed under the joint sponsorship of the Society of Abdominal Radiologists and the American Pancreatic Association. Adoption of this standardized imaging reporting template should improve the decision-making process for the management of patients with pancreatic ductal adenocarcinoma by providing a complete, pertinent, and accurate reporting of disease staging to optimize treatment recommendations that can be offered to the patient. Standardization can also help to facilitate research and clinical trial design by using appropriate and consistent staging by means of resectability status, thus allowing for comparison of results among different institutions.

Related: USA

Gnemmi V, Leroy X, Triboulet JP, et al.
Pancreatic metastases of renal clear cell carcinoma: a clinicopathological study of 11 cases with special emphasis on the usefulness of PAX2 and mesothelin for the distinction from primary ductal adenocarcinoma of the pancreas.
Anal Quant Cytol Histol. 2013; 35(3):157-62 [PubMed] Related Publications
OBJECTIVE: To determine whether PAX2 and mesothelin immunohistochemistry add additional diagnostic value in discriminating between pancreatic metastasis of renal clear cell carcinoma (PMRCC) and primary ductal adenocarcinoma of the pancreas (PDAC).
STUDY DESIGN: We retrospectively collected tissue from PMRCC and PDAC. Eleven cases of PMRCC registered at Lille University Hospitals from 2001 to 2010 were included. Eleven cases of PDAC were randomly selected from our files. A comparative immunohistochemical study with anti-PAX2, anti-mesothelin, and the classical renal antibodies anti-CD10 and anti-vimentin was performed on PMRCC and PDAC.
RESULTS: We found that PMRCC displays a clinical presentation that might mimic primary pancreatic tumor, as PMRCC presented as a solitary mass in 8 cases and appeared a long time after diagnosis of a renal tumor (12.8 years, mean for metachronous metastasis). By immunohistochemistry we observed that PAX2, mesothelin, CD10 and vimentin stainings were noted in 10/11 (91%), 0/11 (0%), 11/11 (100%) and 7/11 cases (64%), respectively, among 11 PMRCC cases. All PDACs displayed diffuse mesothelin (100%) expression without PAX2 and vimentin (0%) staining, whereas CD10 was noted in 4/11 cases (36%).
CONCLUSION: These data suggest that in difficult diagnostic cases both PAX2 and mesothelin immunohistochemical study may be useful in discriminating between PMRCC and primary pancreatic carcinoma.

Sikkens EC, Cahen DL, de Wit J, et al.
Prospective assessment of the influence of pancreatic cancer resection on exocrine pancreatic function.
Br J Surg. 2014; 101(2):109-13 [PubMed] Related Publications
BACKGROUND: Exocrine insufficiency frequently develops in patients with pancreatic cancer owing to tumour ingrowth and pancreatic duct obstruction. Surgery might restore this function by removing the primary disease and restoring duct patency, but it may also have the opposite effect, as a result of resection of functional parenchyma and anatomical changes. This study evaluated the course of pancreatic function, before and after pancreatic resection.
METHODS: This prospective cohort study included patients with tumours in the pancreatic region requiring pancreatic resection in a tertiary referral centre between March 2010 and August 2012. Starting before surgery, exocrine function was determined monthly by measuring faecal elastase 1 levels (normal value over 0.200 µg per g faeces). Endocrine function, steatorrhoea-related symptoms and bodyweight were also evaluated before and after surgery. Subjects were followed from diagnosis until 6 months after surgery, or until death.
RESULTS: Twenty-nine patients were included, 12 with pancreatic cancer, 14 with ampullary carcinoma and three with bile duct carcinoma (median tumour size 2.6 cm). Twenty-six patients underwent pancreaticoduodenectomy and three distal pancreatectomy. Thirteen patients had exocrine insufficiency at preoperative diagnosis. After a median follow-up of 6 months, this had increased to 24 patients. Diabetes was present in seven patients at diagnosis, and developed in one additional patient within 1 month after surgery.
CONCLUSION: Most patients with tumours in the pancreatic region requiring pancreatic resection either had exocrine insufficiency at diagnosis or became exocrine-insufficient soon after surgical resection.

Related: Extra-Hepatic Bile duct cancer (cholangiocarcinoma)

Gore AJ, Deitz SL, Palam LR, et al.
Pancreatic cancer-associated retinoblastoma 1 dysfunction enables TGF-β to promote proliferation.
J Clin Invest. 2014; 124(1):338-52 [PubMed] Article available free on PMC after 01/07/2014 Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is often associated with overexpression of TGF-β. Given its tumor suppressor functions, it is unclear whether TGF-β is a valid therapeutic target for PDAC. Here, we found that proliferating pancreatic cancer cells (PCCs) from human PDAC patients and multiple murine models of PDAC (mPDAC) often exhibit abundant levels of phosphorylated retinoblastoma 1 (RB) and Smad2. TGF-β1 treatment enhanced proliferation of PCCs isolated from KrasG12D-driven mPDAC that lacked RB (KRC cells). This mitogenic effect was abrogated by pharmacological inhibition of type I TGF-β receptor kinase, combined inhibition of MEK/Src or MEK/PI3K, and restoration of RB expression. TGF-β1 promoted epithelial-to-mesenchymal transition (EMT), invasion, Smad2/3 phosphorylation, Src activation, Wnt reporter activity, and Smad-dependent upregulation of Wnt7b in KRC cells. Importantly, TGF-β1-induced mitogenesis was markedly attenuated by inhibition of Wnt secretion. In an in vivo syngeneic orthotopic model, inhibition of TGF-β signaling suppressed KRC cell proliferation, tumor growth, stroma formation, EMT, metastasis, ascites formation, and Wnt7b expression, and markedly prolonged survival. Together, these data indicate that RB dysfunction converts TGF-β to a mitogen that activates known oncogenic signaling pathways and upregulates Wnt7b, which synergize to promote PCC invasion, survival, and mitogenesis. Furthermore, this study suggests that concomitantly targeting TGF-β and Wnt7b signaling in PDAC may disrupt these aberrant pathways, which warrants further evaluation in preclinical models.

Teo M, Mohd Sharial MS, McDonnell F, et al.
Prognostic role of neutrophil-to-lymphocyte ratio in advanced pancreatic ductal adenocarcinoma: impact of baseline fluctuation and changes during chemotherapy.
Tumori. 2013 Jul-Aug; 99(4):516-22 [PubMed] Related Publications
AIMS AND BACKGROUND: Inflammation has been implicated in carcinogenesis and progression of pancreatic cancer. The neutrophil-to-lymphocyte ratio is an index of systemic inflammation. We examined the prognostic role of the neutrophil-to-lymphocyte ratio at baseline and the significance of intrapersonal variability of the ratio before and during chemotherapy.
METHODS AND STUDY DESIGN: Advanced pancreatic adenocarcinoma patients who had received chemotherapy were included. Baseline clinical and biochemical parameters, including the neutrophil-to-lymphocyte ratio, were extracted and analyzed. The neutrophil-to-lymphocyte ratio threshold was determined via recursive partitioning and assessed at diagnosis, prior to chemotherapy and during treatment. Overall survival was estimated via the Kaplan-Meier method and compared between groups with the logrank test.
RESULTS: Between 2005 and 2011, 85 patients with locally advanced (n = 38) and metastatic disease were identified: 68% with a neutrophil-to-lymphocyte ratio >3 had shorter median overall survival than patients with a neutrophil-to-lymphocyte ratio <3 (3.4 vs 9.4 months, P = 0.001). Pretreatment, 35% of repeat neutrophil-to-lymphocyte ratios crossed the threshold of 3. A persistently elevated neutrophil-to-lymphocyte ratio >3 suggested a worse overall survival than in patients with a decreasing, increasing or persistently low neutrophil-to-lymphocyte ratio (1.9 vs 8.2, 12.3 and 11.7 months, respectively, P <0.001). Twenty-three percent of patients had a >50% decrease in neutrophil-to-lymphocyte ratio following 4 weeks of chemotherapy, with a trend towards improvement in overall survival (12.5 vs 5.0 mo, P = 0.068).
CONCLUSIONS: The baseline neutrophil-to-lymphocyte ratio is a validated marker for a poor prognosis. Multiple assessments of the pre-treatment neutrophil-to-lymphocyte ratio might be required. Reduction in the neutrophil-to-lymphocyte ratio during chemotherapy may be associated with improved survival.

Morganti AG, Marinelli A, Buwenge M, et al.
Palliative two-dimensional radiotherapy of pancreatic carcinoma: a feasibility study.
Tumori. 2013 Jul-Aug; 99(4):488-92 [PubMed] Related Publications
AIMS AND BACKGROUND: The aim of the study was to analyze the dose to be administered with two-dimensional involved-field palliative radiotherapy in advanced pancreatic carcinoma with respect to current dose-volume constraints (QUANTEC).
METHODS AND STUDY DESIGN: The following standard regimens were evaluated: 30 Gy at 3 Gy/fraction (regimen A), 36 Gy at 2.4 Gy/fraction (regimen B), 45 Gy at 1.8 Gy/fraction (regimen C), and 50 Gy at 2 Gy /fraction (regimen D). The following constraints were considered: spinal cord Dmax <50 Gy, duodenum Dmax <55 Gy, liver Dmean <30 Gy, kidneys Dmean <15 Gy. For dose/fraction different from 1.8-2 Gy, the correction of constraints using a value of alpha/beta = 3 for late effects was considered. The calculation of dose/volume constraints was repeated for three different radiation beams: cobalt unit, 6 MV photons, and 15 MV photons. Standard field sizes were used and adapted according to the different beam types, using the parameters of our previous study. Respect of dose-volume constraints was assessed for each type of beam and treatment (dose per fractionation) in all patients. Treatments were considered acceptable in case of: 1) respect of the constraints for spinal cord and duodenum in all patients; 2) respect in >10/15 patients of constraints for kidneys and liver. Therefore, minor violations (<10%) of the constraints for these organs were accepted (in less than 5/15 patients), in consideration of the palliative aim of treatment.
RESULTS: In regimen A (30 Gy, 3 Gy/fraction), evaluated constraints were respected in all patients, regardless of the type of energy. In regimen B (36 Gy, 2.4 Gy/fraction), constraints were met in all patients undergoing irradiation with 6 and 15 MV photons. However, using the cobalt unit, kidney constraint was respected only in 5 of 15 patients. In regimens C and D (45 Gy, 1.8 Gy/fraction and 50 Gy, 2 Gy/fraction, respectively), the constraint for the kidney was respected only in 2-5 patients, depending on the energy used. Furthermore, using 50 Gy, the spinal cord constraint was not respected in 2-3 patients, depending on the beam used. Therefore, only the following treatments were considered acceptable: 1) 30 Gy, 3 Gy/fraction, regardless of the energy used; 2) 36 Gy, 2.4 Gy/fraction, only for treatments performed with linear accelerator (6-15 MV).
CONCLUSIONS: The clinical benefits of radiotherapy in pancreatic tumors should not be withheld from patients treated in centers only with two-dimensional technology. Prospective trials, particularly in developing countries, would be useful to evaluate the efficacy in this setting of involved-field two-dimensional treatments using the dose and fractionation defined in this analysis.

Shinoto M, Yamada S, Yoshikawa K, et al.
Usefulness of 18F-fluorodeoxyglucose positron emission tomography as predictor of distant metastasis in preoperative carbon-ion radiotherapy for pancreatic cancer.
Anticancer Res. 2013; 33(12):5579-84 [PubMed] Related Publications
AIM: The purpose of this study was to evaluate the role of FDG-PET regarding the indication of preoperative carbon-ion radiotherapy (CIRT) for pancreatic cancer patients.
PATIENTS AND METHODS: Patients with resectable pancreatic cancer underwent preoperative CIRT. The impact of baseline SUVmax on prognosis for patients was assessed by analyzing correlations with distant metastasis-free survival (DMFS) and overall survival (OS).
RESULTS: Out of 21 patients, local recurrence was observed in no patient and distant metastasis was found in 13 patients (62%). 1-year DMFS and OS in low-SUVmax group were significantly higher than those in high-SUVmax group (91% vs. 20% and 91% vs. 56%). SUVmax was significantly correlated with DMFS and OS.
CONCLUSION: Our data indicated a significant correlation between SUVmax and DMFS. FDG-PET might be useful for determining the indication of preoperative short-course CIRT for patients with resectable pancreatic cancer.

Koskela HM, Syrjänen KJ, Korkeila EA
Disease outcome of patients with pancreatic cancer in a cohort treated outside clinical trials.
Anticancer Res. 2013; 33(12):5491-4 [PubMed] Related Publications
This retrospective study included 92 consecutive patients with locally advanced or metastatic pancreatic cancer treated in the Turku University Hospital in 2010. The diagnosis of pancreatic cancer was verified by either histological samples (adenocarcinoma) or by imaging or both, excluding other known histological types of tumours. Median patient survival was 11 months. Smokers had a better median overall survival (20 months) than non-smokers (10 months) (p=0.029). Patients with carcinoma of the head of pancreas had the best survival rates (15 months), whereas those with cancers of the tail of pancreas reached a median survival of only 3 months. The importance of this small trial resides in its retrospective and non-randomized nature, analyzing real-life patients, as encountered in daily practice, out of which, unfortunately, a substantial proportion would not be eligible for any randomized clinical trial.

Kim SA, Kim MS, Kim MS, et al.
Pleomorphic solid pseudopapillary neoplasm of the pancreas: degenerative change rather than high-grade malignant potential.
Hum Pathol. 2014; 45(1):166-74 [PubMed] Related Publications
Solid pseudopapillary neoplasms (SPNs) are rare tumors of the pancreas characterized by poorly cohesive uniform cells with solid and pseudopapillary growth patterns. Nuclear pleomorphism is not a well-recognized feature of SPNs and may complicate differentiation from other pancreatic neoplasms. We compared histologic, immunohistochemical, and clinical features of 18 pleomorphic SPNs with 121 conventional SPNs. The prevalence of pleomorphic SPN was 12.9% (18/139). Pleomorphic SPNs arose in older patients (median, 45 years versus 32 years; P < .001), but no differences were found in sex, tumor location, recurrence, and metastasis when compared with conventional SPNs. Except for pleomorphic nuclei, other cytologic and histologic features of pleomorphic SPNs, such as growth pattern, tumor size, infiltrative pattern, tumor extension, mitosis, and Ki-67 labeling index, were not different from those of conventional SPNs. Pleomorphic SPNs showed a significantly higher p53 protein expression (64.7% [11/17 cases]) than that of conventional SPNs (1.8% [2/112 cases], P < .001). However, immunoreactivity for β-catenin and E-cadherin was not different between pleomorphic and conventional SPNs. A TP53 gene mutation was observed in 2 of 3 p53-immunoreactive pleomorphic SPNs. In summary, nuclear pleomorphism occurs in a subset of SPNs. They are more often p53 immunoreactive than SPNs without pleomorphism, and some harbor TP53 gene mutations. However, pleomorphic SPNs do not appear to be more aggressive than conventional SPNs. Low mitotic rate and Ki-67 labeling index may suggest nuclear pleomorphisms as degenerative changes. Recognition of typical poorly cohesive tumor cells and immunohistochemical features could establish the correct diagnosis of SPNs.

Rosenfeldt MT, O'Prey J, Morton JP, et al.
p53 status determines the role of autophagy in pancreatic tumour development.
Nature. 2013; 504(7479):296-300 [PubMed] Related Publications
Macroautophagy (hereafter referred to as autophagy) is a process in which organelles termed autophagosomes deliver cytoplasmic constituents to lysosomes for degradation. Autophagy has a major role in cellular homeostasis and has been implicated in various forms of human disease. The role of autophagy in cancer seems to be complex, with reports indicating both pro-tumorigenic and tumour-suppressive roles. Here we show, in a humanized genetically-modified mouse model of pancreatic ductal adenocarcinoma (PDAC), that autophagy's role in tumour development is intrinsically connected to the status of the tumour suppressor p53. Mice with pancreases containing an activated oncogenic allele of Kras (also called Ki-Ras)--the most common mutational event in PDAC--develop a small number of pre-cancerous lesions that stochastically develop into PDAC over time. However, mice also lacking the essential autophagy genes Atg5 or Atg7 accumulate low-grade, pre-malignant pancreatic intraepithelial neoplasia lesions, but progression to high-grade pancreatic intraepithelial neoplasias and PDAC is blocked. In marked contrast, in mice containing oncogenic Kras and lacking p53, loss of autophagy no longer blocks tumour progression, but actually accelerates tumour onset, with metabolic analysis revealing enhanced glucose uptake and enrichment of anabolic pathways, which can fuel tumour growth. These findings provide considerable insight into the role of autophagy in cancer and have important implications for autophagy inhibition in cancer therapy. In this regard, we also show that treatment of mice with the autophagy inhibitor hydroxychloroquine, which is currently being used in several clinical trials, significantly accelerates tumour formation in mice containing oncogenic Kras but lacking p53.

Related: TP53

Goransky J, Alvarez FA, Picco P, et al.
Groove pancreatitis vs groove pancreatic adenocarcinoma. Report of two cases and review of the literature.
Acta Gastroenterol Latinoam. 2013; 43(3):248-53 [PubMed] Related Publications
Groove pancreatitis (GP) is a rare form of segmental chronic pancreatitis affecting the groove area (anatomic space between the head of the pancreas, the duodenum and the common bile duct). Its clinical and radiological presentation may be similar to groove pancreatic adenocarcinoma (GPA). Nevertheless, treatment and prognosis are totally different. We report two cases of both GP and GPA and review the relevant aspects that may help to clarify the differential diagnosis between these two rare entities. The first patient is a 57-year-old man with a history of chronic alcohol consumption who presented with persistent abdominal pain. The CT-scan findings suggested GP. Due to the persistence of symptoms despite medical treatment, a pancreaticoduodenectomy was performed. Pathologic evaluation confirmed the diagnosis of GP. The second patient is a 72-year-old male who presented with cholestasis and weight loss. The tumor marker CA 19-9 was increased The CT-scan findings were consistent with duodenal dystrophy. In order to rule out malignancy a pancreaticoduodenectomy was performed. Pathologic evaluation revealed a pancreatic head adenocarcinoma (T3-N1-M0). GP is a rare entity that should be suspected in patients with a history of heavy alcohol consumption who complain of chronic abdominal pain and weight loss. Patients without a clear diagnosis even after a through imaging work-up, or those in whom symptoms are persistent in spite of medical therapy, should undergo surgical exploration.

Giovannetti E, Wang Q, Avan A, et al.
Role of CYB5A in pancreatic cancer prognosis and autophagy modulation.
J Natl Cancer Inst. 2014; 106(1):djt346 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
BACKGROUND: Loss of 18q22.3 is a prognostic marker in pancreatic ductal adenocarcinoma (PDAC). This study investigated genes encoded by this cytoband.
METHODS: We studied mRNA/protein expression in radically resected (n = 130) and metastatic patients (n = 50). The role of CYB5A was tested in 11 PDAC cell lines and five primary cultures through retrovirus-mediated upregulation and small interfering RNA using wound-healing, invasion, annexin-V, electron microscopy, and autophagic assays, as well as autophagy genes and kinases arrays. CYB5A+ orthotopic models (n = 6 mice/group) were monitored by Firefly and Gaussia-luciferase bioluminescence, magnetic resonance imaging, and high-frequency ultrasound. Data were analyzed by t test, Fisher exact-test, log-rank test and Cox proportional hazards models. All statistical tests were two-sided.
RESULTS: Both resected and metastatic patients with low mRNA or protein expression of CYB5A had statistically significantly shorter survival (eg, median = 16.7 months, 95% confidence interval [CI] = 13.5 to 19.9; vs median = 24.8 months, 95% CI = 12.8 to 36.9; P = .02, two-sided log-rank test; n = 82 radically resected PDACs), and multivariable analyses confirmed prognostic relevance. Moreover, we characterized a novel function to CYB5A, autophagy induction, concomitant with reduced proliferation and migration/invasion of PDAC cells. Network analysis of proautophagic pathways suggested CYB5A interaction with TRAF6, which was confirmed by TRAF6 downregulation after CYB5A reconstitution (-69% in SU.86.86-CYB5A+; P = .005, two-sided t test). CYB5A silencing had opposite effects, restoring TRAF6 expression and wound healing. In vivo studies showed that CYB5A induced autophagy while inhibiting tumor growth/metastasis and increasing survival (median = 57 days, 95% CI = 52 to 61; vs median = 44 days, 95% CI = 21 to 57; P = .03, two-sided log-rank test).
CONCLUSIONS: These results define CYB5A as a novel prognostic factor for PDAC that exerts its tumor-suppressor function through autophagy induction and TRAF6 modulation.

Related: Chromosome 18

Greenhalf W, Ghaneh P, Neoptolemos JP, et al.
Pancreatic cancer hENT1 expression and survival from gemcitabine in patients from the ESPAC-3 trial.
J Natl Cancer Inst. 2014; 106(1):djt347 [PubMed] Related Publications
BACKGROUND: Human equilibrative nucleoside transporter 1 (hENT1) levels in pancreatic adenocarcinoma may predict survival in patients who receive adjuvant gemcitabine after resection.
METHODS: Microarrays from 434 patients randomized to chemotherapy in the ESPAC-3 trial (plus controls from ESPAC-1/3) were stained with the 10D7G2 anti-hENT1 antibody. Patients were classified as having high hENT1 expression if the mean H score for their cores was above the overall median H score (48). High and low hENT1-expressing groups were compared using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. All statistical tests were two-sided.
RESULTS: Three hundred eighty patients (87.6%) and 1808 cores were suitable and included in the final analysis. Median overall survival for gemcitabine-treated patients (n = 176) was 23.4 (95% confidence interval [CI] = 18.3 to 26.0) months vs 23.5 (95% CI = 19.8 to 27.3) months for 176 patients treated with 5-fluorouracil/folinic acid (χ(2) 1=0.24; P = .62). Median survival for patients treated with gemcitabine was 17.1 (95% CI = 14.3 to 23.8) months for those with low hENT1 expression vs 26.2 (95% CI = 21.2 to 31.4) months for those with high hENT1 expression (χ(2)₁= 9.87; P = .002). For the 5-fluorouracil group, median survival was 25.6 (95% CI = 20.1 to 27.9) and 21.9 (95% CI = 16.0 to 28.3) months for those with low and high hENT1 expression, respectively (χ(2)₁ = 0.83; P = .36). hENT1 levels were not predictive of survival for the 28 patients of the observation group (χ(2)₁ = 0.37; P = .54). Multivariable analysis confirmed hENT1 expression as a predictive marker in gemcitabine-treated (Wald χ(2) = 9.16; P = .003) but not 5-fluorouracil-treated (Wald χ(2) = 1.22; P = .27) patients.
CONCLUSIONS: Subject to prospective validation, gemcitabine should not be used for patients with low tumor hENT1 expression.

Related: Fluorouracil Leucovorin Gemcitabine

Clarke CN, Sussman JJ, Abbott DE, Ahmad SA
Factors affecting readmission after pancreaticoduodenectomy.
Adv Surg. 2013; 47:99-110 [PubMed] Related Publications
PD continues to be associated with a high rate of failed discharges, despite significant improvements in techniques and postoperative care at high-volume centers. Even in the best hands, 1 in 5 patients undergoing PD can be expected to require readmission in the early postoperative period. Efforts to minimize readmissions must be aimed at identifying high-risk patients, addressing patient expectations, establishing patient care plans, and using outpatient resources to address anticipated problems and complications.

Related: USA

Shin JU, Lee JK, Kim KM, et al.
The differentiation of autoimmune pancreatitis and pancreatic cancer using imaging findings.
Hepatogastroenterology. 2013 Jul-Aug; 60(125):1174-81 [PubMed] Related Publications
BACKGROUND/AIMS: Differentiation of autoimmune pancreatitis (AIP) and pancreatic cancer (PC) is important to avoid unnecessary surgery. The aim of this study was to compare various image findings and facilitate the differentiation of these two diseases.
METHODOLOGY: The radiological features of 36 AIP patients and 36 patients with resected PC diagnosed at Samsung Medical Center from January 1991 to October 2010, were compared.
RESULTS: Regarding CT/MRI findings, diffuse pancreas enlargement, capsule-like rim and delayed homogenous enhancement, were significantly more frequent in AIP. For cholangiopancreatography findings, main pancreatic duct (MPD) narrowing by ≥1/3 of the pancreatic length, skipped lesions of the MPD, the presence of side branches at the narrowed MPD portion, and smooth and straight intrapancreatic common bile duct stenosis were significantly more frequent in AIP. However, according to FDG-PET findings, SUVmax, uptake shape and pattern, and uptake by extrapancreatic lesions were not significantly different for AIP and PC.
CONCLUSIONS: Diffuse pancreas enlargement, a capsule-like rim, delayed homogenous enhancement, MPD narrowing of ≥1/3 of the pancreatic length, skipped lesions and the presence of side branches at the narrow MPD portion were found to have high specificity for AIP. These findings have great power to differentiate AIP and PC.

Zorde Khvalevsky E, Gabai R, Rachmut IH, et al.
Mutant KRAS is a druggable target for pancreatic cancer.
Proc Natl Acad Sci U S A. 2013; 110(51):20723-8 [PubMed] Article available free on PMC after 17/06/2014 Related Publications
Pancreatic ductal adenocarcinoma (PDA) represents an unmet therapeutic challenge. PDA is addicted to the activity of the mutated KRAS oncogene which is considered so far an undruggable therapeutic target. We propose an approach to target KRAS effectively in patients using RNA interference. To meet this challenge, we have developed a local prolonged siRNA delivery system (Local Drug EluteR, LODER) shedding siRNA against the mutated KRAS (siG12D LODER). The siG12D LODER was assessed for its structural, release, and delivery properties in vitro and in vivo. The effect of the siG12D LODER on tumor growth was assessed in s.c. and orthotopic mouse models. KRAS silencing effect was further assessed on the KRAS downstream signaling pathway. The LODER-encapsulated siRNA was stable and active in vivo for 155 d. Treatment of PDA cells with siG12D LODER resulted in a significant decrease in KRAS levels, leading to inhibition of proliferation and epithelial-mesenchymal transition. In vivo, siG12D LODER impeded the growth of human pancreatic tumor cells and prolonged mouse survival. We report a reproducible and safe delivery platform based on a miniature biodegradable polymeric matrix, for the controlled and prolonged delivery of siRNA. This technology provides the following advantages: (i) siRNA is protected from degradation; (ii) the siRNA is slowly released locally within the tumor for prolonged periods; and (iii) the siG12D LODER elicits a therapeutic effect, thereby demonstrating that mutated KRAS is indeed a druggable target.

Related: KRAS gene

Choi JW, Lee JM, Yoon JH, et al.
Iterative reconstruction algorithms of computed tomography for the assessment of small pancreatic lesions: phantom study.
J Comput Assist Tomogr. 2013 Nov-Dec; 37(6):911-23 [PubMed] Related Publications
OBJECTIVE: To evaluate the image quality and radiation dose reduction of iterative reconstruction (IR) used for computed tomographic (CT) scanning of small pancreatic lesions.
METHODS: An anthropomorphic pancreas phantom with 16 small lesions was scanned using 4 kinds of CT scanners with different tube current-time products (75-250 mAs). The CT images were reconstructed using filtered back projection (FBP) and the relevant IR of each vendor (GE Healthcare, Philips Healthcare, Siemens Healthcare, Toshiba Medical Systems). The image qualities, dose reduction rate (in percent), and figure of merit (FOM) were evaluated in comparison with the reference images (250 mAs, FBP).
RESULTS: Image noise was markedly improved with the IR; therefore, a 36 to 60% dose reduction was possible. As a result, the final CT dose index volume can be diminished to 7.05 to 11.40 mGy with the IR algorithms. The IR demonstrated 1.52 to 7.84 times higher FOM than that of FBP. Particularly, an advanced fully IR showed outstanding results of FOM (6.06-7.84 times).
CONCLUSIONS: Because IR can reduce image noise while maintaining image quality for the delineation of small pancreatic lesions, it can be used for pancreatic imaging with substantial radiation dose reduction.

Dholakia AS, Kumar R, Raman SP, et al.
Mapping patterns of local recurrence after pancreaticoduodenectomy for pancreatic adenocarcinoma: a new approach to adjuvant radiation field design.
Int J Radiat Oncol Biol Phys. 2013; 87(5):1007-15 [PubMed] Related Publications
PURPOSE: To generate a map of local recurrences after pancreaticoduodenectomy (PD) for patients with resectable pancreatic ductal adenocarcinoma (PDA) and to model an adjuvant radiation therapy planning treatment volume (PTV) that encompasses a majority of local recurrences.
METHODS AND MATERIALS: Consecutive patients with resectable PDA undergoing PD and 1 or more computed tomography (CT) scans more than 60 days after PD at our institution were reviewed. Patients were divided into 3 groups: no adjuvant treatment (NA), chemotherapy alone (CTA), or chemoradiation (CRT). Cross-sectional scans were centrally reviewed, and local recurrences were plotted to scale with respect to the celiac axis (CA), superior mesenteric artery (SMA), and renal veins on 1 CT scan of a template post-PD patient. An adjuvant clinical treatment volume comprising 90% of local failures based on standard expansions of the CA and SMA was created and simulated on 3 post-PD CT scans to assess the feasibility of this planning approach.
RESULTS: Of the 202 patients in the study, 40 (20%), 34 (17%), and 128 (63%) received NA, CTA, and CRT adjuvant therapy, respectively. The rate of margin-positive resections was greater in CRT patients than in CTA patients (28% vs 9%, P=.023). Local recurrence occurred in 90 of the 202 patients overall (45%) and in 19 (48%), 22 (65%), and 49 (38%) in the NA, CTA, and CRT groups, respectively. Ninety percent of recurrences were within a 3.0-cm right-lateral, 2.0-cm left-lateral, 1.5-cm anterior, 1.0-cm posterior, 1.0-cm superior, and 2.0-cm inferior expansion of the combined CA and SMA contours. Three simulated radiation treatment plans using these expansions with adjustments to avoid nearby structures were created to demonstrate the use of this treatment volume.
CONCLUSIONS: Modified PTVs targeting high-risk areas may improve local control while minimizing toxicities, allowing dose escalation with intensity-modulated or stereotactic body radiation therapy.

Passoni P, Reni M, Cattaneo GM, et al.
Hypofractionated image-guided IMRT in advanced pancreatic cancer with simultaneous integrated boost to infiltrated vessels concomitant with capecitabine: a phase I study.
Int J Radiat Oncol Biol Phys. 2013; 87(5):1000-6 [PubMed] Related Publications
PURPOSE: To determine the maximum tolerated radiation dose (MTD) of an integrated boost to the tumor subvolume infiltrating vessels, delivered simultaneously with radical dose to the whole tumor and concomitant capecitabine in patients with pretreated advanced pancreatic adenocarcinoma.
METHODS AND MATERIALS: Patients with stage III or IV pancreatic adenocarcinoma without progressive disease after induction chemotherapy were eligible. Patients underwent simulated contrast-enhanced four-dimensional computed tomography and fluorodeoxyglucose-labeled positron emission tomography. Gross tumor volume 1 (GTV1), the tumor, and GTV2, the tumor subvolume 1 cm around the infiltrated vessels, were contoured. GTVs were fused to generate Internal Target Volume (ITV)1 and ITV2. Biological tumor volume (BTV) was fused with ITV1 to create the BTV+Internal Target Volume (ITV) 1. A margin of 5/5/7 mm (7 mm in cranium-caudal) was added to BTV+ITV1 and to ITV2 to create Planning Target Volume (PTV) 1 and PTV2, respectively. Radiation therapy was delivered with tomotherapy. PTV1 received a fixed dose of 44.25 Gy in 15 fractions, and PTV2 received a dose escalation from 48 to 58 Gy as simultaneous integrated boost (SIB) in consecutive groups of at least 3 patients. Concomitant chemotherapy was capecitabine, 1250 mg/m(2) daily. Dose-limiting toxicity (DLT) was defined as any treatment-related G3 nonhematological or G4 hematological toxicity occurring during the treatment or within 90 days from its completion.
RESULTS: From June 2005 to February 2010, 25 patients were enrolled. The dose escalation on the SIB was stopped at 58 Gy without reaching the MTD. One patient in the 2(nd) dose level (50 Gy) had a DLT: G3 acute gastric ulcer. Three patients had G3 late adverse effects associated with gastric and/or duodenal mucosal damage. All patients received the planned dose of radiation.
CONCLUSIONS: A dose of 44.25 Gy in 15 fractions to the whole tumor with an SIB of 58 Gy to small tumor subvolumes concomitant with capecitabine is feasible in chemotherapy-pretreated patients with advanced pancreatic cancer.

Related: Fluorouracil Capecitabine

Hashim YM, Trinkaus KM, Linehan DC, et al.
Regional lymphadenectomy is indicated in the surgical treatment of pancreatic neuroendocrine tumors (PNETs).
Ann Surg. 2014; 259(2):197-203 [PubMed] Related Publications
OBJECTIVE: To explore the prognostic importance and preoperative predictors of lymph node metastasis in an effort to guide surgical decision making in patients with pancreatic neuroendocrine tumors (PNETs).
BACKGROUND: PNETs are uncommon, and the natural history of the disease is not well described. As a result, there remains controversy regarding the optimal management of regional lymph nodes during resection of the primary tumor.
METHODS: A retrospective review of a prospectively maintained database of patients who underwent surgery for locoregional PNET between 1994 and 2012 was performed. Logistic regression was used to identify predictors of nodal metastasis. Overall survival and disease-free survival were calculated using Kaplan-Meier method. Results were expressed as P values and odds ratio estimates, with 95% confidence intervals.
RESULTS: One hundred thirty-six patients were identified, of whom 50 (38%) patients had nodal metastasis. The frequency of lymph node metastasis was higher for larger tumors [> 1.5 cm (odds ratio [OR] = 4.7)], tumors of the head as compared with body-tail of the pancreas (OR = 2.8), tumors with Ki-67 greater than 20% (OR = 6.7), and tumors with lymph vascular invasion (OR = 3.6) (P < 0.05). Median disease-free survival was lower for patients with nodal metastases (4.5 vs 14.6 years, P < 0.0001).
CONCLUSIONS: Lymph node metastasis is predictive of poor outcomes in patients with PNETs. Preoperative variables are not able to reliably predict patients where the probability of lymph node involvement was less than 12%. These data support inclusion of regional lymphadenectomy in patients undergoing pancreatic resections for PNET.

Pinato DJ, Tan TM, Toussi ST, et al.
An expression signature of the angiogenic response in gastrointestinal neuroendocrine tumours: correlation with tumour phenotype and survival outcomes.
Br J Cancer. 2014; 110(1):115-22 [PubMed] Article available free on PMC after 07/01/2015 Related Publications
BACKGROUND: Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are heterogeneous with respect to biological behaviour and prognosis. As angiogenesis is a renowned pathogenic hallmark as well as a therapeutic target, we aimed to investigate the prognostic and clinico-pathological role of tissue markers of hypoxia and angiogenesis in GEP-NETs.
METHODS: Tissue microarray (TMA) blocks were constructed with 86 tumours diagnosed from 1988 to 2010. Tissue microarray sections were immunostained for hypoxia inducible factor 1α (Hif-1α), vascular endothelial growth factor-A (VEGF-A), carbonic anhydrase IX (Ca-IX) and somatostatin receptors (SSTR) 1-5, Ki-67 and CD31. Biomarker expression was correlated with clinico-pathological variables and tested for survival prediction using Kaplan-Meier and Cox regression methods.
RESULTS: Eighty-six consecutive cases were included: 51% male, median age 51 (range 16-82), 68% presenting with a pancreatic primary, 95% well differentiated, 51% metastatic. Higher grading (P=0.03), advanced stage (P<0.001), high Hif-1α and low SSTR-2 expression (P=0.03) predicted for shorter overall survival (OS) on univariate analyses. Stage, SSTR-2 and Hif-1α expression were confirmed as multivariate predictors of OS. Median OS for patients with SSTR-2+/Hif-1α-tumours was not reached after median follow up of 8.8 years, whereas SSTR-2-/Hif-1α+ GEP-NETs had a median survival of only 4.2 years (P=0.006).
CONCLUSION: We have identified a coherent expression signature by immunohistochemistry that can be used for patient stratification and to optimise treatment decisions in GEP-NETs independently from stage and grading. Tumours with preserved SSTR-2 and low Hif-1α expression have an indolent phenotype and may be offered less aggressive management and less stringent follow up.

Related: Gastrointestinal System Cancers Angiogenesis and Cancer

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