Study of Efficacy and Safety of PDR001 in Patients With Advanced or Metastatic, Well-differentiated, Non-functional Neuroendocrine Tumors of Pancreatic, Gastrointestinal (GI), or Thoracic Origin or Poorly-differentiated Gastroenteropancreatic Neuroendocrine Carcinoma (GEP-NEC)

ClinicalTrials.gov

2017-11-15

Well-differentiated Non-functional NET of Thoracic Origin; Well-differentiated Non-functional NET of Gastrointestinal Origin; Well-differentiated Non-functional NET of Pancreatic Origin; Poorly-differentiated Gastroenteropancreatic Neuroendocrine Carcinoma

Pancreatic neuroendocrine tumor with complete replacement of the pancreas by serous cystic neoplasms in a patient with von Hippel-Lindau disease: a case report.

PubMed

Maeda, Shimpei; Motoi, Fuyuhiko; Oana, Shuhei; Ariake, Kyohei; Mizuma, Masamichi; Morikawa, Takanori; Hayashi, Hiroki; Nakagawa, Kei; Kamei, Takashi; Naitoh, Takeshi; Unno, Michiaki

2017-09-25

von Hippel-Lindau disease is a dominantly inherited multi-system syndrome with neoplastic hallmarks. Pancreatic lesions associated with von Hippel-Lindau include serous cystic neoplasms, simple cysts, and neuroendocrine tumors. The combination of pancreatic neuroendocrine tumors and serous cystic neoplasms is relatively rare, and the surgical treatment of these lesions must consider both preservation of pancreatic function and oncological clearance. We report a patient with von Hippel-Lindau disease successfully treated with pancreas-sparing resection of a pancreatic neuroendocrine tumor where the pancreas had been completely replaced by serous cystic neoplasms, in which pancreatic function was preserved. A 39-year-old female with von Hippel-Lindau disease was referred to our institution for treatment of a pancreatic neuroendocrine tumor. Abdominal computed tomography demonstrated a well-enhanced mass, 4 cm in diameter in the tail of the pancreas, and two multilocular tumors with several calcifications, 5 cm in diameter, in the head of the pancreas. There was complete replacement of the pancreas by multiple cystic lesions with diameters ranging from 1 to 3 cm. Magnetic resonance cholangiopancreatography showed innumerable cystic lesions on the whole pancreas and no detectable main pancreatic duct. Endoscopic ultrasound-guided fine-needle aspiration of the mass in the pancreatic tail showed characteristic features of a neuroendocrine tumor. A diagnosis of pancreatic neuroendocrine tumor in the tail of the pancreas and mixed-type serous cystic neoplasms replacing the whole pancreas was made and she underwent distal pancreatectomy while avoiding total pancreatectomy. The stump of the pancreas was sutured as firm as possible using a fish-mouth closure. The patient made a good recovery and was discharged on postoperative day 9. She is currently alive and well with no symptoms of endocrine or exocrine pancreatic insufficiency 8 months after surgery. A pancreas

Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment (PDQ®)—Health Professional Version

Cancer.gov

Pancreatic neuroendocrine tumors (islet cell tumors) treatment includes surgery with curative intent and surgery for metastatic disease. Hormone therapy, chemotherapy and targeted therapy are sometimes used. Get detailed information on the treatment of this disease in this clinician summary.

Diabetes and pancreatic neuroendocrine tumours: Which interplays, if any?

PubMed

Gallo, Marco; Ruggeri, Rosaria Maddalena; Muscogiuri, Giovanna; Pizza, Genoveffa; Faggiano, Antongiulio; Colao, Annamaria

2018-06-01

Pancreatic neuroendocrine tumours (PanNETs) represent an uncommon type of pancreatic neoplasm, whose incidence is increasing worldwide. As per exocrine pancreatic cancer, a relationship seems to exist between PanNETs and glycaemic alterations. Diabetes mellitus (DM) or impaired glucose tolerance often occurs in PanNET patients as a consequence of hormonal hypersecretion by the tumour, specifically affecting glucose metabolism, or due to tumour mass effects. On the other hand, pre-existing DM may represent a risk factor for developing PanNETs and is likely to worsen the prognosis of such patients. Moreover, the surgical and/or pharmacological treatment of the tumour itself may impair glucose tolerance, as well as antidiabetic therapies may impact tumour behaviour and patients outcome. Differently from exocrine pancreatic tumours, few data are available for PanNETs as yet on this issue. In the present review, the bidirectional association between glycaemic disorders and PanNETs has been extensively examined, since the co-existence of both diseases in the same individual represents a further challenge for the clinical management of PanNETs. Copyright © 2018 Elsevier Ltd. All rights reserved.

CYTOLOGY ASSESSMENT CAN PREDICT SURVIVAL FOR PATIENTS WITH METASTATIC PANCREATIC NEUROENDOCRINE NEOPLASMS

PubMed Central

Sigel, Carlie S.; Guo, Huimin; Sigel, Keith M.; Zhang, Ming; Rekhtman, Natasha; Lin, Oscar; Klimstra, David S.; Jungbluth, Achim A.; Tang, Laura K.

2017-01-01

Background Histological features and Ki67 index have known utility for predicting prognosis and guiding therapy for metastatic pancreatic neuroendocrine neoplasms. Fine needle aspiration (FNA) may offer advantages for Ki67 assessment because the technique obtains highly cellular, well-preserved specimens with potential for broader tumor sampling. We evaluated concordance for grade and differentiation between concurrent core biopsy and cytology preparations. Secondly, cytological features and grade were correlated with survival. Methods Differentiation, grade by Ki67 index, and correlation of these features with survival were compared between concurrent core biopsy and cytology from 44 metastatic pancreatic neuroendocrine neoplasms. Results Differentiation by cytology smear was 38 (86%) well and 6 (14%) poor. Agreement for differentiation between smear and cell block, smear and biopsy, and cell block and biopsy was: 88%, 94%, and 83%, respectively and agreement for grade were: 68%, 54%, and 22%, respectively. Cytology differentiation and cytology grade were strong predictors of outcome with respective hazard ratio of 8.3 (95% CI: 3.1–22.1; p<0.001) and 1.9 (95% CI: 1.2–2.9) for each ascending grade. Cytology median disease specific survival projections (months) were G1= 121 (95% CI: 57–185 (estimated)); G2= 45 (95% CI 29–87); and G3=19 (95% CI 1–44) and WD=45; PD= 3; (P<.001)). Conclusions Pancreatic neuroendocrine neoplasm grading on cytology may not exactly correlate with concurrent core biopsy, but cytology differentiation and grade are predictive of survival based on stage-adjusted analysis. PMID:28094897

Neoplasms of the Neuroendocrine Pancreas: An Update in the Classification, Definition, and Molecular Genetic Advances.

PubMed

Guilmette, Julie M; Nosé, Vania

2018-06-14

This review focuses on discussing the main modifications of the recently published 2017 WHO Classification of Neoplasms of the Neuroendocrine Pancreas (panNEN). Recent updates separate pancreatic neuroendocrine tumors into 2 broad categories: well-differentiated pancreatic neuroendocrine tumors (panNET) and poorly differentiated pancreatic neuroendocrine carcinoma (panNEC), and incorporates a new subcategory of "well-differentiated high-grade NET (G3)" to the well-differentiated NET category. This new classification algorithm aims to improve the prediction of clinical outcomes and survival and help clinicians select better therapeutic strategies for patient care and management. In addition, these neuroendocrine neoplasms are capable of producing large quantity of hormones leading to clinical hormone hypersecretion syndromes. These functioning tumors include, insulinomas, glucagonomas, somatostatinomas, gastrinomas, VIPomas, serotonin-producing tumors, and ACTH-producing tumors. Although most panNENs arise as sporadic diseases, a subset of these heterogeneous tumors present as parts on inherited genetic syndromes, such as multiple endocrine neoplasia type 1, von Hippel-Lindau, neurofibromatosis type 1, tuberous sclerosis, and glucagon cell hyperplasia and neoplasia syndromes. Characteristic clinical and morphologic findings for certain functioning and syndromic panNENs should alert both pathologists and clinicians as appropriate patient management and possible genetic counseling may be necessary.

A malignant cause of hypoglycaemia: a metastatic insulin-secreting pancreatic neuroendocrine carcinoma.

PubMed

Sandoval, Mark Anthony; Pagsisihan, Daveric; Berberabe, A'Ericson; Palugod-Lopez, Elaine Gayle

2016-03-18

Most cases of insulinomas are benign. We report a case of a malignant form of insulinoma. A 46-year-old man presented with behavioural changes associated with hypoglycaemia. Diagnostic work up revealed high serum insulin, high C-peptide and low glucose levels, compatible with endogenous hyperinsulinaemic hypoglycaemia. CT imaging of the abdomen revealed a pancreatic head mass and multiple liver masses. Biopsy of the pancreatic mass revealed a grade three pancreatic neuroendocrine carcinoma. Histological analysis of a liver mass showed that it was identical to the pancreatic mass, confirming its metastatic nature. The patient underwent distal pancreatectomy with en bloc splenectomy. There was persistence of hypoglycaemic symptoms after removal of the pancreatic mass, suggesting that the liver metastases were also functioning. Symptoms were controlled by diazoxide and octreotide long-acting release. The patient is already 1 year postsurgery with no recurrence of severe hypoglycaemia, and he has good functional capacity and has returned to his office job. 2016 BMJ Publishing Group Ltd.

A malignant cause of hypoglycaemia: a metastatic insulin-secreting pancreatic neuroendocrine carcinoma

PubMed Central

Sandoval, Mark Anthony; Pagsisihan, Daveric; Berberabe, A'Ericson; Palugod-Lopez, Elaine Gayle

2016-01-01

Most cases of insulinomas are benign. We report a case of a malignant form of insulinoma. A 46-year-old man presented with behavioural changes associated with hypoglycaemia. Diagnostic work up revealed high serum insulin, high C-peptide and low glucose levels, compatible with endogenous hyperinsulinaemic hypoglycaemia. CT imaging of the abdomen revealed a pancreatic head mass and multiple liver masses. Biopsy of the pancreatic mass revealed a grade three pancreatic neuroendocrine carcinoma. Histological analysis of a liver mass showed that it was identical to the pancreatic mass, confirming its metastatic nature. The patient underwent distal pancreatectomy with en bloc splenectomy. There was persistence of hypoglycaemic symptoms after removal of the pancreatic mass, suggesting that the liver metastases were also functioning. Symptoms were controlled by diazoxide and octreotide long-acting release. The patient is already 1 year postsurgery with no recurrence of severe hypoglycaemia, and he has good functional capacity and has returned to his office job. PMID:26994053

Everolimus for the Treatment of Advanced Pancreatic Neuroendocrine Tumors: Overall Survival and Circulating Biomarkers From the Randomized, Phase III RADIANT-3 Study.

PubMed

Yao, James C; Pavel, Marianne; Lombard-Bohas, Catherine; Van Cutsem, Eric; Voi, Maurizio; Brandt, Ulrike; He, Wei; Chen, David; Capdevila, Jaume; de Vries, Elisabeth G E; Tomassetti, Paola; Hobday, Timothy; Pommier, Rodney; Öberg, Kjell

2016-11-10

Purpose Everolimus improved median progression-free survival by 6.4 months in patients with advanced pancreatic neuroendocrine tumors (NET) compared with placebo in the RADIANT-3 study. Here, we present the final overall survival (OS) data and data on the impact of biomarkers on OS from the RADIANT-3 study. Methods Patients with advanced, progressive, low- or intermediate-grade pancreatic NET were randomly assigned to everolimus 10 mg/day (n = 207) or placebo (n = 203). Crossover from placebo to open-label everolimus was allowed on disease progression. Ongoing patients were unblinded after final progression-free survival analysis and could transition to open-label everolimus at the investigator's discretion (extension phase). OS analysis was performed using a stratified log-rank test in the intent-to-treat population. The baseline levels of chromogranin A, neuron-specific enolase, and multiple soluble angiogenic biomarkers were determined and their impact on OS was explored. Results Of 410 patients who were enrolled between July 2007 and March 2014, 225 received open-label everolimus, including 172 patients (85%) randomly assigned initially to the placebo arm. Median OS was 44.0 months (95% CI, 35.6 to 51.8 months) for those randomly assigned to everolimus and 37.7 months (95% CI, 29.1 to 45.8 months) for those randomly assigned to placebo (hazard ratio, 0.94; 95% CI, 0.73 to 1.20; P = .30). Elevated baseline chromogranin A, neuron-specific enolase, placental growth factor, and soluble vascular endothelial growth factor receptor 1 levels were poor prognostic factors for OS. The most common adverse events included stomatitis, rash, and diarrhea. Conclusion Everolimus was associated with a median OS of 44 months in patients with advanced, progressive pancreatic NET, the longest OS reported in a phase III study for this population. Everolimus was associated with a survival benefit of 6.3 months, although this finding was not statistically significant. Crossover of

Identification of tumorigenic cells and therapeutic targets in pancreatic neuroendocrine tumors

PubMed Central

Krampitz, Geoffrey Wayne; George, Benson M.; Willingham, Stephen B.; Volkmer, Jens-Peter; Weiskopf, Kipp; Jahchan, Nadine; Newman, Aaron M.; Sahoo, Debashis; Zemek, Allison J.; Yanovsky, Rebecca L.; Nguyen, Julia K.; Schnorr, Peter J.; Mazur, Pawel K.; Sage, Julien; Longacre, Teri A.; Visser, Brendan C.; Poultsides, George A.; Norton, Jeffrey A.; Weissman, Irving L.

2016-01-01

Pancreatic neuroendocrine tumors (PanNETs) are a type of pancreatic cancer with limited therapeutic options. Consequently, most patients with advanced disease die from tumor progression. Current evidence indicates that a subset of cancer cells is responsible for tumor development, metastasis, and recurrence, and targeting these tumor-initiating cells is necessary to eradicate tumors. However, tumor-initiating cells and the biological processes that promote pathogenesis remain largely uncharacterized in PanNETs. Here we profile primary and metastatic tumors from an index patient and demonstrate that MET proto-oncogene activation is important for tumor growth in PanNET xenograft models. We identify a highly tumorigenic cell population within several independent surgically acquired PanNETs characterized by increased cell-surface protein CD90 expression and aldehyde dehydrogenase A1 (ALDHA1) activity, and provide in vitro and in vivo evidence for their stem-like properties. We performed proteomic profiling of 332 antigens in two cell lines and four primary tumors, and showed that CD47, a cell-surface protein that acts as a “don’t eat me” signal co-opted by cancers to evade innate immune surveillance, is ubiquitously expressed. Moreover, CD47 coexpresses with MET and is enriched in CD90hi cells. Furthermore, blocking CD47 signaling promotes engulfment of tumor cells by macrophages in vitro and inhibits xenograft tumor growth, prevents metastases, and prolongs survival in vivo. PMID:27035983

Dictating genomic destiny: Epigenetic regulation of pancreatic neuroendocrine tumours.

PubMed

Gundara, Justin S; Jamal, Karim; Kurzawinski, Tom

2018-07-05

Pancreatic neuroendocrine tumours are a diverse group of neoplasms with an increasingly well-defined genomic basis. Despite this, much of what drives this disease is still unknown and epigenetic influences represent the next tier of gene, and hence disease modifiers that are of unquestionable importance. Moreover, they are of arguably more significance than the genes themselves given their malleable nature and potential to be exploited for not only diagnosis and prognosis, but also therapy. This review summarises what is known regarding the key epigenetic modifiers of disease through the domains of diagnosis, prognosis and treatment. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Correlation of monoclonal and polyclonal somatostatin receptor 5 antibodies in pancreatic neuroendocrine tumors

PubMed Central

Kaemmerer, Daniel; Lupp, Amelie; Peter, Luisa; Fischer, Elke; Schulz, Stefan; Klöppel, Günter; Hommann, Merten

2013-01-01

Aims: To evaluate the frequency of somatostatin-receptor 5 (SSTR 5) in pancreatic neuroendocrine tumors by using monoclonal and polyclonal antibodies. Material and Method: we analyzed 66 proven pancreatic neuroendocrine tumors immunohistochemically with monoclonal (clone UMB-4) and polyclonal SSTR 5-antibodies. Immunoreactive score (IRS) and DAKO-score Her2/neu were evaluated. Results: Immunohistochemistry analysis demonstrated for the IRS a significant higher staining of all specimen using the monoclonal antibodies ( IRS SSTR5 poly vs IRS SSTR 5 mono; 20.0% vs 30.3% p < 0.001) by a correlation of 0.21; p = 0.04. For the HER2 score there was also a significant higher staining in the monoclonal group (Her2 SSTR 5 poly vs Her2 SSTR 5 mono; 21.5% vs 28.8% p < 0.001) by a correlation of 0.20; p = 0.08. Conclusion: Both antibodies are useful in staining of SSTR, although UMB-4 demonstrated a 10% higher SSTR 5 staining. Due to the previous underestimated expression rate of SSTR 5, current standards in diagnostics and therapy should be reconsidered. The increasing usage of long-acting pansomatostatin receptor analogues will rise the adverse effects connected to SSTR5 binding. PMID:23236542

Treatment Response and Outcomes of Grade 3 Pancreatic Neuroendocrine Neoplasms Based on Morphology: Well Differentiated Versus Poorly Differentiated.

PubMed

Raj, Nitya; Valentino, Emily; Capanu, Marinela; Tang, Laura H; Basturk, Olca; Untch, Brian R; Allen, Peter J; Klimstra, David S; Reidy-Lagunes, Diane

2017-03-01

Emerging data suggest that not all grade 3 (G3) pancreatic neuroendocrine neoplasms (panNENs) behave the same; tumor differentiation may predict outcome. Patients with G3 panNENs treated at our institution between 1999 and 2014 were identified. Demographics, response to therapy, and overall survival were determined. Forty-five patients were identified, 16 with G3 well differentiated pancreatic neuroendocrine tumors (WD-panNETs) and 29 with poorly differentiated neuroendocrine carcinomas (PDNEC). Median overall survival in G3 WD-panNET patients was 52.2 months (95% confidence interval, 19.3-86.9 months) compared with 10.1 months (95% confidence interval, 6.9-12.4 months) in PDNEC patients (P = 0.0009). Response rate to platinum agents was 10% in G3 WD-panNETs and 37% in PDNEC. Response rate to alkylating agents was 50% in G3 WD-panNETs and 50% in PDNEC. Both G3 WD-panNETs and PDNEC responded to platinum and alkylating agents. Overall survival was significantly greater in G3 WD-panNETs compared with PDNEC. These findings challenge current classification and suggest that G3 panNENs should be classified by morphology.

Surgical and molecular pathology of pancreatic neoplasms.

PubMed

Hackeng, Wenzel M; Hruban, Ralph H; Offerhaus, G Johan A; Brosens, Lodewijk A A

2016-06-07

Histologic characteristics have proven to be very useful for classifying different types of tumors of the pancreas. As a result, the major tumor types in the pancreas have long been classified based on their microscopic appearance. Recent advances in whole exome sequencing, gene expression profiling, and knowledge of tumorigenic pathways have deepened our understanding of the underlying biology of pancreatic neoplasia. These advances have not only confirmed the traditional histologic classification system, but also opened new doors to early diagnosis and targeted treatment. This review discusses the histopathology, genetic and epigenetic alterations and potential treatment targets of the five major malignant pancreatic tumors - pancreatic ductal adenocarcinoma, pancreatic neuroendocrine tumor, solid-pseudopapillary neoplasm, acinar cell carcinoma and pancreatoblastoma.

Pancreatic mixed serous neuroendocrine neoplasm with clear cells leading to diagnosis of von Hippel Lindau disease.

PubMed

Kakkar, Aanchal; Sharma, Mehar C; Yadav, Rajni; Panwar, Rajesh; Mathur, Sandeep R; Iyer, Venkateswaran K; Sahni, Peush

2016-08-01

Mixed serous neuroendocrine neoplasms are extremely rare tumors that are usually seen in female patients and are often associated with von Hippel Lindau (VHL) disease. We describe the case of a 38-year-old male who presented with complaints of anorexia, weight loss, and abdominal pain. CT abdomen showed a mass in the head of the pancreas, multiple small nodules in the body of pancreas, and bilateral adrenal masses. Fine needle aspiration cytology (FNAC) from the mass showed features of a neuroendocrine tumor, with many of the cells demonstrating abundant clear cytoplasm. Histopathological examination of the pancreaticoduodenectomy specimen showed a mixed serous neuroendocrine neoplasm with two components viz. serous cystadenoma and neuroendocrine tumor (NET) World Health Organization (WHO) grade 2. In addition, he was diagnosed to have bilateral pheochromocytomas and a paraganglioma. The synchronicity of these tumors suggested the possibility of VHL disease. Thus, identification of a NET with clear cells or of a mixed serous neuroendocrine neoplasm should raise suspicion of VHL disease. In a mixed tumor, FNAC may identify only one of the two components. Thorough processing of all pancreatic serous tumors for pathological examination is recommended, as NET may occur as a small nodule within the serous cystadenoma. Copyright © 2016 Elsevier GmbH. All rights reserved.

[Latest advances in chronic pancreatitis].

PubMed

Domínguez Muñoz, J Enrique

2015-09-01

This article summarizes some of the recent and clinically relevant advances in chronic pancreatitis. These advances mainly concern the early diagnosis of the disease, the treatment of symptoms and complications, mainly pain and pancreatic exocrine insufficiency, and the diagnosis and therapy of autoimmune pancreatitis. The multimodal dynamic endoscopic ultrasound-guided secretin-stimulated evaluation of the pancreas provides relevant morphological and functional information for the diagnosis of chronic pancreatitis at early stages. Extracorporeal shock wave lithotripsy in patients with calcifying pancreatitis and endoscopic pancreatic stent placement are effective alternatives for pain therapy in patients with chronic pancreatitis. Presence of pancreatic exocrine insufficiency in patients with chronic pancreatitis is associated with a significantly increase of mortality rate. Despite that, pancreatic enzyme replacement therapy is not prescribed in the majority of patients with pancreatic exocrine insufficiency, or it is prescribed at a low dose. The newly developed and commercialized needles for endoscopic ultrasound-guided pancreatic biopsy are effective in retrieving appropriate tissue samples for the histological diagnosis of autoimmune pancreatitis. Maintenance therapy with azathioprine is effective and safe to prevent relapses in patients with autoimmune pancreatitis. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

Whole-genome landscape of pancreatic neuroendocrine tumours.

PubMed

Scarpa, Aldo; Chang, David K; Nones, Katia; Corbo, Vincenzo; Patch, Ann-Marie; Bailey, Peter; Lawlor, Rita T; Johns, Amber L; Miller, David K; Mafficini, Andrea; Rusev, Borislav; Scardoni, Maria; Antonello, Davide; Barbi, Stefano; Sikora, Katarzyna O; Cingarlini, Sara; Vicentini, Caterina; McKay, Skye; Quinn, Michael C J; Bruxner, Timothy J C; Christ, Angelika N; Harliwong, Ivon; Idrisoglu, Senel; McLean, Suzanne; Nourse, Craig; Nourbakhsh, Ehsan; Wilson, Peter J; Anderson, Matthew J; Fink, J Lynn; Newell, Felicity; Waddell, Nick; Holmes, Oliver; Kazakoff, Stephen H; Leonard, Conrad; Wood, Scott; Xu, Qinying; Nagaraj, Shivashankar Hiriyur; Amato, Eliana; Dalai, Irene; Bersani, Samantha; Cataldo, Ivana; Dei Tos, Angelo P; Capelli, Paola; Davì, Maria Vittoria; Landoni, Luca; Malpaga, Anna; Miotto, Marco; Whitehall, Vicki L J; Leggett, Barbara A; Harris, Janelle L; Harris, Jonathan; Jones, Marc D; Humphris, Jeremy; Chantrill, Lorraine A; Chin, Venessa; Nagrial, Adnan M; Pajic, Marina; Scarlett, Christopher J; Pinho, Andreia; Rooman, Ilse; Toon, Christopher; Wu, Jianmin; Pinese, Mark; Cowley, Mark; Barbour, Andrew; Mawson, Amanda; Humphrey, Emily S; Colvin, Emily K; Chou, Angela; Lovell, Jessica A; Jamieson, Nigel B; Duthie, Fraser; Gingras, Marie-Claude; Fisher, William E; Dagg, Rebecca A; Lau, Loretta M S; Lee, Michael; Pickett, Hilda A; Reddel, Roger R; Samra, Jaswinder S; Kench, James G; Merrett, Neil D; Epari, Krishna; Nguyen, Nam Q; Zeps, Nikolajs; Falconi, Massimo; Simbolo, Michele; Butturini, Giovanni; Van Buren, George; Partelli, Stefano; Fassan, Matteo; Khanna, Kum Kum; Gill, Anthony J; Wheeler, David A; Gibbs, Richard A; Musgrove, Elizabeth A; Bassi, Claudio; Tortora, Giampaolo; Pederzoli, Paolo; Pearson, John V; Waddell, Nicola; Biankin, Andrew V; Grimmond, Sean M

2017-03-02

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.

Latest advances in chronic pancreatitis.

PubMed

Enrique Domínguez-Muñoz, J

2016-09-01

This article summarizes some of the recent and clinically relevant advances in chronic pancreatitis. These advances mainly concern the definition of the disease, the etiological diagnosis of idiopathic disease, the correlation between fibrosis degree and pancreatic secretion in the early stages of chronic pancreatitis, the treatment of the disease and of pain, the clinical relevance of pancreatic exocrine insufficiency, and the diagnosis of autoimmune pancreatitis. A new mechanistic definition of chronic pancreatitis has been proposed. Genetic testing is mainly of help in patients with relapsing idiopathic pancreatitis. A significant correlation has been shown between the degree of pancreatic fibrosis as evaluated by elastography and pancreatic secretion of bicarbonate. New data supports the efficacy of antioxidants and simvastatin for the therapy of chronic pancreatitis. The pancreatoscopy-guided intraductal lithotripsy is an effective alternative to extracorporeal shock wave lithotripsy in patients with chronic calcifying pancreatitis. The presence of pancreatic exocrine insufficiency in patients with chronic pancreatitis is associated with a significant risk of cardiovascular events. Fine needle biopsy and contrast enhanced harmonic endoscopic ultrasonography are of help for the diagnosis of autoimmune pancreatitis and its differential diagnosis with pancreatic cancer. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

Pancreatic neuroendocrine neoplasms: a current summary of diagnostic, prognostic, and differential diagnostic information.

PubMed

Wick, M R; Graeme-Cook, F M

2001-06-01

Pancreatic endocrine tumors (PETs) continue to be challenging diagnostic and prognostic lesions in surgical pathology and clinical medicine. These neoplasms can be graded into 1 of 3 tiers, based on histologic characteristics in likeness to epithelial neuroendocrine tumors in other anatomic sites. However, grade 1 tumors are by far the most common and are the most difficult to prognosticate. The most helpful features by which to gauge the behavior of such lesions include size (3 cm or larger); mitotic activity (2 or more mitoses per 10 high-power [x400] microscopic fields); marked nuclear atypia, especially with atypical mitoticfigures; predominant tumor synthesis of gastrin, vasoactive intestinal polypeptide, somatostatin, glucagon, calcitonin, or adrenocorticotropic hormone; complete nonfunctionality of the tumor at an immunohistochemical level; or invasion of blood vessels, nerves, or adjacent organs by the neoplasm. Differential diagnosis of PETs includes lesions such as solid-pseudopapillary neoplasms, acinar carcinomas, metastatic neuroendocrine tumors, and plasmacytomas.

Cost-effectiveness of everolimus vs sunitinib in treating patients with advanced, progressive pancreatic neuroendocrine tumors in the United States.

PubMed

Casciano, Roman; Chulikavit, Maruit; Perrin, Allison; Liu, Zhimei; Wang, Xufang; Garrison, Louis P

2012-01-01

Everolimus (Afinitor) and sunitinib (Sutent) were recently approved to treat patients with advanced, progressive pancreatic neuroendocrine tumors (pNETs). (Afinitor is a registered trademark of Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; Sutent is a registered trademark of Pfizer Inc., New York, NY, USA.) This analysis examined the projected cost-effectiveness of everolimus vs sunitinib in this setting from a US payer perspective. A semi-Markov model was developed to simulate a cohort of patients with advanced, progressive pNET and to estimate the cost per life-year gained (LYG) and per quality-adjusted life-year (QALY) gained when treating with everolimus vs sunitinib. Efficacy data were based on a weight-adjusted indirect comparison of the agents using phase 3 trial data. Model health states included: stable disease with no adverse events, stable disease with adverse events, disease progression, and death. Therapy costs were based on wholesale acquisition cost. Other costs such as physician visits, tests, hospitalizations, and adverse event costs were obtained from literature and/or primary research. Utility inputs were based on primary research. Sensitivity analyses were conducted to test the model's robustness. In the base-case analysis, everolimus was associated with an incremental 0.448 LYG (0.304 QALYs) at an incremental cost of $12,673, resulting in an incremental cost-effectiveness ratio (ICER) of $28,281/LYG ($41,702/QALY gained). The ICER fell within the cost per QALY range for many widely used oncology drugs. Sensitivity analyses demonstrated that, overall, there is a trend that everolimus is cost-effective compared to sunitinib in this setting. Results of the indirect analysis were not statistically significant (p > 0.05). Assumptions that treatment patterns are the same across therapies may not represent real-world practice. While the analysis is limited by its reliance on an indirect comparison of two phase 3 studies, everolimus is

Marital status is an independent prognostic factor for pancreatic neuroendocrine tumors patients: An analysis of the Surveillance, Epidemiology, and End Results (SEER) database.

PubMed

Zhou, Huaqiang; Zhang, Yuanzhe; Song, Yiyan; Tan, Wulin; Qiu, Zeting; Li, Si; Chen, Qinchang; Gao, Shaowei

2017-09-01

Marital status's prognostic impact on pancreatic neuroendocrine tumors (PNET) has not been rigorously studied. We aimed to explore the relationship between marital status and outcomes of PNET. We retrospectively investigated 2060 PNET cases between 2004 and 2010 from Surveillance, Epidemiology, and End Results (SEER) database. Variables were compared by Chi 2 test, t-test as appropriate. Kaplan-Meier methods and COX proportional hazard models were used to ascertain independent prognostic factors. Married patients had better 5-year overall survival (OS) (53.37% vs. 42.27%, P<0.001) and 5-year pancreatic neuroendocrine tumor specific survival (PNSS) (67.76% vs. 59.82%, P=0.001) comparing with unmarried patients. Multivariate analysis revealed marital status is an independent prognostic factor, with married patients showing better OS (HR=0.74; 95% CI: 0.65-0.84; P<0.001) and PNSS (HR=0.78; 95% CI: 0.66-0.92; P=0.004). Subgroup analysis suggested marital status plays a more important role in the PNET patients with distant stage rather than regional or localized disease. Marital status is an independent prognostic factor for survival in PNET patients. Poor prognosis in unmarried patients may be associated with a delayed diagnosis with advanced tumor stage, psychosocial and socioeconomic factors. Further studies are needed. Copyright © 2017. Published by Elsevier Masson SAS.

Advances in Pancreatic CT Imaging.

PubMed

Almeida, Renata R; Lo, Grace C; Patino, Manuel; Bizzo, Bernardo; Canellas, Rodrigo; Sahani, Dushyant V

2018-07-01

The purpose of this article is to discuss the advances in CT acquisition and image postprocessing as they apply to imaging the pancreas and to conceptualize the role of radiogenomics and machine learning in pancreatic imaging. CT is the preferred imaging modality for assessment of pancreatic diseases. Recent advances in CT (dual-energy CT, CT perfusion, CT volumetry, and radiogenomics) and emerging computational algorithms (machine learning) have the potential to further increase the value of CT in pancreatic imaging.

Gastroenteropancreatic Neuroendocrine Tumors in Multiple Endocrine Neoplasia Type 1

PubMed Central

Tonelli, Francesco; Giudici, Francesco; Giusti, Francesca; Brandi, Maria Luisa

2012-01-01

We reviewed the literature about entero-pancreatic neuroendocrine tumors in Multiple Endocrine Neoplasia type 1 syndrome (MEN1) to clarify their demographic features, localization imaging, practice, and appropriate therapeutical strategies, analyzing the current approach to entero-pancreatic neuroendocrine tumors in MEN1. Despite the fact that hyperparathyroidism is usually the first manifestation of MEN1, the penetrance of these tumors is similar. They are characterized by multiplicity of lesions, variable expression of the tumors, and propensity for malignant degeneration. Both the histological type and the size of MEN1 neuroendocrine tumors correlate with malignancy. Monitoring of pancreatic peptides and use of imaging exams allow early diagnosis and prompt surgical treatment, resulting in prevention of metastatic disease and improvement of long-term survival. Surgery is often the treatment of choice for MEN1-neuroendocrine tumors. The rationale for surgical approach is to curtail malignant progression of the disease, and to cure the associated biochemical syndrome, should it be present. PMID:24213321

Identification of novel serum autoantibodies against EID3 in non-functional pancreatic neuroendocrine tumors

PubMed Central

Hontani, Koji; Tsuchikawa, Takahiro; Hiwasa, Takaki; Nakamura, Toru; Ueno, Takashi; Kushibiki, Toshihiro; Takahashi, Mizuna; Inoko, Kazuho; Takano, Hironobu; Takeuchi, Satoshi; Dosaka-Akita, Hirotoshi; Kuwatani, Masaki; Sakamoto, Naoya; Hatanaka, Yutaka; Mitsuhashi, Tomoko; Shimada, Hideaki; Shichinohe, Toshiaki; Hirano, Satoshi

2017-01-01

Pancreatic neuroendocrine tumors (pNETs) are relatively rare heterogenous tumors, comprising only 1–2% of all pancreatic neoplasms. The majority of pNETs are non-functional tumors (NF-pNETs) that do not produce hormones, and as such, do not cause any hormone-related symptoms. As a result, these tumors are often diagnosed at an advanced stage because patients do not present with specific symptoms. Although tumor markers are used to help diagnosis and predict some types of cancers, chromogranin A, a widely used tumor marker of pNETs, has significant limitations. To identify novel NF-pNET-associated antigens, we performed serological identification of antigens by recombinant cDNA expression cloning (SEREX) and identified five tumor antigens (phosphatase and tensin homolog, EP300-interacting inhibitor of differentiation 3 [EID3], EH domain-containing protein 1, galactoside-binding soluble 9, and BRCA1-associated protein). Further analysis using the AlphaLISA® immunoassay to compare serum antibody levels revealed that antibody levels against the EID3 antigen was significantly higher in the patient group than in the healthy donor group (n = 25, both groups). In addition, higher serum anti-EID3 antibody levels in NF-pNET patients correlated with shorter disease-free survival. The AUC calculated by ROC analysis was 0.784 with moderate diagnostic accuracy. In conclusion, serum anti-EID3 antibody levels may be useful as a tumor marker for prediction of tumor recurrence in NF-pNETs. PMID:29290942

Temsirolimus and Bevacizumab in Treating Patients With Advanced Endometrial, Ovarian, Liver, Carcinoid, or Islet Cell Cancer

ClinicalTrials.gov

2017-07-10

Adult Hepatocellular Carcinoma; Advanced Adult Hepatocellular Carcinoma; Endometrial Serous Adenocarcinoma; Localized Non-Resectable Adult Liver Carcinoma; Lung Carcinoid Tumor; Malignant Pancreatic Gastrinoma; Malignant Pancreatic Glucagonoma; Malignant Pancreatic Insulinoma; Malignant Pancreatic Somatostatinoma; Metastatic Digestive System Neuroendocrine Tumor G1; Ovarian Carcinosarcoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Surface Papillary Adenocarcinoma; Pancreatic Alpha Cell Adenoma; Pancreatic Beta Cell Adenoma; Pancreatic Delta Cell Adenoma; Pancreatic G-Cell Adenoma; Pancreatic Polypeptide Tumor; Recurrent Adult Liver Carcinoma; Recurrent Digestive System Neuroendocrine Tumor G1; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Pancreatic Neuroendocrine Carcinoma; Recurrent Primary Peritoneal Carcinoma; Recurrent Uterine Corpus Carcinoma; Regional Digestive System Neuroendocrine Tumor G1; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIA Uterine Corpus Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIB Uterine Corpus Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IIIC Uterine Corpus Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer; Uterine Carcinosarcoma

[Latest advances in chronic pancreatitis].

PubMed

Domínguez-Muñoz, J Enrique

2014-09-01

This article summarizes some of the recent and clinically relevant advances in chronic pancreatitis. These advances mainly concern the early diagnosis of the disease, the prediction of the fibrosis degree of the gland, the evaluation of patients with asymptomatic hyperenzimemia, the medical and surgical treatment of abdominal pain and the knowledge of the natural history of the autoimmune pancreatitis. In patients with indetermined EUS findings of chronic pancreatitis, a new endoscopic ultrasound examination in the follow-up is of help to confirm or to exclude the disease. Smoking, number of relapses, results of pancreatic function tests and EUS findings allow predicting the degree of pancreatic fibrosis in patients with chronic pancreatitis. Antioxidant therapy has shown to be effective in reducing pain secondary to chronic pancreatitis, although the type and optimal dose of antioxidants remains to be elucidated. Development of intestinal bacterial overgrowth is frequent in patients with chronic pancreatitis, but its impact on symptoms is unknown and deserves further investigations. Finally, autoimmune pancreatitis relapses in about half of the patients with either type 1 or type 2 disease; relapses frequently occur within the first two years of follow-up. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Can histogram analysis of MR images predict aggressiveness in pancreatic neuroendocrine tumors?

PubMed

De Robertis, Riccardo; Maris, Bogdan; Cardobi, Nicolò; Tinazzi Martini, Paolo; Gobbo, Stefano; Capelli, Paola; Ortolani, Silvia; Cingarlini, Sara; Paiella, Salvatore; Landoni, Luca; Butturini, Giovanni; Regi, Paolo; Scarpa, Aldo; Tortora, Giampaolo; D'Onofrio, Mirko

2018-06-01

To evaluate MRI derived whole-tumour histogram analysis parameters in predicting pancreatic neuroendocrine neoplasm (panNEN) grade and aggressiveness. Pre-operative MR of 42 consecutive patients with panNEN >1 cm were retrospectively analysed. T1-/T2-weighted images and ADC maps were analysed. Histogram-derived parameters were compared to histopathological features using the Mann-Whitney U test. Diagnostic accuracy was assessed by ROC-AUC analysis; sensitivity and specificity were assessed for each histogram parameter. ADC entropy was significantly higher in G2-3 tumours with ROC-AUC 0.757; sensitivity and specificity were 83.3 % (95 % CI: 61.2-94.5) and 61.1 % (95 % CI: 36.1-81.7). ADC kurtosis was higher in panNENs with vascular involvement, nodal and hepatic metastases (p= .008, .021 and .008; ROC-AUC= 0.820, 0.709 and 0.820); sensitivity and specificity were: 85.7/74.3 % (95 % CI: 42-99.2 /56.4-86.9), 36.8/96.5 % (95 % CI: 17.2-61.4 /76-99.8) and 100/62.8 % (95 % CI: 56.1-100/44.9-78.1). No significant differences between groups were found for other histogram-derived parameters (p >.05). Whole-tumour histogram analysis of ADC maps may be helpful in predicting tumour grade, vascular involvement, nodal and liver metastases in panNENs. ADC entropy and ADC kurtosis are the most accurate parameters for identification of panNENs with malignant behaviour. • Whole-tumour ADC histogram analysis can predict aggressiveness in pancreatic neuroendocrine neoplasms. • ADC entropy and kurtosis are higher in aggressive tumours. • ADC histogram analysis can quantify tumour diffusion heterogeneity. • Non-invasive quantification of tumour heterogeneity can provide adjunctive information for prognostication.

Sequential changes from minimal pancreatic inflammation to advanced alcoholic pancreatitis.

PubMed

Noronha, M; Dreiling, D A; Bordalo, O

1983-11-01

A correlation of several clinical parameters and pancreatitis morphological alterations observed in chronic alcoholics with and without pancreatic is presented. Three groups of patients were studied: asymptomatic chronic alcoholics (24); non-alcoholic controls (10); and cases with advanced chronic pancreatitis (6). Clinical, biochemical and functional studies were performed. Morphological studies were made on surgical biopsy specimens in light and electron microscopy. The results of this study showed: 1) fat accumulates within pancreatic acinar cells in alcoholics drinking more than 80 g of ethanol per day; 2) ultrastructural changes found in acinar cells of the alcoholics are similar to those described for liver cells; 3) the alterations found in alcoholics without pancreatitis are also observed in those with advanced chronic pancreatitis. An attempt to correlate the sequential changes in the histopathology of alcoholic pancreatic disease with the clinical picture and secretory patterns was made. According to these observations, admitting the ultrastructural similarities between the liver and the pancreas and the recently demonstrated abnormalities of lipid metabolism in pancreatic cells in experimental animal research, the authors postulate a toxic-metabolic mechanism as a likely hypothesis for the pathogenesis of chronic alcoholic inflammation of the pancreas.

Advances in cryoablation for pancreatic cancer.

PubMed

Luo, Xiao-Mei; Niu, Li-Zhi; Chen, Ji-Bing; Xu, Ke-Cheng

2016-01-14

Pancreatic carcinoma is a common cancer of the digestive system with a poor prognosis. It is characterized by insidious onset, rapid progression, a high degree of malignancy and early metastasis. At present, radical surgery is considered the only curative option for treatment, however, the majority of patients with pancreatic cancer are diagnosed too late to undergo surgery. The sensitivity of pancreatic cancer to chemotherapy or radiotherapy is also poor. As a result, there is no standard treatment for patients with advanced pancreatic cancer. Cryoablation is generally considered to be an effective palliative treatment for pancreatic cancer. It has the advantages of minimal invasion and improved targeting, and is potentially safe with less pain to the patients. It is especially suitable in patients with unresectable pancreatic cancer. However, our initial findings suggest that cryotherapy combined with 125-iodine seed implantation, immunotherapy or various other treatments for advanced pancreatic cancer can improve survival in patients with unresectable or metastatic pancreatic cancer. Although these findings require further in-depth study, the initial results are encouraging. This paper reviews the safety and efficacy of cryoablation, including combined approaches, in the treatment of pancreatic cancer.

Irreversible electroporation of locally advanced pancreatic neck/body adenocarcinoma

PubMed Central

2015-01-01

Objective Irreversible electroporation (IRE) of locally advanced pancreatic adenocarcinoma of the neck has been used to palliate appropriate stage 3 pancreatic cancers without evidence of metastasis and who have undergone appropriate induction therapy. Currently there has not been a standardized reported technique for pancreatic mid-body tumors for patient selection and intra-operative technique. Patients Subjects are patients with locally advanced pancreatic adenocarcinoma of the body/neck who have undergone appropriate induction chemotherapy for a reasonable duration. Main outcome measures Technique of open IRE of locally advanced pancreatic adenocarcinoma of the neck/body is described, with the emphasis on intra-operative ultrasound and intra-operative electroporation management. Results The technique of open IRE of the pancreatic neck/body with bracketing of the celiac axis and superior mesenteric artery with continuous intraoperative ultrasound imaging and consideration of intraoperative navigational system is described. Conclusions IRE of locally advanced pancreatic adenocarcinoma of the body/neck is feasible for appropriate patients with locally advanced unresectable pancreatic cancer. PMID:26029461

Determinants of surgical resection for pancreatic neuroendocrine tumors.

PubMed

Doi, Ryuichiro

2015-08-01

Pancreatic neuroendocrine tumors (pNETs) include functioning and non-functional tumors. Functioning tumors consist of tumors that produce a variety of hormones and their clinical effects. Therefore, determinants of resection of pNETs should be discussed for each group of tumors. Less than 10% of insulinomas are malignant, therefore more than 90% of the cases can be cured by surgical resection. Lymphadenectomy is generally not necessary in insulinoma operation. If preoperative localization of the insulinoma is completed, enucleation from the pancreatic body or tail, and distal pancreatectomy can be performed safely by laparoscopy. When preoperative localization of a sporadic insulinoma is not confirmed, surgical exploration is needed. Intraoperative localization of a tumor, intraoperative insulin sampling and frozen section are required. The crucial purpose of surgical resection is to control inappropriate insulin secretion by removing all insulinomas. Gastrinomas are usually located in the duodenum or pancreas, which secrete gastrin and cause Zollinger-Ellison syndrome (ZES). Duodenal gastrinomas are usually small, therefore they are not seen on preoperative imaging studies or endoscopic ultrasound, and can be found only at surgery if a duodenotomy is performed. In addition, lymph node metastasis is found in 40-60% of cases. Therefore, the experienced surgeons should direct operation for gastrinomas. Surgical exploration with duodenotomy should be performed at a laparotomy. Other functioning pNETs can occur in the pancreas or in other locations. Curative resection is always recommended whenever possible after optimal symptomatic control of the clinical syndrome by medical treatment. Indications for surgery depend on clinical symptom control, tumor size, location, extent, malignancy and presence of metastasis. A lot of non-functioning pNETs are found incidentally according to the quality improvement of imaging techniques. Localized, small, malignant non

A rare case with synchronous gastric gastrointestinal stromal tumor, pancreatic neuroendocrine tumor, and uterine leiomyoma.

PubMed

Arabadzhieva, Elena; Yonkov, Atanas; Bonev, Sasho; Bulanov, Dimitar; Taneva, Ivanka; Vlahova, Alexandrina; Dikov, Tihomir; Dimitrova, Violeta

2016-11-15

Although gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, they comprise less than 1% of all gastrointestinal tumors. Neuroendocrine tumors (NET) of the gastro-enteropancreatic system are also rare, representing about 2% of all gastrointestinal neoplasms. Pancreatic localization of NET is extremely uncommon-these tumors are only 1-5% of all pancreatic cancers. We describe an unusual case with triple tumor localization-a gastric tumor, a formation in the pancreas, which involves the retroperitoneal space, and a uterine leiomyoma. The exact diagnosis was confirmed with immunohistochemical study after surgical treatment of the patient. Distal pancreatic resection, splenectomy, partial gastrectomy, omentectomy, and hysterectomy were performed. The histological examination proved an epithelioid type of gastric GIST. Immunostaining showed focal positive expression of c-kit and no mitotic figures per 50 HPF. Histology of the pancreatic and retroperitoneal formation proved a well-differentiated NET with origin from the islets of Langerhans. The immunohistochemical study demonstrated co-expression of chromogranin A and synaptophysin. This is the fourth case published so far of a patient with synchronous pancreatic NET and gastric GIST. The main objective of the study is to present a unique case because we have not found any reports for coexistence of the described three types of neoplasm, as in our patient, and we hope that it will be valuable in the future investigations about the genesis, diagnosis, and treatment of these types of tumors.

Broncho-biliary fistula secondary to biliary obstruction and lung abscess in a patient with pancreatic neuro-endocrine tumor.

PubMed

Panda, Dipanjan; Aggarwal, Mayank; Yadav, Vikas; Kumar, Sachin; Mukund, Amar; Baghmar, Saphalta

2016-06-01

We present a case report of broncho-biliary fistula that developed due to the blockage of biliary stent placed during the management of pancreatic neuroendocrine tumor (pNET); diagnosed on high clinical suspicion, percutaneous cholangiogram and contrast enhanced computed tomography (CECT); and successfully treated with percutaneous transhepatic biliary drainage (PTBD). Copyright © 2016 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V. All rights reserved.

Current Status of Interventional Radiology in the Management of Gastro-Entero-Pancreatic Neuroendocrine Tumours (GEP-NETs)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Orgera, Gianluigi; Krokidis, Miltiadis, E-mail: mkrokidis@hotmail.com; Cappucci, Matteo

2015-02-15

Within the group of Gastro-Entero-Pancreatic Neuroendocrine tumours (GEP-NETs), several heterogeneous malignancies are included with a variety of clinical manifestations and imaging characteristics. Often these cases are inoperable and minimal invasive treatment offered by image-guided procedures appears to be the only option. Interventional radiology offers a valid solution in the management of primary and metastatic GEP-NETs. The purpose of this review article is to describe the current status of the role of Interventional Radiology in the management of GEP-NETs.

Novel agents for advanced pancreatic cancer

PubMed Central

Akinleye, Akintunde; Iragavarapu, Chaitanya; Furqan, Muhammad; Cang, Shundong; Liu, Delong

2015-01-01

Pancreatic cancer is relatively insensitive to conventional chemotherapy. Therefore, novel agents targeting dysregulated pathways (MAPK/ERK, EGFR, TGF-β, HEDGEHOG, NOTCH, IGF, PARP, PI3K/AKT, RAS, and Src) are being explored in clinical trials as monotherapy or in combination with cytotoxic chemotherapy. This review summarizes the most recent advances with the targeted therapies in the treatment of patients with advanced pancreatic cancer. PMID:26369833

Pancreatic cancer: Advances in treatment

PubMed Central

Mohammed, Somala; Van Buren II, George; Fisher, William E

2014-01-01

Pancreatic cancer is a leading cause of cancer mortality and the incidence of this disease is expected to continue increasing. While patients with pancreatic cancer have traditionally faced a dismal prognosis, over the past several years various advances in diagnosis and treatment have begun to positively impact this disease. Identification of effective combinations of existing chemotherapeutic agents, such as the FOLFIRINOX and the gemcitabine + nab-paclitaxel regimen, has improved survival for selected patients although concerns regarding their toxicity profiles remain. A better understanding of pancreatic carcinogenesis has identified several pre-malignant precursor lesions, such as pancreatic intraepithelial neoplasias, intraductal papillary mucinous neoplasms, and cystic neoplasms. Imaging technology has also evolved dramatically so as to allow early detection of these lesions and thereby facilitate earlier management. Surgery remains a cornerstone of treatment for patients with resectable pancreatic tumors, and advances in surgical technique have allowed patients to undergo resection with decreasing perioperative morbidity and mortality. Surgery has also become feasible in selected patients with borderline resectable tumors as a result of neoadjuvant therapy. Furthermore, pancreatectomy involving vascular reconstruction and pancreatectomy with minimally invasive techniques have demonstrated safety without significantly compromising oncologic outcomes. Lastly, a deeper understanding of molecular aberrations contributing to the development of pancreatic cancer shows promise for future development of more targeted and safe therapeutic agents. PMID:25071330

Pancreatic cancer: advances in treatment.

PubMed

Mohammed, Somala; Van Buren, George; Fisher, William E

2014-07-28

Pancreatic cancer is a leading cause of cancer mortality and the incidence of this disease is expected to continue increasing. While patients with pancreatic cancer have traditionally faced a dismal prognosis, over the past several years various advances in diagnosis and treatment have begun to positively impact this disease. Identification of effective combinations of existing chemotherapeutic agents, such as the FOLFIRINOX and the gemcitabine + nab-paclitaxel regimen, has improved survival for selected patients although concerns regarding their toxicity profiles remain. A better understanding of pancreatic carcinogenesis has identified several pre-malignant precursor lesions, such as pancreatic intraepithelial neoplasias, intraductal papillary mucinous neoplasms, and cystic neoplasms. Imaging technology has also evolved dramatically so as to allow early detection of these lesions and thereby facilitate earlier management. Surgery remains a cornerstone of treatment for patients with resectable pancreatic tumors, and advances in surgical technique have allowed patients to undergo resection with decreasing perioperative morbidity and mortality. Surgery has also become feasible in selected patients with borderline resectable tumors as a result of neoadjuvant therapy. Furthermore, pancreatectomy involving vascular reconstruction and pancreatectomy with minimally invasive techniques have demonstrated safety without significantly compromising oncologic outcomes. Lastly, a deeper understanding of molecular aberrations contributing to the development of pancreatic cancer shows promise for future development of more targeted and safe therapeutic agents.

Pancreatic neuroendocrine tumours: hypoenhancement on arterial phase computed tomography predicts biological aggressiveness.

PubMed

Worhunsky, David J; Krampitz, Geoffrey W; Poullos, Peter D; Visser, Brendan C; Kunz, Pamela L; Fisher, George A; Norton, Jeffrey A; Poultsides, George A

2014-04-01

Contrary to pancreatic adenocarcinoma, pancreatic neuroendocrine tumours (PNET) are commonly hyperenhancing on arterial phase computed tomography (APCT). However, a subset of these tumours can be hypoenhancing. The prognostic significance of the CT appearance of these tumors remains unclear. From 2001 to 2012, 146 patients with well-differentiated PNET underwent surgical resection. The degree of tumour enhancement on APCT was recorded and correlated with clinicopathological variables and overall survival. APCT images were available for re-review in 118 patients (81%). The majority had hyperenhancing tumours (n = 80, 68%), 12 (10%) were isoenhancing (including cases where no mass was visualized) and 26 (22%) were hypoenhancing. Hypoenhancing PNET were larger, more commonly intermediate grade, and had higher rates of lymph node and synchronous liver metastases. Hypoenhancing PNET were also associated with significantly worse overall survival after a resection as opposed to isoenhancing and hyperenhancing tumours (5-year, 54% versus 89% versus 93%). On multivariate analysis of factors available pre-operatively, only hypoenhancement (HR 2.32, P = 0.02) was independently associated with survival. Hypoenhancement on APCT was noted in 22% of well-differentiated PNET and was an independent predictor of poor outcome. This information can inform pre-operative decisions in the multidisciplinary treatment of these neoplasms. © 2013 International Hepato-Pancreato-Biliary Association.

Everolimus as first line therapy for pancreatic neuroendocrine tumours: current knowledge and future perspectives.

PubMed

Gallo, Marco; Malandrino, Pasqualino; Fanciulli, Giuseppe; Rota, Francesca; Faggiano, Antongiulio; Colao, Annamaria

2017-07-01

Everolimus has been shown to be effective for advanced pancreatic neuroendocrine tumours (pNETs), but its positioning in the therapeutic algorithm for pNETs is matter of debate. With the aim to shed light on this point, we performed an up-to-date critical review taking into account the results of both retrospective and prospective published studies, and the recommendations of international guidelines. In addition, we performed an extensive search on the Clinical Trial Registries databases worldwide, to gather information on the ongoing clinical trials related to this specific topic. We identified eight retrospective published studies, two prospective published studies, and five registered clinical trials. Moreover, we analyzed the content of four widespread international guidelines. Our critical review confirms the lack of high-quality data to recommend everolimus as the first line therapy for pNETs. The ongoing clinical trials reported in this review will hopefully help clinicians, in the near future, to better evaluate the role of everolimus as the first line therapy for pNETs. However, at the moment, there is already enough evidence to recommend everolimus as the first line therapy for patients with symptomatic malignant unresectable insulin-secreting pNETs, to control the endocrine syndrome regardless of tumour growth.

Pancreatic non-functioning neuroendocrine tumor: a new entity genetically related to Lynch syndrome

PubMed Central

Serracant Barrera, Anna; Serra Pla, Sheila; Blázquez Maña, Carmen María; Salas, Rubén Carrera; García Monforte, Neus; Bejarano González, Natalia; Romaguera Monzonis, Andreu; Andreu Navarro, Francisco Javier; Bella Cueto, Maria Rosa

2017-01-01

Some pancreatic neuroendocrine tumors (P-NETs) are associated with hereditary syndromes. An association between Lynch syndrome (LS) and P-NETs has been suggested, however it has not been confirmed to date. We describe the first case associating LS and P-NETs. Here we report a 65-year-old woman who in the past 20 years presented two colorectal carcinomas (CRC) endometrial carcinoma (EC), infiltrating ductal breast carcinoma, small intestine adenocarcinoma, two non-functioning P-NETs and sebomatricoma. With the exception of one P-NET, all these conditions were associated with LS, as confirmed by immunohistochemistry (IHC) and polymerase chain reaction (PCR). LS is caused by a mutation of a mismatch repair (MMR) gene which leads to a loss of expression of its protein. CRC is the most common tumor, followed by EC. Pancreatic tumors have also been associated with LS. Diagnosis of LS is based on clinical criteria (Amsterdam II and Bethesda) and genetic study (MMR gene mutation). The association between LS and our patient’s tumors was confirmed by IHC (loss of expression of proteins MLH1 and its dimer PMS2) and the detection of microsatellite instability (MSI) using PCR. PMID:29184699

Treatment of pancreatic insufficiency using pancreatic extract in patients with advanced pancreatic cancer: a pilot study (PICNIC).

PubMed

Zdenkowski, Nicholas; Radvan, George; Pugliese, Leanna; Charlton, Julie; Oldmeadow, Christopher; Fraser, Allison; Bonaventura, Antonino

2017-06-01

Survival with advanced pancreatic cancer is less than 12 months. Pancreatic exocrine insufficiency may contribute to pancreatic cancer-related cachexia, via nutrient malabsorption. We aimed to determine the feasibility of prescribing pancreatic extract (Creon®) for patients with advanced pancreatic cancer. Patients with advanced pancreatic cancer, without frank malabsorption, were randomised in this feasibility study to pancreatic extract 50,000 units with meals and 25,000 units with snacks, or placebo. Standardised dietary advice was given. Anti-cancer and supportive care treatments were permitted. Outcomes included weight, body mass index (BMI), quality of life (QLQC30, PAN26), survival and nutritional assessment (PG-SGA). Eighteen patients were randomised before study closure due to slow recruitment. Baseline characteristics were well matched. Weight loss prior to randomisation was numerically greater in the pancreatic extract group (mean 0.7 vs 2.2 kg). Weight loss was numerically greater in the placebo group, however not significantly. No differences in BMI or nutrition score were seen. Quality of life did not differ between study groups. Median overall survival was 17 (95% CI 8.1-48.7) weeks in the control group, and 67.6 (95% CI 14.1-98.4) weeks in the pancreatic extract group (p = 0.1063). Only 17% (18/106) of potentially eligible patients were recruited, related to patient/family reluctance, rapid clinical deterioration and patients already prescribed pancreatic extract. A moderate pill burden was noted. Despite intriguing survival results, this study was not sufficiently feasible to proceed to a fully powered comparative study. A multi-centre study would be required to exclude a significant difference in outcomes.

Postoperative Outcomes of Enucleation and Standard Resections in Patients with a Pancreatic Neuroendocrine Tumor.

PubMed

Jilesen, Anneke P J; van Eijck, Casper H J; Busch, Olivier R C; van Gulik, Thomas M; Gouma, Dirk J; van Dijkum, Els J M Nieveen

2016-03-01

Either enucleation or more extended resection is performed to treat patients with pancreatic neuroendocrine tumor (pNET). Aim was to analyze the postoperative complications for each operation separately. Furthermore, independent risk factors for complications and incidence of pancreatic insufficiency were analyzed. Retrospective all resected patients from two academic hospitals in The Netherlands between 1992 and 2013 were included. Postoperative complications were scored by both ISGPS and Clavien-Dindo criteria. Based on tumor location, operations were compared. Independent risk factors for overall complications were identified. During long-term follow-up, pancreatic insufficiency and recurrent disease were analyzed. Tumor enucleation was performed in 60/205 patients (29%), pancreatoduodenectomy in 65/205 (31%), distal pancreatectomy in 72/205 (35%) and central pancreatectomy in 8/205 (4%) patients. Overall complications after tumor enucleation of the pancreatic head and pancreatoduodenectomy were comparable, 24/35 (69%) versus 52/65 (80%). The same was found after tumor enucleation and resection of the pancreatic tail (36 vs.58%). Number of re-interventions and readmissions were comparable between all operations. After pancreatoduodenectomy, 33/65 patients had lymph node metastasis and in patients with tumor size ≤2 cm, 55% had lymph node metastasis. Tumor in the head and BMI ≥25 kg/m(2) were independent risk factors for complications after enucleation. During follow-up, incidence of exocrine and endocrine insufficiency was significant higher after pancreatoduodenectomy (resp. 55 and 19%) compared to the tumor enucleation and distal pancreatectomy (resp. 5 and 7% vs. 8 and 13%). After tumor enucleation 19% developed recurrent disease. Since the complication rate, need for re-interventions and readmissions were comparable for all resections, tumor enucleation may be regarded as high risk. Appropriate operation should be based on tumor size, location, and

Pancreatic Cancer—Health Professional Version

Cancer.gov

Exocrine pancreatic cancer is cancer of the exocrine gland of the pancreas, whereas cancer of the endocrine gland usually forms as a collection of tumor cell types referred to as pancreatic neuroendocrine tumors. Find evidence-based information on pancreatic cancer treatment, research, and statistics.

[Pancreatic acinar neoplasms : Comparative molecular characterization].

PubMed

Bergmann, F

2016-11-01

Pancreatic acinar cell carcinomas are biologically aggressive neoplasms for which treatment options are very limited. The molecular mechanisms of tumor initiation and progression are largely not understood and precursor lesions have not yet been identified. In this study, pancreatic acinar cell carcinomas were cytogenetically characterized as well as by molecular and immunohistochemical analyses. Corresponding investigations were carried out on pancreatic ductal adenocarcinomas and pancreatic neuroendocrine neoplasms augmented by functional analyses. We show that pancreatic acinar cell carcinomas display a microsatellite stable, chromosomal unstable genotype, characterized by recurrent chromosomal imbalances that clearly discriminate them from pancreatic ductal adenocarcinomas and neuroendocrine neoplasms. Based on findings obtained from comparative genomic hybridization, candidate genes could be identified, such as deleted in colorectal cancer (DCC) and c-MYC. Furthermore, several therapeutic targets were identified in acinar cell carcinomas and other pancreatic neoplasms, including epidermal growth factor receptor (EGFR), L1 cell adhesion molecule (L1CAM) and heat shock protein 90 (HSP90). Moreover, L1CAM was shown to play a significant role in the tumorigenesis of pancreatic ductal adenocarcinoma. Functional analyses in cell lines derived from pancreatic neuroendocrine neoplasms revealed promising anti-tumorigenic effects using EGFR and HSP90 inhibitors affecting the cell cycle and in the case of HSP90, regulating several other oncogenes. Finally, based on mutational analyses of mitochondrial DNA, molecular evidence is provided that acinar cell cystadenomas (or better cystic acinar transformation) represent non-clonal lesions, suggesting an inflammatory reactive non-neoplastic nature.

Treatment Patterns and Burden of Illness in Patients Initiating Targeted Therapy or Chemotherapy for Pancreatic Neuroendocrine Tumors.

PubMed

Broder, Michael S; Chang, Eunice; Reddy, Sheila R; Neary, Maureen P

2017-08-01

The aim of this study was to characterize treatment patterns and burden of pancreatic neuroendocrine tumors (PNET). Using 2 claims databases, we identified patients with PNET initiating targeted therapy (everolimus, sunitinib) or chemotherapy from 2009 to 2012. The first targeted/cytotoxic therapy was considered index treatment. Treatment patterns were graphically evaluated from index treatment initiation until enrollment or study end, whichever occurred first. Disease burden was examined by index group for first follow-up year. In treatment pattern analyses (582 newly treated patients with PNET), 72.2% received chemotherapy index treatment, 16.2% everolimus, and 11.7% received sunitinib. Median index treatment duration was 242, 146, and 126 days for everolimus, sunitinib, and cytotoxics (P < 0.01). Sunitinib initiators switched most often followed by everolimus and cytotoxic initiators. In disease burden analyses, 338 patients met inclusion criteria, with mean age of 54.5 (standard deviation, 9.9) years, 45.6% were female, and there were no significant between-group differences. Targeted therapy initiators had more prior somatostatin analog use versus cytotoxics (53.4% vs 25.1%, P < 0.001); 72.5% had comorbidities after treatment initiation; 42.9% had 1 or more inpatient hospitalization; and 47.9% had 1 or more emergency department visit. Pancreatic neuroendocrine tumor treatment patterns varied; cytotoxics were more often used as early therapy than targeted agents, but for less time. Patients had high health care utilization, irrespective of treatment, potentially from burdensome symptoms and comorbidities.

Alcohol and the pancreas. II. Pancreatic morphology of advanced alcoholic pancreatitis.

PubMed

Noronha, M; Bordalo, O; Dreiling, D A

1981-08-01

The histopathology of advanced chronic alcoholic pancreatitis is dominated by cellular degeneration, atrophy and fibrosis. Sequential changes in the histopathology of alcoholic pancreatic disease has been defined and traced from initial injury to end-stage disease. These sequential histopathologies have been correlated with clinical syndrome and secretory patterns. The data are more consistent with a toxic-metabolic pathogenesis of alcoholic pancreatitis than the previous Big Duct and Small Duct hypotheses.

Molecular genetics of pancreatic neoplasms and their morphologic correlates: an update on recent advances and potential diagnostic applications.

PubMed

Reid, Michelle D; Saka, Burcu; Balci, Serdar; Goldblum, Andrew S; Adsay, N Volkan

2014-02-01

To summarize the most clinically and biologically relevant advances in molecular/genetic characteristics of various pancreatic neoplasms, with morphologic correlation. 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. 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. 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.

High Intensity Focused Ultrasound Ablation of Pancreatic Neuroendocrine Tumours: Report of Two Cases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Orgera, Gianluigi, E-mail: gianluigi.orgera@ieo.it; Krokidis, Miltiadis; Monfardini, Lorenzo

2011-04-15

We describe the use of ultrasound-guided high-intensity focused ultrasound (HIFU) for ablation of two pancreatic neuroendocrine tumours (NETs; insulinomas) in two inoperable young female patients. Both suffered from episodes of severe nightly hypoglycemia that was not efficiently controlled by medical treatment. After HIFU ablation, local disease control and symptom relief were achieved without postinterventional complications. The patients remained free of symptoms during 9-month follow-up. The lesions appeared to be decreased in volume, and there was decreased enhancing pattern in the multidetector computed tomography control (MDCT). HIFU is likely to be a valid alternative for symptoms control in patients with pancreaticmore » NETs. However, currently the procedure should be reserved for inoperable patients for whom symptoms cannot be controlled by medical therapy.« less

Somatostatin analogue-induced pancreatic exocrine insufficiency in patients with neuroendocrine tumours: results of a prospective observational study.

PubMed

Lamarca, Angela; McCallum, Lynne; Nuttall, Christina; Barriuso, Jorge; Backen, Alison; Frizziero, Melissa; Leon, Rebecca; Mansoor, Was; McNamara, Mairéad G; Hubner, Richard A; Valle, Juan W

2018-06-20

Background Patients with advanced well-differentiated neuroendocrine tumours(Wd-NETs) are commonly treated with somatostatin analogues(SSAs). Some patients may develop SSA-related side effects such as pancreatic exocrine insufficiency(PEI). Methods In this single-institution, prospective, observational study, the frequency of SSA-induced PEI in 50 sequential patients with advanced Wd-NETs treated with SSAs was investigated. Toxicity was assessed monthly and faecal elastase-1 (FE1) and quality of life (QoL) were assessed 3-monthly. Results The median age was 65.8 years, 58% were male and the majority (92%) of patients had metastatic disease; patients received 4-weekly long acting octreotide (60%) or lanreotide (40%). Twelve patients (24%) developed SSA-related PEI after a median of 2.9 months from SSA initiation; FE1 was a reliable screening tool, especially in symptomatic patients (risk ratio 8.25 (95% confidence interval 1.15-59.01)). Most of these patients (11/12; 92%) required PERT. Other SSA-related adverse events (any grade) included flatulence (50%), abdominal pain (32%), diarrhoea (30%) and fatigue (20%). Development of PEI did not significantly worsen overall QoL, however gastrointestinal symptoms and diarrhoea were increased. Conclusion This study demonstrated that PEI occurs at a higher rate than previously reported; clinicians need to diagnose and treat this SSA-related adverse-event which occurs in 1 in 4 patients with Wd-NETs treated with SSAs.

GLP1 and glucagon co-secreting pancreatic neuroendocrine tumor presenting as hypoglycemia after gastric bypass

PubMed Central

Guimarães, Marta; Rodrigues, Pedro; Pereira, Sofia S; Nora, Mário; Gonçalves, Gil; Albrechtsen, Nicolai Wewer; Hartmann, Bolette; Holst, Jens Juul

2015-01-01

Summary Post-prandial hypoglycemia is frequently found after bariatric surgery. Although rare, pancreatic neuroendocrine tumors (pNET), which occasionally are mixed hormone secreting, can lead to atypical clinical manifestations, including reactive hypoglycemia. Two years after gastric bypass surgery for the treatment of severe obesity, a 54-year-old female with previous type 2 diabetes, developed post-prandial sweating, fainting and hypoglycemic episodes, which eventually led to the finding by ultrasound of a 1.8-cm solid mass in the pancreatic head. The 72-h fast test and the plasma chromogranin A levels were normal but octreotide scintigraphy showed a single focus of abnormal radiotracer uptake at the site of the nodule. There were no other clinical signs of hormone secreting pNET and gastrointestinal hormone measurements were not performed. The patient underwent surgical enucleation with complete remission of the hypoglycemic episodes. Histopathology revealed a well-differentiated neuroendocrine carcinoma with low-grade malignancy with positive chromogranin A and glucagon immunostaining. An extract of the resected tumor contained a high concentration of glucagon (26.707 pmol/g tissue), in addition to traces of GLP1 (471 pmol/g), insulin (139 pmol/g) and somatostatin (23 pmol/g). This is the first report of a GLP1 and glucagon co-secreting pNET presenting as hypoglycemia after gastric bypass surgery. Although pNET are rare, they should be considered in the differential diagnosis of the clinical approach to the post-bariatric surgery hypoglycemia patient. Learning points pNETs can be multihormonal-secreting, leading to atypical clinical manifestations.Reactive hypoglycemic episodes are frequent after gastric bypass.pNETs should be considered in the differential diagnosis of hypoglycemia after bariatric surgery. PMID:26266036

Triple bypass for advanced pancreatic head cancer associated with biliary stricture, duodenal stenosis, and recurrent obstructive pancreatitis.

PubMed

Kudo, Yuzan; Sato, Norihiro; Tamura, Toshihisa; Hirata, Keiji

2016-12-01

Bypass surgery for cancer of the pancreatic head is usually done to palliate the obstructive symptoms in the biliary and/or digestive system. However, it is uncommon for patients to require pancreatic duct drainage for recurrent obstructive pancreatitis. In this article, we report a surgical technique of triple bypass consisting of Roux-en-Y hepaticojejunostomy, gastrojejunostomy, and pancreaticojejunostomy for advanced pancreatic cancer. A 76-year-old male patient with locally advanced and metastatic pancreatic head cancer was referred to our department for biliary stricture, duodenal stenosis, and recurrent obstructive pancreatitis associated with persistent pancreatic pseudocyst. In an attempt to resolve all these problems simultaneously, a triple bypass was performed. The patient survived and continued to receive chemotherapy for almost 1 year after surgery without any serious complications. Thus, triple bypass is a useful surgical technique that could relief symptoms and offer better quality of life to patients with advanced pancreatic cancer presenting with biliary stricture, duodenal stenosis, and severe obstructive pancreatitis difficult to treat by medication or endoscopic procedures.

A case of positive 68Ga-DOTATOC-PET/CT pancreatic heterotopia mimicking an intestinal neuroendocrine tumor.

PubMed

Zilli, Alessandra; Fanetti, Ilaria; Conte, Dario; Massironi, Sara

Gallium-68 DOTA-peptide positron emission tomography/computed tomography ( 68 Ga-PET/CT) has emerged as a promising tool for the diagnosis and staging of gastro-entero-pancreatic neoplasms, thanks to its high sensitivity and specificity. Heterotopic pancreas, which is relatively rare, has never been reported as a possible cause of false positives of 68 Ga-PET/CT. We report on the first case of a heterotopic pancreas showing pathological uptake at 68 Ga-PET/CT, thus mimicking an intestinal neuroendocrine tumor. The present case suggests that heterotopic pancreas should be included among the possible causes of false positives at 68 Ga PET. Copyright © 2018 Elsevier Inc. All rights reserved.

Multimodality Management of "Borderline Resectable" Pancreatic Neuroendocrine Tumors: Report of a Single-Institution Experience.

PubMed

Ambe, Chenwi M; Nguyen, Phuong; Centeno, Barbara A; Choi, Junsung; Strosberg, Jonathan; Kvols, Larry; Hodul, Pamela; Hoffe, Sarah; Malafa, Mokenge P

2017-01-01

Pancreatic neuroendocrine tumors (PanNETs) constitute approximately 3% of pancreatic neoplasms. Like patients with pancreatic ductal adenocarcinoma (PDAC), some of these patients present with "borderline resectable disease." For these patients, an optimal treatment approach is lacking. We report our institution's experience with borderline resectable PanNETs using multimodality treatment. We identified patients with borderline resectable PanNETs who had received neoadjuvant therapy at our institution between 2000 and 2013. The definition of borderline resectability was based on National Comprehensive Cancer Network criteria for PDAC. Neoadjuvant regimen, radiographic response, pathologic response, surgical margins, nodal retrieval, number of positive nodes, and recurrence were documented. Statistics were descriptive. Of 112 patients who underwent surgical resection for PanNETs during the study period, 23 received neoadjuvant therapy, 6 of whom met all inclusion criteria and had borderline resectable disease. These 6 patients received at least 1 cycle of temozolomide and capecitabine, with 3 also receiving radiation. All had radiographic evidence of treatment response. Four (67%) had negative-margin resections. Four patients had histologic evidence of a moderate response. Follow-up (3.0-4.3 years) indicated that all patients were alive, with 5/6 free of disease (1 patient with metastatic disease still on treatment without progression). A multimodality treatment strategy (neoadjuvant temozolomide and capecitabine ± radiation) can be successfully applied to patients with PanNETs who meet NCCN borderline resectable criteria for PDAC. To our knowledge, this is the first report of the use of a multimodality protocol in the treatment of patients with borderline resectable PanNETs.

Surgical resection after TNFerade therapy for locally advanced pancreatic cancer.

PubMed

Chadha, Manpreet K; Litwin, Alan; Levea, Charles; Iyer, Renuka; Yang, Gary; Javle, Milind; Gibbs, John F

2009-09-04

Treatment of pancreatic cancer remains a major oncological challenge and survival is dismal. Most patients, present with advanced disease at diagnosis and are not candidates for curative resection. Preoperative chemoradiation may downstage and improve survival in locally advanced pancreatic cancer. This has prompted investigators to look for novel neoadjuvant therapies. Gene therapy for pancreatic cancer is a novel investigational approach that may have promise. TNFerade is a replication deficient adenovirus vector carrying the human tumor necrosis factor (TNF)-alpha gene regulated under control of a radiation-inducible gene promoter. Transfection of tumor cells with TNFerade maximizes the antitumor effect of TNF-alpha under influence of radiation leading to synergistic effects in preclinical studies. We describe a case of locally advanced unresectable pancreatic cancer treated with a novel multimodal approach utilizing gene therapy with TNFerade and concurrent chemoradiation that was followed by successful surgical resection. Neoadjuvant TNFerade based chemoradiation therapy may be a useful adjunct to treatment of locally advanced pancreatic cancer.

Hormone profiling, WHO 2010 grading, and AJCC/UICC staging in pancreatic neuroendocrine tumor behavior

PubMed Central

Morin, Emilie; Cheng, Sonia; Mete, Ozgur; Serra, Stefano; Araujo, Paula B; Temple, Sara; Cleary, Sean; Gallinger, Steven; Greig, Paul D; McGilvray, Ian; Wei, Alice; Asa, Sylvia L; Ezzat, Shereen

2013-01-01

Pancreatic neuroendocrine tumors (pNETs) are the second most common pancreatic neoplasms, exhibiting a complex spectrum of clinical behaviors. To examine the clinico-pathological characteristics associated with long-term prognosis we reviewed 119 patients with pNETs treated in a tertiary referral center using the WHO 2010 grading and the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) staging systems, with a median follow-up of 38 months. Tumor size, immunohistochemistry (IHC) profiling and patient characteristics-determining stage were analyzed. Primary clinical outcomes were disease progression or death. The mean age at presentation was 52 years; 55% were female patients, 11% were associated with MEN1 (multiple endocrine neoplasia 1) or VHL (Von Hippel–Lindau); mean tumor diameter was 3.3 cm (standard deviation, SD) (2.92). The clinical presentation was incidental in 39% with endocrine hypersecretion syndromes in only 24% of cases. Nevertheless, endocrine hormone tissue immunoreactivity was identified in 67 (56.3%) cases. According to WHO 2010 grading, 50 (42%), 38 (31.9%), and 3 (2.5%) of tumors were low grade (G1), intermediate grade (G2), and high grade (G3), respectively. Disease progression occurred more frequently in higher WHO grades (G1: 6%, G2: 10.5%, G3: 67%, P = 0.026) and in more advanced AJCC stages (I: 2%, IV: 63%, P = 0.033). Shorter progression free survival (PFS) was noted in higher grades (G3 vs. G2; 21 vs. 144 months; P = 0.015) and in more advanced AJCC stages (stage I: 218 months, IV: 24 months, P < 0.001). Liver involvement (20 vs. 173 months, P < 0.001) or histologically positive lymph nodes (33 vs. 208 months, P < 0.001) were independently associated with shorter PFS. Conversely, tissue endocrine hormone immunoreactivity, independent of circulating levels was significantly associated with less aggressive disease. Age, gender, number of primary tumors, and heredity were not

DNA methylation profiles distinguish different subtypes of gastroenteropancreatic neuroendocrine tumors.

PubMed

How-Kit, Alexandre; Dejeux, Emelyne; Dousset, Bertrand; Renault, Victor; Baudry, Marion; Terris, Benoit; Tost, Jörg

2015-01-01

Most studies have considered gastroenteropancreatic neuroendocrine tumors (GEP-NETs) as a homogenous group of samples or distinguish only gastrointestinal from pancreatic endocrine tumors. This article investigates if DNA methylation patterns could distinguish subtypes of GEP-NETs. The DNA methylation level of 807 cancer-related genes was investigated in insulinomas, gastrinomas, non-functioning pancreatic endocrine tumors and small intestine endocrine tumors. DNA methylation patterns were found to be tumor type specific for each of the pancreatic tumor subtypes and identified two distinct methylation-based groups in small intestine endocrine tumors. Differences of DNA methylation levels were validated by pyrosequencing for 20 candidate genes and correlated with differences at the transcriptional level for four candidate genes. The heterogeneity of DNA methylation patterns in the different subtypes of gastroenteropancreatic neuroendocrine tumors suggests different underlying pathways and, therefore, these tumors should be considered as distinct entities in molecular and clinical studies.

Technical Advances in Endoscopic Ultrasound (EUS)-Guided Tissue Acquisition for Pancreatic Cancers: How Can We Get the Best Results with EUS-Guided Fine Needle Aspiration?

PubMed Central

Kedia, Prashant; Gaidhane, Monica

2013-01-01

Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is one of the least invasive and most effective modality in diagnosing pancreatic adenocarcinoma in solid pancreatic lesions, with a higher diagnostic accuracy than cystic tumors. EUS-FNA has been shown to detect tumors less than 3 mm, due to high spatial resolution allowing the detection of very small lesions and vascular invasion, particularly in the pancreatic head and neck, which may not be detected on transverse computed tomography. Furthermore, this minimally invasive procedure is often ideal in the endoscopic procurement of tissue in patients with unresectable tumors. While EUS-FNA has been increasingly used as a diagnostic tool, most studies have collectively looked at all primary pancreatic solid lesions, including lymphomas and pancreatic neuroendocrine neoplasms, whereas very few studies have examined the diagnostic utility of EUS-FNA of pancreatic ductal carcinoma only. As with any novel and advanced endoscopic procedure that may incorporate several practices and approaches, endoscopists have adopted diverse techniques to improve the tissue procurement practice and increase diagnostic accuracy. In this article, we present a review of literature to date and discuss currently practiced EUS-FNA technique, including indications, technical details, equipment, patient selection, and diagnostic accuracy. PMID:24143320

Advances in Hereditary Colorectal and Pancreatic Cancer

PubMed Central

Underhill, Meghan L.; Germansky, Katharine A.; Yurgelun, Matthew B.

2017-01-01

Purpose Innovations in genetic medicine have lead to improvements in the early detection, prevention, and treatment of cancer for patients with inherited risks of gastrointestinal cancer, particularly hereditary colorectal cancer and hereditary pancreatic cancer. Methods This review provides an update on recent data and key advances that have improved the identification, understanding, and management of patients with hereditary colorectal cancer and hereditary pancreatic cancer. Findings This review details recent and emerging data that highlight the developing landscape of genetics in hereditary colorectal and pancreatic cancer risk. A summary is provided of the current state-of-the-art practices for identifying, evaluating, and managing patients with suspected hereditary colorectal cancer and pancreatic cancer risk. The impact of next-generation sequencing technologies in the clinical diagnosis of hereditary gastrointestinal cancer and also in discovery efforts of novel genes linked to familial cancer risk are discussed. Emerging targeted therapies that may play a particularly important role in the treatment of patients with hereditary forms of colorectal cancer and pancreatic cancer are also reviewed. Current approaches for pancreatic cancer screening and the psychosocial impact of such procedures are also detailed. Implications Given the availability of novel diagnostic, risk-reducing, and therapeutic strategies that exist for patients with hereditary risk for colorectal or pancreatic cancer, it is imperative that clinicians be vigilant about evaluating patients for hereditary cancer syndromes. Continuing to advance genetics research in hereditary gastrointestinal cancers will allow for more progress to be made in personalized medicine and prevention. PMID:27045993

Therapy of Pancreatic Neuroendocrine Tumors: Fine Needle Intervention including Ethanol and Radiofrequency Ablation

PubMed Central

Lakhtakia, Sundeep

2017-01-01

Pancreatic neuroendocrine tumors (PNETs) are increasingly being detected, though usually as incidental findings. Majority of the PNETs are non-functional and surgical resection is the standard of care for most of them. However, in patients with small PNETs localized within the pancreas, who are unfit or unwilling for surgery, alternate methods of treatment are needed. Direct methods of ablation of PNETs, using either ethanol injection or radiofrequency ablation (RFA), are emerging as effective methods. The limited literature available as case reports or case series on endoscopic ultrasound (EUS)-guided local ablation using either ethanol or RFA has demonstrated safety and efficacy along with short- to medium-term sustained relief. Long-term benefits with these local ablative therapies are awaited. Comparative studies are needed to show which of these two competing technologies is superior. Finally, comparative trials of EUS-guided ablation with surgical resection in terms of efficacy and safety will ensure their place in the management algorithm. PMID:29207860

Case report: Irreversible electroporation for locally advanced pancreatic cancer.

PubMed

Orcutt, Sonia; Kis, Bela; Malafa, Mokenge

2017-01-01

For patients with pancreatic adenocarcinoma who are not candidates for surgical resection, long-term survival is poor, even with currently available systemic and radiation therapy options. However, for those with locally advanced disease who do not have distant metastasis, locoregional control of the tumor has the potential to improve long-term outcomes. A newly developed technology, irreversible electroporation, has advantages over traditional thermal ablation with unresectable cancers in this location. In our case report, we describe the first patient treated with irreversible electroporation at our institution for locally advanced pancreatic cancer. The patient is a 63-year-old man who had a partial response to standard chemotherapy and radiation, but was found on operative assessment to have persistently unresectable disease. He therefore underwent irreversible electroporation to the pancreatic mass. His postoperative course was complicated by delayed gastric emptying and wound infection. Three months after surgery, he had no evidence of distant or recurrent disease. Irreversible electroporation for locally advanced pancreatic cancer is an emerging technique which attempts to improve local control of locally advanced, non-metastatic pancreatic cancer. Early data have demonstrated the potential for improved long-term survival in these patients, although further studies are needed to confirm safety and efficacy of this technique. While there is a positive outlook for the use of irreversible electroporation for locally advanced pancreas cancer, there remain some uncertainties surrounding this therapy, which underscores the importance of future research in this area. Copyright © 2017. Published by Elsevier Ltd.

Management of neuroendocrine tumors.

PubMed

Chung, Clement

2016-11-01

Current strategies for managing neuroendocrine tumors (NETs) in adult patients are reviewed, with a focus on medication safety concerns. NETs usually originate in the gastrointestinal or bronchopulmonary tract. Symptoms due to hormonal hypersecretion often occur in patients with foregut or midgut NETs or liver metastases. Surgical resection is recommended for most localized NETs, while systemic cytotoxic chemotherapy is typically used for high-grade and pancreatic tumors. The standard of care for metastatic NETs is somatostatin analog therapy with octreotide (available in both short- and long-acting formulations) or a depot formulation of lanreotide. Everolimus and sunitinib are targeted therapies with approved indications for use in treating advanced pancreatic NETs. Some patients with liver-predominant disease or liver metastases may undergo regional chemoembolization procedures. Pharmacists should be cognizant of differences between newer and older chemoembolization agents and procedures, as well as differences between somatostatin analog products used as medications and the radiolabelled forms used in diagnostic scintigraphy. Other medication safety issues in NET management arise during perioperative supportive care, patient education, compliance counseling, and management of adverse effects of targeted therapies and chemotherapy, including stomatitis, hyperthyroidism, and hand-foot skin reaction. Somatostatin analog therapy is the mainstay for management of locally advanced or metastatic NETs. Liver-directed therapy is an option for localized unresectable disease; platinum-based chemotherapy is the first-line treatment for poorly differentiated tumors. Optimal sequencing of these treatments and targeted therapies such as everolimus and tyrosine kinase inhibitors remains to be elucidated. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Rb Loss and KRAS Mutation Are Predictors of the Response to Platinum-Based Chemotherapy in Pancreatic Neuroendocrine Neoplasm with Grade 3: A Japanese Multicenter Pancreatic NEN-G3 Study.

PubMed

Hijioka, Susumu; Hosoda, Waki; Matsuo, Keitaro; Ueno, Makoto; Furukawa, Masayuki; Yoshitomi, Hideyuki; Kobayashi, Noritoshi; Ikeda, Masafumi; Ito, Tetsuhide; Nakamori, Shoji; Ishii, Hiroshi; Kodama, Yuzo; Morizane, Chigusa; Okusaka, Takuji; Yanagimoto, Hiroaki; Notohara, Kenji; Taguchi, Hiroki; Kitano, Masayuki; Yane, Kei; Maguchi, Hiroyuki; Tsuchiya, Yoshiaki; Komoto, Izumi; Tanaka, Hiroki; Tsuji, Akihito; Hashigo, Syunpei; Kawaguchi, Yoshiaki; Mine, Tetsuya; Kanno, Atsushi; Murohisa, Go; Miyabe, Katsuyuki; Takagi, Tadayuki; Matayoshi, Nobutaka; Yoshida, Tsukasa; Hara, Kazuo; Imamura, Masayuki; Furuse, Junji; Yatabe, Yasushi; Mizuno, Nobumasa

2017-08-15

Purpose: Patients with pancreatic neuroendocrine neoplasm grade-3 (PanNEN-G3) show variable responses to platinum-based chemotherapy. Recent studies indicated that PanNEN-G3 includes well-differentiated neuroendocrine tumor with G3 (NET-G3). Here, we examined the clinicopathologic and molecular features of PanNEN-G3 and assessed the responsiveness to chemotherapy and survival. Experimental Design: A total of 100 patients with PanNEN-G3 were collected from 31 institutions, and after central review characteristics of each histologic subtype [NET-G3 vs. pancreatic neuroendocrine carcinoma (NEC-G3)] were analyzed, including clinical, radiological, and molecular features. Factors that correlate with response to chemotherapy and survival were assessed. Results: Seventy patients analyzed included 21 NETs-G3 (30%) and 49 NECs-G3 (70%). NET-G3 showed lower Ki67-labeling index (LI; median 28.5%), no abnormal Rb expression (0%), and no mutated KRAS (0%), whereas NEC-G3 showed higher Ki67-LI (median 80.0%), Rb loss (54.5%), and KRAS mutations (48.7%). Chemotherapy response rate (RR), platinum-based chemotherapy RR, and prognosis differed significantly between NET-G3 and NEC-G3. Chemotherapeutic outcomes were worse in NET-G3 ( P < 0.001). When we stratified PanNEN-G3 with Rb and KRAS , PanNENs-G3 with Rb loss and those with mutated KRAS showed significantly higher RRs to platinum-based chemotherapy than those without (Rb loss, 80% vs. normal Rb, 24%, P = 0.006; mutated KRAS , 77% versus wild type, 23%, P = 0.023). Rb was a predictive marker of response to platinum-based chemotherapy even in NEC-G3 ( P = 0.035). Conclusions: NET-G3 and NEC-G3 showed distinct clinicopathologic characteristics. Notably, NET-G3 does not respond to platinum-based chemotherapy. Rb and KRAS are promising predictors of response to platinum-based chemotherapy for PanNEN-G3, and Rb for NEC-G3. Clin Cancer Res; 23(16); 4625-32. ©2017 AACR . ©2017 American Association for Cancer Research.

Von Hippel–Lindau and myotonic dystrophy of Steinert along with pancreatic neuroendocrine tumor and renal clear cell carcinomal neoplasm: Case report and review of the literature

PubMed Central

Addeo, A.; Bini, R.; Viora, T.; Bonaccorsi, L.; Leli, R.

2013-01-01

INTRODUCTION Myotonic dystrophy of Steinert, DM1, is the most common adult muscular dystrophy and generally is not associated to development on multiple site neoplasm. Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome that is associated to tumors such as hemangioblastoma of the retina or central nervous system, clear-cell renal carcinoma (RCC) and endocrine tumors, most commonly pheochromocytoma and non-secretory pancreatic islet cell cancers. No data exist in literature describing the coexistence of both DM1 and VHL. PRESENTATION OF CASE Herein we report a case of renal and pancreatic neoplasm in a young adult female affected by DM1 and VHL simultaneously. DISCUSSION DM1 is due to an unstable trinucleotide (CTG) expansion in the 30 antranslated region of the dystrophia myotonica-protein kinase (DMPK) gene, located on chromosome 19q13.3. Several molecular mechanisms thought to be determining the classical DM phenotype have been shown. VHL disease is characterized by marked phenotypic variability and the most common tumors are hemangioblastomas of the retina or central nervous system, clear-cell renal carcinoma (RCC) and endocrine tumors, most commonly pheochromocytoma and non-secretory pancreatic islet cell cancers. The pancreatic manifestations seen in patients with VHL disease are divided into 2 categories: pancreatic neuroendocrine tumor (PNET) as solid tumors, and cystic lesions, including a simple cyst and serous cystadenoma. The surgical approach for these cistic lesions is to consider as golden standard. Blansfield has proposed 3 criteria to predict metastatic disease of PNET in patients with VHL disease: (1) tumor size greater than or equal to 3 cm; (2) presence of a mutation in exon 3; and (3) tumor doubling time less than 500 d. If the patient has none of these criteria the patient could be followed with physical examination and radiological surveillance on a 2/3 years base.4 If the patient has 1 criterion, the patient

Stages of Pancreatic Neuroendocrine Tumors

MedlinePlus

... Leukemia Liver Cancer Lung Cancer Lymphoma Pancreatic Cancer Prostate Cancer Skin Cancer Thyroid Cancer Uterine Cancer All Cancer ... also called nuclear magnetic resonance imaging (NMRI). Somatostatin receptor scintigraphy : A type of radionuclide scan that may ...

Pancreatic Cancer: Multicenter Prospective Data Collection and Analysis by the Hungarian Pancreatic Study Group.

PubMed

Lakatos, Gábor; Balázs, Anita; Kui, Balázs; Gódi, Szilárd; Szücs, Ákos; Szentesi, Andrea; Szentkereszty, Zsolt; Szmola, Richárd; Kelemen, Dezső; Papp, Róbert; Vincze, Áron; Czimmer, József; Pár, Gabriella; Bajor, Judit; Szabó, Imre; Izbéki, Ferenc; Halász, Adrienn; Leindler, László; Farkas, Gyula; Takács, Tamás; Czakó, László; Szepes, Zoltán; Hegyi, Péter; Kahán, Zsuzsanna

2016-06-01

Pancreatic cancer is a devastating disease with poor prognosis. There is very limited information available regarding the epidemiology and treatment strategies of pancreatic cancer in Central Europe. The purpose of the study was to prospectively collect and analyze data of pancreatic cancer in the Hungarian population. The Hungarian Pancreatic Study Group (HPSG) organized prospective, uniform data collection. Altogether 354 patients were enrolled from 14 Hungarian centers. Chronic pancreatitis was present in 3.7% of the cases, while 33.7% of the patients had diabetes. Family history for pancreatic cancer was positive in 4.8%. The most frequent presenting symptoms included pain (63.8%), weight loss (63%) and jaundice (52.5%). The reported frequency of smoking and alcohol consumption was lower than expected (28.5% and 27.4%, respectively). The majority of patients (75.6%) were diagnosed with advanced disease. Most patients (83.6%) had a primary tumor located in the pancreatic head. The histological diagnosis was ductal adenocarcinoma in 90.7% of the cases, while neuroendocrine tumor was present in 5.3%. Biliary stent implantation was performed in 166 patients, 59.2% of them received metal stents. Primary tumor resection was performed in 60 (16.9%) patients. Enteral or biliary bypass was done in 35 and 49 patients, respectively. In a multivariate Cox-regression model, smoking status and presence of gemcitabine-based chemotherapy were identified as independent predictors for overall survival. We report the first data from a large cohort of Hungarian pancreatic cancer patients. We identified smoking status and chemotherapy as independent predictors in this cohort.

Anti-Hu paraneoplastic brainstem encephalitis caused by a pancreatic neuroendocrine tumor presenting with central hypoventilation.

PubMed

Najjar, Marc; Taylor, Andrew; Agrawal, Surbhi; Fojo, Tito; Merkler, Alexander E; Rosenblum, Marc K; Lennihan, Laura; Kluger, Michael D

2017-06-01

Paraneoplastic neurological syndromes are rare autoimmune manifestations of malignancies associated with specific antibodies. Anti-Hu associated brainstem encephalitis, a well-described syndrome, usually presents subacutely with preferential involvement of the medulla. Anti-Hu antibodies target intraneuronal antigens and are therefore highly correlated with neurological syndromes when present concomitantly with a neoplasm. Reported is a case of anti-Hu brainstem encephalitis associated with a pancreatic neuroendocrine tumor (PNET) presenting with central hypoventilation. This is the first described case of brainstem encephalitis associated with a well-differentiated PNET as well as the first case of Anti-Hu antibodies associated with a PNET. There are no standardized protocols for the treatment of paraneoplastic brainstem encephalitis however, as in the present case, surgical resection and oncological treatment of the tumor is the first line treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemotherapy for neuroendocrine tumors: the Beatson Oncology Centre experience.

PubMed

Hatton, M Q; Reed, N S

1997-01-01

The role of chemotherapy in malignant neuroendocrine tumours is difficult to assess because of their rarity and variation in biological behaviour. We present a retrospective review of chemotherapy given to 18 patients with metastatic and one with locally advanced neuroendocrine tumours. There were eight poorly differentiated neuroendocrine tumours, six thyroid medullary carcinomas, two phaeochromocytomas, two pancreatic islet cell tumours and one undifferentiated neuroblastoma. Four patients were given 3-weekly dacarbazine, vincristine and cyclophosphamide (DOC) chemotherapy. In eight patients, this regimen was modified by substituting the dacarbazine and cisplatin and etoposide (OPEC). A further six patients were treated with dacarbazine reintroduced into the 3-weekly regimen (DOPEC). The remaining patient received cisplatin and etoposide. There were two complete responses (both with OPEC) and eight partial responses (two with DOC, three with OPEC and three with DOPEC). Five patients had stable disease and four progressed. Four received further chemotherapy on relapse, producing one complete and one partial response. The median response duration to initial chemotherapy was 10 months (range 3-34). The median survival was 12 months (range 1-42). The main toxicity was haematological, with grade 3-4 neutropenia in 12 patients; eight suffered episodes of sepsis. One death was treatment related. Other toxicity was mild although three patients discontinued vincristine with grade 2 neurotoxicity. The response rate and side effects of these three regimens appear comparable. We conclude that, although these patient numbers are small, combination chemotherapy produces an encouraging response rate (53%; 95% CI 30-75) in malignant neuroendocrine tumours, with acceptable toxicity.

Advances in pancreatic cancer research: moving towards early detection.

PubMed

He, Xiang-Yi; Yuan, Yao-Zong

2014-08-28

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer. Substantial progress has been made in the understanding of the biology of pancreatic cancer, and advances in patient management have been significant. However, most patients (nearly 80%) who present with locally advanced or metastatic disease have an extremely poor prognosis. Survival is better for those with malignant disease localized to the pancreas, because surgical resection at present offers the only chance of cure. Therefore, the early detection of pancreatic cancer may benefit patients with PDAC. However, its low rate of incidence and the limitations of current screening strategies make early detection difficult. Recent advances in the understanding of the pathogenesis of PDAC suggest that it is possible to detect PDAC in early stages and even identify precursor lesions. The presence of new-onset diabetes mellitus in the early phase of pancreatic cancer may provide clues for its early diagnosis. Advances in the identification of novel circulating biomarkers including serological signatures, autoantibodies, epigenetic markers, circulating tumor cells and microRNAs suggest that they can be used as potential tools for the screening of precursors and early stage PDAC in the future. However, proper screening strategies based on effective screening methodologies need to be tested for clinical application.

Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors.

PubMed

Yachida, Shinichi; Vakiani, Efsevia; White, Catherine M; Zhong, Yi; Saunders, Tyler; Morgan, Richard; de Wilde, Roeland F; Maitra, Anirban; Hicks, Jessica; Demarzo, Angelo M; Shi, Chanjuan; Sharma, Rajni; Laheru, Daniel; Edil, Barish H; Wolfgang, Christopher L; Schulick, Richard D; Hruban, Ralph H; Tang, Laura H; Klimstra, David S; Iacobuzio-Donahue, Christine A

2012-02-01

Poorly differentiated neuroendocrine carcinomas (NECs) of the pancreas are rare malignant neoplasms with a poor prognosis. The aim of this study was to determine the clinicopathologic and genetic features of poorly differentiated NECs and compare them with other types of pancreatic neoplasms. We investigated alterations of KRAS, CDKN2A/p16, TP53, SMAD4/DPC4, DAXX, ATRX, PTEN, Bcl2, and RB1 by immunohistochemistry and/or targeted exomic sequencing in surgically resected specimens of 9 small cell NECs, 10 large cell NECs, and 11 well-differentiated neuroendocrine tumors (PanNETs) of the pancreas. Abnormal immunolabeling patterns of p53 and Rb were frequent (p53, 18 of 19, 95%; Rb, 14 of 19, 74%) in both small cell and large cell NECs, whereas Smad4/Dpc4, DAXX, and ATRX labeling was intact in virtually all of these same carcinomas. Abnormal immunolabeling of p53 and Rb proteins correlated with intragenic mutations in the TP53 and RB1 genes. In contrast, DAXX and ATRX labeling was lost in 45% of PanNETs, whereas p53 and Rb immunolabeling was intact in these same cases. Overexpression of Bcl-2 protein was observed in all 9 small cell NECs (100%) and in 5 of 10 (50%) large cell NECs compared with only 2 of 11 (18%) PanNETs. Bcl-2 overexpression was significantly correlated with higher mitotic rate and Ki67 labeling index in neoplasms in which it was present. Small cell NECs are genetically similar to large cell NECs, and these genetic changes are distinct from those reported in PanNETs. The finding of Bcl-2 overexpression in poorly differentiated NECs, particularly small cell NEC, suggests that Bcl-2 antagonists/inhibitors may be a viable treatment option for these patients.

Challenges and advances in mouse modeling for human pancreatic tumorigenesis and metastasis

PubMed Central

Qiu, Wanglong

2013-01-01

Pancreatic cancer is critical for developed countries, where its rate of diagnosis has been increasing steadily annually. In the past decade, the advances of pancreatic cancer research have not contributed to the decline in mortality rates from pancreatic cancer—the overall 5-year survival rate remains about 5% low. This number only underscores an obvious urgency for us to better understand the biological features of pancreatic carcinogenesis, to develop early detection methods, and to improve novel therapeutic treatments. To achieve these goals, animal modeling that faithfully recapitulates the whole process of human pancreatic cancer is central to making the advancements. In this review, we summarize the currently available animal models for pancreatic cancer and the advances in pancreatic cancer animal modeling. We compare and contrast the advantages and disadvantages of three major categories of these models: (1) carcinogen-induced; (2) xenograft and allograft; and (3) genetically engineered mouse models. We focus more on the genetically engineered mouse models, a category which has been rapidly expanded recently for their capacities to mimic human pancreatic cancer and metastasis, and highlight the combinations of these models with various newly developed strategies and cell-lineage labeling systems. PMID:23114842

Gastric neuroendocrine carcinomas in bearded dragons (Pogona vitticeps).

PubMed

Ritter, J M; Garner, M M; Chilton, J A; Jacobson, E R; Kiupel, M

2009-11-01

This article describes a newly recognized highly malignant neoplastic entity in young bearded dragons (Pogona vitticeps), gastric neuroendocrine carcinomas, which readily metastasize. Ten bearded dragons with histories of anorexia (8), vomiting (3), hyperglycemia (2), and anemia (3) were included in this study. All animals had neoplastic masses in their stomach, with metastasis to the liver. Microscopically, 6 of these neuroendocrine carcinomas were well-differentiated and 4 were poorly differentiated. For further characterization, immunohistochemistry for protein gene product 9.5, neuron-specific enolase, endorphin, chromogranins A and B, synaptophysin, somatostatin, insulin, glucagon, gastrin, pancreatic polypeptide, and vasoactive intestinal peptide was performed on 5 animals. Because only immunolabeling for somatostatin was consistently observed in all neoplasms, a diagnosis of somatostatinoma was made for these 5 bearded dragons. Some neoplasms also exhibited multihormonal expression. Electron microscopy performed on 1 tumor confirmed the presence of neuroendocrine granules within neoplastic cells. Gastric neuroendocrine carcinomas, and specifically somatostatinomas, have not been previously reported in bearded dragons, or other reptiles, and may be underdiagnosed due to inconsistent, ambiguous clinical signs. In humans, pancreatic somatostatinomas are associated with a syndrome of hypersomatostatinemia, which includes hyperglycemia, weight loss, and anemia, as observed in some of these bearded dragons. Somatostatinomas in humans are commonly associated with neurofibromatosis type 1 (Von Recklinghausen's disease), caused by a mutation in the tumor suppressor gene NF1, which results in decreased expression of neurofibromin. In all 5 animals examined, neoplasms exhibited decreased neurofibromin expression compared with control tissues, suggesting that decreased functional neurofibromin may play a role in the pathogenesis of somatostatinomas in bearded dragons.

Glyoxalase 1 copy number variation in patients with well differentiated gastro-entero-pancreatic neuroendocrine tumours (GEP-NET)

PubMed Central

Xue, Mingzhan; Shafie, Alaa; Qaiser, Talha; Rajpoot, Nasir M.; Kaltsas, Gregory; James, Sean; Gopalakrishnan, Kishore; Fisk, Adrian; Dimitriadis, Georgios K.; Grammatopoulos, Dimitris K.; Rabbani, Naila; Thornalley, Paul J.; Weickert, Martin O.

2017-01-01

Background The glyoxalase-1 gene (GLO1) is a hotspot for copy-number variation (CNV) in human genomes. Increased GLO1 copy-number is associated with multidrug resistance in tumour chemotherapy, but prevalence of GLO1 CNV in gastro-entero-pancreatic neuroendocrine tumours (GEP-NET) is unknown. Methods GLO1 copy-number variation was measured in 39 patients with GEP-NET (midgut NET, n = 25; pancreatic NET, n = 14) after curative or debulking surgical treatment. Primary tumour tissue, surrounding healthy tissue and, where applicable, additional metastatic tumour tissue were analysed, using real time qPCR. Progression and survival following surgical treatment were monitored over 4.2 ± 0.5 years. Results In the pooled GEP-NET cohort, GLO1 copy-number in healthy tissue was 2.0 in all samples but significantly increased in primary tumour tissue in 43% of patients with pancreatic NET and in 72% of patients with midgut NET, mainly driven by significantly higher GLO1 copy-number in midgut NET. In tissue from additional metastases resection (18 midgut NET and one pancreatic NET), GLO1 copy number was also increased, compared with healthy tissue; but was not significantly different compared with primary tumour tissue. During mean 3 - 5 years follow-up, 8 patients died and 16 patients showed radiological progression. In midgut NET, a high GLO1 copy-number was associated with earlier progression. In NETs with increased GLO1 copy number, there was increased Glo1 protein expression compared to non-malignant tissue. Conclusions GLO1 copy-number was increased in a large percentage of patients with GEP-NET and correlated positively with increased Glo1 protein in tumour tissue. Analysis of GLO1 copy-number variation particularly in patients with midgut NET could be a novel prognostic marker for tumour progression. PMID:29100361

Gastrointestinal Neuroendocrine Tumors: Pancreatic Endocrine Tumors

PubMed Central

Metz, David C.

2008-01-01

Pancreatic endocrine tumors (PETs) have long fascinated clinicians and investigators despite their relative rarity. Their clinical presentation varies depending upon whether the tumor is functional or not and also according to the specific hormonal syndrome produced. Tumors may be sporadic or inherited but little is known about their molecular pathology, especially the sporadic forms. Chromogranin A appears to be the most useful serum marker for diagnosis, staging and monitoring. Initially, therapy should be directed at the hormonal syndrome as this has the major initial impact on the patient's health. Most PETs are relatively indolent but ultimately malignant, except for insulinomas which are predominantly benign. Surgery is the only modality that offers the possibility of cure although it is generally noncurative in patients with Zollinger-Ellison syndrome or nonfunctional PETs with MEN1. Preoperative staging of disease extent is necessary to determine the likelihood of complete resection though debulking surgery is often felt to be useful in unresectable patients. Once metastatic, biotherapy is usually the first modality employed because it is generally well tolerated. Systemic or regional therapies are generally reserved until symptoms occur or tumor growth is rapid. Recently a number of newer agents, as well as receptor-directed radiotherapy, are being evalulated for patients with advanced disease. This review addresses a number of recent advances regarding the molecular pathology, diagnosis, localization and management of PETs including discussion of peptide receptor radionuclide therapy and other novel antitumor approaches. We conclude with a discussion of future directions and unsettled problems in the field. PMID:18703061

Pancreatic surgery.

PubMed

Donahue, Timothy R; Reber, Howard A

2013-09-01

To summarize published research on pancreatic surgery over the past year. A number of studies aiming to reduce the costs associated with pancreatic surgery were reported. Retrospective analyses confirmed previous findings that neither the routine use of pancreatic duct stents decreases the rate of fistula formation nor does placement of a drain at the time of surgery change the morbidity in patients who develop one. Minimally invasive approaches, both laparoscopic and robot-assisted, are being performed more frequently to remove pancreatic cancers. A randomized trial confirmed that reinforcement of stapled closure during distal pancreatectomy reduces the rate of fistula formation. Controversy remains over whether small pancreatic neuroendocrine tumors need to be surgically resected or can be treated nonoperatively. Patients with chronic pancreatitis should be screened thoroughly before being offered surgical treatment; two studies reported preoperative factors that can be used to identify those most likely to experience pain relief. Studies published on pancreatic surgery last year focused on a wide-range of topics. The morbidity and mortality of patients undergoing pancreatic surgery continues to improve, and we anticipate that incorporation of these new findings will lead to even better outcomes.

Molecular targeted therapy in enteropancreatic neuroendocrine tumors: from biology to clinical practice.

PubMed

Fazio, N; Scarpa, A; Falconi, M

2014-01-01

Advanced enteropancreatic (EP) neuroendocrine tumors (NETs) can be treated with several different therapies, including chemotherapy, biotherapy, and locoregional treatments. Over the last few decades, impressive progress has been made in the biotherapy field. Three main druggable molecular targets have been studied and developed in terms of therapy: somatostatin receptor (sstr), mammalian target of rapamycin (mTOR), and angiogenic factors. In particular, research has moved from the old somatostatin analogs (SSAs), such as octreotide (OCT) and lanreotide (LAN), specifically binding to the sstr-2, to the newer pasireotide (PAS), which presents a wider sstr spectrum. Over the last ten years, several molecular targeted agents (MTAs) have been studied in phase II trials, and very few of them have reached phase III. The mTOR inhibitor everolimus and the multitargeted inhibitor sunitinib have been approved for clinical use by the FDA and EMA in advanced well/moderately-differentiated (WD, MD) progressive pancreatic neuroendocrine tumors (PNETs), on the basis of the positive results of two international large randomized phase III trials vs. placebo. Bevacizumab has been studied in a large US phase III trial vs. interferon (IFN)-alfa2b, and results are pending. In this review, the biological and clinical aspects of MTAs introduced into clinical practice or which are currently in an advanced phase of clinical investigation are addressed.

Survival benefit with proapoptotic molecular and pathologic responses from dual targeting of mammalian target of rapamycin and epidermal growth factor receptor in a preclinical model of pancreatic neuroendocrine carcinogenesis.

PubMed

Chiu, Christopher W; Nozawa, Hiroaki; Hanahan, Douglas

2010-10-10

Pancreatic neuroendocrine tumors (PNETs), although rare, often metastasize, such that surgery, the only potentially curative therapy, is not possible. There is no effective systemic therapy for patients with advanced PNETs. Therefore, new strategies are needed. Toward that end, we investigated the potential benefit of dual therapeutic targeting of the epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR) kinases, using a preclinical mouse model of PNET. Rapamycin and erlotinib, inhibitors of mTOR and EGFR, respectively, were used to treat RIP-Tag2 transgenic mice bearing advanced multifocal PNET. Tumor growth and survival were monitored, and tumors were surveyed for potential biomarkers of response to the therapeutics. Rapamycin monotherapy was notably efficacious, prolonging survival concomitant with tumor stasis (stable disease). However, the tumors developed resistance, as evidenced by eventual relapse to progressive tumor growth. Erlotinib monotherapy slowed tumor growth and elicited a marginal survival benefit. In combination, there was an unprecedented survival benefit in the face of this aggressive multifocal cancer and, in contrast to either monotherapy, the development of adaptive resistance was not apparent. Additionally, the antiapoptotic protein survivin was implicated as a biomarker of sensitivity and beneficial responses to the dual targeted therapy. Preclinical trials in a mouse model of endogenous PNET suggest that combined targeting of the mTOR and EGFR signaling pathways could have potential clinical benefit in treating PNET. These results have encouraged development of an ongoing phase II clinical trial aimed to evaluate the efficacy of this treatment regimen in human neuroendocrine tumors.

Overview of exocrine pancreatic pathobiology.

PubMed

Pandiri, Arun R

2014-01-01

Exocrine pancreas is a source of several enzymes that are essential for the digestive process. The exocrine pancreatic secretion is tightly regulated by the neuroendocrine system. The endocrine pancreas is tightly integrated anatomically and physiologically with the exocrine pancreas and modulates its function. Compound-induced pancreatitis is not a common event in toxicology or drug development, but it becomes a significant liability when encountered. Understanding the species-specific differences in physiology is essential to understand the underlying pathobiology of pancreatic disease in animal models and its relevance to human disease. This review will mainly focus on understanding the morphology and physiology of the pancreas, unique islet-exocrine interactions, and pancreatitis.

Anti-proliferative and anti-secretory effects of everolimus on human pancreatic neuroendocrine tumors primary cultures: is there any benefit from combination with somatostatin analogs?

PubMed

Mohamed, Amira; Romano, David; Saveanu, Alexandru; Roche, Catherine; Albertelli, Manuela; Barbieri, Federica; Brue, Thierry; Niccoli, Patricia; Delpero, Jean-Robert; Garcia, Stephane; Ferone, Diego; Florio, Tullio; Moutardier, Vincent; Poizat, Flora; Barlier, Anne; Gerard, Corinne

2017-06-20

Therapeutic management of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is challenging. The mammalian target of rapamycin (mTOR) inhibitor everolimus recently obtained approval from the Food and Drug Administration for the treatment of patients with advanced pancreatic neuroendocrine tumors (pNETs). Despite its promising antitumor efficacy observed in cell lines, clinical benefit for patients is unsatisfactory. The limited therapeutic potential of everolimus in cancer cells has been attributed to Akt activation due to feedback loops relief following mTOR inhibition. Combined inhibition of Akt might then improve everolimus antitumoral effect. In this regard, the somatostatin analog (SSA) octreotide has been shown to repress the PI3K/Akt pathway in some tumor cell lines. Moreover, SSAs are well tolerated and routinely used to reduce symptoms caused by peptide release in patients carrying functional GEP-NETs. We have recently established and characterized primary cultures of human pNETs and demonstrated the anti-proliferative effects of both octreotide and pasireotide. In this study, we aim at determining the antitumor efficacy of everolimus alone or in combination with the SSAs octreotide and pasireotide in primary cultures of pNETs. Everolimus reduced both Chromogranin A secretion and cell viability and upregulated Akt activity in single treatment. Its anti-proliferative and anti-secretory efficacy was not improved combined with the SSAs. Both SSAs did not overcome everolimus-induced Akt upregulation. Furthermore, caspase-dependent apoptosis induced by SSAs was lost in combined treatments. These molecular events provide the first evidence supporting the lack of marked benefit in patients co-treated with everolimus and SSA.

Anti-proliferative and anti-secretory effects of everolimus on human pancreatic neuroendocrine tumors primary cultures: is there any benefit from combination with somatostatin analogs?

PubMed Central

Mohamed, Amira; Romano, David; Saveanu, Alexandru; Roche, Catherine; Albertelli, Manuela; Barbieri, Federica; Brue, Thierry; Niccoli, Patricia; Delpero, Jean-Robert; Garcia, Stephane; Ferone, Diego; Florio, Tullio; Moutardier, Vincent; Gerard, Corinne

2017-01-01

Therapeutic management of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is challenging. The mammalian target of rapamycin (mTOR) inhibitor everolimus recently obtained approval from the Food and Drug Administration for the treatment of patients with advanced pancreatic neuroendocrine tumors (pNETs). Despite its promising antitumor efficacy observed in cell lines, clinical benefit for patients is unsatisfactory. The limited therapeutic potential of everolimus in cancer cells has been attributed to Akt activation due to feedback loops relief following mTOR inhibition. Combined inhibition of Akt might then improve everolimus antitumoral effect. In this regard, the somatostatin analog (SSA) octreotide has been shown to repress the PI3K/Akt pathway in some tumor cell lines. Moreover, SSAs are well tolerated and routinely used to reduce symptoms caused by peptide release in patients carrying functional GEP-NETs. We have recently established and characterized primary cultures of human pNETs and demonstrated the anti-proliferative effects of both octreotide and pasireotide. In this study, we aim at determining the antitumor efficacy of everolimus alone or in combination with the SSAs octreotide and pasireotide in primary cultures of pNETs. Everolimus reduced both Chromogranin A secretion and cell viability and upregulated Akt activity in single treatment. Its anti-proliferative and anti-secretory efficacy was not improved combined with the SSAs. Both SSAs did not overcome everolimus-induced Akt upregulation. Furthermore, caspase-dependent apoptosis induced by SSAs was lost in combined treatments. These molecular events provide the first evidence supporting the lack of marked benefit in patients co-treated with everolimus and SSA. PMID:28454119

Treatment Options for Pancreatic Neuroendocrine Tumors

MedlinePlus

... Leukemia Liver Cancer Lung Cancer Lymphoma Pancreatic Cancer Prostate Cancer Skin Cancer Thyroid Cancer Uterine Cancer All Cancer ... also called nuclear magnetic resonance imaging (NMRI). Somatostatin receptor scintigraphy : A type of radionuclide scan that may ...

Irreversible electroporation therapy in the management of locally advanced pancreatic adenocarcinoma.

PubMed

Martin, Robert C G; McFarland, Kelli; Ellis, Susan; Velanovich, Vic

2012-09-01

Locally advanced pancreatic cancer patients have limited options for disease control. Local ablation technologies based on thermal damage have been used but are associated with major complications in this region of the pancreas. Irreversible electroporation (IRE) is a nonthermal ablation technology that we have shown is safe near vital vascular and ductal structures. The aim of this study was to evaluate the safety and efficacy of IRE as a therapy in the treatment of locally advanced pancreatic cancer. We performed a prospective multi-institutional pilot evaluation of patients undergoing IRE for locally advanced pancreatic cancer from December 2009 to March 2011. These patients were evaluated for 90-day morbidity, mortality, and local disease control. Twenty-seven patients (13 women and 14 men) underwent IRE, with median age of 61 years (range 45 to 80 years). Eight patients underwent margin accentuation with IRE in combination with left-sided resection (n = 4) or pancreatic head resection (n = 4). Nineteen patients had in situ IRE. All patients underwent successful IRE, with intraoperative imaging confirming effective delivery of therapy. All 27 patients demonstrated nonclinically relevant elevation of their amylase and lipase, which peaked at 48 hours and returned to normal at 72 hour postprocedure. There has been one 90-day mortality. No patient has shown evidence of clinical pancreatitis or fistula formation. After all patients have completed 90-day follow-up, there has been 100% ablation success. IRE ablation of locally advanced pancreatic cancer tumors is a safe and feasible primary local treatment in unresectable, locally advanced disease. Confirming these early results must occur in a planned phase II investigational device exemption (IDE) study to be initiated in 2012. Copyright © 2012 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Quantitative CT analysis for the preoperative prediction of pathologic grade in pancreatic neuroendocrine tumors

NASA Astrophysics Data System (ADS)

Chakraborty, Jayasree; Pulvirenti, Alessandra; Yamashita, Rikiya; Midya, Abhishek; Gönen, Mithat; Klimstra, David S.; Reidy, Diane L.; Allen, Peter J.; Do, Richard K. G.; Simpson, Amber L.

2018-02-01

Pancreatic neuroendocrine tumors (PanNETs) account for approximately 5% of all pancreatic tumors, affecting one individual per million each year.1 PanNETs are difficult to treat due to biological variability from benign to highly malignant, indolent to very aggressive. The World Health Organization classifies PanNETs into three categories based on cell proliferative rate, usually detected using the Ki67 index and cell morphology: low-grade (G1), intermediate-grade (G2) and high-grade (G3) tumors. Knowledge of grade prior to treatment would select patients for optimal therapy: G1/G2 tumors respond well to somatostatin analogs and targeted or cytotoxic drugs whereas G3 tumors would be targeted with platinum or alkylating agents.2, 3 Grade assessment is based on the pathologic examination of the surgical specimen, biopsy or ne-needle aspiration; however, heterogeneity in the proliferative index can lead to sampling errors.4 Based on studies relating qualitatively assessed shape and enhancement characteristics on CT imaging to tumor grade in PanNET,5 we propose objective classification of PanNET grade with quantitative analysis of CT images. Fifty-five patients were included in our retrospective analysis. A pathologist graded the tumors. Texture and shape-based features were extracted from CT. Random forest and naive Bayes classifiers were compared for the classification of G1/G2 and G3 PanNETs. The best area under the receiver operating characteristic curve (AUC) of 0:74 and accuracy of 71:64% was achieved with texture features. The shape-based features achieved an AUC of 0:70 and accuracy of 78:73%.

Pasireotide and octreotide antiproliferative effects and sst2 trafficking in human pancreatic neuroendocrine tumor cultures.

PubMed

Mohamed, Amira; Blanchard, Marie-Pierre; Albertelli, Manuela; Barbieri, Federica; Brue, Thierry; Niccoli, Patricia; Delpero, Jean-Robert; Monges, Genevieve; Garcia, Stephane; Ferone, Diego; Florio, Tullio; Enjalbert, Alain; Moutardier, Vincent; Schonbrunn, Agnes; Gerard, Corinne; Barlier, Anne; Saveanu, Alexandru

2014-10-01

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) raise difficult therapeutic problems despite the emergence of targeted therapies. Somatostatin analogs (SSA) remain pivotal therapeutic drugs. However, the tachyphylaxis and the limited antitumoral effects observed with the classical somatostatin 2 (sst2) agonists (octreotide and lanreotide) led to the development of new SSA, such as the pan sst receptor agonist pasireotide. Our aim was to compare the effects of pasireotide and octreotide on cell survival, chromogranin A (CgA) secretion, and sst2 phosphorylation/trafficking in pancreatic NET (pNET) primary cells from 15 tumors. We established and characterized the primary cultures of human pancreatic tumors (pNETs) as powerful preclinical models for understanding the biological effects of SSA. At clinically relevant concentrations (1-10 nM), pasireotide was at least as efficient as octreotide in inhibiting CgA secretion and cell viability through caspase-dependent apoptosis during short treatments, irrespective of the expression levels of the different sst receptors or the WHO grade of the parental tumor. Interestingly, unlike octreotide, which induces a rapid and persistent partial internalization of sst2 associated with its phosphorylation on Ser341/343, pasireotide did not phosphorylate sst2 and induced a rapid and transient internalization of the receptor followed by a persistent recycling at the cell surface. These results provide the first evidence, to our knowledge, of striking differences in the dynamics of sst2 trafficking in pNET cells treated with the two SSAs, but with similar efficiency in the control of CgA secretion and cell viability. © 2014 Society for Endocrinology.

Laparoscopic versus open distal pancreatectomy for nonfunctioning pancreatic neuroendocrine tumors: a large single-center study.

PubMed

Han, Sang Hyup; Han, In Woong; Heo, Jin Seok; Choi, Seong Ho; Choi, Dong Wook; Han, Sunjong; You, Yung Hun

2018-01-01

Pancreatic neuroendocrine tumors (PNETs) account for 1-2% of all pancreatic neoplasms. Nonfunctioning PNETs (NF-PNETs) account for 60-90% of all PNETs. Laparoscopic distal pancreatectomy (LDP) is becoming the treatment of choice for benign lesions in the body and tail of the pancreas. However, LDP has not yet been widely accepted as the gold standard for NF-PNETs. The purpose of this study is to evaluate the clinical and oncologic outcomes after laparoscopic versus open distal pancreatectomy (ODP) for NF-PNETs. Between April 1995 and September 2016, 94 patients with NF-PNETs underwent open or laparoscopic distal pancreatectomy at Samsung Medical Center. Patients were divided into two groups: those who underwent LDP and those who underwent ODP. Both groups were compared in terms of clinical and oncologic variables. LDP patients had a significantly shorter hospital stay compared with ODP patients, amounting to a mean difference of 2 days (p < 0.001). Overall complication rates did not differ significantly between the ODP and LDP groups (p = 0.379). The 3-year overall survival rates in the ODP and LDP groups were 93.7 and 100%, respectively (p = 0.069). In this study, LDP for NF-PNETs had similar oncologic outcomes compared with ODP. In addition, LDP was associated with a shorter hospital stay compared with ODP. Therefore, LDP is a safe and effective procedure for patients with NF-PNETs. A multicenter study and a randomized controlled trial are needed to better assess the clinical and oncologic outcomes.

Common germline variants within the CDKN2A/2B region affect risk of pancreatic neuroendocrine tumors

PubMed Central

Campa, Daniele; Capurso, Gabriele; Pastore, Manuela; Talar-Wojnarowska, Renata; Milanetto, Anna Caterina; Landoni, Luca; Maiello, Evaristo; Lawlor, Rita T.; Malecka-Panas, Ewa; Funel, Niccola; Gazouli, Maria; De Bonis, Antonio; Klüter, Harald; Rinzivillo, Maria; Delle Fave, Gianfranco; Hackert, Thilo; Landi, Stefano; Bugert, Peter; Bambi, Franco; Archibugi, Livia; Scarpa, Aldo; Katzke, Verena; Dervenis, Christos; Liço, Valbona; Furlanello, Sara; Strobel, Oliver; Tavano, Francesca; Basso, Daniela; Kaaks, Rudolf; Pasquali, Claudio; Gentiluomo, Manuel; Rizzato, Cosmeri; Canzian, Federico

2016-01-01

Pancreatic neuroendocrine tumors (PNETs) are heterogeneous neoplasms which represent only 2% of all pancreatic neoplasms by incidence, but 10% by prevalence. Genetic risk factors could have an important role in the disease aetiology, however only a small number of case control studies have been performed yet. To further our knowledge, we genotyped 13 SNPs belonging to the pleiotropic CDKN2A/B gene region in 320 PNET cases and 4436 controls, the largest study on the disease so far. We observed a statistically significant association between the homozygotes for the minor allele of the rs2518719 SNP and an increased risk of developing PNET (ORhom = 2.08, 95% CI 1.05–4.11, p = 0.035). This SNP is in linkage disequilibrium with another polymorphic variant associated with increased risk of several cancer types. In silico analysis suggested that the SNP could alter the sequence recognized by the Neuron-Restrictive Silencer Factor (NRSF), whose deregulation has been associated with the development of several tumors. The mechanistic link between the allele and the disease has not been completely clarified yet but the epidemiologic evidences that link the DNA region to increased cancer risk are convincing. In conclusion, our results suggest rs2518719 as a pleiotropic CDKN2A variant associated with the risk of developing PNETs. PMID:28008994

Common germline variants within the CDKN2A/2B region affect risk of pancreatic neuroendocrine tumors.

PubMed

Campa, Daniele; Capurso, Gabriele; Pastore, Manuela; Talar-Wojnarowska, Renata; Milanetto, Anna Caterina; Landoni, Luca; Maiello, Evaristo; Lawlor, Rita T; Malecka-Panas, Ewa; Funel, Niccola; Gazouli, Maria; De Bonis, Antonio; Klüter, Harald; Rinzivillo, Maria; Delle Fave, Gianfranco; Hackert, Thilo; Landi, Stefano; Bugert, Peter; Bambi, Franco; Archibugi, Livia; Scarpa, Aldo; Katzke, Verena; Dervenis, Christos; Liço, Valbona; Furlanello, Sara; Strobel, Oliver; Tavano, Francesca; Basso, Daniela; Kaaks, Rudolf; Pasquali, Claudio; Gentiluomo, Manuel; Rizzato, Cosmeri; Canzian, Federico

2016-12-23

Pancreatic neuroendocrine tumors (PNETs) are heterogeneous neoplasms which represent only 2% of all pancreatic neoplasms by incidence, but 10% by prevalence. Genetic risk factors could have an important role in the disease aetiology, however only a small number of case control studies have been performed yet. To further our knowledge, we genotyped 13 SNPs belonging to the pleiotropic CDKN2A/B gene region in 320 PNET cases and 4436 controls, the largest study on the disease so far. We observed a statistically significant association between the homozygotes for the minor allele of the rs2518719 SNP and an increased risk of developing PNET (OR hom  = 2.08, 95% CI 1.05-4.11, p = 0.035). This SNP is in linkage disequilibrium with another polymorphic variant associated with increased risk of several cancer types. In silico analysis suggested that the SNP could alter the sequence recognized by the Neuron-Restrictive Silencer Factor (NRSF), whose deregulation has been associated with the development of several tumors. The mechanistic link between the allele and the disease has not been completely clarified yet but the epidemiologic evidences that link the DNA region to increased cancer risk are convincing. In conclusion, our results suggest rs2518719 as a pleiotropic CDKN2A variant associated with the risk of developing PNETs.

Calcified pancreatic and peripancreatic neoplasms: spectrum of pathologies.

PubMed

Verde, Franco; Fishman, Elliot K

2017-11-01

A variety of pancreatic and peripancreatic neoplasms may contain calcifications. We present a review of common to uncommon pancreatic neoplasms that may contain calcifications to include ductal adenocarcinoma, pancreatic neuroendocrine tumors, serous cystadenomas, solid pseudopapillary tumors, intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, and lymphoepithelial cysts. In addition, duodenal mucinous adenocarcinoma can present as a peripancreatic mass that may contain calcification. Knowledge of the spectrum of calcification patterns can help the interpreting radiologist provide a meaningful differential.

Low dose DTIC is effective and safe in pretreated patients with well differentiated neuroendocrine tumors.

PubMed

Mueller, Daniela; Krug, Sebastian; Majumder, Moushumee; Rinke, Anja; Gress, Thomas Matthias

2016-08-18

Streptozocin (STZ) based chemotherapy is recommended for patients with metastatic pancreatic neuroendocrine tumors (pNET). Temozolomide as mono- or combination therapy has been suggested to be a promising alternative. However, the treatment is costly and not approved for the treatment of pNETs. Dacarbazine (DTIC) shares the active metabolite with temozolomide and is broadly available at a low cost. The aim of this study was a retrospective evaluation of the efficacy and tolerability of a lower dose DTIC-regimen in patients with progressive advanced NETs. We retrospectively analyzed 75 patients with NETs predominantly of pancreatic origin treated at our center between 1998 and 2013. 650 mg/m(2) of DTIC were administered intravenously over 60 min every 4 weeks. Morphological response was assessed according to RECIST1.1 criteria. The median progression free survival (PFS) was calculated using Kaplan-Meier and Cox regression methods, respectively. Univariate analyses of possible prognostic markers were performed. The objective response rate (ORR) was 27 % for the entire cohort and 32 % in 50 pNET patients, respectively. Stable disease (SD) was documented in 29 patients (39 %). Median PFS (mPFS) in patients receiving DTIC was 7 months (3.9-10; 95 % confidence interval). Radiological and biochemical response were the only significant prognostic markers for longer PFS in univariate analysis. Treatment was well tolerated. Nausea was the most common side effect (31 %), only one case (1.3 %) of grade 3 toxicity (vomiting) occurred. Low dose DTIC chemotherapy is an effective and well-tolerated treatment option in patients with progressive well differentiated neuroendocrine neoplasms, especially of pancreatic origin.

Conditional deletion of p53 and Rb in the renin-expressing compartment of the pancreas leads to a highly penetrant metastatic pancreatic neuroendocrine carcinoma

PubMed Central

Glenn, Sean T.; Jones, Craig A.; Sexton, Sandra; LeVea, Charles M.; Caraker, Susan M.; Hajduczok, George; Gross, Kenneth W.

2014-01-01

Efforts to model human pancreatic neuroendocrine tumors (PanNET) in animals have been moderately successful, with minimal evidence for glucagonomas or metastatic spread. The renin gene while classically associated with expression in the kidney is also expressed in many other extra-renal tissues including the pancreas. To induce tumorigenesis within renin specific tissues, floxed alleles of p53 and Rb were selectively abrogated using Cre-recombinase driven by the renin promoter. The primary neoplasm generated is a highly metastatic islet cell carcinoma of the pancreas. Lineage tracing identifies descendants of renin-expressing cells as pancreatic alpha cells despite a lack of active renin expression in the mature pancreas. Both primary and metastatic tumors express high levels of glucagon, furthermore an increased level of glucagon is found in the serum identifying the pancreatic cancer as a functional glucagonoma. This new model is highly penetrant and exhibits robust frequency of metastases to lymph nodes and liver, mimicking human disease and provides a useful platform for better understanding pancreatic endocrine differentiation and development, as well as islet cell carcinogenesis. The use of fluorescent reporters for lineage tracing of the cells contributing to disease initiation and progression provides a unique opportunity to dissect the timeline of disease, examining mechanisms of the metastatic process, as well as recovering primary and metastatic cells for identifying co-operating mutations that are necessary for progression of disease. PMID:24292676

Conditional deletion of p53 and Rb in the renin-expressing compartment of the pancreas leads to a highly penetrant metastatic pancreatic neuroendocrine carcinoma.

PubMed

Glenn, S T; Jones, C A; Sexton, S; LeVea, C M; Caraker, S M; Hajduczok, G; Gross, K W

2014-12-11

Efforts to model human pancreatic neuroendocrine tumors (PanNETs) in animals have been moderately successful, with minimal evidence for glucagonomas or metastatic spread. The renin gene, although classically associated with expression in the kidney, is also expressed in many other extrarenal tissues including the pancreas. To induce tumorigenesis within rennin-specific tissues, floxed alleles of p53 and Rb were selectively abrogated using Cre-recombinase driven by the renin promoter. The primary neoplasm generated is a highly metastatic islet cell carcinoma of the pancreas. Lineage tracing identifies descendants of renin-expressing cells as pancreatic alpha cells despite a lack of active renin expression in the mature pancreas. Both primary and metastatic tumors express high levels of glucagon; furthermore, an increased level of glucagon is found in the serum, identifying the pancreatic cancer as a functional glucagonoma. This new model is highly penetrant and exhibits robust frequency of metastases to the lymph nodes and the liver, mimicking human disease, and provides a useful platform for better understanding pancreatic endocrine differentiation and development, as well as islet cell carcinogenesis. The use of fluorescent reporters for lineage tracing of the cells contributing to disease initiation and progression provides an unique opportunity to dissect the timeline of disease, examining mechanisms of the metastatic process, as well as recovering primary and metastatic cells for identifying cooperating mutations that are necessary for progression of disease.

Prognostic relevance of aberrant DNA methylation in g1 and g2 pancreatic neuroendocrine tumors.

PubMed

Stefanoli, Michele; La Rosa, Stefano; Sahnane, Nora; Romualdi, Chiara; Pastorino, Roberta; Marando, Alessandro; Capella, Carlo; Sessa, Fausto; Furlan, Daniela

2014-01-01

The occurrence and clinical relevance of DNA hypermethylation and global hypomethylation in pancreatic neuroendocrine tumours (PanNETs) are still unknown. We evaluated the frequency of both epigenetic alterations in PanNETs to assess the relationship between methylation profiles and chromosomal instability, tumour phenotypes and prognosis. In a well-characterized series of 56 sporadic G1 and G2 PanNETs, methylation-sensitive multiple ligation-dependent probe amplification was performed to assess hypermethylayion of 33 genes and copy number alterations (CNAs) of 53 chromosomal regions. Long interspersed nucleotide element-1 (LINE-1) hypomethylation was quantified by pyrosequencing. Unsupervised hierarchical clustering allowed to identify a subset of 22 PanNETs (39%) exhibiting high frequency of gene-specific methylation and low CNA percentages. This tumour cluster was significantly associated with stage IV (p = 0.04) and with poor prognosis in univariable analysis (p = 0.004). LINE-1 methylation levels in PanNETs were significantly lower than in normal samples (p < 0.01) and were approximately normally distributed. 12 tumours (21%) were highly hypomethylated, showing variable levels of CNA. Interestingly, only 5 PanNETs (9%) were observed to show simultaneously LINE-1 hypomethylation and high frequency of gene-specific methylation. LINE-1 hypomethylation was strongly correlated with advanced stage (p = 0.002) and with poor prognosis (p < 0.0001). In the multivariable analysis, low LINE-1 methylation status and methylation clusters were the only independent significant predictors of outcome (p = 0.034 and p = 0.029, respectively). The combination of global DNA hypomethylation and gene hypermethylation analyses may be useful to define distinct subsets of PanNETs. Both alterations are common in PanNETs and could be directly correlated with tumour progression. © 2014 S. Karger AG, Basel.

Characterization of low active ghrelin ratio in patients with advanced pancreatic cancer.

PubMed

Miura, Tomofumi; Mitsunaga, Shuichi; Ikeda, Masafumi; Ohno, Izumi; Takahashi, Hideaki; Suzuki, Hidetaka; Irisawa, Ai; Kuwata, Takeshi; Ochiai, Atsushi

2018-05-18

Acyl ghrelin is an orexigenic peptide. Active ghrelin ratio, the ratio of acyl ghrelin to total ghrelin, has an important role in physiological functions and gastrointestinal symptoms. However, low active ghrelin ratio-related characteristics, gastrointestinal symptoms, and chemotherapy-induced gastrointestinal toxicity in patients with advanced pancreatic cancer have not been previously evaluated. The goal of this study was to identify low active ghrelin ratio-related factors in treatment-naïve advanced pancreatic cancer patients. Patients with treatment-naïve advanced pancreatic cancer were eligible for inclusion in this study. Active ghrelin ratio and clinical parameters of patients were prospectively recorded. Factors correlated with low active ghrelin ratio and survival were analyzed. In total, 92 patients were analyzed. Low active ghrelin ratio-related factors were advanced age (P < 0.01), severe appetite loss (P < 0.01), and decreased cholinesterase (P < 0.01). The adverse events of grade 2 or higher anorexia tended to increase in patients with low active ghrelin ratio. However, no differences were found in survival and body composition between low and high active ghrelin ratio groups. Low active ghrelin ratio was related to lack of appetite and low cholinesterase and tended to be related to anorexia grade 2 or higher in patients with treatment-naïve advanced pancreatic cancer.

The role of multimodal treatment in patients with advanced lung neuroendocrine tumors

PubMed Central

Ungaro, Antonio; Spada, Francesca; Cella, Chiara Alessandra; Pisa, Eleonora; Barberis, Massimo; Grana, Chiara; Zerini, Dario; Bertani, Emilio; Ribero, Dario; Funicelli, Luigi; Bonomo, Guido; Ravizza, Davide; Guarize, Juliana; De Marinis, Filippo; Petrella, Francesco; Del Signore, Ester; Pelosi, Giuseppe; Spaggiari, Lorenzo

2017-01-01

Lung neuroendocrine tumors (NETs) comprise typical (TC) and atypical carcinoids (AC). They represent the well differentiated (WD) or low/intermediate grade forms of lung neuroendocrine neoplasms (NENs). Unlike the lung poorly differentiated NENs, that are usually treated with chemotherapy, lung NETs can be managed with several different therapies, making a multidisciplinary interaction a key point. We critically discussed the multimodal clinical management of patients with advanced lung NETs. Provided that no therapeutic algorithm has been validate so far, each clinical case should be discussed within a NEN-dedicated multidisciplinary team. Among the systemic therapies available for metastatic lung NETs everolimus is the only approved drug, on the basis of the results of the phase III RADIANT-4 trial. Another phase III trial, the SPINET, is ongoing comparing lanreotide with placebo. Peptide receptor radionuclide therapy and chemotherapy were not studied within phase III trials for lung NETs, and they have been reported to be active within retrospective or phase II prospective studies. Temozolomide and oxaliplatin are two interesting chemotherapeutic agents in lung NETs. While some European Institutions were certificated as Centers of Excellence for gastroenteropancreatic NENs by the European Neuroendocrine Tumor Society (ENETS), an equivalent ENETS certification for lung NENs does not exist yet. Ideally a lung NEN-dedicated multidisciplinary tumor board should include NEN-dedicated medical oncologists, thoracic medical oncologist, thoracic surgeons, pathologists, interventional radiologists, endocrinologists, radiotherapists, interventional pneumologists, nuclear physician. PMID:29201453

Clinical outcome and long-term survival of 150 consecutive patients with pancreatic neuroendocrine tumors: A comprehensive analysis by the World Health Organization 2010 grading classification.

PubMed

Deng, Ben-Yuan; Liu, Fei; Yin, Si-Neng; Chen, An-Ping; Xu, Lin; Li, Bo

2018-06-01

The World Health Organization (WHO) has revised its grading system for pancreatic neuroendocrine tumors (PNETs) in 2010 into three main group, which has not been widely and comprehensively evaluated. We aimed to validate the clinical valve of this system associated with the clinical outcome and long-term survival when applied to PNETs, which were rare and heterogeneous. We retrospectively collected and analyzed the data of 150 consecutive patients with PNETs who underwent a resection. Sixty-four males and 86 females with PNETs were enrolled in our study. The clinical stage from I to IV by European Neuroendocrine Tumor Society were respectively defined in 53, 60, 19 and 18 patients. Seventy-two patients were pathologically diagnosed as neuroendocrine tumor G1 (NET G1), 48 as neuroendocrine tumor G2 (NET G2) and 30 as neuroendocrine carcinoma G3 (NEC G3). Patients with a radical resection obtained a notably higher overall survival (OS) than that of patients who underwent a palliative surgery (P=0.001). The 5-year OS of patients with NET G1 was significantly higher than that of patients with NET G2 (P=0.015) and NEC G3 (P<0.001); the comparison of OS for patients with NET G2 and NEC G3 was also statistically significant (P=0.005). In both univariate and multivariate analysis, clinical staging by ENETS (stage I and II vs. stage III and IV), resection (radical vs. palliative) and WHO 2010 grading classification (NET G1 and G2 vs. NEC G3) were validated to be independent predictors for the survivals of PNETs. The newly-updated WHO 2010 grading classification was prognostic for the OS of PNETs and could be widely adopted in clinical practice. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

[Neuroendocrine differentiation in prostate adenocarcinoma].

PubMed

Ramírez-Balderrama, Lázaro; López-Briones, Sergio; Daza-Benítez, Leonel; Macías, Maciste H; López-Gaytán, Teresa; Pérez-Vázquez, Victoriano

2013-01-01

The human prostate is a gland composed of many types of cells and extracellular components with specific functions. The stromal compartment includes nerve tissue, fibroblasts, lymphocytes, macrophages, endothelial cells, and smooth muscular cells. The epithelial compartment is composed of luminal epithelial cells, basal cells, and a lesser number of neuroendocrine cells, which are transcendental in growth regulation, differentiation, and secretory function. In prostate cancer, neuroendocrine cells replicate especially in high grade and advanced stage, and hormonally treated tumoral cells adopt characteristics that make them resistant to hormonal deprivation. Androgen receptors have a crucial role in tumorigenesis of prostate adenocarcinoma. Deprivation hormone therapy blocks the expression of androgen receptors in the prostatic epithelial cells. Neuroendocrine cells lack androgen receptors; their growth is hormonally independent and that is why deprivation hormonal therapy does not eliminate the neoplasic neuroendocrine cells. In contrast, these types of cells proliferate after therapy and make a paracrine network, stimulating the proliferation of androgen-independent neoplastic cells, which finally lead to tumoral recurrence. In this work we describe the neuroendocrine function in normal tissue and in prostatic adenocarcinoma, including neoplasic proliferation stimulation, invasion, apoptosis resistance, and angiogenesis, and describe some molecular pathways involved in this neuroendocrine differentiation.

Robotic enucleation of benign pancreatic tumors

PubMed Central

Ore, Ana Sofia; Barrows, Courtney E.; Solis-Velasco, Monica; Shaker, Jessica

2017-01-01

Robot-assisted enucleation provides the dual benefits of a minimally-invasive technique and pancreatic parenchymal conservation to selected patients with functional pancreatic neuroendocrine tumors (F-pNETs) and serous cystadenomas. Insulinomas, the most common F-pNETs, are ideal candidates for enucleation when <2 cm given the 80% probability of being benign. Current evidence suggests enucleation for the following: benign, isolated lesions with a distance between tumor and main pancreatic duct ≥3 mm (no focal stricture or dilation), insulinomas, gastrinomas <2 cm, and nonfunctional pancreatic neuroendocrine tumors (NF-pNETs) <1–2 cm and low Ki67 mitotic index. Minimally-invasive enucleation is an imaging-dependent procedure that requires recognizable anatomic landmarks for successful completion, including tumor proximity to the pancreatic duct as well as localization relative to major structures such as the gastroduodenal artery, bile duct, and portal vein. Tumor localization often mandates intraoperative ultrasound aided by duplex studies of intratumoral blood flow and frozen section confirmation. Five patients have undergone robot-assisted enucleation at Beth Israel Deaconess Medical Center between January 2014 and January 2017 with median tumor diameter of 1.3 cm (0.9–1.7 cm) located in the pancreatic head [2] and tail [3]. Surgical indications included insulinoma [2] and NF-pNETs [3]. Median operative time was 204 min (range, 137–347 min) and estimated blood loss of 50 mL. There were no conversions to open or transfusions. Robotic enucleation is a safe and feasible technique that allows parenchymal conservation in a minimally-invasive setting, reducing operative time and length of stay with equivalent pathological outcomes compared to open surgery. PMID:29302427

Identification and characterization of poorly differentiated invasive carcinomas in a mouse model of pancreatic neuroendocrine tumorigenesis.

PubMed

Hunter, Karen E; Quick, Marsha L; Sadanandam, Anguraj; Hanahan, Douglas; Joyce, Johanna A

2013-01-01

Pancreatic neuroendocrine tumors (PanNETs) are a relatively rare but clinically challenging tumor type. In particular, high grade, poorly-differentiated PanNETs have the worst patient prognosis, and the underlying mechanisms of disease are poorly understood. In this study we have identified and characterized a previously undescribed class of poorly differentiated PanNETs in the RIP1-Tag2 mouse model. We found that while the majority of tumors in the RIP1-Tag2 model are well-differentiated insulinomas, a subset of tumors had lost multiple markers of beta-cell differentiation and were highly invasive, leading us to term them poorly differentiated invasive carcinomas (PDICs). In addition, we found that these tumors exhibited a high mitotic index, resembling poorly differentiated (PD)-PanNETs in human patients. Interestingly, we identified expression of Id1, an inhibitor of DNA binding gene, and a regulator of differentiation, specifically in PDIC tumor cells by histological analysis. The identification of PDICs in this mouse model provides a unique opportunity to study the pathology and molecular characteristics of PD-PanNETs.

Gastric GIST with synchronous neuroendocrine tumour of the pancreas in a patient without neurofibromatosis type 1

PubMed Central

Tavares, Amelia Brandao; Viveiros, Fernando Arruda; Cidade, Cassilda Neves; Maciel, Jorge

2012-01-01

The gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract. These are rare tumours with an incidence of 15 new cases per million per year. The occurrence of neuroendocrine tumours of the pancreas is rare, representing 1–5% of pancreatic cancers, and it is estimated that its incidence does not exceed five to one million. GISTs are common in patients with neurofibromatosis type 1 (NF1); there are few reported cases of synchronous neuroendocrine tumours in these patients and most are pheochromocytomas. The case reports a 64-year-old woman referred to the General Surgery Outpatient for incidental finding of gastric and pancreatic tumours. She underwent a radical subtotal pancreatectomy + partial gastrectomy with jejunal transposition. The pathological examination revealed: gastric GISTs and a well-differentiated neuroendocrine carcinoma of the pancreas. This is the second case published so far of a patient with both tumours  and without NF1. Posterior studies must be performed to evaluate if some other genetic disorder is involved in these patients without NF1. PMID:22675144

Advances in counselling and surveillance of patients at risk for pancreatic cancer

PubMed Central

Brand, Randall E; Lerch, Markus M; Rubinstein, Wendy S; Neoptolemos, John P; Whitcomb, David C; Hruban, Ralph H; Brentnall, Teresa A; Lynch, Henry T; Canto, Marcia I

2007-01-01

Even with significant advances in imaging and our understanding of pancreatic cancer genetics, the survival rates for pancreatic cancer remain quite dismal. Although still at an early stage, there are efforts in place to develop surveillance and prevention strategies for people at high risk for pancreatic cancer. This comprehensive review article summarises the predispositions that put people at a high risk of developing pancreatic cancer and the current status in the counselling and surveillance of these people using not only available medical literature, but also incorporating international expert opinion. PMID:17872573

Management of advanced pancreatic cancer in daily clinical practice.

PubMed

Giuliani, Jacopo; Piacentini, Paolo; Bonetti, Andrea

2016-01-01

The aim of this outcome study was to evaluate the management of advanced pancreatic cancer in a real-world clinical practice; few such experiences have been reported in the literature. A retrospective analysis was performed of all consecutive patients with advanced pancreatic ductal adenocarcinoma followed at our medical oncology unit between January 2003 and December 2013. We evaluated 78 patients, mostly with metastatic disease (64.1%). Median follow-up was 10.77 months, by which time 74 patients (94.9%) had died. Median overall survival was 8.29 months. Median age was 67 years. In univariate analysis, pain at onset (p = 0.020), ECOG performance status (p<0.001), stage (p = 0.047), first-line chemotherapy (p<0.001), second-line chemotherapy (p<0.001) and weight loss at diagnosis (p = 0.029) were factors that had an impact on overall survival. In multivariate analysis, the presence of pain at onset (p = 0.043), stage (p = 0.003) and second-line chemotherapy (p = 0.004) were confirmed as independent prognostic factors. Our data, derived from daily clinical practice, confirmed advanced pancreatic cancer as an aggressive malignant disease with a very short expected survival. Second-line treatment seems to provide an advantage in terms of overall survival in patients who showed a partial response as their best response to first-line treatment.

Therapeutic benefit of selective inhibition of p110α PI3-kinase in pancreatic neuroendocrine tumors

PubMed Central

Soler, Adriana; Figueiredo, Ana M; Castel, Pau; Martin, Laura; Monelli, Erika; Angulo-Urarte, Ana; Milà-Guasch, Maria; Viñals, Francesc; Casanovas, Oriol

2017-01-01

Purpose Mutations in the PI3-kinase (PI3K) pathway occur in 16% of patients with pancreatic neuroendocrine tumors (PanNETs), which suggests that these tumors are an exciting setting for PI3K/AKT/mTOR pharmacological intervention. Everolimus, an mTOR inhibitor, is being used to treat patients with advanced PanNETs. However, resistance to mTOR targeted therapy is emerging partially due to the loss of mTOR-dependent feedback inhibition of AKT. In contrast, the response to PI3K inhibitors in PanNETs is unknown. Experimental Design In the present study, we assessed the frequency of PI3K pathway activation in human PanNETs and in RIP1-Tag2 mice, a preclinical tumor model of PanNETs, and we investigated the therapeutic efficacy of inhibiting PI3K in RIP1-Tag2 mice using a combination of pan (GDC-0941) and p110α selective (GDC-0326) inhibitors and isoform specific PI3K kinase-dead mutant mice. Results Human and mouse PanNETs showed enhanced pAKT, pPRAS40 and pS6 positivity compared to normal tissue. While treatment of RIP1-Tag2 mice with GDC-0941 led to reduced tumor growth with no impact on tumor vessels, the selective inactivation of the p110α PI3K isoform, either genetically or pharmacologically, reduced tumor growth as well as vascular area. Furthermore, GDC-0326 reduced the incidence of liver and lymph node (LN) metastasis compared to vehicle treated mice. We also demonstrated that tumor and stromal cells are implicated in the anti-tumor activity of GDC-0326 in RIP1-Tag2 tumors. Conclusion Our data provide a rationale for p110α selective intervention in PanNETs and unravel a new function of this kinase in cancer biology through its role in promoting metastasis. PMID:27225693

KI-67 heterogeneity in well differentiated gastro-entero-pancreatic neuroendocrine tumors: when is biopsy reliable for grade assessment?

PubMed

Grillo, Federica; Valle, Luca; Ferone, Diego; Albertelli, Manuela; Brisigotti, Maria Pia; Cittadini, Giuseppe; Vanoli, Alessandro; Fiocca, Roberto; Mastracci, Luca

2017-09-01

Ki-67 heterogeneity can impact on gastroenteropancreatic neuroendocrine tumor grade assignment, especially when tissue is scarce. This work is aimed at devising adequacy criteria for grade assessment in biopsy specimens. To analyze the impact of biopsy size on reliability, 360 virtual biopsies of different thickness and lengths were constructed. Furthermore, to estimate the mean amount of non-neoplastic tissue component present in biopsies, 28 real biopsies were collected, the non-neoplastic components (fibrosis and inflammation) quantified and the effective area of neoplastic tissue calculated for each biopsy. Heterogeneity of Ki-67 distribution, G2 tumors and biopsy size all play an important role in reducing the reliability of biopsy samples in Ki-67-based grade assignment. In particular in G2 cases, 59.9% of virtual biopsies downgraded the tumor and the smaller the biopsy, the more frequent downgrading occurs. In real biopsies the presence of non-neoplastic tissue reduced the available total area by a mean of 20%. By coupling the results from these two different approaches we show that both biopsy size and non-neoplastic component must be taken into account for biopsy adequacy. In particular, we can speculate that if the minimum biopsy area, necessary to confidently (80% concordance) grade gastro-entero-pancreatic neuroendocrine tumors on virtual biopsies ranges between 15 and 30 mm 2 , and if real biopsies are on average composed of only 80% of neoplastic tissue, then biopsies with a surface area not <12 mm 2 should be performed; using 18G needles, this corresponds to a minimum total length of 15 mm.

Afatinib Dimaleate and Capecitabine in Treating Patients With Advanced Refractory Solid Tumors, Pancreatic Cancer or Biliary Cancer

ClinicalTrials.gov

2017-10-26

Advanced Malignant Solid Neoplasm; Bile Duct Carcinoma; Recurrent Malignant Solid Neoplasm; Recurrent Pancreatic Carcinoma; Stage III Pancreatic Cancer AJCC v6 and v7; Stage IVA Pancreatic Cancer; Stage IVB Pancreatic Cancer

Long Noncoding RNA MEG3 Is an Epigenetic Determinant of Oncogenic Signaling in Functional Pancreatic Neuroendocrine Tumor Cells

PubMed Central

Iyer, Sucharitha; Modali, Sita D.

2017-01-01

ABSTRACT The long noncoding RNA (lncRNA) MEG3 is significantly downregulated in pancreatic neuroendocrine tumors (PNETs). MEG3 loss corresponds with aberrant upregulation of the oncogenic hepatocyte growth factor (HGF) receptor c-MET in PNETs. Meg3 overexpression in a mouse insulin-secreting PNET cell line, MIN6, downregulates c-Met expression. However, the molecular mechanism by which MEG3 regulates c-MET is not known. Using chromatin isolation by RNA purification and sequencing (ChIRP-Seq), we identified Meg3 binding to unique genomic regions in and around the c-Met gene. In the absence of Meg3, these c-Met regions displayed distinctive enhancer-signature histone modifications. Furthermore, Meg3 relied on functional enhancer of zeste homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2), to inhibit c-Met expression. Another mechanism of lncRNA-mediated regulation of gene expression utilized triplex-forming GA-GT rich sequences. Transfection of such motifs from Meg3 RNA, termed triplex-forming oligonucleotides (TFOs), in MIN6 cells suppressed c-Met expression and enhanced cell proliferation, perhaps by modulating other targets. This study comprehensively establishes epigenetic mechanisms underlying Meg3 control of c-Met and the oncogenic consequences of Meg3 loss or c-Met gain. These findings have clinical relevance for targeting c-MET in PNETs. There is also the potential for pancreatic islet β-cell expansion through c-MET regulation to ameliorate β-cell loss in diabetes. PMID:28847847

99mTc-EDDA/HYNIC-Tyr(3)-octreotide for staging and follow-up of patients with neuroendocrine gastro-entero-pancreatic tumors.

PubMed

Gabriel, M; Muehllechner, P; Decristoforo, C; von Guggenberg, E; Kendler, D; Prommegger, R; Profanter, C; Moncayo, R; Virgolini, I

2005-09-01

To evaluate the use of 99mTc-EDDA-hydrazinonicotinyl-Tyr3-octreotide (Tc-TOC) for staging and follow-up of neuroendocrine gastro-entero-pancreatic (GEP) tumors with special focus on the acquisition protocol including single photon emission computed tomography (SPECT). Eighty-eight patients (37 female, 51 male; age range: 16 to 81 years; mean age: 56.3 years) were studied: 42 patients for staging after initial histological confirmation and 46 patients during post-therapy follow-up. An average activity of 400 MBq of the radiopharmaceutical was injected. All tumors originated from neuroendocrine tissue of the gastroenteropancreatic tract. Whole body scintigrams at 4 h postinjection and SPECT of the abdomen were obtained in all patients. Additional planar images of the abdomen were acquired at 2 h after injection in 68 patients. The Tc-TOC scan result was true-positive in 56 patients, true-negative in 17, false-negative in 14, and false-positive in 1 patient. The false-positive finding was caused by a colonic adenoma. Overall, a scan sensitivity of 80% (56/70 patients), specificity of 94.4% (17/18 patients) and accuracy of 82.9% (73/88 patients) were calculated on patient basis. In total, Tc-TOC detected 357 foci in 69 patients. In 7 patients equivocal findings were observed in the bowel at 4 h postinjection without corresponding tracer uptake in the scan 2 h earlier, meaning that these abnormal findings were correctly classified as non-malignant. In addition to planar views, SPECT revealed further 62 lesions. Tc-TOC with one-day, dual-time acquisition protocol is an accurate staging procedure in patients with neuroendocrine GEP tumors. SPECT shows high sensitivity for detection of abdominal lesions, while earlier images improve the reliability of abnormal abdominal findings.

Hotspot detection in pancreatic neuroendocrine tumors: density approximation by α-shape maps

NASA Astrophysics Data System (ADS)

Niazi, M. K. K.; Hartman, Douglas J.; Pantanowitz, Liron; Gurcan, Metin N.

2016-03-01

The grading of neuroendocrine tumors of the digestive system is dependent on accurate and reproducible assessment of the proliferation with the tumor, either by counting mitotic figures or counting Ki-67 positive nuclei. At the moment, most pathologists manually identify the hotspots, a practice which is tedious and irreproducible. To better help pathologists, we present an automatic method to detect all potential hotspots in neuroendocrine tumors of the digestive system. The method starts by segmenting Ki-67 positive nuclei by entropy based thresholding, followed by detection of centroids for all Ki-67 positive nuclei. Based on geodesic distance, approximated by the nuclei centroids, we compute two maps: an amoeba map and a weighted amoeba map. These maps are later combined to generate the heat map, the segmentation of which results in the hotspots. The method was trained on three and tested on nine whole slide images of neuroendocrine tumors. When evaluated by two expert pathologists, the method reached an accuracy of 92.6%. The current method does not discriminate between tumor, stromal and inflammatory nuclei. The results show that α-shape maps may represent how hotspots are perceived.

[Latest advances in acute pancreatitis].

PubMed

de-Madaria, Enrique

2015-09-01

The present article analyses the main presentations on acute pancreatitis at Digestive Disease Week 2015. Arterial pseudoaneurysm is an uncommon complication of acute pancreatitis (incidence 0.7%) and mortality from this cause is currently anecdotal. Diabetes mellitus has little impact on the clinical course of acute pancreatitis, unlike cirrhosis, which doubles the risk of mortality. Intake of unsaturated fat could be associated with an increased severity of acute pancreatitis and is a confounding factor in studies evaluating the relationship between obesity and morbidity and mortality. PET-CT (positron emission tomography-computed tomography) could be a non-invasive tool to detect infection of collections in acute pancreatitis. Peripancreatic fat necrosis is less frequent than pancreatic fat necrosis and is associated with a better clinical course. If the clinical course is poor, increasing the calibre of the percutaneous drains used in the treatment of infected necrosis can avoid surgery in 20% of patients. The use of low molecular-weight heparin in moderate or severe pancreatitis could be associated with a better clinical course, specifically with a lower incidence of necrosis. In acute recurrent pancreatitis, simvastatin is a promising drug for prophylaxis of new episodes of acute pancreatitis. Nutritional support through a nasogastric tube does not improve clinical course compared with oral nutrition. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

Autoimmune Pancreatitis Can Transform Into Chronic Features Similar to Advanced Chronic Pancreatitis With Functional Insufficiency Following Severe Calcification.

PubMed

Kanai, Keita; Maruyama, Masahiro; Kameko, Fumiko; Kawasaki, Kenji; Asano, Junpei; Oguchi, Takaya; Watanabe, Takayuki; Ito, Tetsuya; Muraki, Takashi; Hamano, Hideaki; Matsumoto, Akihiro; Arakura, Norikazu; Kawa, Shigeyuki

2016-09-01

Because several studies for autoimmune pancreatitis (AIP) have revealed pancreatic calcification resembling that in chronic pancreatitis (CP), we sought to clarify whether AIP could transform into chronic features similar to advanced CP with severe pancreatic dysfunction. Pancreatic functions of 92 AIP patients, 47 definite CP patients, and 30 healthy controls were assessed by fecal elastase-1 concentration (FEC), fasting immunoreactive insulin (IRI), and homeostatic model assessment (HOMA)-R. The 92 AIP patients included 17 (18%) with severe calcification (SC) and 75 without. The FEC levels in AIP and CP patients were significantly lower than that in controls. Exocrine insufficiency defined as FEC less than 200 μg/g was 39% in AIP without SC, 56% in AIP with SC, and 74% in CP. Fasting IRI and C-peptide reactivity values in CP were significantly lower than those in AIP, with no significant differences between AIP subgroups. The prevalence of endocrine insufficiency according to fasting IRI less than 5.0 μU/mL was 26% in AIP without SC, 31% in AIP with SC, and 59% in CP, respectively. HOMA-R values were significantly higher in all AIP groups than in CP. Autoimmune pancreatitis can transform into a state of pancreatic insufficiency after calcification that is less severe than that in definite CP.

Multicenter retrospective analysis of systemic chemotherapy for advanced neuroendocrine carcinoma of the digestive system.

PubMed

Yamaguchi, Tomohiro; Machida, Nozomu; Morizane, Chigusa; Kasuga, Akiyoshi; Takahashi, Hideaki; Sudo, Kentaro; Nishina, Tomohiro; Tobimatsu, Kazutoshi; Ishido, Kenji; Furuse, Junji; Boku, Narikazu; Okusaka, Takuji

2014-09-01

This study analyzed outcomes of systemic chemotherapy for advanced neuroendocrine carcinoma (NEC) of the digestive system. Clinical data from 258 patients with unresectable or recurrent NEC of the gastrointestinal tract (GI) or hepato-biliary-pancreatic system (HBP), who received chemotherapy, were collected from 23 Japanese institutions and analyzed retrospectively. Patients had primary sites in the esophagus (n = 85), stomach (n = 70), small bowel (n = 6), colorectum (n = 31), hepato-biliary system (n = 31) and pancreas (n = 31). Median overall survival (OS) was 13.4 months the esophagus, 13.3 months for the stomach, 29.7 months for the small bowel, 7.6 months for the colorectum, 7.9 months for the hepato-biliary system and 8.5 months for the pancreas. Irinotecan plus cisplatin (IP) and etoposide plus cisplatin (EP) were most commonly selected for GI-NEC and HBP-NEC. For patients treated with IP/EP (n = 160/46), the response rate was 50/28% and median OS was 13.0/7.3 months. Multivariate analysis among patients treated with IP or EP showed that the primary site (GI vs HBP; hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.35-0.97) and baseline serum lactate dehydrogenase levels (not elevated vs elevated; HR 0.65, 95% CI 0.46-0.94) were independent prognostic factors for OS, while the efficacy of IP was slightly better than for EP (HR 0.80, 95% CI 0.48-1.33; P = 0.389). IP and EP are the most common treatment regimens for NEC of the digestive system. HBP primary sites and elevated lactate dehydrogenase levels are unfavorable prognostic factors for survival. A randomized controlled trial is required to establish the appropriate chemotherapy regimen for advanced NEC of the digestive system. This study was registered at UMIN as trial number 000005176. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Incidence and prognostic value of serotonin secretion in pancreatic neuroendocrine tumours.

PubMed

Zandee, Wouter T; van Adrichem, Roxanne C; Kamp, Kimberly; Feelders, Richard A; van Velthuysen, Marie-Louise F; de Herder, Wouter W

2017-08-01

Serotonin secretion occurs in approximately 1%-4% of patients with a pancreatic neuroendocrine tumour (PNET), but the incidence is not well defined. The aim of this study was to determine the incidence of serotonin secretion with and without carcinoid syndrome and the prognostic value for overall survival (OS). Data were collected from 255 patients with a PNET if 24-hours urinary 5-hydroxyindoleacetic acid excretion (5-HIAA) was assessed. Patients were diagnosed with serotonin secretion if 24-hours urinary 5-HIAA excretion was more than 3× the upper limit of normal (ULN) of 50 μmol/24 hours during follow-up. The effect of serotonin secretion on OS was estimated with uni- and multivariate analyses using a Cox regression. Two (0.8%) patients were diagnosed with carcinoid syndrome, and another 20 (7.8%) had a serotonin-secreting PNET without symptoms. These patients mostly had ENETS stage IV disease with high chromogranin A (CgA). Serotonin secretion was a negative prognostic factor in univariate analysis (HR 2.2, 95% CI: 1.27-3.81), but in multivariate analysis, only CgA>10× ULN (HR: 1.81, 95% CI: 1.10-2.98) and neuron-specific enolase (NSE) >ULN (HR: 3.51, 95% CI: 2.26-5.46) were predictors for OS. Immunohistochemical staining for serotonin was positive in 28.6% of serotonin-secreting PNETs (one with carcinoid syndrome) and negative in all controls. Carcinoid syndrome is rare in patients with a PNET, but serotonin secretion occurs often. This is a negative prognostic factor for OS, but after correction for CgA and NSE, it is no longer a predictor and probably only a "not-so innocent bystander" in patients with high tumour burden. © 2017 John Wiley & Sons Ltd.

Preventive medicine for von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors.

PubMed

Krauss, Tobias; Ferrara, Alfonso Massimiliano; Links, Thera P; Wellner, Ulrich; Bancos, Irina; Kvachenyuk, Andrey; Villar Gómez de Las Heras, Karina; Yukina, Marina; Petrov, Roman; Bullivant, Garrett; von Duecker, Laura; Jadhav, Swati S; Ploeckinger, Ursula; Welin, Staffan; Schalin-Jantti, Camilla; Gimm, Oliver; Pfeifer, Marija; Ngeow, Joanne; Hasse-Lazar, Kornelia; Sanso, Gabriela; Qi, Xiao-Ping; Ugurlu, Umit; Diaz, Rene Eduardo; Wohllk, Nelson; Peczkowska, Mariola; Aberle, Jens; Lourenço, Delmar Muniz; Pereira, Maria Adelaide; Fragoso, Maria Candida Barisson Villares; Hoff, Ana O; Almeida, Madson Queiroz; Violante, Alice H D; Quidute, Ana R P; Zhang, Zheiwei; Recasens, Monica; Robles Diaz, Luis; Kunavisarut, Tada; Wannachalee, Taweesak; Sirinvaravong, Sirinart; Jonasch, Eric; Grozinsky-Glasberg, Simona; Fraenkel, Merav; Beltsevich, Dmitry; Egorov, Viacheslav I; Bausch, Dirk; Schott, Matthias; Tiling, Nikolaus; Pennelli, Gianmaria; Zschiedrich, Stefan; Därr, Roland; Ruf, Juri; Denecke, Timm; Link, Karl-Heinrich; Zovato, Stefania; von Dobschuetz, Ernst; Yaremchuk, Svetlana; Amthauer, Holger; Makay, Ozer; Patocs, Attila; Walz, Martin K; Huber, Tobias B; Seufert, Jochen; Hellman, Per; Kim, Raymond H; Kuchinskaya, Ekaterina; Schiavi, Francesca; Malinoc, Angelica; Reisch, Nicole; Jarzab, Barbara; Barontini, Marta; Januszewicz, Andrzej; Shah, Nalini; Young, William; Opocher, Giuseppe; Eng, Charis; Neumann, Hartmut P H; Bausch, Birke

2018-05-10

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2,330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P<0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P=0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cutoff ≥2.8 cm, 44% and 91% for TVDT cutoff of ≤24 months). In 117/273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8cm vs ≥2.8 cm (94% vs 85% by 10 years; P=0.020; 80% vs 50% at 10 years; P=0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.

Alternative lengthening of telomeres predicts site of origin in neuroendocrine tumor liver metastases.

PubMed

Dogeas, Epameinondas; Karagkounis, Georgios; Heaphy, Christopher M; Hirose, Kenzo; Pawlik, Timothy M; Wolfgang, Christopher L; Meeker, Alan; Hruban, Ralph H; Cameron, John L; Choti, Michael A

2014-04-01

The determination of the primary tumor origin in patients with neuroendocrine tumor liver metastases (NELM) can pose a considerable management challenge. Recent studies have shown that the alternative lengthening of telomeres (ALT) is prevalent in some human tumors, including pancreatic neuroendocrine tumors (PanNET), and can be useful in predicting tumor biology. In this study, we aimed to evaluate the use of ALT as a biomarker in patients with NELM, in particular to predict the site of origin of metastases. Tissue microarrays (TMAs) were constructed using tumor tissue from NELM patients undergoing liver resection between 1998 and 2010. These included 43 PanNET and 47 gastrointestinal carcinoid tumors. The TMAs were tested for ALT using telomere-specific fluorescent in situ hybridization. The association between ALT positivity and clinicopathologic features and long-term outcomes was investigated. Alternative lengthening of telomeres was positive (ALT+) in 26 (29%) of the 90 tumors included in the TMAs. Pancreatic neuroendocrine tumors were ALT+ in 56% of patients, compared with only 4% ALT+ among gastrointestinal carcinoid tumors (p < 0.001). The specificity of ALT for detecting pancreatic origin was 96% and the positive predictive value was 92%, and sensitivity was 56% and the negative predictive value was 70%. Additionally, ALT was associated with the pattern of metastatic disease: ALT+ NELM were more likely to have oligometastases (p = 0.001) and less likely to be bilateral in distribution (p = 0.05) than were ALT tumors. In addition, ALT+ was associated with improved prognosis in the PanNET patient population. Alternative lengthening of telomeres was found to be a useful biomarker in patients with NELM. This marker can be helpful in guiding therapy by identifying the site of origin in patients in whom the primary site is unknown. Copyright © 2014 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Predictive factors of response to mTOR inhibitors in neuroendocrine tumours.

PubMed

Zatelli, Maria Chiara; Fanciulli, Giuseppe; Malandrino, Pasqualino; Ramundo, Valeria; Faggiano, Antongiulio; Colao, Annamaria

2016-03-01

Medical treatment of neuroendocrine tumours (NETs) has drawn a lot of attention due to the recent demonstration of efficacy of several drugs on progression-free survival, including somatostatin analogs, small tyrosine kinase inhibitors and mTOR inhibitors (or rapalogs). The latter are approved as therapeutic agents in advanced pancreatic NETs and have been demonstrated to be effective in different types of NETs, with variable efficacy due to the development of resistance to treatment. Early detection of patients that may benefit from rapalogs treatment is of paramount importance in order to select the better treatment and avoid ineffective and expensive treatments. Predictive markers for therapeutic response are under intensive investigation, aiming at a tailored patient management and more appropriate resource utilization. This review summarizes the available data on the tissue, circulating and imaging markers that are potentially predictive of rapalog efficacy in NETs. © 2016 Society for Endocrinology.

A Continuation Study Using Sunitinib Malate For Patients Leaving Treatment On A Previous Sunitinib Study.

ClinicalTrials.gov

2015-10-07

Metastatic Breast Cancer [F]; Advanced Breast Cancer; Metastatic Castration Resistant Prostate Cancer; Metastatic Renal Cell Cancer; Non-Small Cell Lung Cancer; Thyroid Cancer; Advanced/Metastatic Non-Small Cell Lung Cancer; Advanced Gastric Cancer; Gastrointestinal Stromal Tumor; Hepatocellular Carcinoma; Pancreatic Islet Cell Carcinoma; Pancreatic Neuroendocrine Tumor

New therapeutic directions for advanced pancreatic cancer: cell cycle inhibitors, stromal modifiers and conjugated therapies.

PubMed

Matera, Robert; Saif, Muhammad Wasif

2017-09-01

Pancreatic adenocarcinoma is a devastating malignancy with an extremely poor prognosis. These tumors progress rapidly and somewhat silently with few specific symptoms and are relatively resistant to chemotherapeutic agents. Many agents, including cell cycle inhibitors, are under development for the treatment of this cancer for which there are disappointingly few treatment options. Areas covered: Here we outline the existing approved treatments for advanced pancreatic disease and discuss a range of novel therapies currently under development including cell cycle inhibitors, stromal modifiers and conjugated therapies. We also describe the current state of the pancreatic cancer therapeutics market both past and future. Expert opinion: Despite the recent explosion of novel therapies with an array of unique targets, the core treatment of pancreatic cancer still with traditional cytotoxic agents with a few exceptions. However, as these novel treatments move through the pipeline, we are hopeful that there will soon be a number of effective options for patients with advanced pancreatic cancer.

Fast neutron irradiation for locally advanced pancreatic cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, F.P.; Schein, P.S.; MacDonald, J.S.

1981-11-01

Nineteen patients with locally advanced pancreatic cancer and one patient with islet cell cancer were treated with 1700-1500 neutron rad alone or in combination with 5-fluorouracil to exploit the theoretic advantages of higher linear energy of transfer, and lower oxygen enhancement ratio of neutrons. Only 5 of 14 (36%) obtained partial tumor regression. The median survival for all patients with pancreatic cancer was 6 months, which is less than that reported with 5-fluorouracil and conventional photon irradiation. Gastrointestinal toxicity was considerable; hemorhagic gastritis in five patients, colitis in two and esophagitis in one. One patient developed radiation myelitis. We therefore,more » caution any enthusiasm for this modality of therapy until clear evidence of a therapeutic advantage over photon therapy is demonstrated in controlled clinical trials.« less

Contemporary strategies to improve the outcome in locally advanced pancreatic cancer.

PubMed

Schneider, Rick; Späth, Christoph; Nitsche, Ulrich; Erkan, Mert; Kleeff, Jörg

2017-10-01

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an overall 5-year survival rate of less than 7%. After many years of basic and clinical research efforts, pancreatic cancer patients presenting with locally advanced, unresectable tumors remain a therapeutic challenge. Despite the lack of high quality randomized controlled trials, perioperative/neoadjuvant treatment strategies seem to be beneficial in these patients. At present the FOLFIRINOX regimen, which was established in the palliative setting, is increasingly recognized as the backbone of neoadjuvant therapy for locally advanced PDAC. Surgical resection follows the same principles and guidelines as upfront surgery specifically regarding the extent of resection including lymphadenectomy, vascular resections and multivisceral resections. Because of the limited diagnostic accuracy of restaging after neoadjuvant treatment, an adjusted intraoperative strategy is necessary to minimize the risk of debulking procedures and maximize the chance of a potential curative resection. Locally advanced PDAC requires a multidisciplinary and individualized treatment approach, and further research efforts for novel and innovative therapies. This article provides an updated overview on strategies to improve the outcome in locally advanced PDAC.

Therapeutic Benefit of Selective Inhibition of p110α PI3-Kinase in Pancreatic Neuroendocrine Tumors.

PubMed

Soler, Adriana; Figueiredo, Ana M; Castel, Pau; Martin, Laura; Monelli, Erika; Angulo-Urarte, Ana; Milà-Guasch, Maria; Viñals, Francesc; Baselga, Jose; Casanovas, Oriol; Graupera, Mariona

2016-12-01

Mutations in the PI3K pathway occur in 16% of patients with pancreatic neuroendocrine tumors (PanNETs), which suggests that these tumors are an exciting setting for PI3K/AKT/mTOR pharmacologic intervention. Everolimus, an mTOR inhibitor, is being used to treat patients with advanced PanNETs. However, resistance to mTOR-targeted therapy is emerging partially due to the loss of mTOR-dependent feedback inhibition of AKT. In contrast, the response to PI3K inhibitors in PanNETs is unknown. In the current study, we assessed the frequency of PI3K pathway activation in human PanNETs and in RIP1-Tag2 mice, a preclinical tumor model of PanNETs, and we investigated the therapeutic efficacy of inhibiting PI3K in RIP1-Tag2 mice using a combination of pan (GDC-0941) and p110α-selective (GDC-0326) inhibitors and isoform-specific PI3K kinase-dead-mutant mice. Human and mouse PanNETs showed enhanced pAKT, pPRAS40, and pS6 positivity compared with normal tissue. Although treatment of RIP1-Tag2 mice with GDC-0941 led to reduced tumor growth with no impact on tumor vessels, the selective inactivation of the p110α PI3K isoform, either genetically or pharmacologically, reduced tumor growth as well as vascular area. Furthermore, GDC-0326 reduced the incidence of liver and lymph node metastasis compared with vehicle-treated mice. We also demonstrated that tumor and stromal cells are implicated in the antitumor activity of GDC-0326 in RIP1-Tag2 tumors. Our data provide a rationale for p110α-selective intervention in PanNETs and unravel a new function of this kinase in cancer biology through its role in promoting metastasis. Clin Cancer Res; 22(23); 5805-17. ©2016 AACR. ©2016 American Association for Cancer Research.

[Chemotherapy for GI and pancreatic NETs].

PubMed

Doi, Toshihiko

2013-07-01

Neuroendocrine tumors(NETs)describe a heterogeneous group of tumors with a wide range of morphologic, functional, and behavioral characteristics. Pancreatic neuroendocrine tumors(pNET)are a subset of NETs which are increasing in incidence and prevalence. These tumors are generally slow growing and behave in an indolent fashion. However, when these tumors spread they can be life threatening and difficult to treat with current modalities. Recently, the basic treatment for pNET was changed with the approval of two targeted agents, sunitinib and everolimus. Clinical trials conducting various combinations of somatostatin analogues, mTOR inhibitors, tyrosine kinase inhibitors, and cytotoxic agents are ongoing under-evaluation, and a multitargeted approach to therapy will translate into improved patient outcomes.

Irreversible electroporation of stage 3 locally advanced pancreatic cancer: optimal technique and outcomes

PubMed Central

2015-01-01

Objective Irreversible electroporation (IRE) of stage 3 pancreatic adenocarcinoma has been used to provide quality of life time in patients who have undergone appropriate induction therapy. The optimal technique has been reported within the literature, but not in video form. IRE of locally advanced pancreatic cancer is technically demanding requiring precision ultrasound use for continuous imaging in multiple needle placements and during IRE energy delivery. Methods Appropriate patients with locally advanced pancreatic cancer should have undergone appropriate induction chemotherapy for a reasonable duration. The safe and effective technique for irreversible electroporation is preformed through an open approach with the emphasis on intra-operative ultrasound and intra-operative electroporation management. Results The technique of open irreversible electroporation of the pancreas involves bracketing the target tumor with IRE probes and any and all invaded vital structures including the celiac axis, superior mesenteric artery (SMA), superior mesenteric-portal vein, and bile duct with continuous intraoperative ultrasound imaging through a caudal to cranial approach. Optimal IRE delivery requires a change in amperage of at least 12 amps from baseline tissue conductivity in order to achieve technical success. Multiple pull-backs are necessary since the IRE ablation probe lengths are 1 cm and thus needed to achieve technical success along the caudal to cranial plane. Conclusions Irreversible electroporation in combination with multi-modality therapy for locally advanced pancreatic carcinoma is feasible for appropriate patients with locally advanced cancer. Technical demands are high and require the highest quality ultrasound for precise spacing measurements and optimal delivery to ensure adequate change in tissue resistance. PMID:29075594

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD.

PubMed

Cortez, Eliane; Gladh, Hanna; Braun, Sebastian; Bocci, Matteo; Cordero, Eugenia; Björkström, Niklas K; Miyazaki, Hideki; Michael, Iacovos P; Eriksson, Ulf; Folestad, Erika; Pietras, Kristian

2016-02-16

Intratumoral heterogeneity is an inherent feature of most human cancers and has profound implications for cancer therapy. As a result, there is an emergent need to explore previously unmapped mechanisms regulating distinct subpopulations of tumor cells and to understand their contribution to tumor progression and treatment response. Aberrant platelet-derived growth factor receptor beta (PDGFRβ) signaling in cancer has motivated the development of several antagonists currently in clinical use, including imatinib, sunitinib, and sorafenib. The discovery of a novel ligand for PDGFRβ, platelet-derived growth factor (PDGF)-DD, opened the possibility of a previously unidentified signaling pathway involved in tumor development. However, the precise function of PDGF-DD in tumor growth and invasion remains elusive. Here, making use of a newly generated Pdgfd knockout mouse, we reveal a functionally important malignant cell heterogeneity modulated by PDGF-DD signaling in pancreatic neuroendocrine tumors (PanNET). Our analyses demonstrate that tumor growth was delayed in the absence of signaling by PDGF-DD. Surprisingly, ablation of PDGF-DD did not affect the vasculature or stroma of PanNET; instead, we found that PDGF-DD stimulated bulk tumor cell proliferation by induction of paracrine mitogenic signaling between heterogeneous malignant cell clones, some of which expressed PDGFRβ. The presence of a subclonal population of tumor cells characterized by PDGFRβ expression was further validated in a cohort of human PanNET. In conclusion, we demonstrate a previously unrecognized heterogeneity in PanNET characterized by signaling through the PDGF-DD/PDGFRβ axis.

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

PubMed Central

Cortez, Eliane; Gladh, Hanna; Braun, Sebastian; Bocci, Matteo; Cordero, Eugenia; Björkström, Niklas K.; Miyazaki, Hideki; Michael, Iacovos P.; Eriksson, Ulf; Folestad, Erika; Pietras, Kristian

2016-01-01

Intratumoral heterogeneity is an inherent feature of most human cancers and has profound implications for cancer therapy. As a result, there is an emergent need to explore previously unmapped mechanisms regulating distinct subpopulations of tumor cells and to understand their contribution to tumor progression and treatment response. Aberrant platelet-derived growth factor receptor beta (PDGFRβ) signaling in cancer has motivated the development of several antagonists currently in clinical use, including imatinib, sunitinib, and sorafenib. The discovery of a novel ligand for PDGFRβ, platelet-derived growth factor (PDGF)-DD, opened the possibility of a previously unidentified signaling pathway involved in tumor development. However, the precise function of PDGF-DD in tumor growth and invasion remains elusive. Here, making use of a newly generated Pdgfd knockout mouse, we reveal a functionally important malignant cell heterogeneity modulated by PDGF-DD signaling in pancreatic neuroendocrine tumors (PanNET). Our analyses demonstrate that tumor growth was delayed in the absence of signaling by PDGF-DD. Surprisingly, ablation of PDGF-DD did not affect the vasculature or stroma of PanNET; instead, we found that PDGF-DD stimulated bulk tumor cell proliferation by induction of paracrine mitogenic signaling between heterogeneous malignant cell clones, some of which expressed PDGFRβ. The presence of a subclonal population of tumor cells characterized by PDGFRβ expression was further validated in a cohort of human PanNET. In conclusion, we demonstrate a previously unrecognized heterogeneity in PanNET characterized by signaling through the PDGF-DD/PDGFRβ axis. PMID:26831065

Heterogeneity for IGF-II production maintained by public goods dynamics in neuroendocrine pancreatic cancer.

PubMed

Archetti, Marco; Ferraro, Daniela A; Christofori, Gerhard

2015-02-10

The extensive intratumor heterogeneity revealed by sequencing cancer genomes is an essential determinant of tumor progression, diagnosis, and treatment. What maintains heterogeneity remains an open question because competition within a tumor leads to a strong selection for the fittest subclone. Cancer cells also cooperate by sharing molecules with paracrine effects, such as growth factors, and heterogeneity can be maintained if subclones depend on each other for survival. Without strict interdependence between subclones, however, nonproducer cells can free-ride on the growth factors produced by neighboring producer cells, a collective action problem known in game theory as the "tragedy of the commons," which has been observed in microbial cell populations. Here, we report that similar dynamics occur in cancer cell populations. Neuroendocrine pancreatic cancer (insulinoma) cells that do not produce insulin-like growth factor II (IGF-II) grow slowly in pure cultures but have a proliferation advantage in mixed cultures, where they can use the IGF-II provided by producer cells. We show that, as predicted by evolutionary game theory, producer cells do not go extinct because IGF-II acts as a nonlinear public good, creating negative frequency-dependent selection that leads to a stable coexistence of the two cell types. Intratumor cell heterogeneity can therefore be maintained even without strict interdependence between cell subclones. Reducing the amount of growth factors available within a tumor may lead to a reduction in growth followed by a new equilibrium, which may explain relapse in therapies that target growth factors.

[Neuroendocrine prostate cancer: Natural history, molecular features, therapeutic management and future directions].

PubMed

Campedel, Luca; Kossaï, Myriam; Blanc-Durand, Paul; Rouprêt, Morgan; Seisen, Thomas; Compérat, Eva; Spano, Jean-Philippe; Malouf, Gabriel

2017-09-01

Neuroendocrine prostate cancer is a rare malignancy with a an adverse prognostic. Histologically, It can be pure (small cells or large cells neuroendocrine carcinoma) or mixed with a adenocarcinoma component. Rarely diagnosed de novo, neuroendocrine prostate cancer is generally associated with advanced stage disease resistant to castration. As such, this histological subtype could represent an aggressive evolution of prostatic adenocarcinoma, through the epithelio-neuroendocrine transdifferentiation mechanism (phenomenon of lineage plasticity). Nonetheless, neuroendocrine prostate cancer is a heterogeneous malignancy with multiple histopathological variants showing distinct clinical features. The broad variety of molecular analyses could help to understand the ontogeny of this histological subtype and its signaling pathways. This may also allow identifying diagnostic and prognostic biomarkers as well as potential molecular targets. However, treatment options are currently limited and consist only in platinium-based chemotherapy for advanced stage disease. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Percutaneous Irreversible Electroporation of Locally Advanced Pancreatic Carcinoma Using the Dorsal Approach: A Case Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Scheffer, Hester J., E-mail: hj.scheffer@vumc.nl; Melenhorst, Marleen C. A. M., E-mail: m.melenhorst@vumc.nl; Vogel, Jantien A., E-mail: j.a.vogel@amc.uva.nl

Irreversible electroporation (IRE) is a novel image-guided ablation technique that is increasingly used to treat locally advanced pancreatic carcinoma (LAPC). We describe a 67-year-old male patient with a 5 cm stage III pancreatic tumor who was referred for IRE. Because the ventral approach for electrode placement was considered dangerous due to vicinity of the tumor to collateral vessels and duodenum, the dorsal approach was chosen. Under CT-guidance, six electrodes were advanced in the tumor, approaching paravertebrally alongside the aorta and inferior vena cava. Ablation was performed without complications. This case describes that when ventral electrode placement for pancreatic IRE is impaired,more » the dorsal approach could be considered alternatively.« less

Advances in the Diagnosis of Neuroendocrine Neoplasms.

PubMed

Kulkarni, Harshad R; Singh, Aviral; Baum, Richard P

2016-09-01

Somatostatin receptor PET/CT using (68)Ga-labeled somatostatin analogs, is a mainstay for the evaluation of the somatostatin receptor status in neuroendocrine neoplasms. In addition, the assessment of glucose metabolism by (18)F-FDG PET/CT at diagnosis can overcome probable shortcomings of histopathologic grading. This offers a systematic theranostic approach for the management of neuroendocrine neoplasms, that is, patient selection for the appropriate treatment-surgery, somatostatin analogs, peptide receptor radionuclide therapy, targeted therapies like everolimus and sunitinib, or chemotherapy-and also for therapy response monitoring. Novel targets, for example, the chemokine receptor CXCR4 in higher-grade tumors and glucagon like peptide-1 receptor in insulinomas, appear promising for imaging. Scandium-44 and Copper-64, especially on account of their longer half-life (for pretherapeutic dosimetry) and cyclotron production (which favors mass production), might be the potential alternatives to (68)Ga for PET/CT imaging. The future of molecular imaging lies in Radiomics, that is, qualitative and quantitative characterization of tumor phenotypes in correlation with tumor genomics and proteomics, for a personalized cancer management. Copyright © 2016 Elsevier Inc. All rights reserved.

KRAS and DAXX/ATRX Gene Mutations Are Correlated with the Clinicopathological Features, Advanced Diseases, and Poor Prognosis in Chinese Patients with Pancreatic Neuroendocrine Tumors

PubMed Central

Yuan, Fei; Shi, Min; Ji, Jun; Shi, Hailong; Zhou, Chenfei; Yu, Yingyan; Liu, Bingya; Zhu, Zhenggang; Zhang, Jun

2014-01-01

Background and Aim: Pancreatic neuroendocrine tumor (pNET) is a clinically rare and heterogeneous group of tumors; its pharmacogenetic characteristics are not fully understood. This study was designed to examine the relationship between key gene variations and disease development and prognosis among Chinese patients with pNET. Methods: Various pNET associated genes such as DAXX/ATRX, KRAS, MEN1, PTEN, TSC2, SMAD4/DPC, TP53 and VHL were analyzed in high-throughput sequencing. The links between the gene mutations and the clinicopathological features and prognosis of the patients were determined. Results: The somatic mutation frequencies of the DAXX/ATRX, KRAS, MEN1, mTOR pathway genes (PTEN and TSC2), SMAD4/DPC, TP53, and VHL in Chinese pNET patients were 54.05%, 10.81%, 35.14%, 54.05%, 2.70%, 13.51%, and 40.54%, respectively, while the same figures in Caucasians pNET patients were 43%, 0%, 44%, 15%, 0%, 3%, and 0%, respectively. The numbers of mutated genes were from 0 to 6; 4 patients with more than 3 mutated genes had higher proliferation (Ki-67) index or nerve vascular invasion or organ involvement, but only 9 of 27 patients with 3 or few mutated genes had such features. Mutations in KRAS and DAXX/ATRX, but not other genes analyzed, were associated with a shortened survival. Conclusion: The mutation rates of these genes in Chinese pNET patients are different from those in Caucasians. A higher number of gene mutations and the DAXX/ATRX and KRAS gene mutations are correlated with a poor prognosis of patients with pNET. PMID:25210493

Somatostatin Receptor SSTR-2a Expression Is a Stronger Predictor for Survival Than Ki-67 in Pancreatic Neuroendocrine Tumors

PubMed Central

Mehta, Shreya; de Reuver, Philip R.; Gill, Preetjote; Andrici, Juliana; D’Urso, Lisa; Mittal, Anubhav; Pavlakis, Nick; Clarke, Stephen; Samra, Jaswinder S.; Gill, Anthony J.

2015-01-01

Abstract Somatostatin receptors (SSTR) are commonly expressed by neuroendocrine tumors. Expression of SSTR-2a and SSTR-5 may impact symptomatic management; however, the impact on survival is unclear. The aim of this study is to correlate SSTR-2a and SSTR-5 expression in pancreatic neuroendocrine tumors (PNETs) with survival. This study is designed to determine the prognostic significance of somatostatin receptors SSTR-2a and SSTR-5 in PNETs. This retrospective cohort study included cases of resected PNETs between 1992 and 2014. Clinical data, histopathology, expression of SSTR and Ki-67 by immunohistochemistry, and long-term survival were analyzed. A total of 99 cases were included in this study. The mean age was 57.8 years (18–87 years) and median tumor size was 25 mm (range 8–160 mm). SSTR-2a and SSTR-5 expression was scored as negative (n = 19, 19.2%; n = 75, 75.8%, respectively) and positive (n = 80, 80.1%; n = 24, 24.2%). The median follow-up was 49 months. SSTR-2a expression was associated with improved overall survival, with cumulative survival rates at 1, 3, and 5 years being 97.5%, 91.5%, and 82.9%, respectively. Univariate analysis demonstrated better survival in SSTR-2a positive patients (log rank P = 0.04). SSTR-5 expression was not associated with survival outcomes (log rank P = 0.94). Multivariate analysis showed that positive SSTR-2a expression is a stronger prognostic indicator for overall survival [Hazard Ratio (HR): 0.2, 95% Confidence interval (CI): 0.1–0.8] compared to high Ki-67 (HR: 0.8, 95% CI: 0.1–5.7). Expression of SSTR-2a is an independent positive prognostic factor for survival in PNETs. PMID:26447992

Treatment Option Overview (Pancreatic Neuroendocrine Tumors / Islet Cell Tumors)

MedlinePlus

... Leukemia Liver Cancer Lung Cancer Lymphoma Pancreatic Cancer Prostate Cancer Skin Cancer Thyroid Cancer Uterine Cancer All Cancer ... also called nuclear magnetic resonance imaging (NMRI). Somatostatin receptor scintigraphy : A type of radionuclide scan that may ...

Poxvirus-based vaccine therapy for patients with advanced pancreatic cancer

PubMed Central

Kaufman, Howard L; Kim-Schulze, Seunghee; Manson, Kelledy; DeRaffele, Gail; Mitcham, Josephine; Seo, Kang Seok; Kim, Dae Won; Marshall, John

2007-01-01

Purpose An open-label Phase 1 study of recombinant prime-boost poxviruses targeting CEA and MUC-1 in patients with advanced pancreatic cancer was conducted to determine safety, tolerability and obtain preliminary data on immune response and survival. Patients and methods Ten patients with advanced pancreatic cancer were treated on a Phase I clinical trial. The vaccination regimen consisted of vaccinia virus expressing tumor antigens carcinoembryonic antigen (CEA) and mucin-1 (MUC-1) with three costimulatory molecules B7.1, ICAM-1 and LFA-3 (TRICOM) (PANVAC-V) and fowlpox virus expressing the same antigens and costimulatory molecules (PANVAC-F). Patients were primed with PANVAC-V followed by three booster vaccinations using PANVAC-F. Granulocyte-macrophage colony-stimulating factor (GM-CSF) was used as a local adjuvant after each vaccination and for 3 consecutive days thereafter. Monthly booster vaccinations for up to 12 months were provided for patients without progressive disease. Peripheral blood was collected before, during and after vaccinations for immune analysis. Results The most common treatment-related adverse events were mild injection-site reactions. Antibody responses against vaccinia virus was observed in all 10 patients and antigen-specific T cell responses were observed in 5 out of 8 evaluable patients (62.5%). Median overall survival was 6.3 months and a significant increase in overall survival was noted in patients who generated anti CEA- and/or MUC-1-specific immune responses compared with those who did not (15.1 vs 3.9 months, respectively; P = .002). Conclusion Poxvirus vaccination is safe, well tolerated, and capable of generating antigen-specific immune responses in patients with advanced pancreatic cancer. PMID:18039393

Pancreatic neuroendocrine tumors containing areas of iso- or hypoattenuation in dynamic contrast-enhanced computed tomography: Spectrum of imaging findings and pathological grading.

PubMed

Hyodo, Ryota; Suzuki, Kojiro; Ogawa, Hiroshi; Komada, Tomohiro; Naganawa, Shinji

2015-11-01

To evaluate dynamic contrast-enhanced computed tomography (CT) features of pancreatic neuroendocrine tumors (PNETs) containing areas of iso- or hypoattenuation and the relationship with pathological grading. Between June 2006 and March 2014, 61 PNETs in 58 consecutive patients (29 male, 29 female; median-age 55 years), which were surgically diagnosed, underwent preoperative dynamic contrast-enhanced CT. PNETs were classified based on contrast enhancement patterns in the pancreatic phase: iso/hypo-PNETs were defined as tumors containing areas of iso- or hypoattenuation except for cystic components, and hyper-PNETs were tumors showing hyperattenuation over the whole area. CT findings and contrast-enhancement patterns of the tumors were evaluated retrospectively by two radiologists and compared with the pathological grading. Iso/hypo-PNETs comprised 26 tumors, and hyper-PNETs comprised 35 tumors. Not only hyper-PNETs but also most iso/hypo-PNETs showed peak enhancement in the pancreatic phase and a washout from the portal venous phase to the delayed phase. Iso/hypo-PNETs showed larger tumor size than the hyper-PNETs (mean, 3.7 cm vs. 1.6 cm; P<0.001), and were significantly correlated with unclear tumor margins (n=4 vs. n=0; P=0.029), the existence of cystic components (n=10 vs. n=3; P=0.006), intratumoral blood vessels in the early arterial phase (n=13 vs. n=3; P<0.001), and a smooth rim enhancement in the delayed phase (n=12 vs. n=6; P=0.019). Iso/hypo-PNETs also showed significantly higher pathological grading (WHO 2010 classification; iso/hypo, G1=14, G2=11, G3=1; hyper, G1=34, G2=1; P<0.001). PNETs containing iso/hypo-areas showed a rapid enhancement pattern as well as hyper-PNETs, various radiological features and higher malignant potential. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Pancreatic cancer

PubMed Central

Vincent, Audrey; Herman, Joseph; Schulick, Rich; Hruban, Ralph H; Goggins, Michael

2011-01-01

Substantial progress has been made in our understanding of the biology of pancreatic cancer, and advances in patients’ management have also taken place. Evidence is beginning to show that screening first-degree relatives of individuals with several family members affected by pancreatic cancer can identify non-invasive precursors of this malignant disease. The incidence of and number of deaths caused by pancreatic tumours have been gradually rising, even as incidence and mortality of other common cancers have been declining. Despite developments in detection and management of pancreatic cancer, only about 4% of patients will live 5 years after diagnosis. Survival is better for those with malignant disease localised to the pancreas, because surgical resection at present offers the only chance of cure. Unfortunately, 80–85% of patients present with advanced unresectable disease. Furthermore, pancreatic cancer responds poorly to most chemotherapeutic agents. Hence, we need to understand the biological mechanisms that contribute to development and progression of pancreatic tumours. In this Seminar we will discuss the most common and deadly form of pancreatic cancer, pancreatic ductal adenocarcinoma. PMID:21620466

A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer and other neuroendocrine tumors

PubMed Central

Jahchan, Nadine S; Dudley, Joel T; Mazur, Pawel K; Flores, Natasha; Yang, Dian; Palmerton, Alec; Zmoos, Anne-Flore; Vaka, Dedeepya; Tran, Kim QT; Zhou, Margaret; Krasinska, Karolina; Riess, Jonathan W; Neal, Joel W; Khatri, Purvesh; Park, Kwon S; Butte, Atul J; Sage, Julien

2013-01-01

Small cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer with high mortality. We used a systematic drug-repositioning bioinformatics approach querying a large compendium of gene expression profiles to identify candidate FDA-approved drugs to treat SCLC. We found that tricyclic antidepressants and related molecules potently induce apoptosis in both chemonaïve and chemoresistant SCLC cells in culture, in mouse and human SCLC tumors transplanted into immunocompromised mice, and in endogenous tumors from a mouse model for human SCLC. The candidate drugs activate stress pathways and induce cell death in SCLC cells, at least in part by disrupting autocrine survival signals involving neurotransmitters and their G protein-coupled receptors. The candidate drugs inhibit the growth of other neuroendocrine tumors, including pancreatic neuroendocrine tumors and Merkel cell carcinoma. These experiments identify novel targeted strategies that can be rapidly evaluated in patients with neuroendocrine tumors through the repurposing of approved drugs. PMID:24078773

Advances in the Diagnosis and Management of Well-Differentiated and Intermediate-Differentiated Neuroendocrine Tumors of the Lung.

PubMed

Wolin, Edward M

2017-05-01

Neuroendocrine tumors (NETs) are a rare, heterogeneous group of malignancies that arise from neuroendocrine cells throughout the body, with the lungs and GI tract being the most common sites of origin. Despite increasing incidence, awareness of lung NETs remains low among thoracic specialists who are often involved in the assessment and early treatment of these patients. Successful treatment requires accurate and timely diagnosis; however, classification can be challenging, particularly for well-differentiated and intermediate-differentiated lung NET types (typical carcinoids [TC] and atypical carcinoids [AC]). Diagnosis and management of lung NETs are further complicated by the nonspecificity of symptoms, variable natural history, and lack of high-level clinical evidence; a multidisciplinary approach is required, which has been shown to improve prognosis. Currently, surgery remains the only curative option for TC/AC. Inconsistencies between guideline recommendations for systemic therapies, especially for chemotherapy, result in a lack of consensus on a standardized treatment for unresectable disease. Recent data from the Phase III RAD001 in Advanced Neuroendocrine Tumors, Fourth Trial (RADIANT-4), which contained a large population of patients with advanced, well-differentiated, nonfunctional lung NETs in addition to those with GI NETs, found a reduced risk of disease progression and death with everolimus compared with placebo, leading to US approval of everolimus in these patient populations. This study is the first high-level therapeutic evidence in patients with TC/AC, and everolimus is currently the only agent approved for treatment of TC/AC. Increased awareness, prompt diagnosis, and additional adequately powered controlled clinical trials of patients with well-differentiated and intermediate-differentiated lung NETs are needed to further improve evidence-based care. Copyright © 2016 The Author. Published by Elsevier Inc. All rights reserved.

Acoustic radiation force impulse shear wave elastography (ARFI) of acute and chronic pancreatitis and pancreatic tumor.

PubMed

Goertz, Ruediger S; Schuderer, Johanna; Strobel, Deike; Pfeifer, Lukas; Neurath, Markus F; Wildner, Dane

2016-12-01

Acoustic Radiation Force Impulse (ARFI) elastography evaluates tissue stiffness non-invasively and has rarely been applied to pancreas examinations so far. In a prospective and retrospective analysis, ARFI shear wave velocities of healthy parenchyma, pancreatic lipomatosis, acute and chronic pancreatitis, adenocarcinoma and neuroendocrine tumor (NET) of the pancreas were evaluated and compared. In 95 patients ARFI elastography of the pancreatic head, and also of the tail for a specific group, was analysed retrospectively. Additionally, prospectively in 100 patients ARFI was performed in the head and tail of the pancreas. A total of 195 patients were included in the study. Healthy parenchyma (n=21) and lipomatosis (n=30) showed similar shear wave velocities of about 1.3m/s. Acute pancreatitis (n=35), chronic pancreatitis (n=53) and adenocarcinoma (n=52) showed consecutively increasing ARFI values, respectively. NET (n=4) revealed the highest shear wave velocities amounting to 3.62m/s. ARFI elastography showed relevant differences between acute pancreatitis and chronic pancreatitis or adenocarcinoma. With a cut-off value of 1.74m/s for the diagnosis of a malignant disease the sensitivity was 91.1% whereas the specificity amounted to 60.4%. ARFI shear wave velocities present differences in various pathologies of the pancreas. Acute and chronic pancreatitis as well as neoplastic lesions show high ARFI values. Very high elasticity values may indicate malignant disease of the pancreas. However, there is a considerable overlap between the entities. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

FDA Approves Lutathera for Neuroendocrine Tumors

Cancer.gov

FDA has approved Lutathera® for some people with neuroendocrine tumors (NETs) that affect the digestive tract. On January 29, FDA approved Lutathera® for adult patients with advanced NETs that affect the pancreas or gastrointestinal tract, known as GEP-NETs.

Neuroendocrine Tumors of the Lung: Current Challenges and Advances in the Diagnosis and Management of Well-Differentiated Disease.

PubMed

Hendifar, Andrew E; Marchevsky, Alberto M; Tuli, Richard

2017-03-01

Neuroendocrine tumors (NETs) comprise a heterogeneous group of malignancies that arise from neuroendocrine cells throughout the body, most commonly originating from the lungs and gastrointestinal tract. Lung NETs can be classified as well differentiated (low-grade typical carcinoids [TCs] and intermediate-grade atypical carcinoids [ACs]) and poorly differentiated (high-grade large cell neuroendocrine carcinoma or SCLC). The incidence of these tumors is increasing, but disease awareness remains low among thoracic specialists, who are often involved in the diagnosis and early treatment for these patients. An accurate and timely diagnosis can ensure the implementation of appropriate treatment and have a substantial impact on prognosis. However, lung NET classification and diagnosis, particularly for TCs/ACs, are complicated by several factors, including a variable natural history and nonspecific symptoms. Surgery remains the only curative option for TCs/ACs, but there is a lack of consensus between lung NET management guidelines regarding optimal treatment approaches in the unresectable/metastatic setting on account of the limited availability of high-level clinical evidence. As a result, a multidisciplinary approach to management of lung NETs is required to ensure a consistent and optimal level of care. RADIANT-4 is the first phase III trial involving a large subpopulation of patients with advanced well-differentiated lung NETs to report reductions in the risk for disease progression and death with everolimus over placebo. This led to the recent U.S. approval of everolimus-the first agent approved for advanced lung TCs/ACs. To further improve evidence-based care, additional randomized controlled trials in patients with lung carcinoids are needed. Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Management of synchronous tumours of the oesophagus and pancreatic head: a novel approach.

PubMed

Gyorki, D E; Clarke, N E; Hii, M W; Banting, S W; Cade, R J

2011-09-01

Synchronous tumours of the oesophagus and pancreatic head are very rare. This report describes a unique case of an adenocarcinoma of the distal oesophagus and a neuroendocrine tumour of the pancreatic head diagnosed synchronously but successfully managed metachronously. Initially, the patient underwent an oesophagectomy, with a colonic reconstruction following some months later by pylorus-preserving pancreaticoduodenectomy. A staged resection was performed after a review of the literature suggested increased morbidity with synchronous major abdominal operations.

Glucose Homeostasis, Pancreatic Endocrine Function, and Outcomes in Advanced Heart Failure.

PubMed

Melenovsky, Vojtech; Benes, Jan; Franekova, Janka; Kovar, Jan; Borlaug, Barry A; Segetova, Marketa; Tura, Andrea; Pelikanova, Tereza

2017-08-07

The mechanisms and relevance of impaired glucose homeostasis in advanced heart failure (HF) are poorly understood. The study goals were to examine glucose regulation, pancreatic endocrine function, and metabolic factors related to prognosis in patients with nondiabetic advanced HF. In total, 140 advanced HF patients without known diabetes mellitus and 21 sex-, age-, and body mass index-matched controls underwent body composition assessment, oral glucose tolerance testing, and measurement of glucose-regulating hormones to model pancreatic β-cell secretory response. Compared with controls, HF patients had similar fasting glucose and insulin levels but higher levels after oral glucose tolerance testing. Insulin secretion was not impaired, but with increasing HF severity, there was a reduction in glucose, insulin, and insulin/glucagon ratio-a signature of starvation. The insulin/C-peptide ratio was decreased in HF, indicating enhanced insulin clearance, and this was correlated with lower cardiac output, hepatic insufficiency, right ventricular dysfunction, and body wasting. After a median of 449 days, 41% of patients experienced an adverse event (death, urgent transplant, or assist device). Increased glucagon and, paradoxically, low fasting plasma glucose displayed the strongest relations to outcome ( P =0.01). Patients in the lowest quartile of fasting plasma glucose (3.8-5.1 mmol·L -1 , 68-101 mg·dL -1 ) had 3-times higher event risk than in the top quartile (6.0-7.9 mmol·L -1 , 108-142 mg·dL -1 ; relative risk: 3.05 [95% confidence interval, 1.46-6.77]; P =0.002). Low fasting plasma glucose and increased glucagon are robust metabolic predictors of adverse events in advanced HF. Pancreatic insulin secretion is preserved in advanced HF, but levels decrease with increasing HF severity due to enhanced insulin clearance that is coupled with right heart failure and cardiac cachexia. © 2017 The Authors. Published on behalf of the American Heart Association, Inc

State-of-the-art magnetic resonance imaging of pancreatic cancer.

PubMed

Schima, Wolfgang; Ba-Ssalamah, Ahmed; Goetzinger, Peter; Scharitzer, Martina; Koelblinger, Claus

2007-12-01

Technical advances of magnetic resonance imaging (MRI), including ultrahigh-field magnetic resonance at 3.0 T, parallel imaging techniques, and multichannel receive coils of the abdomen, have promoted MRI of the pancreas. For adenocarcinoma, which is the most common malignant pancreatic tumor, helical CT has been most often used for detection and staging, but it has limitations in the detection of small cancers 2 cm in diameter or less (sensitivity, 63%). Moreover, it is not very accurate in determining nonresectability, because small liver metastases, peritoneal carcinomatosis, and subtle signs of vascular infiltration may be missed. At ultrahigh field at 3.0 T, gadolinium-enhanced MRI using volume-interpolated 3-dimensional gradient-recalled echo pulse sequences with near-isotropic voxels are very useful for detection of subtle abnormalities. Mangafodipir-enhanced MRI reveals a very high tumor-pancreas contrast, which helps to diagnose small cancers. Contrast-enhanced MRI is a problem-solving tool in case of equivocal CT: it helps to differentiate between cancer and focal pancreatitis. Neuroendocrine carcinoma may present with a spectrum of appearances at MRI, but the primary tumor and liver metastases are hypervascular in approximately 70%. In this article, pancreas imaging protocols for 1.5 and 3.0 T are explained. We present the imaging features of pancreatic cancer and the important questions in staging, which should be addressed by the radiologist.

Mixed acinar-neuroendocrine-ductal carcinoma of the pancreas: a tale of three lineages.

PubMed

Anderson, Mark J; Kwong, Christina A; Atieh, Mohammed; Pappas, Sam G

2016-06-02

Most pancreatic cancers arise from a single cell type, although mixed pancreatic carcinomas represent a rare exception. The rarity of these aggressive malignancies and the limitations of fine-needle aspiration (FNA) pose significant barriers to diagnosis and appropriate management. We report a case of a 54-year-old man presenting with abdominal pain, jaundice and a hypodense lesion within the uncinate process on CT. FNA suggested poorly differentiated adenocarcinoma, which was subsequently resected via pancreaticoduodenectomy. Pathological analysis yielded diagnosis of invasive mixed acinar-neuroendocrine-ductal pancreatic carcinoma. Given the rare and deadly nature of these tumours, clinicians must be aware of their pathophysiology and do practice with a high degree of clinical suspicion, when appropriate. Surgical resection and thorough pathological analysis with immunohistochemical staining and electron microscopy remain the standards of care for mixed pancreatic tumours without gross evidence of metastasis. Diligent characterisation of the presentation and histological findings associated with these neoplasms should continue in order to promote optimal diagnostic and therapeutic strategies. 2016 BMJ Publishing Group Ltd.

Pancreatic cancer ascites xenograft–an expeditious model mirroring advanced therapeutic resistant disease

PubMed Central

Schvimer, Michael; Atias, Dikla; Halperin, Sharon; Buzhor, Ella; Raitses-Gurevich, Maria; Cohen, Keren; Pri-Chen, Sara; Wilson, Julie; Denroche, Robert E.; Lungu, Ilinca; Bartlett, John M.S.; Mbabaali, Faridah; Yarden, Yosef; Nataraj, Nishanth Belugali; Gallinger, Steven; Berger, Raanan

2017-01-01

Pancreatic ductal adenocarcinoma has limited treatment options. There is an urgent need for developing appropriate pre-clinical models recapitulating metastatic disease, the most common clinical scenario at presentation. Ascites accumulation occurs in up to 20–30% of patients with pancreatic cancer; this milieu represents a highly cellular research resource of metastatic peritoneal spread. In this study, we utilized pancreatic ascites/pleural effusion cancer cells to establish patient derived xenografts. Ascites/pleural effusion-patient derived xenografts were established from twelve independent cases. Xenografts were serially passed in nude mice and tissue bio-specimen banking has been established. Histopathology of emergent tumors demonstrates poorly to moderately differentiated, glandular and mucin producing tumors, mirroring morphology of primary pancreatic cancer tumors. Whole genome sequencing of six patient derived xenografts samples demonstrates common mutations and structural variations similar to those reported in primary pancreatic cancer. Xenograft tumors were dissociated to single-cells and in-vitro drug sensitivity screen assays demonstrated chemo-resistance, correlating with patient clinical scenarios, thus serving as a platform for clinically relevant translational research. Therefore, establishment of this novel ascites/pleural effusion patient derived xenograft model, with extensive histopathology and genomic characterization, opens an opportunity for the study of advanced aggressive pancreatic cancer. Characterization of metastatic disease and mechanisms of resistance to therapeutics may lead to the development of novel drug combinations. PMID:28489577

Pancreatoduodenectomy for circumportal pancreas accompanying the retroportal pancreatic duct: a case report and review of the literature.

PubMed

Shonaka, Tatsuya; Inagaki, Mitsuhiro; Akabane, Hiromitsu; Yanagida, Naoyuki; Shomura, Hiroki; Kudo, Takeaki; Orimo, Tatsuya; Oikawa, Futoshi; Aiyama, Takeshi; Yanagawa, Nobuyuki; Oikawa, Kensuke; Nakano, Shiro

2012-10-01

Circumportal pancreas (CP) is an extremely rare pancreatic fusion anomaly which is usually asymptomatic. This report presents the case of a patient with a tumor in the head of a CP and the retroportal accessory pancreatic duct in the pancreatic tissue behind the portal vein. A 53-year-old male was diagnosed with a nonfunctioning neuroendocrine tumor of the pancreas and resection of the tumor was scheduled. The patient was revealed to have CP on preoperative computed tomography and endoscopic retrograde cholangiopancreatography, which showed the pancreatic tissue encircling the portal vein and the retroportal accessory pancreatic duct. The patient safely underwent pylorus-preserving pancreatoduodenectomy reconstructed with pancreaticogastrostomy.

Multicenter Phase II Trial of Temsirolimus and Bevacizumab in Pancreatic Neuroendocrine Tumors

PubMed Central

Hobday, Timothy J.; Qin, Rui; Reidy-Lagunes, Diane; Moore, Malcolm J.; Strosberg, Jonathan; Kaubisch, Andreas; Shah, Manisha; Kindler, Hedy Lee; Lenz, Heinz-Josef; Chen, Helen; Erlichman, Charles

2015-01-01

Purpose There are few effective therapies for pancreatic neuroendocrine tumors (PNETs). Recent placebo-controlled phase III trials of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor inhibitor sunitinib have noted improved progression-free survival (PFS). Preclinical studies have suggested enhanced antitumor effects with combined mTOR and VEGF pathway–targeted therapy. We conducted a clinical trial to evaluate combination therapy against these targets in PNETs. Patients and Methods We conducted a two-stage single-arm phase II trial of the mTOR inhibitor temsirolimus 25 mg intravenously (IV) once per week and the VEGF-A monoclonal antibody bevacizumab 10 mg/kg IV once every 2 weeks in patients with well or moderately differentiated PNETs and progressive disease by RECIST within 7 months of study entry. Coprimary end points were tumor response rate and 6-month PFS. Results A total of 58 patients were enrolled, and 56 patients were eligible for response assessment. Confirmed response rate (RR) was 41% (23 of 56 patients). PFS at 6 months was 79% (44 of 56). Median PFS was 13.2 months (95% CI, 11.2 to 16.6). Median overall survival was 34 months (95% CI, 27.1 to not reached). For evaluable patients, the most common grade 3 to 4 adverse events attributed to therapy were hypertension (21%), fatigue (16%), lymphopenia (14%), and hyperglycemia (14%). Conclusion The combination of temsirolimus and bevacizumab had substantial activity and reasonable tolerability in a multicenter phase II trial, with RR of 41%, well in excess of single targeted agents in patients with progressive PNETs. Six-month PFS was a notable 79% in a population of patients with disease progression by RECIST criteria within 7 months of study entry. On the basis of this trial, continued evaluation of combination mTOR and VEGF pathway inhibitors is warranted. PMID:25488966

Impact of Therapy Sequence with Alkylating Agents and MGMT Status in Patients with Advanced Neuroendocrine Tumors.

PubMed

Krug, Sebastian; Boch, Michael; Rexin, Peter; Gress, Thomas M; Michl, Patrick; Rinke, Anja

2017-05-01

Alkylating chemotherapeutics with either a streptozotocin-(STZ) or temozolomide-(TEM) backbone are routinely used in patients with progressive and unresectable pancreatic neuroendocrine tumors (PNET). In addition, dacarbazine (DTIC) was described as an alternative alkylating therapy option for PNETs. The optimal treatment sequence with alkylating compounds and a potential use of O6-methylguanine-DNA methyltransferase (MGMT) level as predictive biomarker have not yet been sufficiently elucidated. The aim of our study was the evaluation of therapy sequence with either STZ-based treatment followed by DTIC (group A) or the inverse schedule with upfront DTIC (group B) and to correlate MGMT status with clinicopathological characteristics and response to therapy. We retrospectively analyzed 28 patients with neuroendocrine tumors (NET) who were treated with STZ-based therapy and DTIC. Additionally, in a second group MGMT immunohistochemistry was performed from primary and metastatic tumor sites. For statistical evaluation Kaplan-Meier analysis, Cox regression methods and Fisher's exact test were used. There was no difference of objective response and disease control between either STZ-based therapy followed by DTIC treatment (group A) after progression or the reverse sequence (group B). Median time to progression (TTP) was estimated to be 21 months in both arms. First-line STZ-based chemotherapy was not superior to first-line DTIC treatment (16 vs. 13 months; p=0.8). MGMT status did not correlate with clinicopathological characteristics or response to therapy with these alkylating agents. Upfront chemotherapy with either STZ-based treatment or DTIC monotherapy showed similar efficacy and median TTP rates. In this study, MGMT protein expression assessed by immunohistochemistry did not play an important role as a predictive marker for alkylating agents. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Pancreatic neuroendocrine tumour: Correlation of apparent diffusion coefficient or WHO classification with recurrence-free survival.

PubMed

Kim, Mimi; Kang, Tae Wook; Kim, Young Kon; Kim, Seong Hyun; Kwon, Wooil; Ha, Sang Yun; Ji, Sang A

2016-03-01

To evaluate the correlation between grade of pancreatic neuroendocrine tumours (pNETs) based on the 2010 World Health Organization (WHO) classification and the apparent diffusion coefficient (ADC), and to assess whether the ADC value and WHO classification can predict recurrence-free survival (RFS) after surgery for pNETs. This retrospective study was approved by the Institutional Review Board. The requirement for informed consent was waived. Between March 2009 and November 2014, forty-nine patients who underwent magnetic resonance (MR) imaging with diffusion-weighted image and subsequent surgery for single pNETs were included. Correlations among qualitative MR imaging findings, quantitative ADC values, and WHO classifications were assessed. An ordered logistic regression test was used to control for tumour size as a confounding factor. The association between ADC value (or WHO classification) and RFS was analysed. All tumors (n=49) were classified as low- (n=29, grade 1), intermediate- (n=17, grade 2), and high-grade (n=3, grade 3), respectively. The mean ADC of pNETs was moderately negatively correlated with WHO classification before and after adjustment for tumour size (ρ=-0.64, p<0.001 and ρ=-0.55, p=0.001 respectively). RFS was significantly associated with WHO classification (p=0.007), but not with the ADC value (p=0.569). The ADC value of pNETs is moderately correlated with WHO tumour grade, regardless of tumour size. However, the WHO tumour classification of pNET may be more suitable for predicting RFS than the ADC value. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Prognostic factors of non-functioning pancreatic neuroendocrine tumor revisited: The value of WHO 2010 classification.

PubMed

Bu, Jiyoung; Youn, Sangmin; Kwon, Wooil; Jang, Kee Taek; Han, Sanghyup; Han, Sunjong; You, Younghun; Heo, Jin Seok; Choi, Seong Ho; Choi, Dong Wook

2018-02-01

Various factors have been reported as prognostic factors of non-functional pancreatic neuroendocrine tumors (NF-pNETs). There remains some controversy as to the factors which might actually serve to successfully prognosticate future manifestation and diagnosis of NF-pNETs. As well, consensus regarding management strategy has never been achieved. The aim of this study is to further investigate potential prognostic factors using a large single-center cohort to help determine the management strategy of NF-pNETs. During the time period 1995 through 2013, 166 patients with NF-pNETs who underwent surgery in Samsung Medical Center were entered in a prospective database, and those factors thought to represent predictors of prognosis were tested in uni- and multivariate models. The median follow-up time was 46.5 months; there was a maximum follow-up period of 217 months. The five-year overall survival and disease-free survival rates were 88.5% and 77.0%, respectively. The 2010 WHO classification was found to be the only prognostic factor which affects overall survival and disease-free survival in multivariate analysis. Also, pathologic tumor size and preoperative image tumor size correlated strongly with the WHO grades ( p <0.001, and p <0.001). Our study demonstrates that 2010 WHO classification represents a valuable prognostic factor of NF-pNETs and tumor size on preoperative image correlated with WHO grade. In view of the foregoing, the preoperative image size is thought to represent a reasonable reference with regard to determination and development of treatment strategy of NF-pNETs.

Management of advanced pancreatic cancer with gemcitabine plus erlotinib: efficacy and safety results in clinical practice.

PubMed

Diaz Beveridge, Robert; Alcolea, Vicent; Aparicio, Jorge; Segura, Ángel; García, Jose; Corbellas, Miguel; Fonfría, María; Giménez, Alejandra; Montalar, Joaquin

2014-01-10

The combination of gemcitabine and erlotinib is a standard first-line treatment for unresectable, locally advanced or metastatic pancreatic cancer. We reviewed our single centre experience to assess its efficacy and toxicity in clinical practice. Clinical records of patients with unresectable, locally advanced or metastatic pancreatic cancer who were treated with the combination of gemcitabine and erlotinib were reviewed. Univariate survival analysis and multivariate analysis were carried out to indentify independent predictors factors of overall survival. Our series included 55 patients. Overall disease control rate was 47%: 5% of patients presented complete response, 20% partial response and 22% stable disease. Median overall survival was 8.3 months). Cox regression analysis indicated that performance status and locally advanced versus metastatic disease were independent factors of overall survival. Patients who developed acne-like rash toxicity, related to erlotinib administration, presented a higher survival than those patients who did not develop this toxicity. Gemcitabine plus erlotinib doublet is active in our series of patients with advanced pancreatic cancer. This study provides efficacy and safety results similar to those of the pivotal phase III clinical trial that tested the same combination.

Current knowledge on the sensitivity of the (68)Ga-somatostatin receptor positron emission tomography and the SUVmax reference range for management of pancreatic neuroendocrine tumours.

PubMed

Virgolini, Irene; Gabriel, Michael; Kroiss, Alexander; von Guggenberg, Elisabeth; Prommegger, Rupert; Warwitz, Boris; Nilica, Bernhard; Roig, Llanos Geraldo; Rodrigues, Margarida; Uprimny, Christian

2016-10-01

Physiologically increased pancreatic uptake at the head/uncinate process is observed in more than one-third of patients after injection of one of the three (68)Ga-labelled octreotide-based peptides used for somatostatin (sst) receptor (r) imaging. There are minor differences between these (68)Ga-sstr-binding peptides in the imaging setting. On (68)Ga-sstr-imaging the physiological uptake can be diffuse or focal and usually remains stable over time. Differences in the maximal standardised uptake values (SUVmax) reported for the normal pancreas as well as for pancreatic neuroendocrine tumour (PNET) lesions may be related to several factors, including (a) differences in the peptide binding affinities as well as differences in sstr subtype expression of pancreatic α- and β-cells, and heterogeneity / density of tumour cells, (b) differences in scanner resolution, image reconstruction techniques and acquisition protocols, (c) mostly retrospective study designs, (d) mixed patient populations, or (e) interference with medications such as treatment with long-acting sst analogues. The major limitation in most of the studies lies in the lack of histopathological confirmation of abnormal findings. There is a significant overlap between the calculated SUVmax-values for physiological pancreas and PNET-lesions of the head/uncinate process that do not favour the use of quantitative parameters in the clinical setting. Anecdotal long-term follow-up studies have even indicated that increased uptake in the head/uncinate process still can turn out to be malignant over years of follow up. SUVmax-data for the pancreatic body and tail are limited. Therefore, any visible focal tracer uptake in the pancreas must be considered as suspicious for malignancy irrespective of quantitative parameters. In general, sstr-PET/CT has significant implications for the management of NET patients leading to a change in treatment decision in about one-third of patients. Therefore, follow-up with (68)Ga

Surgical Management of Chronic Pancreatitis.

PubMed

Parekh, Dilip; Natarajan, Sathima

2015-10-01

Advances over the past decade have indicated that a complex interplay between environmental factors, genetic predisposition, alcohol abuse, and smoking lead towards the development of chronic pancreatitis. Chronic pancreatitis is a complex disorder that causes significant and chronic incapacity in patients and a substantial burden on the society. Major advances have been made in the etiology and pathogenesis of this disease and the role of genetic predisposition is increasingly coming to the fore. Advances in noninvasive diagnostic modalities now allow for better diagnosis of chronic pancreatitis at an early stage of the disease. The impact of these advances on surgical treatment is beginning to emerge, for example, patients with certain genetic predispositions may be better treated with total pancreatectomy versus lesser procedures. Considerable controversy remains with respect to the surgical management of chronic pancreatitis. Modern understanding of the neurobiology of pain in chronic pancreatitis suggests that a window of opportunity exists for effective treatment of the intractable pain after which central sensitization can lead to an irreversible pain syndrome in patients with chronic pancreatitis. Effective surgical procedures exist for chronic pancreatitis; however, the timing of surgery is unclear. For optimal treatment of patients with chronic pancreatitis, close collaboration between a multidisciplinary team including gastroenterologists, surgeons, and pain management physicians is needed.

The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines

PubMed Central

Hofving, Tobias; Arvidsson, Yvonne; Almobarak, Bilal; Inge, Linda; Pfragner, Roswitha; Persson, Marta; Stenman, Göran; Kristiansson, Erik; Johanson, Viktor; Nilsson, Ola

2018-01-01

Experimental models of neuroendocrine tumour disease are scarce, and no comprehensive characterisation of existing gastroenteropancreatic neuroendocrine tumour (GEPNET) cell lines has been reported. In this study, we aimed to define the molecular characteristics and therapeutic sensitivity of these cell lines. We therefore performed immunophenotyping, copy number profiling, whole-exome sequencing and a large-scale inhibitor screening of seven GEPNET cell lines. Four cell lines, GOT1, P-STS, BON-1 and QGP-1, displayed a neuroendocrine phenotype while three others, KRJ-I, L-STS and H-STS, did not. Instead, these three cell lines were identified as lymphoblastoid. Characterisation of remaining authentic GEPNET cell lines by copy number profiling showed that GOT1, among other chromosomal alterations, harboured losses on chromosome 18 encompassing the SMAD4 gene, while P-STS had a loss on 11q. BON-1 had a homozygous loss of CDKN2A and CDKN2B, and QGP-1 harboured amplifications of MDM2 and HMGA2. Whole-exome sequencing revealed both disease-characteristic mutations (e.g. ATRX mutation in QGP-1) and, for patient tumours, rare genetic events (e.g. TP53 mutation in P-STS, BON-1 and QGP-1). A large-scale inhibitor screening showed that cell lines from pancreatic NETs to a greater extent, when compared to small intestinal NETs, were sensitive to inhibitors of MEK. Similarly, neuroendocrine NET cells originating from the small intestine were considerably more sensitive to a group of HDAC inhibitors. Taken together, our results provide a comprehensive characterisation of GEPNET cell lines, demonstrate their relevance as neuroendocrine tumour models and explore their therapeutic sensitivity to a broad range of inhibitors. PMID:29444910

Advanced pancreatic adenocarcinoma outcomes with transition from devolved to centralised care in a regional Cancer Centre.

PubMed

Faluyi, Olusola O; Connor, Joanna L; Chatterjee, Madhuchanda; Ikin, Carl; Wong, Helen; Palmer, Daniel H

2017-02-14

Previous observations suggest suboptimal 'real world' survival outcomes for advanced pancreatic adenocarcinoma. We hypothesized that centralisation of advanced pancreatic adenocarcinoma management would improve chemotherapy treatment and survival from the disease. The data was prospectively collected on all cases of advanced pancreatic adenocarcinoma reviewed through Clatterbridge Cancer Centre according to two groups; 1 October 2009-31st Dec 2010 (devolved care) or 1 January 2013-31 March 2014 (centralised care). Analysis included treatment received, 30-day chemotherapy mortality rate and overall survival (OS). More patients received chemotherapy with central care (67.0% (n=115) vs 43.0% (n=121); P=2.2 × 10 -4 ) with no difference in 30-day mortality (20.8% vs 25%; P=0.573) but reduced time to commencement of chemotherapy (18 vs 28 days, P=1.0 × 10 -3 ). More patients received second-line chemotherapy with central care (23.4% vs 1.9%, P=1.4 × 10 -4 ), while OS was significantly increased with central care (median: Five vs three months, HR 0.785, P=0.045). Exploratory analysis suggested that it was those with a poorer performance status, elderly or with metastatic disease who benefited the most from transition to central care. A centralised clinic model for advanced pancreatic cancer management resulted in prompt, safe and higher use of chemotherapy compared with devolved care. This was associated with a modest survival benefit. Prospective studies are required to validate the findings reported and the basis for improved survival with centralised care.

Pharmacogenetics in neuroendocrine tumors of the pancreas.

PubMed

Rizvi, Syed Mujtaba; Wong, Joyce; Saif, Muhammad Wasif; Jia, Yuxia

2014-07-28

Neuroendocrine tumors (NETs) arise from cells distributed throughout the endocrine system. Although, NETs are heterogeneous in their behavior, they tend to be more aggressive when arising in the pancreas. Pancreatic NET (panNET) represents three percent of all primary pancreatic neoplasms. Symptomatic and progressive panNETs are generally treated with cytotoxic chemotherapy, whereas molecular targeted therapy is used for nonfunctional tumors without aggressive features. Pharmacogenetics has increasingly been used recently to better identify potential targets for therapy and help select patient-specific therapy. In this review, we discuss two abstracts (Abstracts #4113 and #e15169) presented at the ASCO Annual Meeting in Chicago this year, outlining the potential role of tumor gene and gene product profiling in disease management. We describe what is known about the pathogenesis of these tumors, role of decreased gene product expression (MGMT, RRM1, MET) and its application in cytotoxic therapy selection, as well as genetic mutations that can be used for molecular targeted therapy. With an overall shift towards personalized medicine, it has become ever more important to identify the molecular signature of a tumor as it appears to dictate the clinical behavior and response to therapy.

A phase I study of imexon plus gemcitabine as first-line therapy for advanced pancreatic cancer.

PubMed

Cohen, Steven J; Zalupski, Mark M; Modiano, Manuel R; Conkling, Paul; Patt, Yehuda Z; Davis, Peg; Dorr, Robert T; Boytim, Michelle L; Hersh, Evan M

2010-07-01

Imexon is an aziridine-derived iminopyrrolidone which has synergy with gemcitabine in pancreatic cancer cell lines. Gemcitabine is a standard therapy for pancreatic cancer. We performed a phase I trial of imexon and gemcitabine to evaluate safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) in patients with advanced pancreatic cancer. Patients with untreated locally advanced or metastatic pancreatic adenocarcinoma received therapy in sequential cohorts on regimen A (n = 19; imexon 200 or 280 mg/m(2) intravenously (IV) over 30 min days 1-5, 15-19 and gemcitabine 800 or 1,000 mg/m(2) IV over 30 min on days 1,8,15 every 28 days) or regimen B (n = 86; imexon 280-1,300 mg/m(2) IV over 30-60 min days 1, 8, and 15 and gemcitabine 1,000 mg/m(2) IV over 30 min on days 1, 8, and 15 every 28 days). One hundred five patients received 340 treatment cycles (median 2, range 1-16). median age 63, 61% male, ECOG PS 0/1 50%/50%, 93% metastatic. DLT was abdominal cramping and pain, often with transient, acute diarrhea. Best response was confirmed partial response (PR) in 11.4%, 8.9% unconfirmed PR, and 48.1% with stable disease. There was a dose proportional increase in imexon AUC across the doses tested with terminal half life 69 min at the MTD and no alteration of gemcitabine pharmacokinetics. The recommended phase II dose of imexon is 875 mg/m(2) with gemcitabine 1,000 mg/m(2). DLT was acute abdominal pain and cramping. Encouraging antitumor responses support further evaluation of this combination in advanced pancreatic cancer.

Autoimmune pancreatitis can develop into chronic pancreatitis

PubMed Central

2014-01-01

Autoimmune pancreatitis (AIP) has been recognized as a distinct type of pancreatitis that is possibly caused by autoimmune mechanisms. AIP is characterized by high serum IgG4 and IgG4-positive plasma cell infiltration in affected pancreatic tissue. Acute phase AIP responds favorably to corticosteroid therapy and results in the amelioration of clinical findings. However, the long-term prognosis and outcome of AIP remain unclear. We have proposed a working hypothesis that AIP can develop into ordinary chronic pancreatitis resembling alcoholic pancreatitis over a long-term course based on several clinical findings, most notably frequent pancreatic stone formation. In this review article, we describe a series of study results to confirm our hypothesis and clarify that: 1) pancreatic calcification in AIP is closely associated with disease recurrence; 2) advanced stage AIP might have earlier been included in ordinary chronic pancreatitis; 3) approximately 40% of AIP patients experience pancreatic stone formation over a long-term course, for which a primary risk factor is narrowing of both Wirsung’s and Santorini’s ducts; and 4) nearly 20% of AIP patients progress to confirmed chronic pancreatitis according to the revised Japanese Clinical Diagnostic Criteria, with independent risk factors being pancreatic head swelling and non-narrowing of the pancreatic body duct. PMID:24884922

Autoimmune pancreatitis can develop into chronic pancreatitis.

PubMed

Maruyama, Masahiro; Watanabe, Takayuki; Kanai, Keita; Oguchi, Takaya; Asano, Jumpei; Ito, Tetsuya; Ozaki, Yayoi; Muraki, Takashi; Hamano, Hideaki; Arakura, Norikazu; Kawa, Shigeyuki

2014-05-21

Autoimmune pancreatitis (AIP) has been recognized as a distinct type of pancreatitis that is possibly caused by autoimmune mechanisms. AIP is characterized by high serum IgG4 and IgG4-positive plasma cell infiltration in affected pancreatic tissue. Acute phase AIP responds favorably to corticosteroid therapy and results in the amelioration of clinical findings. However, the long-term prognosis and outcome of AIP remain unclear. We have proposed a working hypothesis that AIP can develop into ordinary chronic pancreatitis resembling alcoholic pancreatitis over a long-term course based on several clinical findings, most notably frequent pancreatic stone formation. In this review article, we describe a series of study results to confirm our hypothesis and clarify that: 1) pancreatic calcification in AIP is closely associated with disease recurrence; 2) advanced stage AIP might have earlier been included in ordinary chronic pancreatitis; 3) approximately 40% of AIP patients experience pancreatic stone formation over a long-term course, for which a primary risk factor is narrowing of both Wirsung's and Santorini's ducts; and 4) nearly 20% of AIP patients progress to confirmed chronic pancreatitis according to the revised Japanese Clinical Diagnostic Criteria, with independent risk factors being pancreatic head swelling and non-narrowing of the pancreatic body duct.

"Puestow modified procedure in the era of advanced endoscopic interventions for the management of chronic lithiasic pancreatitis. A two cases report".

PubMed

Fragulidis, Georgios P; Vezakis, Αntonios; Dellaportas, Dionissios; Sotirova, Ira; Koutoulidis, Vassilis; Kontis, Elliseos; Polydorou, Andreas

2015-01-01

Pancreatic duct calculi in chronic pancreatitis (CP) patients are the main cause of intractable pain which is their main symptom. Decompression options of for the main pancreatic duct are both surgical and advanced endoscopic procedures. A 64-year-old male with known CP due to alcohol consumption and a 36-year-old female with known idiopathic CP and pancreatic duct calculi were managed recently in our hospital where endoscopic procedures were unsuccessful. A surgical therapy was considered and a longitudinal pancreaticojejunostomy (modified Puestow procedure) in both patients was performed with excellent results. Over the last 30 years, endoscopic procedures are developed to manage pancreatic duct strictures and calculi of the main pancreatic duct in CP patients. In both of our cases endoscopic therapy was first attempted but failed to extract the pancreatic duct stones, due to their size and speculations. Modified Puestow procedure was performed for both and it was successful for long term pain relief. Despite advancement in endoscopic interventions and less invasive therapies for the management of chronic lithiasic pancreatitis we consider that classic surgical management can be appropriate in certain cases. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chronic pancreatitis.

PubMed

DiMagno, Matthew J; DiMagno, Eugene P

2012-09-01

We review important new clinical observations in chronic pancreatitis reported in 2011. Smoking increases the risk of nongallstone acute pancreatitis and the progression of acute pancreatitis to chronic pancreatitis. Binge drinking during Oktoberfest did not associate with increased hospital admissions for acute pancreatitis. The unfolded protein response is an adaptive mechanism to maintain pancreatic health in response to noxious stimuli such as alcohol. Onset of diabetes mellitus in chronic pancreatitis is likely due to progressive disease rather than individual variables. Insufficient pancreatic enzyme dosing is common for treatment of pancreatic steatorrhea; 90 000 United States Pharmacopeia units of lipase should be given with meals. Surgical drainage provides sustained, superior pain relief compared with endoscopic treatment in patients advanced chronic pancreatitis with a dilated main duct ± pancreatic stones. The central acting gabapentoid pregabalin affords a modest 12% pain reduction in patients with chronic pancreatitis but approximately 30% of patients have significant side effects. Patients with nongallstone-related acute pancreatitis or chronic pancreatitis of any cause should cease smoking. Results of this year's investigations further elucidated the pancreatic pathobiology due to alcohol, onset of diabetes mellitus in chronic pancreatitis, and the mechanisms and treatment of neuropathic pain in chronic pancreatitis.

Apatinib concurrent gemcitabine for controlling malignant ascites in advanced pancreatic cancer patient

PubMed Central

Liang, Lijun; Wang, Lei; Zhu, Panrong; Xia, Youyou; Qiao, Yun; Hui, Kaiyuan; Hu, Chenxi; Ren, Yan; Jiang, Xiaodong

2017-01-01

Abstract Rationale: Malignant ascites (MA) is one of the poor prognostic factors for advanced pancreatic cancer and can bring about serious symptoms. The improvement of quality of life for patients is priority. However, there is no standard method for the treatment for pancreatic cancer-mediated MA. Apatinib is a novel and highly selective tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2. There are no reports of concurrent apatinib with gemcitabine in patients with pancreatic cancer-mediated MA. Patient concerns: Herein, we presented a 64-year-old man patient who visited hospital due to abdominal pain for 1 month. Diagnoses: He was initially diagnosed with pancreatic cancer and his first symptom was MA. Interventions: After failing in tube drainage and gemcitabine therapy, the patient received gemcitabine combined apatinib orally and after administrated 1 month, the MA was evaluated as nearly clear response according to the RECIST 1.1 standard, and without further need of paracentesis. The CEA and CA199 reached the lowest level after administrating for 2.5 months during the treatment process. Outcomes: 10.5 months following apatinib administration, the patient achieved a progression-free survival for more than 11 months. Hypertension (grade IV), hand-foot syndrome (grade I) and proteinuria (grade II) were observed. Lessons: It indicated that apatinib concurrent gemcitabine may be a superior choice for pancreatic cancer-mediated MA. Further clinical trials required to confirm its efficacy and safety. PMID:29381963

O6-Methylguanine DNA Methyltransferase Status Does Not Predict Response or Resistance to Alkylating Agents in Well-Differentiated Pancreatic Neuroendocrine Tumors.

PubMed

Raj, Nitya; Klimstra, David S; Horvat, Natally; Zhang, Liying; Chou, Joanne F; Capanu, Marinela; Basturk, Olca; Do, Richard Kinh Gian; Allen, Peter J; Reidy-Lagunes, Diane

2017-07-01

Alkylating agents have activity in well-differentiated pancreatic neuroendocrine tumors (WD panNETs). In glioblastoma multiforme, decreased activity of O-methylguanine DNA methyltransferase (MGMT) predicts response; in panNETs, MGMT relevance is unknown. We identified patients with WD panNETs treated with alkylating agents, determined best overall response by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, and performed MGMT activity testing. Fifty-six patients were identified; 26 (46%) of the 56 patients experienced partial response, 24 (43%) of 56 experienced stable disease, and 6 (11%) of 56 experienced progression of disease. O-methylguanine DNA methyltransferase status was available for 36 tumors. For tumors with partial response, 10 (67%) of 15 were MGMT deficient, and 5 (33%) of 15 were MGMT intact. For tumors with stable disease, 7 (47%) of 15 were MGMT deficient, and 8 (53%) of 15 were MGMT intact. For tumors with progression of disease, 3 (50%) of 6 were MGMT deficient, and 3 (50%) of 6 were MGMT intact. We observed response and resistance to alkylating agents in MGMT-deficient and MGMT-intact tumors. O-methylguanine DNA methyltransferase status should not guide alkylating agent therapy in WD panNETs.

Acute pancreatitis: recent advances through randomised trials.

PubMed

van Dijk, Sven M; Hallensleben, Nora D L; van Santvoort, Hjalmar C; Fockens, Paul; van Goor, Harry; Bruno, Marco J; Besselink, Marc G

2017-11-01

Acute pancreatitis is one of the most common GI conditions requiring acute hospitalisation and has a rising incidence. In recent years, important insights on the management of acute pancreatitis have been obtained through numerous randomised controlled trials. Based on this evidence, the treatment of acute pancreatitis has gradually developed towards a tailored, multidisciplinary effort, with distinctive roles for gastroenterologists, radiologists and surgeons. This review summarises how to diagnose, classify and manage patients with acute pancreatitis, emphasising the evidence obtained through randomised controlled trials. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Sexual dimorphism of liver metastasis by murine pancreatic neuroendocrine tumors is affected by expression of complement C5.

PubMed

Contractor, Tanupriya; Kobayashi, Shinta; da Silva, Edaise; Clausen, Richard; Chan, Chang; Vosburgh, Evan; Tang, Laura H; Levine, Arnold J; Harris, Chris R

2016-05-24

In a mouse model for neuroendocrine tumors of the pancreas (PanNETs), liver metastasis occurred at a higher frequency in males. Male mice also had higher serum and intratumoral levels of the innate immunity protein complement C5. In mice that lost the ability to express complement C5, there was a lower frequency of metastasis, and males no longer had a higher frequency of metastasis than females. Treatment with PMX53, a small molecule antagonist of C5aR1/CD88, the receptor for complement C5a, also reduced metastasis. Mice lacking a functional gene for complement C5 had smaller primary tumors, which were less invasive and lacked the CD68+ macrophages that have previously been associated with metastasis in this type of tumor. This is the first report of a gene that causes sexual dimorphism of metastasis in a mouse model. In the human disease, which also shows sexual dimorphism for metastasis, clinically advanced tumors expressed more complement C5 than less advanced tumors.

Advances in therapeutic vaccines for pancreatic cancer.

PubMed

Plate, Janet M D

2012-08-01

Pancreatic cancer is one of the most difficult-to-treat cancers. Despite surgical resection, radiation and/or chemotherapy, greater than 94% of people with pancreatic cancer do not survive beyond 5 years. In fact, median survival after diagnosis of metastatic pancreatic cancer is 4.5 months. The majority of patients are diagnosed with nonresectable, metastatic disease, and chemotherapy only extends their median survival by less than 2 months with only 18% of those treated surviving beyond 1 year. Despite the severity of their disease, most patients exhibit tumor specific cellular immunity to their pancreatic cancer antigens. Obviously their immunity is ineffective in preventing tumor growth. Recent studies have demonstrated that the tumor microenvironment may hold the key to determining the nature of the tumors' ability to escape from immune attack. Preliminary clinical trials have suggested that blocking these escape mechanisms may result in survival benefit to the patients, and phase I and II clinical trials with tumor vaccines have led to some survival benefits. Perhaps combining therapies directed against immune escape mechanisms with tumor vaccines will result in even greater survival benefit for patients with pancreatic cancer. While therapeutic vaccines for pancreatic cancers have been reviewed previously (Plate, 2011), updates on recent preliminary reports of two clinical vaccine trials are worthy of our attention.

Everolimus and Vatalanib in Treating Patients With Advanced Solid Tumors

ClinicalTrials.gov

2018-01-12

Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Metastatic Pheochromocytoma; Pancreatic Polypeptide Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Recurrent Melanoma; Recurrent Neuroendocrine Carcinoma of the Skin; Recurrent Non-small Cell Lung Cancer; Recurrent Pheochromocytoma; Recurrent Renal Cell Cancer; Somatostatinoma; Stage III Neuroendocrine Carcinoma of the Skin; Stage IV Melanoma; Stage IV Non-small Cell Lung Cancer; Stage IV Renal Cell Cancer; Thyroid Gland Medullary Carcinoma; Unspecified Adult Solid Tumor, Protocol Specific

The Symptom Experience of Patients With Advanced Pancreatic Cancer: An Integrative Review.

PubMed

Tang, Chia-Chun; Von Ah, Diane; Fulton, Janet S

Pancreatic cancer is a devastating disease with limited treatment options. More than 80% of pancreatic cancers are diagnosed in advanced stages and often have debilitating symptoms, making symptom management paramount, yet the symptom experience of patients with advanced pancreatic cancer (APC) is not well understood. The purpose of this integrative review is to synthesize the current evidence regarding the symptom experience of patients with APC. An integrative literature review was conducted to identify the patient symptom experience in studies published from 2005 to 2015. Sixteen studies met the inclusion criteria. All studies used a quantitative approach; 44% were quasi-experimental, 31% were descriptive, and 25% were correlational. Physical symptoms, especially pain, were the primary focus in most studies. Fatigue, loss of appetite, and impaired sense of well-being were prevalent and reported by patients to be of high intensity. Few studies examined psychological symptoms in patients with APC, although anxiety and depression were noted. Findings suggest that physical and psychological symptoms are prevalent, some with high intensity. Preselection of symptom inventories limits our ability to fully understand the symptom experience of patients with APC. Future qualitative work is needed to provide a more in-depth understanding of symptoms, especially symptom quality and distress level, from patients' perspectives. More studies are needed to explore psychological symptoms and the interaction of physical and psychological symptoms. Findings help healthcare givers to better understand the symptom experience of their APC patients.

“Puestow modified procedure in the era of advanced endoscopic interventions for the management of chronic lithiasic pancreatitis. A two cases report”

PubMed Central

Fragulidis, Georgios P.; Vezakis, Αntonios; Dellaportas, Dionissios; Sotirova, Ira; Koutoulidis, Vassilis; Kontis, Elliseos; Polydorou, Andreas

2015-01-01

Introduction Pancreatic duct calculi in chronic pancreatitis (CP) patients are the main cause of intractable pain which is their main symptom. Decompression options of for the main pancreatic duct are both surgical and advanced endoscopic procedures. Presentation of cases A 64-year-old male with known CP due to alcohol consumption and a 36-year-old female with known idiopathic CP and pancreatic duct calculi were managed recently in our hospital where endoscopic procedures were unsuccessful. A surgical therapy was considered and a longitudinal pancreaticojejunostomy (modified Puestow procedure) in both patients was performed with excellent results. Discussion Over the last 30 years, endoscopic procedures are developed to manage pancreatic duct strictures and calculi of the main pancreatic duct in CP patients. In both of our cases endoscopic therapy was first attempted but failed to extract the pancreatic duct stones, due to their size and speculations. Modified Puestow procedure was performed for both and it was successful for long term pain relief. Conclusion Despite advancement in endoscopic interventions and less invasive therapies for the management of chronic lithiasic pancreatitis we consider that classic surgical management can be appropriate in certain cases. PMID:26318135

Incidental Finding of a Neuroendocrine Tumor Arising from Meckel Diverticulum During Hernia Repair - A Case Report and Literature Review.

PubMed

Bacalbasa, Nicolae; Costin, Radu; Orban, Carmen; Iliescu, Laura; Hurjui, Ioan; Hurjui, Marcela; Niculescu, Nicoleta; Cristea, Mirela; Balescu, Irina

2016-04-01

Meckel diverticulum is the most common abnormality of the gastrointestinal tract arising from an incomplete obliteration of the vitelline duct during the intrauterine life. Although tumor development in Meckel diverticulum is not a common situation, it can occur due to the persistence of cellular islets with gastric, pancreatic or intestinal origin. The presence of a neuroendocrine tumor arising from Meckel diverticulum is even scarcer. We present the case of a 59-year-old patient in whom a Meckel diverticulum was found during surgery for inguinal hernia; the histopathological and immunohistochemical studies revealed the presence of a well-differentiated neuroendocrine tumor with low mitotic index. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Redefining the Ki-67 Index Stratification for Low-Grade Pancreatic Neuroendocrine Tumors: Improving Its Prognostic Value for Recurrence of Disease.

PubMed

Lopez-Aguiar, Alexandra G; Ethun, Cecilia G; Postlewait, Lauren M; Zhelnin, Kristen; Krasinskas, Alyssa; El-Rayes, Bassel F; Russell, Maria C; Sarmiento, Juan M; Kooby, David A; Staley, Charles A; Maithel, Shishir K; Cardona, Kenneth

2018-01-01

The Ki-67 index is an established prognostic marker for recurrence after resection of pancreatic neuroendocrine tumors (PanNETs) that groups tumors into three categories: low grade (< 3%), intermediate grade (3-20%), and high grade (> 20%). Given that the majority of resected PanNETs have a Ki-67 less than 3%, this study aimed to stratify this group further to predict disease recurrence more accurately. The Ki-67 index was pathologically re-reviewed and scored by a pathologist blinded to all other clinicopathologic variables using tissue microarray blocks made in triplicate. All patients who underwent curative-intent resection of non-metastatic PanNETs at a single institution from 2000 to 2013 were included in the study. The primary outcome was recurrence-free survival (RFS). Of 113 patients with well-differentiated PanNETs resected, 83 had tissue available for pathologic re-review. The Ki-67 index was lower than 3% for 72 tumors (87%) and between 3 and 20% for 11 tumors (13%). Considering only Ki-67 less than 3%, the tumors were further stratified by Ki-67 into three groups: group A (< 1%, n = 43), group B (1-1.99%, n = 23), and group C (2-2.99%, n = 6). Compared with group A, groups B and C more frequently had advanced T stage (T3: 44% and 67% vs 12%; p = 0.003) and lymphovascular invasion (50% and 83% vs 23%; p = 0.007). Groups B and C had similar 1- and 3-year RFS, both less than group A. After combining groups B and C, a Ki-67 of 1-2.99% was associated with decreased RFS compared with group A (< 1%). This persisted in the multivariable analysis (hazard ratio [HR] 8.6; 95% confidence interval [CI] 1.0-70.7; p = 0.045), with control used for tumor size, margin-positivity, lymph node involvement, and advanced T stage. PanNETs with a Ki-67 of 1-2.99% exhibit distinct biologic behavior and earlier disease recurrence than those with a Ki-67 lower than 1%. This new stratification scheme, if externally validated, should be incorporated into future

Detection of CTCs in portal vein was associated with intrahepatic metastases and prognosis in patients with advanced pancreatic cancer

PubMed Central

Liu, Xiaoyu; Li, Changyu; Li, Junhao; Yu, Tianzhu; Zhou, Guofeng; Cheng, Jiemin; Li, Guoping; Zhou, Yang; Lou, Wenhui; Wang, Xiaolin; Gong, Gaoquan; Liu, Lingxiao; Chen, Yi

2018-01-01

Pancreatic cancer is amongst the most lethal malignancies with increasing incidence and mortality worldwide. Distant metastases, especially intrahepatic metastases, is the leading cause of death for pancreatic cancer. Circulating tumor cells (CTCs) are neoplastic cells released from the primary tumor into circulation, and play critical roles in metastases of various types of cancers. Though clinical studies showed that detection of CTCs in peripheral circulation was associated with worse prognosis in patients with breast cancer and hepatocellular carcinoma, detection CTCs in peripheral blood of pancreatic cancer was still challenging due to hepatic filtration and technical limitations. Previous studies have demonstrated that CTCs could be detected in portal vein circulation in patients with pancreaticobiliary carcinoma. In the present study, taking advantage of ultrasonography-guided transhepatic puncture, we analysis CTCs in portal vein blood obtained from patients with advanced pancreatic cancer. CTCs were detected in all 29-portal vein blood of samples, and absolute numbers of circulating pancreatic cancer cells in portal vein was significantly higher than that in peripheral circulation. Furthermore, we found that CTC counts in portal vein was highly associated with intrahepatic metastases and indicated poorer prognosis in patients with advanced pancreatic cancer. Short-term expansion and in vitro drug sensitivity assay showed that CTCs derived from portal vein blood were highly resistant to several chemotherapy regimens. In summary, detection of CTCs in portal vein could be a powerful tool to stratify the risk of intrahepatic metastases of pancreatic cancer, and provided new insight into the biological feature of pancreatic cancer metastases and drug resistance. PMID:29896289

Sapanisertib and Ziv-Aflibercept in Treating Patients With Recurrent Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

ClinicalTrials.gov

2018-03-07

Advanced Malignant Solid Neoplasm; Fibrolamellar Carcinoma; Metastatic Malignant Solid Neoplasm; Ovarian Carcinoma; Pancreatic Neuroendocrine Tumor; Recurrent Malignant Solid Neoplasm; Refractory Malignant Solid Neoplasm; Unresectable Solid Neoplasm

American Gastroenterological Association guidelines are inaccurate in detecting pancreatic cysts with advanced neoplasia: a clinicopathologic study of 225 patients with supporting molecular data.

PubMed

Singhi, Aatur D; Zeh, Herbert J; Brand, Randall E; Nikiforova, Marina N; Chennat, Jennifer S; Fasanella, Kenneth E; Khalid, Asif; Papachristou, Georgios I; Slivka, Adam; Hogg, Melissa; Lee, Kenneth K; Tsung, Allan; Zureikat, Amer H; McGrath, Kevin

2016-06-01

The American Gastroenterological Association (AGA) recently reported evidence-based guidelines for the management of asymptomatic neoplastic pancreatic cysts. These guidelines advocate a higher threshold for surgical resection than prior guidelines and imaging surveillance for a considerable number of patients with pancreatic cysts. The aims of this study were to assess the accuracy of the AGA guidelines in detecting advanced neoplasia and present an alternative approach to pancreatic cysts. The study population consisted of 225 patients who underwent EUS-guided FNA for pancreatic cysts between January 2014 and May 2015. For each patient, clinical findings, EUS features, cytopathology results, carcinoembryonic antigen analysis, and molecular testing of pancreatic cyst fluid were reviewed. Molecular testing included the assessment of hotspot mutations and deletions for KRAS, GNAS, VHL, TP53, PIK3CA, and PTEN. Diagnostic pathology results were available for 41 patients (18%), with 13 (6%) harboring advanced neoplasia. Among these cases, the AGA guidelines identified advanced neoplasia with 62% sensitivity, 79% specificity, 57% positive predictive value, and 82% negative predictive value. Moreover, the AGA guidelines missed 45% of intraductal papillary mucinous neoplasms with adenocarcinoma or high-grade dysplasia. For cases without confirmatory pathology, 27 of 184 patients (15%) with serous cystadenomas (SCAs) based on EUS findings and/or VHL alterations would continue magnetic resonance imaging (MRI) surveillance. In comparison, a novel algorithmic pathway using molecular testing of pancreatic cyst fluid detected advanced neoplasias with 100% sensitivity, 90% specificity, 79% positive predictive value, and 100% negative predictive value. The AGA guidelines were inaccurate in detecting pancreatic cysts with advanced neoplasia. Furthermore, because the AGA guidelines manage all neoplastic cysts similarly, patients with SCAs will continue to undergo unnecessary MRI

Clinical Use of High-Intensity Focused Ultrasound (HIFU) for Tumor and Pain Reduction in Advanced Pancreatic Cancer.

PubMed

Strunk, H M; Henseler, J; Rauch, M; Mücke, M; Kukuk, G; Cuhls, H; Radbruch, L; Zhang, L; Schild, H H; Marinova, M

2016-07-01

Evaluation of ultrasound-guided high-intensity focused ultrasound (HIFU) used for the first time in Germany in patients with inoperable pancreatic cancer for reduction of tumor volume and relief of tumor-associated pain. 15 patients with locally advanced inoperable pancreatic cancer and tumor-related pain symptoms were treated by HIFU (n = 6 UICC stage III, n = 9 UICC stage IV). 13 patients underwent simultaneous standard chemotherapy. Ablation was performed using the JC HIFU system (Chongqing, China HAIFU Company) with an ultrasonic device for real-time imaging. Imaging follow-up (US, CT, MRI) and clinical assessment using validated questionnaires (NRS, BPI) was performed before and up to 15 months after HIFU. Despite biliary or duodenal stents (4/15) and encasement of visceral vessels (15/15), HIFU treatment was performed successfully in all patients. Treatment time and sonication time were 111 min and 1103 s, respectively. The applied total energy was 386 768 J. After HIFU ablation, contrast-enhanced imaging showed devascularization of treated tumor regions with a significant average volume reduction of 63.8 % after 3 months. Considerable pain relief was achieved in 12 patients after HIFU (complete or partial pain reduction in 6 patients). US-guided HIFU with a suitable acoustic pathway can be used for local tumor control and relief of tumor-associated pain in patients with locally advanced pancreatic cancer. • US-guided HIFU allows an additive treatment of unresectable pancreatic cancer.• HIFU can be used for tumor volume reduction.• Using HIFU, a significant reduction of cancer-related pain was achieved.• HIFU provides clinical benefit in patients with pancreatic cancer. Citation Format: • Strunk HM, Henseler J, Rauch M et al. Clinical Use of High-Intensity Focused Ultrasound (HIFU) for Tumor and Pain Reduction in Advanced Pancreatic Cancer. Fortschr Röntgenstr 2016; 188: 662 - 670. © Georg Thieme Verlag KG

A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics.

PubMed

Sadanandam, Anguraj; Wullschleger, Stephan; Lyssiotis, Costas A; Grötzinger, Carsten; Barbi, Stefano; Bersani, Samantha; Körner, Jan; Wafy, Ismael; Mafficini, Andrea; Lawlor, Rita T; Simbolo, Michele; Asara, John M; Bläker, Hendrik; Cantley, Lewis C; Wiedenmann, Bertram; Scarpa, Aldo; Hanahan, Douglas

2015-12-01

Seeking to assess the representative and instructive value of an engineered mouse model of pancreatic neuroendocrine tumors (PanNET) for its cognate human cancer, we profiled and compared mRNA and miRNA transcriptomes of tumors from both. Mouse PanNET tumors could be classified into two distinctive subtypes, well-differentiated islet/insulinoma tumors (IT) and poorly differentiated tumors associated with liver metastases, dubbed metastasis-like primary (MLP). Human PanNETs were independently classified into these same two subtypes, along with a third, specific gene mutation-enriched subtype. The MLP subtypes in human and mouse were similar to liver metastases in terms of miRNA and mRNA transcriptome profiles and signature genes. The human/mouse MLP subtypes also similarly expressed genes known to regulate early pancreas development, whereas the IT subtypes expressed genes characteristic of mature islet cells, suggesting different tumorigenesis pathways. In addition, these subtypes exhibit distinct metabolic profiles marked by differential pyruvate metabolism, substantiating the significance of their separate identities. This study involves a comprehensive cross-species integrated analysis of multi-omics profiles and histology to stratify PanNETs into subtypes with distinctive characteristics. We provide support for the RIP1-TAG2 mouse model as representative of its cognate human cancer with prospects to better understand PanNET heterogeneity and consider future applications of personalized cancer therapy. ©2015 American Association for Cancer Research.

A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics

PubMed Central

Sadanandam, Anguraj; Wullschleger, Stephan; Lyssiotis, Costas A.; Grötzinger, Carsten; Barbi, Stefano; Bersani, Samantha; Körner, Jan; Wafy, Ismael; Mafficini, Andrea; Lawlor, Rita T.; Simbolo, Michele; Asara, John M.; Bläker, Hendrik; Cantley, Lewis C.; Wiedenmann, Bertram; Scarpa, Aldo; Hanahan, Douglas

2016-01-01

Seeking to assess the representative and instructive value of an engineered mouse model of pancreatic neuroendocrine tumors (PanNET) for its cognate human cancer, we profiled and compared mRNA and miRNA transcriptomes of tumors from both. Mouse PanNET tumors could be classified into two distinctive subtypes, well-differentiated islet/insulinoma tumors (IT) and poorly differentiated tumors associated with liver metastases, dubbed metastasis-like primary (MLP). Human PanNETs were independently classified into these same two subtypes, along with a third, specific gene mutation–enriched subtype. The MLP subtypes in human and mouse were similar to liver metastases in terms of miRNA and mRNA transcriptome profiles and signature genes. The human/mouse MLP subtypes also similarly expressed genes known to regulate early pancreas development, whereas the IT subtypes expressed genes characteristic of mature islet cells, suggesting different tumorigenesis pathways. In addition, these subtypes exhibit distinct metabolic profiles marked by differential pyruvate metabolism, substantiating the significance of their separate identities. SIGNIFICANCE This study involves a comprehensive cross-species integrated analysis of multi-omics profiles and histology to stratify PanNETs into subtypes with distinctive characteristics. We provide support for the RIP1-TAG2 mouse model as representative of its cognate human cancer with prospects to better understand PanNET heterogeneity and consider future applications of personalized cancer therapy. PMID:26446169

Chronic pancreatitis.

PubMed

Yang, Dennis; Forsmark, Chris E

2017-09-01

Summarize key clinical advances in chronic pancreatitis reported in 2016. Early diagnosis of chronic pancreatitis remains elusive. Recent studies suggest that endoscopic ultrasound may be less accurate than previously thought and new MRI techniques may be helpful. Genetic predisposition may independently affect the clinical course of chronic pancreatitis and the risk for pancreatic cancer. Cigarette smoking may have a greater negative impact on chronic pancreatitis than previously thought and moderate alcohol consumption may be protective. A multidisciplinary approach is necessary for the treatment of type 3 diabetes and nutritional deficiencies in chronic pancreatitis. Although endoscopic therapy remains a reasonable first-line option in treating chronic pancreatitis and its complications, early surgical intervention may be indicated for pain in select patients. Newer endoscopic ultrasound and MRI techniques are being evaluated to help with the early diagnosis of chronic pancreatitis. Both genetic predisposition and cigarette smoking are increasingly recognized as having a major impact in the course of the disease and the risk for pancreatic cancer. Endoscopic therapy is well tolerated and effective for the treatment of chronic pancreatitis and its complications although an early surgical approach for pain may be associated with improved clinical outcomes.

Outcomes analysis of laparoscopic resection of pancreatic neoplasms.

PubMed

Pierce, R A; Spitler, J A; Hawkins, W G; Strasberg, S M; Linehan, D C; Halpin, V J; Eagon, J C; Brunt, L M; Frisella, M M; Matthews, B D

2007-04-01

Experience with laparoscopic resection of pancreatic neoplasms remains limited. The purpose of this study is to critically analyze the indications for and outcomes after laparoscopic resection of pancreatic neoplasms. The medical records of all patients undergoing laparoscopic resection of pancreatic neoplasms from July 2000 to February 2006 were reviewed. Data are expressed as mean +/- standard deviation. Laparoscopic pancreatic resection was performed in 22 patients (M:F, 8:14) with a mean age of 56.3 +/- 15.1 years and mean body mass index (BMI) of 26.3 +/- 4.5 kg/m2. Nine patients had undergone previous intra-abdominal surgery. Indications for pancreatic resection were cyst (1), glucagonoma (1), gastrinoma (2), insulinoma (3), metastatic tumor (2), IPMT (4), nonfunctioning neuroendocrine tumor (3), and mucinous/serous cystadenoma (6). Mean tumor size was 2.4 +/- 1.6 cm. Laparoscopic distal pancreatectomy was attempted in 18 patients and completed in 17, and enucleation was performed in 4 patients. Laparoscopic ultrasound (n = 10) and a hand-assisted technique (n = 4) were utilized selectively. Mean operative time was 236 +/- 60 min and mean blood loss was 244 +/- 516 ml. There was one conversion to an open procedure because of bleeding from the splenic vein. The mean postoperative LOS was 4.5 +/- 2.0 days. Seven patients experienced a total of ten postoperative complications, including a urinary tract infection (UTI) (1), lower-extremity deep venous thrombosis (DVT) and pulmonary embolus (1), infected peripancreatic fluid collection (1), pancreatic pseudocyst (1), and pancreatic fistula (6). Five pancreatic fistulas were managed by percutaneous drainage. The reoperation rate was 4.5% and the overall pancreatic-related complication rate was 36.4%. One patient developed pancreatitis and a pseudocyst 5 months postoperatively, which was managed successfully with a pancreatic duct stent. There was no 30-day mortality. Laparoscopic pancreatic resection is safe and

Assessment of the American Joint Commission on Cancer 8th Edition Staging System for Patients with Pancreatic Neuroendocrine Tumors: A Surveillance, Epidemiology, and End Results analysis.

PubMed

Li, Xiaogang; Gou, Shanmiao; Liu, Zhiqiang; Ye, Zeng; Wang, Chunyou

2018-03-01

Although several staging systems have been proposed for pancreatic neuroendocrine tumors (pNETs), the optimal staging system remains unclear. Here, we aimed to assess the application of the newly revised 8th edition American Joint Committee on Cancer (AJCC) staging system for exocrine pancreatic carcinoma (EPC) to pNETs, in comparison with that of other staging systems. We identified pNETs patients from the Surveillance, Epidemiology, and End Results (SEER) database (2004-2014). Overall survival was analyzed using Kaplan-Meier curves with the log-rank test. The predictive accuracy of each staging system was assessed by the concordance index (c-index). Cox proportional hazards regression was conducted to calculate the impact of different stages. In total, 2424 patients with pNETs, including 2350 who underwent resection, were identified using SEER data. Patients with different stages were evenly stratified based on the 8th edition AJCC staging system for EPC. Kaplan-Meier curves were well separated in all patients and patients with resection using the 8th edition AJCC staging system for EPC. Moreover, the hazard ratio increased with worsening disease stage. The c-index of the 8th edition AJCC staging system for EPC was similar to that of the other systems. For pNETs patients, the 8th edition AJCC staging system for EPC exhibits good prognostic discrimination among different stages in both all patients and those with resection. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Pancreatic cancer clinical trials and accrual in the United States.

PubMed

Hoos, William A; James, Porsha M; Rahib, Lola; Talley, Anitra W; Fleshman, Julie M; Matrisian, Lynn M

2013-09-20

Pancreatic cancer clinical trials open in the United States and their accrual were examined to identify opportunities to accelerate progress in the treatment of pancreatic cancer. Pancreatic cancer-specific clinical trials open in the United States in the years 2011 and 2012 were obtained from the Pancreatic Cancer Action Network database. Accrual information was obtained from trial sponsors. The portfolio of pancreatic cancer clinical trials identified by type (adenocarcinoma or neuroendocrine), phase, disease stage, and treatment approach is reported. More than half of trials for patients with pancreatic ductal adenocarcinoma applied biologic insights to new therapeutic approaches, and 38% focused on optimization of radiation or chemotherapy delivery or regimens. In 2011, pancreatic cancer trials required total enrollment of 11,786 patients. Actual accrual to 93.2% of trials was 1,804 patients, an estimated 4.57% of the patients with pancreatic cancer alive in that year. The greatest need was for patients with resectable cancer. Trials open in 2011 enrolled an average of 15% of their total target accrual. Physician recommendations greatly influenced patients' decision to enroll or not enroll onto a clinical trial. Matching to a clinical trial within a 50-mile radius and identifying trials for recurrent/refractory disease were documented as challenges for patient accrual. Overall trial enrollment indicates that pancreatic cancer trials open in 2011 would require 6.7 years on average to complete accrual. These results suggest that harmonizing patient supply and demand for clinical trials is required to accelerate progress toward improving survival in pancreatic cancer.

Cost-effectiveness of modern radiotherapy techniques in locally advanced pancreatic cancer.

PubMed

Murphy, James D; Chang, Daniel T; Abelson, Jon; Daly, Megan E; Yeung, Heidi N; Nelson, Lorene M; Koong, Albert C

2012-02-15

Radiotherapy may improve the outcome of patients with pancreatic cancer but at an increased cost. In this study, the authors evaluated the cost-effectiveness of modern radiotherapy techniques in the treatment of locally advanced pancreatic cancer. A Markov decision-analytic model was constructed to compare the cost-effectiveness of 4 treatment regimens: gemcitabine alone, gemcitabine plus conventional radiotherapy, gemcitabine plus intensity-modulated radiotherapy (IMRT); and gemcitabine with stereotactic body radiotherapy (SBRT). Patients transitioned between the following 5 health states: stable disease, local progression, distant failure, local and distant failure, and death. Health utility tolls were assessed for radiotherapy and chemotherapy treatments and for radiation toxicity. SBRT increased life expectancy by 0.20 quality-adjusted life years (QALY) at an increased cost of $13,700 compared with gemcitabine alone (incremental cost-effectiveness ratio [ICER] = $69,500 per QALY). SBRT was more effective and less costly than conventional radiotherapy and IMRT. An analysis that excluded SBRT demonstrated that conventional radiotherapy had an ICER of $126,800 per QALY compared with gemcitabine alone, and IMRT had an ICER of $1,584,100 per QALY compared with conventional radiotherapy. A probabilistic sensitivity analysis demonstrated that the probability of cost-effectiveness at a willingness to pay of $50,000 per QALY was 78% for gemcitabine alone, 21% for SBRT, 1.4% for conventional radiotherapy, and 0.01% for IMRT. At a willingness to pay of $200,000 per QALY, the probability of cost-effectiveness was 73% for SBRT, 20% for conventional radiotherapy, 7% for gemcitabine alone, and 0.7% for IMRT. The current results indicated that IMRT in locally advanced pancreatic cancer exceeds what society considers cost-effective. In contrast, combining gemcitabine with SBRT increased clinical effectiveness beyond that of gemcitabine alone at a cost potentially acceptable by

Neuroendocrine Tumor: Statistics

MedlinePlus

... Tumor > Neuroendocrine Tumor: Statistics Request Permissions Neuroendocrine Tumor: Statistics Approved by the Cancer.Net Editorial Board , 01/ ... the body. It is important to remember that statistics on the survival rates for people with a ...

Influence of high intensity focused ultrasound (HIFU) treatment to the pancreatic function in pancreatic cancer patients.

PubMed

Shi, Yulan; Ying, Xiao; Hu, Xiaoye; Zhao, Jing; Fang, Xuefeng; Wu, Minghui; Chen, Tian Zhou; Shen, Hong

2015-05-01

Present study was designed to investigate the pancreatic endocrine and exocrine function damage after High Intensity Focused Ultrasound (HIFU) therapy in patients with advanced pancreatic cancer. It was a retrospective analysis of blood glucose and amylase changes in 59 advanced pancreatic cancer patients treated with HIFU from 2010 February to 2014 January. The mean glucose and amylase before HIFU treatment were 6.02mmol/L and 59.17 U/L respectively. After HIFU treatment, it was shown that the mean glucose and amylase levels were 5.66mmol/L and 57.86/L respectively. There was no statistical significance between them. No acute pancreatitis was observed. The endocrine and exocrine function of pancreatic cancer patients was not damaged by HIFU treatment. HIFU treatment for the pancreatic cancer patients seems to be safe.

Safety and Tolerability of Everolimus as Second-line Treatment in Poorly Differentiated Neuroendocrine Carcinoma / Neuroendocrine Carcinoma G3 (WHO 2010) and Neuroendocrine Tumor G3 - an Investigator Initiated Phase II Study

ClinicalTrials.gov

2018-01-19

Poorly Differentiated Malignant Neuroendocrine Carcinoma; Neuroendocrine Carcinoma, Grade 3; Neuroendocrine Carcinoma, Grade 1 [Well-differentiated Neuroendocrine Carcinoma] That Switched to G3; Neuroendocrine Carcinoma, Grade 2 [Moderately Differentiated Neuroendocrine Carcinoma] That Switched to G3; Neuroendocrine Tumor, Grade 3 and Disease Progression as Measured by Response Evaluation Criteria in Solid Tumors (RECIST 1.1.)

New clinical trial explores precision treatment for advanced pancreatic cancer | Center for Cancer Research

Cancer.gov

A new phase II clinical trial to assess the safety and efficacy of a drug called selumetinib for treating patients with advanced pancreatic cancer whose tumors harbor a specific genetic marker has opened at the Center for Cancer Research and is currently recruiting participants. Read more...

Value of endoscopic ultrasound guided fine needle aspiration biopsy in the diagnosis of solid pancreatic masses

PubMed Central

Voss, M; Hammel, P; Molas, G; Palazzo, L; Dancour, A; O'Toole, D; Terris, B; Degott, C; Bernades, P; Ruszniewski, P

2000-01-01

AIM—To assess the feasibility and diagnostic accuracy of endoscopic ultrasound guided fine needle biopsy (EUS-FNAB) in patients with solid pancreatic masses.
METHODS—Ninety nine consecutive patients with pancreatic masses were studied. Histological findings obtained by EUS-FNAB were compared with the final diagnosis assessed by surgery, biopsy of other tumour site or at postmortem examination, or by using a combination of clinical course, imaging features, and tumour markers.
RESULTS—EUS-FNAB was feasible in 90 patients (adenocarcinomas, n = 59; neuroendocrine tumours, n = 15; various neoplasms, n = 6; pancreatitis, n = 10), and analysable material was obtained in 73. Tumour size (⩾ or < 25 mm in diameter) did not influence the ability to obtain informative biopsy samples. Diagnostic accuracy was 74.4% (adenocarcinomas, 81.4%; neuroendocrine tumours, 46.7%; other lesions, 75%; p<0.02). Overall, the diagnostic yield in all 99 patients was 68%. Successful biopsies were performed in six patients with portal hypertension. Minor complications (moderate bleeding or pain) occurred in 5% of cases.
CONCLUSIONS—EUS-FNAB is a useful and safe method for the investigation of pancreatic masses, with a high feasibility rate even when lesions are small. Overall diagnostic accuracy of EUS-FNAB seems to depend on the tumour type.


Keywords: pancreas; tumour; endoscopic ultrasound; fine needle aspiration biopsy PMID:10644320

Pathological characteristics and clinical specifications in gastroenteropancreatic neuroendocrine tumors: a study of 68 cases.

PubMed

Stoica-Mustafa, Elena; Pechianu, C; Iorgescu, Andreea; Hortopan, Monica; Dima, Simona Olimpia; Tomulescu, V; Dumitraşcu, T; Ungureanu, C; Andronesi, D; Popescu, I; Herlea, V

2012-01-01

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) represent a group of tumors, having their origin in cells of diffuse endocrine system, with particular clinical course, diagnosis and treatment. In our study, were included 68 patients with neuroendocrine digestive tumors admitted, diagnosed and treated in Fundeni Clinical Institute, Bucharest, in the last ten years--2000-2010 (retrospective study). Thirty-three (49%) patients were males, 35 (51%) females, and the main age was 58.9 years. In 62 (90.3%) cases was possible to find the primary tumor. The examined tumors had different localizations: pancreas--32 (47.04%) cases (head--17 (24.99%) cases, and body and tail--15 (22.05%) cases), stomach--7 (10.29%) cases, small intestine--7 (10.29%) cases, 6 (8.82%) cases--unknown primary site (diagnosis was established on metastases), right colon--6 (8.82%) cases, liver--6 (8.82%) cases, rectum--2 (2.94%) cases, and retroperitoneum--2 (2.94%) cases. Microscopic examination revealed 59 (86.8%) malignant tumors and 9 (13.2%) benign tumors. Using WHO 2000 Classification, 28 cases of malignant tumors were well-differentiated neuroendocrine carcinomas, and 31 cases were poor differentiated neuroendocrine carcinomas. From malignant cases, 25 (42.3%) have distant metastases and 15 (25.9%) lymph node metastases. Cases of gastroenteropancreatic neuroendocrine tumors included in our study had clinical and histopathological features in correspondence with data from literature--slight predominance in women, predominance in 5th and 6th decades of life, the most frequent localizations were at pancreatic level--both head and body and tail, but the rarest were in colon and retroperitoneum. Most of the cases studied, were malignant tumors, from these more than a half were poor differentiated, and a quarter of them having lymph node or distant metastases.

Modified fully covered self-expandable metal stents with antimigration features for benign pancreatic-duct strictures in advanced chronic pancreatitis, with a focus on the safety profile and reducing migration.

PubMed

Moon, Sung-Hoon; Kim, Myung-Hwan; Park, Do Hyun; Song, Tae Joon; Eum, Junbum; Lee, Sang Soo; Seo, Dong Wan; Lee, Sung Koo

2010-07-01

Fully covered self-expandable metal stent (FCSEMS) placement has recently been tried in the management of refractory pancreatic-duct strictures associated with advanced chronic pancreatitis. The major limitation of FCSEMSs was frequent migration. To assess the safety, migration rate, and removability of modified FCSEMSs with antimigration features used for the treatment of benign pancreatic-duct strictures. Prospective study. Tertiary academic center. Thirty-two patients with chronic painful pancreatitis and dominant ductal stricture. Transpapillary endoscopic placement of FCSEMSs in the pancreatic duct with removal after 3 months. Technical and functional success and adverse events associated with the placement of metal stents. FCSEMSs were successfully placed in all patients through the major (n = 27) or minor (n = 5) duodenal papilla. All patients achieved pain relief from stent placement. There was no occurrence of stent-induced pancreatitis or pancreatic sepsis. No stent migrated, and all stents were easily removed. Follow-up ERCP 3 months after stent placement showed resolution of duct strictures in all patients. Pancreatograms obtained at FCSEMS removal displayed de novo focal pancreatic duct strictures in 5 patients, but all were asymptomatic. No long-term follow-up. Temporary 3-month placement of FCSEMSs was effective in resolving pancreatic-duct strictures in chronic pancreatitis, with an acceptable morbidity profile. Modified FCSEMSs can prevent stent migration, but may be associated with de novo duct strictures. Further trials are needed to assess long-term safety and efficacy. Copyright 2010 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.

Immune Checkpoint Inhibitors in the Treatment of Patients with Neuroendocrine Neoplasia.

PubMed

Weber, Matthias M; Fottner, Christian

2018-01-01

Well-differentiated neuroendocrine neoplasms (NENs) are usually controlled by antiproliferative, local ablative and/or radionuclide therapies, whereas poorly differentiated NENs generally require cytotoxic chemotherapy. However, treatment options for patients with advanced/metastatic high-grade NENs remain limited. Review of the literature and international congress abstracts on the efficacy and safety of immunotherapy by checkpoint inhibition in advanced/metastatic NENs. Evidence points to an important role of immune phenomena in the pathogenesis and treatment of neuroendocrine tumors (NETs). Programmed cell death 1 (PD-1) protein and its ligand are mainly expressed in poorly differentiated NENs. Microsatellite instability and high mutational load are more pronounced in high-grade NENs and may predict response to immunotherapy. Clinical experience of immune checkpoint blockade mainly exists for Merkel cell carcinoma, a high-grade cutaneous neuroendocrine carcinoma (NEC), which has led to approval of the anti-PD-1 antibody avelumab. In addition, there is anecdotal evidence for the efficacy of checkpoint inhibitors in large-cell lung NECs, ovarian NECs and others, including gastroenteropancreatic NENs. Currently, phase II studies investigate PDR001, pembrolizumab, combined durvalumab and tremelimumab, and avelumab treatment in patients with advanced/metastatic NENs. Immune checkpoint inhibitors are a promising therapeutic option, especially in progressive NECs or high-grade NETs with high tumor burden, microsatellite instability, and/or mutational load. © 2018 S. Karger GmbH, Freiburg.

Identification of human somatostatin receptor 2 domains involved in internalization and signaling in QGP-1 pancreatic neuroendocrine tumor cell line.

PubMed

Cambiaghi, Valeria; Vitali, Eleonora; Morone, Diego; Peverelli, Erika; Spada, Anna; Mantovani, Giovanna; Lania, Andrea Gerardo

2017-04-01

Somatostatin exerts inhibitory effects on hormone secretion and cell proliferation via five receptor subtypes (SST1-SST5), whose internalization is regulated by β-arrestins. The receptor domains involved in these effects have been only partially elucidated. The aim of the study is to characterize the molecular mechanism and determinants responsible for somatostatin receptor 2 internalization and signaling in pancreatic neuroendocrine QGP-1 cell line, focusing on the third intracellular loop and carboxyl terminal domains. We demonstrated that in cells transfected with somatostatin receptor 2 third intracellular loop mutant, no differences in β-arrestins recruitment and receptor internalization were observed after somatostatin receptor 2 activation in comparison with cells bearing wild-type somatostatin receptor 2. Conversely, the truncated somatostatin receptor 2 failed to recruit β-arrestins and to internalize after somatostatin receptor 2 agonist (BIM23120) incubation. Moreover, the inhibitory effect of BIM23120 on cell proliferation, cyclin D1 expression, P-ERK1/2 levels, apoptosis and vascular endothelial growth factor secretion was completely lost in cells transfected with either third intracellular loop or carboxyl terminal mutants. In conclusion, we demonstrated that somatostatin receptor 2 internalization requires intact carboxyl terminal while the effects of SS on cell proliferation, angiogenesis and apoptosis mediated by somatostatin receptor 2 need the integrity of both third intracellular loop and carboxyl terminal.

Radiofrequency ablation for unresectable locally advanced pancreatic cancer: a systematic review

PubMed Central

Fegrachi, Samira; Besselink, Marc G; van Santvoort, Hjalmar C; van Hillegersberg, Richard; Molenaar, Izaak Quintus

2014-01-01

Background: Median survival in patients with unresectable locally advanced pancreatic cancer lies in the range of 9–15 months. Radiofrequency ablation (RFA) may prolong survival, but data on its safety and efficacy are scarce. Methods: A systematic literature search was performed in PubMed, EMBASE and the Cochrane Library with the syntax ‘(radiofrequency OR RFA) AND (pancreas OR pancreatic)’ for studies published until 1 January 2012. In addition, a search of the proceedings of conferences on pancreatic disease that took place during 2009–2011 was performed. Studies with fewer than five patients were excluded as they were considered to be case reports. The primary endpoint was survival. Secondary endpoints included morbidity and mortality. Results: Five studies involving a total of 158 patients with pancreatic cancer treated with RFA fulfilled the eligibility criteria. These studies reported median survival after RFA of 3–33 months, morbidity related to RFA of 4–37%, mortality of 0–19% and overall morbidity of 10–43%. Pooling of data was not appropriate as the study populations and reported outcomes were heterogeneous. Crucial safety aspects included ensuring a maximum RFA tip temperature of < 90 °C and ensuring minimum distances between the RFA probe and surrounding structures. Conclusions: Radiofrequency ablation seems to be feasible and safe when it is used with the correct temperature and at an appropriate distance from vital structures. It appears to have a positive impact on survival. Multicentre randomized trials are necessary to determine the true effect size of RFA and to minimize the impacts of selection and publication biases. PMID:23600801

Coexistent Ampullary Squamous Cell Carcinoma with Adenocarcinoma of the Pancreatic Duct

PubMed Central

Pathak, Gayatri S.; Deshmukh, Sanjay D.; Yavalkar, Prasanna A.; Ashturkar, Amrut V.

2011-01-01

Primary squamous cell carcinoma (SCC) of ampulla has seldom been reported. However, metastatic SCC to ampulla of Vater is well known. We report a case of primary SCC of ampulla of Vater coexistent with well-differentiated adenocarcinoma of the distal pancreatic duct. A 50-year-old female presented with evidence of obstructive jaundice. Endoscopic retrograde cholangio-pancreatography revealed bulging papilla with ulcero-infiltrative growth at the ampulla of Vater. An initial endoscopic biopsy of the ampullary mass showed a well-differentiated SCC. The patient underwent Whipple's operation. Thorough sampling of the dilated portion of the pancreatic duct showed presence of well-differentiated adenocarcinoma of the distal pancreatic duct. Immunohistochemical study with synaptophysin and chromogranin was done with negative result, ruling out neuroendocrine differentiation. Also, a detailed clinical, endoscopic and radiological examination was carried out, that excluded the presence of primary SCC elsewhere. PMID:22064341

CD133 expression in well-differentiated pancreatic neuroendocrine tumors: a potential predictor of progressive clinical courses.

PubMed

Sakai, Yasuhiro; Hong, Seung-Mo; An, Soyeon; Kim, Joo Young; Corbeil, Denis; Karbanová, Jana; Otani, Kyoko; Fujikura, Kohei; Song, Ki-Byung; Kim, Song Cheol; Akita, Masayuki; Nanno, Yoshihide; Toyama, Hirochika; Fukumoto, Takumi; Ku, Yonson; Hirose, Takanori; Itoh, Tomoo; Zen, Yoh

2017-03-01

The present study aimed to elucidate whether the stemness molecule, CD133, is expressed in well-differentiated pancreatic neuroendocrine tumors (PanNETs; World Health Organization grades 1 and 2) and establish its clinical relevance using 2 separate cohorts. In the first series (n = 178) in which tissue microarrays were available, immunohistochemistry revealed that CD133 was expressed in 14 cases (8%). CD133+ PanNETs had higher TNM stages (P < .01), more frequent lymphovascular invasion (P = .01), and higher recurrence rates (P = .01). In the second cohort (n = 56), the expression of CD133 and CK19 was examined in whole tissue sections. CD133 and CK19 were positive in 10 (18%) and 36 (64%) cases, respectively. CD133 expression correlated with higher pT scores (P < .01), the presence of microscopic venous infiltration (P = .03), and shorter disease-free periods (P < .01). When cases were divided into grade 1 and 2 neoplasms, patients with CD133+ PanNET continued to have shorter disease-free periods than did those with CD133- tumors in both groups (P < .01 and P = .02, respectively). Although CK19+ cases had shorter disease-free periods than did CK19- cases in the whole cohort (P = .02), this difference was less apparent in subanalyses of grade 1 and 2 cases. CD133 expression also appeared to be an independent predictive factor for tumor recurrence in a multivariate analysis (P = .018). The CD133 phenotype was identical between primary and metastatic foci in 17 of 18 cases from which tissues of metastatic deposits were available. In conclusion, the combination of CD133 phenotyping and World Health Organization grading may assist in stratifying patients in terms of the risk of progressive clinical courses. Copyright © 2016 Elsevier Inc. All rights reserved.

The Need for Speed: Neuroendocrine Regulation of Socially-controlled Sex Change.

PubMed

Lamm, Melissa S; Liu, Hui; Gemmell, Neil J; Godwin, John R

2015-08-01

Socially-controlled functional sex change in fishes is a dramatic example of adaptive reproductive plasticity. Functional gonadal sex change can occur within a week while behavioral sex change can begin within minutes. Significant progress has been made in understanding the neuroendocrine bases of this phenomenon at both the gonadal and the neurobiological levels, but a detailed mechanistic understanding remains elusive. We are working with sex-changing wrasses to identify evolutionarily-conserved neuroendocrine pathways underlying this reproductive adaptation. One key model is the bluehead wrasse (Thalassoma bifasciatum), in which sex change is well studied at the behavioral, ecological, and neuroendocrine levels. Bluehead wrasses show rapid increases in aggressive and courtship behaviors with sex change that do not depend on the presence of gonads. The display of male-typical behavior is correlated with the expression of arginine vasotocin, and experiments support a role for this neuropeptide. Estrogen synthesis is also critical in the process. Female bluehead wrasses have higher abundance of aromatase mRNA in the brain and gonads, and estrogen implants block behavioral sex change. While established methods have advanced our understanding of sex change, a full understanding will require new approaches and perspectives. First, contributions of other neuroendocrine systems should be better characterized, particularly glucocorticoid and thyroid signaling. Second, advances in genomics for non-traditional model species should allow conserved mechanisms to be identified with a key next-step being manipulative tests of these mechanisms. Finally, advances in genomics now also allow study of the role of epigenetic modifications and other regulatory mechanisms in the dramatic alterations across the sex-change process. © The Author 2015. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For

The specific localization of advanced glycation end-products (AGEs) in rat pancreatic islets.

PubMed

Morioka, Yuta; Teshigawara, Kiyoshi; Tomono, Yasuko; Wang, Dengli; Izushi, Yasuhisa; Wake, Hidenori; Liu, Keyue; Takahashi, Hideo Kohka; Mori, Shuji; Nishibori, Masahiro

2017-08-01

Advanced glycation end-products (AGEs) are produced by non-enzymatic glycation between protein and reducing sugar such as glucose. Although glyceraldehyde-derived AGEs (Glycer-AGEs), one of the AGEs subspecies, have been reported to be involved in the pathogenesis of various age-relating diseases such as diabetes mellitus or arteriosclerosis, little is known about the pathological and physiological mechanism of AGEs in vivo. In present study, we produced 4 kinds of polyclonal antibodies against AGEs subspecies and investigated the localization of AGEs-modified proteins in rat peripheral tissues, making use of these antibodies. We found that Glycer-AGEs and methylglyoxal-derived AGEs (MGO-AGEs) were present in pancreatic islets of healthy rats, distinguished clearly into the pancreatic α and β cells, respectively. Although streptozotocin-induced diabetic rats suffered from remarkable impairment of pancreatic islets, the localization and deposit levels of the Glycer- and MGO-AGEs were not altered in the remaining α and β cells. Remarkably, the MGO-AGEs in pancreatic β cells were localized into the insulin-secretory granules. These results suggest that the cell-specific localization of AGEs-modified proteins are presence generally in healthy peripheral tissues, involved in physiological intracellular roles, such as a post-translational modulator contributing to the secretory and/or maturational functions of insulin. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

[Advance in the biology of pancreatic of cancer].

PubMed

Buscail, Louis; Bournet, Barbara; Dufresne, Marlène; Torrisani, Jérôme; Cordelier, Pierre

2015-06-01

The understanding of the biology of pancreatic carcinoma has greatly benefited from studies of genetic/epigenetic alterations and molecular expression in experimental models as well as precancerous and cancerous tissues by mean of molecular amplification and large-scale transcriptoma analysis. P16, TP53, DPC4/Smad4 tumor suppressor pathways are genetically inactivated in the majority of pancreatic carcinomas, whereas oncogenic k-ras is activated. The activating point mutation of the KRAS oncogene on codon 12 is the major event and occurs early in pancreatic carcinogenesis. At a late stage of tumor development, an increase of telomerase activity, an over expression of growth factors and/or their receptors (EGF, Nerve Growth Factor, gastrin), of pro-angiogenic factors (VEGF, FGF, PDGF), of invasiveness factors (metalloproteinases, tissue plasminogen activators) occurs. The microenvironment plays also a key role in the invasive and metastatic process of pancreatic carcinoma with a strong relationship between cancerous cells and pancreatic stellate cells as well as extracellular matrix. This microenvironment strongly participates to the tumor fibrosis, hypoxia and hypovascularization inducing an inaccessibility of drugs. Nowadays, the targeting of microenvironment takes a special place in the new therapeutic strategies of pancreatic cancer in combination with chemotherapy. Copyright © 2015 Société Françise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS. All rights reserved.

Strategies for early detection of resectable pancreatic cancer

PubMed Central

Okano, Keiichi; Suzuki, Yasuyuki

2014-01-01

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. PMID:25170207

Volumetric laser endomicroscopy in the biliary and pancreatic ducts: a feasibility study with histological correlation.

PubMed

Corral, Juan E; Mousa, Omar Y; Krishna, Murli; Levink, Iris J M; Pursell, Khela R; Afsh, Mohammad; Kröner, Paul T; Harnois, Denise M; Wolfsen, Herbert C; Wallace, Michael B; Lukens, Frank J

2018-06-18

 Volumetric laser endomicroscopy (VLE) provides circumferential images 3 mm into the biliary and pancreatic ducts. We aimed to correlate VLE images with the normal and abnormal microstructure of these ducts. Samples from patients undergoing hepatic or pancreatic resection were evaluated. VLE images were collected using a low-profile VLE catheter inserted manually into the biliary and pancreatic ducts ex vivo. Histological correlation was assessed by two unblinded investigators.  25 patients (20 liver and 5 pancreatic samples) and 111 images were analyzed. VLE revealed three histological layers: epithelium, connective tissue, and parenchyma. It identified distinctive patterns for primary sclerosing cholangitis (PSC), pancreatic cysts, neuroendocrine tumor, and adenocarcinoma adjacent to the pancreatic duct or ampulla. VLE failed to identify dysplasia in a dominant stricture and inflammatory infiltrates in PSC. Reflectivity measurements of the liver parenchyma diagnosed liver cirrhosis with high sensitivity.  VLE can identify histological changes in the biliary and pancreatic ducts allowing real-time diagnosis. Further studies are needed to measure the accuracy of VLE in a larger sample and to validate our findings in vivo. © Georg Thieme Verlag KG Stuttgart · New York.

Phase II Study of Oral S-1 and Concurrent Radiotherapy in Patients With Unresectable Locally Advanced Pancreatic Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sudo, Kentaro, E-mail: kentarosudo9@yahoo.co.j; Yamaguchi, Taketo; Ishihara, Takeshi

2011-05-01

Purpose: S-1 is an oral fluoropyrimidine derivative that has demonstrated favorable antitumor activity in patients with metastatic pancreatic cancer. The aim of this study was to evaluate safety and efficacy of S-1 and concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer. Methods and Materials: Patients with histopathologically proven, unresectable, locally advanced pancreatic cancer were eligible. Radiotherapy was delivered in 1.8 Gy daily fractions to a total dose of 50.4 Gy over 5.5 weeks. S-1 was administered orally twice a day at a dose of 80 mg/m{sup 2}/day from day 1 to 14 and 22 to 35. Two weeksmore » after the completion of chemoradiotherapy, maintenance chemotherapy with S-1 was administered for 28 days every 6 weeks until progression. Results: Thirty-four patients were enrolled in this study. The most common Grade 3 toxicities during chemoradiotherapy were anorexia (24%) and nausea (12%). The overall response rate was 41% (95% confidence interval, 25%-58%) and overall disease control rate (partial response plus stable disease) was 97%. More than 50% decrease in serum CA 19-9 was seen in 27 of 29 evaluable patients (93%). The median progression-free survival was 8.7 months. The median overall survival and 1-year survival rate were 16.8 months and 70.6%, respectively. Conclusions: Oral S-1 and concurrent radiotherapy exerted a promising antitumor activity with acceptable toxicity in patients with locally advanced pancreatic cancer. This combination therapy seems to be an attractive alternative to conventional chemoradiotherapy using 5-fluorouracil infusion.« less

Theranostics of Neuroendocrine Tumors.

PubMed

Lee, Sze Ting; Kulkarni, Harshad R; Singh, Aviral; Baum, Richard P

2017-10-01

Somatostatin receptor positron emission tomography/computed tomography using 68 Ga-labeled somatostatin analogs is the mainstay for the evaluation of receptor status in neuroendocrine tumors (NETs). This translates towards better therapy options, with increasing evidence of peptide receptor radionuclide therapy (PRRT) as the treatment of choice for advanced or progressive NETs. There are benefits in progression-free and overall survival as well as a significant improvement in clinical condition. In patients with progressive NETs, fractionated, personalized PRRT results in good therapeutic responses with no significant severe hematological and/or renal toxicity, thus improving quality of life.

A Pilot Trial of Early Specialty Palliative Care for Patients with Advanced Pancreatic Cancer: Challenges Encountered and Lessons Learned.

PubMed

Schenker, Yael; Bahary, Nathan; Claxton, Rene; Childers, Julie; Chu, Edward; Kavalieratos, Dio; King, Linda; Lembersky, Barry; Tiver, Greer; Arnold, Robert M

2018-01-01

Patients with advanced pancreatic cancer suffer from high morbidity and mortality. Specialty palliative care may improve quality of life. Assess the feasibility, acceptability, and perceived effectiveness of early specialty physician-led palliative care for patients with advanced pancreatic cancer and their caregivers. A mixed-methods pilot randomized controlled trial in which patient-caregiver pairs were randomized (2:1) to receive specialty palliative care, in addition to standard oncology care versus standard oncology care alone. At a National Cancer Institute-designated comprehensive cancer center in Western Pennsylvania, 30 patients with advanced pancreatic adenocarcinoma and their caregivers (N = 30), oncologists (N = 4), and palliative care physicians (N = 3) participated. Feasibility (enrollment, three-month outcome-assessment, and intervention completion rates), acceptability, and perceived effectiveness (process interviews with patients, caregivers, and physicians). Consent:approach rate was 49%, randomized:consent rate 55%, and three-month outcome assessment rate 75%. Two patients and three caregivers withdrew early. The three-month mortality rate was 13%. Patients attended a mean of 1.3 (standard deviation 1.1) palliative care visits during the three-month period. Positive experiences with palliative care included receiving emotional support and symptom management. Negative experiences included inconvenience, long travel times, spending too much time at the cancer center, and no perceived palliative care needs. Physicians suggested embedding palliative care within oncology clinics, tailoring services to patient needs, and facilitating face-to-face communication between oncologists and palliative physicians. A randomized trial of early palliative care for advanced pancreatic cancer did not achieve feasibility goals. Integrating palliative care within oncology clinics may increase acceptability and perceived effectiveness.

Current Concepts in Neuroendocrine Disruption

PubMed Central

2014-01-01

In the last few years, it has become clear that a wide variety of environmental contaminants have specific effects on neuroendocrine systems in fish, amphibians, birds and mammals. While it is beyond the scope of this review to provide a comprehensive examination of all of these neuroendocrine disruptors, we will focus on select representative examples. Organochlorine pesticides bioaccumulate in neuroendocrine areas of the brain that directly regulate GnRH neurons, thereby altering the expression of genes downstream of GnRH signaling. Organochlorine pesticides can also agonize or antagonize hormone receptors, adversely affecting crosstalk between neurotransmitter systems. The impacts of polychlorinated biphenyls are varied and in many cases subtle. This is particularly true for neuroedocrine and behavioral effects of exposure. These effects impact sexual differentiation of the hypothalamic-pituitary-gonadal axis, and other neuroendocrine systems regulating the thyroid, metabolic, and stress axes and their physiological responses. Weakly estrogenic and anti-androgenic pollutants such as bisphenol A, phthalates, phytochemicals, and the fungicide vinclozolin can lead to severe and widespread neuroendocrine disruptions in discrete brain regions, including the hippocampus, amygdala, and hypothalamus, resulting in behavioral changes in a wide range of species. Behavioral features that have been shown to be affected by one or more these chemicals include cognitive deficits, heightened anxiety or anxiety-like, sociosexual, locomotor, and appetitive behaviors. Neuroactive pharmaceuticals are now widely detected in aquatic environments and water supplies through the release of wastewater treatment plant effluents. The antidepressant fluoxetine is one such pharmaceutical neuroendocrine disruptor. Fluoxetine is a selective serotonin reuptake inhibitor that can affect multiple neuroendocrine pathways and behavioral circuits, including disruptive effects on reproduction and

Incidence of and risk factors for developing pancreatic cancer in patients with chronic pancreatitis.

PubMed

Kudo, Yujin; Kamisawa, Terumi; Anjiki, Hajime; Takuma, Kensuke; Egawa, Naoto

2011-01-01

Pancreatic cancer sometimes occurs during the course of chronic pancreatitis. This study aimed to identify risk factors for developing pancreatic cancer associated with chronic pancreatitis. The incidence of pancreatic cancer developing in 218 patients with chronic pancreatitis and clinical features of the chronic pancreatitis patients who developed pancreatic cancer were studied. Nine patients developed pancreatic cancer. Average period from the diagnosis of chronic pancreatitis to the diagnosis of pancreatic cancer was 9.6 years. All pancreatic cancers were diagnosed at an advanced stage. Only 2 patients had been followed-up periodically. There were no significant differences between chronic pancreatitis patients who developed pancreatic cancer and those who did not in male/female ratio (3.5 vs. 8), average age on diagnosis (65.0 vs. 56.5), alcoholic/non-alcoholic chronic pancreatitis (1.6 vs. 2.6), smoking habits (62.5% vs. 70.7%), diabetes mellitus (77.8% vs. 54.4%), and continued alcohol drinking (37.5% vs. 53.1%). Over the period examined, 4% of chronic pancreatitis patients developed pancreatic cancer. Sex ratio, onset age, etiology, smoking habits, diabetes mellitus, and continued alcohol drinking were not significant risk factors for developing pancreatic cancer in chronic pancreatitis patients. Periodic follow-up due to the possibility of pancreatic cancer is necessary in chronic pancreatitis patients.

Recent Progress in Pancreatic Cancer

PubMed Central

Wolfgang, Christopher L.; Herman, Joseph M.; Laheru, Daniel A.; Klein, Alison P.; Erdek, Michael A.; Fishman, Elliot K.; Hruban, Ralph H.

2013-01-01

Pancreatic cancer is currently one of the deadliest of the solid malignancies. However, surgery to resect neoplasms of the pancreas is safer and less invasive than ever, novel drug combinations have been shown to improve survival, advances in radiation therapy have resulted in less toxicity, and enormous strides have been made in our understanding of the fundamental genetics of pancreatic cancer. These advances provide hope but they also increase the complexity of caring for patients. It is clear that multidisciplinary care that provides comprehensive and coordinated evaluation and treatment is the most effective way to manage patients with pancreatic cancer. PMID:23856911

Supportive and palliative care of pancreatic cancer.

PubMed

Fazal, Salman; Saif, Muhammad Wasif

2007-03-10

Pancreatic cancer is one of the most lethal malignancies. An estimated 32,300 patients will die of pancreatic cancer in year 2006. It is the tenth most common malignancy in the United States. Despite recent advances in pathology, molecular basis and treatment, the overall survival rate remains 4% for all stages and races. Palliative care represents an important aspect of care in patient with pancreatic malignancy. Identifying and treating disease related symptomology are priorities. As a physician taking care of these patients it is essential to know these symptoms and treatment modalities. This review discusses symptom management and supportive care strategies. Common problems include pain, intestinal obstruction, biliary obstruction, pancreatic insufficiency, anorexia-cachexia and depression. Success is needed in managing these symptoms to palliate patients with advanced pancreatic cancer. Pancreatic cancer is a model illness to learn the palliative and supportive management in cancer patient. It is important for oncologists to recognize the importance of control measures and supportive measures that can minimize the symptoms of advanced disease and side effects of cancer treatment.

Quality of life of patients with advanced pancreatic cancer during treatment with mistletoe: a randomized controlled trial.

PubMed

Tröger, Wilfried; Galun, Danijel; Reif, Marcus; Schumann, Agnes; Stanković, Nikola; Milićević, Miroslav

2014-07-21

The treatment of cancer patients with mistletoe extract is said to prolong their survival and, above all, improve their quality of life. We studied whether the quality of life of patients with advanced pancreatic cancer could be improved by mistletoe extract. An open, single-center, group-sequential, randomized phase III trial (ISRCTN70760582) was conducted. From January 2009 to December 2010, 220 patients with locally advanced or metastatic pancreatic cancer who were receiving no further treatment for pancreatic cancer other than best supportive care were included in this trial. They were stratified by prognosis and randomly allocated either to a group that received mistletoe treatment or to one that did not. Mistletoe extract was given in escalating doses by subcutaneous injection three times a week. The planned interim evaluation of data from 220 patients indicated that mistletoe treatment was associated with longer overall survival, and the trial was terminated prematurely. After termination of the study, the results with respect to quality of life (assessed with the QLO-C30 scales of the European Organisation for Research and Treatment of Cancer) and trends in body weight were evaluated. Data on quality of life and body weight were obtained from 96 patients treated with mistletoe and 72 control patients. Those treated with mistletoe did better on all 6 functional scales and on 7 of 9 symptom scales, including pain (95% confidence interval [CI] -29 to -17), fatigue (95% CI -36.1 to -25.0), appetite loss (95% CI -51 to -36.7), and insomnia (95% CI -45.8 to -28.6). This is reflected by the trend in body weight during the trial. In patients with locally advanced or metastatic pancreatic carcinoma, mistletoe treatment significantly improves the quality of life in comparison to best supportive care alone. Mistletoe is an effective second-line treatment for this disease.

Advances in the endoscopic management of pancreatic collections.

PubMed

Ruiz-Clavijo, David; de la Higuera, Belen González; Vila, Juan J

2015-04-16

Treatment of pancreatic collections has experienced great progress in recent years with the emergence of alternative minimally invasive techniques comparing to the classic surgical treatment. Such techniques have been shown to improve outcomes of morbidity vs surgical treatment. The recent emergence of endoscopic drainage is noteworthy. The advent of endoscopic ultrasonography has been crucial for treatment of these specific lesions. They can be characterized, their relationships with neighboring structures can be evaluated and the drainage guided by this technique has been clearly improved compared with the conventional endoscopic drainage. Computed tomography is the technique of choice to characterize the recently published new classification of pancreatic collections. For this reason, the radiologist's role establishing and classifying in a rigorously manner the collections according to the new nomenclature is essential to making therapeutic decisions. Ideal scenario for comprehensive treatment of these collections would be those centers with endoscopic ultrasound and interventional radiology expertise together with hepatobiliopancreatic surgery. This review describes the different types of pancreatic collections: acute peripancreatic fluid collection, pancreatic pseudocysts, acute necrotic collection and walled-off necrosis; the indications and the contraindications for endoscopic drainage, the drainage technique and their outcomes. The integrated management of pancreatic collections according to their type and evolution time is discussed.

Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium

PubMed Central

Wroblewski, Kristen; Wallace, James A.; Hall, Michael J.; Locker, Gershon; Nattam, Sreenivasa; Agamah, Edem; Stadler, Walter M.; Vokes, Everett E.

2015-01-01

Summary Background Sorafenib, an inhibitor of B-raf, VEGFR2, and PDGFR-β, has activity against pancreatic cancer in preclinical models. In a phase I trial of gemcitabine plus sorafenib, 57% of pancreatic cancer patients achieved stable disease. Patients and methods We conducted a multi-center phase II trial of sorafenib plus gemcitabine in chemo-naïve patients with histologicallyconfirmed, advanced pancreatic cancer. Patients received sorafenib 400 mg twice daily and gemcitabine 1,000 mg/m2 on days 1, 8 and 15 of a 28 day cycle. Results Seventeen patients enrolled at 4 centers; 13 were evaluable for response. There were no objective responses; 18% had stable disease. Median overall survival was 4.0 months (95% CI: 3.4, 5.9); median progression-free survival was 3.2 months (95% CI: 1.6, 3.6). Grade 3/4 toxicities included thrombosis in 18% of patients, dehydration or hand-foot syndrome in 12%, and hypertension or gastrointestinal bleeding in 6%. Conclusion Gemcitabine plus sorafenib is inactive in advanced pancreatic cancer. PMID:20803052

Ultrasonography in diagnosing chronic pancreatitis: New aspects

PubMed Central

Dimcevski, Georg; Erchinger, Friedemann G; Havre, Roald; Gilja, Odd Helge

2013-01-01

The course and outcome is poor for most patients with pancreatic diseases. Advances in pancreatic imaging are important in the detection of pancreatic diseases at early stages. Ultrasonography as a diagnostic tool has made, virtually speaking a technical revolution in medical imaging in the new millennium. It has not only become the preferred method for first line imaging, but also, increasingly to clarify the interpretation of other imaging modalities to obtain efficient clinical decision. We review ultrasonography modalities, focusing on advanced pancreatic imaging and its potential to substantially improve diagnosis of pancreatic diseases at earlier stages. In the first section, we describe scanning techniques and examination protocols. Their consequences for image quality and the ability to obtain complete and detailed visualization of the pancreas are discussed. In the second section we outline ultrasonographic characteristics of pancreatic diseases with emphasis on chronic pancreatitis. Finally, new developments in ultrasonography of the pancreas such as contrast enhanced ultrasound and elastography are enlightened. PMID:24259955

New Insights into the Pathogenesis of Pancreatitis

PubMed Central

Sah, Raghuwansh P.; Dawra, Rajinder K.; Saluja, Ashok K.

2014-01-01

Purpose of review In this article, we review important advances in our understanding of the mechanisms of pancreatitis. Recent Findings The relative contribution of intra-pancreatic trypsinogen activation and NFκB activation, the two major early independent cellular events in the etiology of pancreatitis, have been investigated using novel genetic models. Trypsinogen activation has traditionally held the spotlight for many decades as it is believed to be the central pathogenic event of pancreatitis However, recent experimental evidence points to the role of trypsin activation in early acinar cell damage but not in the inflammatory response of acute pancreatitis through NFκB activation. Further, chronic pancreatitis in the caerulein model develops independently of typsinogen activation. Sustained activation of the NFκB pathway, but not persistent intra-acinar expression of active trypsin, was shown to result in chronic pancreatitis. Calcineurin-NFAT signaling was shown to mediate downstream effects of pathologic rise in intracellular calcium. IL-6 was identified as a key cytokine mediating pancreatitis-associated lung injury. Summary Recent advances challenge the long-believed trypsin-centered understanding of pancreatitis. It is becoming increasingly clear that activation of intense inflammatory signaling mechanisms in acinar cells is crucial to the pathogenesis of pancreatitis, which may explain the strong systemic inflammatory response in pancreatitis. PMID:23892538

Apatinib concurrent gemcitabine for controlling malignant ascites in advanced pancreatic cancer patient: A case report.

PubMed

Liang, Lijun; Wang, Lei; Zhu, Panrong; Xia, Youyou; Qiao, Yun; Hui, Kaiyuan; Hu, Chenxi; Ren, Yan; Jiang, Xiaodong

2017-11-01

Malignant ascites (MA) is one of the poor prognostic factors for advanced pancreatic cancer and can bring about serious symptoms. The improvement of quality of life for patients is priority. However, there is no standard method for the treatment for pancreatic cancer-mediated MA. Apatinib is a novel and highly selective tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2. There are no reports of concurrent apatinib with gemcitabine in patients with pancreatic cancer-mediated MA. Herein, we presented a 64-year-old man patient who visited hospital due to abdominal pain for 1 month. He was initially diagnosed with pancreatic cancer and his first symptom was MA. After failing in tube drainage and gemcitabine therapy, the patient received gemcitabine combined apatinib orally and after administrated 1 month, the MA was evaluated as nearly clear response according to the RECIST 1.1 standard, and without further need of paracentesis. The CEA and CA199 reached the lowest level after administrating for 2.5 months during the treatment process. 10.5 months following apatinib administration, the patient achieved a progression-free survival for more than 11 months. Hypertension (grade IV), hand-foot syndrome (grade I) and proteinuria (grade II) were observed. It indicated that apatinib concurrent gemcitabine may be a superior choice for pancreatic cancer-mediated MA. Further clinical trials required to confirm its efficacy and safety. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

Screening for Pancreatic Cancer

PubMed Central

Brand, Randall E.

2007-01-01

Despite improvements in the clinical and surgical management of pancreatic cancer, limited strides have been made in the early detection of this highly lethal malignancy. The majority of localized pancreatic tumors are asymptomatic, and the recognized presenting symptoms of pancreatic adenocarcinoma are often vague and heterogeneous in nature. These factors, coupled with the lack of a sensitive and noninvasive screening method, have made population-based screening for pancreatic cancer impossible. Nevertheless, at least two large institutions have performed multimodality-screening protocols for individuals with high risk of pancreatic cancer based on genetic predisposition and strong family history. Abnormalities noted during these screening protocols prompted further investigation or surgery that resulted in the discovery of benign, potentially malignant, and malignant pancreatic lesions. In addition to ductal epithelial pancreatic intraepithelial neoplasia, greater sensitivity has recently been achieved in the identification and characterization of precancerous mucinous pancreatic tumors. Advancements in proteomics and DNA microarray technology may confirm serum-based biomarkers that could be incorporated into future screening algorithms for pancreatic cancer. PMID:21960811

Necrolytic migratory erythema associated with a glucagon-producing primary hepatic neuroendocrine carcinoma in a cat.

PubMed

Asakawa, Midori G; Cullen, John M; Linder, Keith E

2013-08-01

In humans, necrolytic migratory erythema (NME) is a syndrome with a characteristic skin rash that is associated most often with a pancreatic glucagonoma and is recognized as part of the glucagonoma syndrome. In veterinary medicine, NME (also called as superficial necrolytic dermatitis, hepatocutaneous syndrome or metabolic epidermal necrosis) has been described in dogs in association with chronic liver diseases or, less frequently, glucagonoma, but NME associated with glucagonoma has not previously been reported in cats. A 6-year-old male neutered domestic short hair cat was diagnosed with NME associated with a glucagon-producing primary hepatic neuroendocrine carcinoma (hepatic carcinoid). The cat presented with a 2 week history of vomiting and anorexia, and a 5-cm-diameter liver mass was detected by abdominal ultrasound. The cat exhibited general weakness, crusted skin lesions and pain in all four limbs. It was euthanized 11 months after the initial presentation. Histopathological review of the paw pads revealed the classic 'red, white and blue' lesion composed of parakeratotic hyperkeratosis, epidermal hydropic change and hyperbasophilia of the deep epidermis. The liver mass was diagnosed as a neuroendocrine carcinoma (hepatic carcinoid). Neoplastic cells were strongly immunoreactive for glucagon. This is the first case report of NME associated with a glucagon-producing primary hepatic neuroendocrine carcinoma in a cat. © 2013 The Authors. Veterinary Dermatology © 2013 ESVD and ACVD.

Management of acute pancreatitis in children.

PubMed

Abu-El-Haija, Maisam; Lin, Tom K; Nathan, Jaimie D

2017-10-01

Pediatric acute pancreatitis has been on the rise in the last decades, with an incidence close to adult pancreatitis. In the majority of cases acute pancreatitis resolves spontaneously, but in a subset of children the disease progresses to severe acute pancreatitis with attendant morbidity and mortality. Pediatric acute pancreatitis in this era is recognized as a separate entity from adult acute pancreatitis given that the causes and disease outcomes are different. There are slow but important advances made in understanding the best management for acute pancreatitis in children from medical, interventional, and surgical aspects. Supportive care with fluids, pain medications, and nutrition remain the mainstay for acute pancreatitis management. For complicated or severe pancreatitis, specialized interventions may be required with endoscopic or drainage procedures. Surgery has an important but limited role in pediatric acute pancreatitis.

Risk and protective factors for the occurrence of sporadic pancreatic endocrine neoplasms.

PubMed

Valente, Roberto; Hayes, Alastair J; Haugvik, Sven-Petter; Hedenström, Per; Siuka, Darko; Korsæth, Emilie; Kämmerer, Daniel; Robinson, Stuart M; Maisonneuve, Patrick; Delle Fave, Gianfranco; Lindkvist, Bjorn; Capurso, Gabriele

2017-08-01

Pancreatic neuroendocrine neoplasms (PNENs) represent 10% of all pancreatic tumors by prevalence. Their incidence has reportedly increased over recent decades in parallel with that of pancreatic adenocarcinoma. PNENs are relatively rare, and of the few institutions that have published potential risk factors, findings have been heterogeneous. Our objective was to investigate the association between potential risk and protective factors for the occurrence of sporadic PNENs across a European population from several institutions. A multinational European case-control study was conducted to examine the association of selected environmental, family and medical exposure factors using a standardized questionnaire in face-to-face interviews. A ratio of 1:3 cases to controls were sex and age matched at each study site. Adjusted univariate and multivariate logistic regression analysis were performed for statistically significant factors. The following results were obtained: In 201 cases and 603 controls, non-recent onset diabetes (OR 2.09, CI 1.27-3.46) was associated with an increased occurrence of PNENs. The prevalence of non-recent onset diabetes was higher both in cases with metastatic disease (TNM stage III-IV) or advanced grade (G3) at the time of diagnosis. The use of metformin in combination with insulin was also associated with a more aggressive phenotype. Drinking coffee was more frequent in cases with localized disease at diagnosis. Our study concluded that non-recent onset diabetes was associated with an increased occurrence of PNENs and the combination of metformin and insulin was consistent with a more aggressive PNEN phenotype. In contrast to previous studies, smoking, alcohol and first-degree family history of cancer were not associated with PNEN occurrence. © 2017 Society for Endocrinology.

Endoscopic ultrasound-guided radiofrequency ablation for management of benign solid pancreatic tumors.

PubMed

Choi, Jun-Ho; Seo, Dong-Wan; Song, Tae Jun; Park, Do Hyun; Lee, Sang Soo; Lee, Sung Koo; Kim, Myung-Hwan

2018-05-04

 Radiofrequency ablation (RFA) has been increasingly employed in experimental and clinical settings for the management of pancreatic lesions. This study aimed to assess the safety and efficacy of endoscopic ultrasound (EUS)-guided RFA for benign solid pancreatic tumors.  In a single-center, prospective study, 10 patients with benign solid pancreatic tumors underwent EUS-RFA. After the RFA electrode had been inserted into the pancreatic mass, the radiofrequency generator was activated to deliver 50 W of ablation power.  Among the 10 patients, 16 sessions of EUS-RFA were successfully performed. Diagnoses included nonfunctioning neuroendocrine tumor (n = 7), solid pseudopapillary neoplasm (n = 2), and insulinoma (n = 1); the median largest diameter of the tumors was 20 mm (range 8 - 28 mm). During follow-up (median 13 months), radiologic complete response was achieved in seven patients. Two adverse events (12.4 %; 1 moderate and 1 mild) occurred.  EUS-RFA may be a safe and potentially effective treatment option in selected patients with benign solid pancreatic tumors. Multiple sessions may be required if there is a remnant tumor, and adverse events must be carefully monitored. © Georg Thieme Verlag KG Stuttgart · New York.

[177Lu-DOTA]0-D-Phe1-Tyr3-Octreotide (177Lu-DOTATOC) For Peptide Receptor Radiotherapy in Patients with Advanced Neuroendocrine Tumours: A Phase-II Study

PubMed Central

Baum, Richard P.; Kluge, Andreas W.; Kulkarni, Harshad; Schorr-Neufing, Ulrike; Niepsch, Karin; Bitterlich, Norman; van Echteld, Cees J.A.

2016-01-01

Purpose: To characterise efficacy and safety of 177Lu-DOTATOC as agent for peptide receptor radiotherapy (PRRT) of advanced neuroendocrine tumours (NET). Patients and methods: Fifty-six subjects with metastasized and progressive NET (50% gastroenteral, 26.8% pancreatic, 23.2% other primary sites) treated consecutively with 177Lu-DOTATOC were analysed retrospectively. Subjects were administered 177Lu-DOTATOC (mean 2.1 cycles; range 1-4) as 7.0GBq (median) doses at three-monthly intervals. Efficacy was analysed using CT and/or MRI according to RECIST 1.1 criteria and results were stratified for the number of administered cycles and the primary tumour origin. Results: In the total NET population (A), median progression-free (PFS) and overall survival (OS) were 17.4 and 34.2 months, respectively, assessed in a follow-up time (mean ± SD) of 16.1 ± 12.4 months. In patients receiving more than one cycle, mean follow-up time was 22.4 ± 11.0 months for all NETs (B) and PFS was 32.0 months for all NETs (B), 34.5 months for GEP-NET (C), and 11.9 months for other NETs (D). Objective response rates (Complete/Partial Responses) were 33.9%, 40.6%, 54.2%, and 0% for A, B, C, and D groups, respectively, while disease control rates in the same were 66.1%, 93.8%, 100%, and 75%. Complete responses (16.1%, 18.8% and 25.0% for groups A, B and C) were high, 78% of which were maintained throughout the follow up. There were no serious adverse events. One case of self-limiting grade 3 myelotoxicity was reported. Although 20% of patients had mild renal insufficiency at baseline, there was no evidence of exacerbated or de novo renal toxicity after treatment. Conclusion: 177Lu-DOTATOC is a novel agent for PRRT with major potential to induce objective tumour responses and sustained disease control in progressive neuroendocrine tumours, even when administered in moderate activities. The observed safety profile suggests a particularly favourable therapeutic index, including in patients with

Characterization of pancreatic glucagon-producing tumors and pituitary gland tumors in transgenic mice overexpressing MYCN in hGFAP-positive cells.

PubMed

Fielitz, Kathrin; Althoff, Kristina; De Preter, Katleen; Nonnekens, Julie; Ohli, Jasmin; Elges, Sandra; Hartmann, Wolfgang; Klöppel, Günter; Knösel, Thomas; Schulte, Marc; Klein-Hitpass, Ludger; Beisser, Daniela; Reis, Henning; Eyking, Annette; Cario, Elke; Schulte, Johannes H; Schramm, Alexander; Schüller, Ulrich

2016-11-15

Amplification or overexpression of MYCN is involved in development and maintenance of multiple malignancies. A subset of these tumors originates from neural precursors, including the most aggressive forms of the childhood tumors, neuroblastoma and medulloblastoma. In order to model the spectrum of MYCN-driven neoplasms in mice, we transgenically overexpressed MYCN under the control of the human GFAP-promoter that, among other targets, drives expression in neural progenitor cells. However, LSL-MYCN;hGFAP-Cre double transgenic mice did neither develop neural crest tumors nor tumors of the central nervous system, but presented with neuroendocrine tumors of the pancreas and, less frequently, the pituitary gland. Pituitary tumors expressed chromogranin A and closely resembled human pituitary adenomas. Pancreatic tumors strongly produced and secreted glucagon, suggesting that they derived from glucagon- and GFAP-positive islet cells. Interestingly, 3 out of 9 human pancreatic neuroendocrine tumors expressed MYCN, supporting the similarity of the mouse tumors to the human system. Serial transplantations of mouse tumor cells into immunocompromised mice confirmed their fully transformed phenotype. MYCN-directed treatment by AuroraA- or Brd4-inhibitors resulted in significantly decreased cell proliferation in vitro and reduced tumor growth in vivo. In summary, we provide a novel mouse model for neuroendocrine tumors of the pancreas and pituitary gland that is dependent on MYCN expression and that may help to evaluate MYCN-directed therapies.

The benefits of modified FOLFIRINOX for advanced pancreatic cancer and its induced adverse events: a systematic review and meta-analysis.

PubMed

Tong, Hongxuan; Fan, Zhu; Liu, Biyuan; Lu, Tao

2018-06-06

FOLFIRINOX has been one of the first-line options for advanced pancreatic cancer, even though it induces significant adverse effects. Several institutions have begun using modified FOLFIRINOX to decrease its side effects and increase its tolerability. We systematically investigated the outcome from patients who initially received modified FOLFIRINOX as a chemotherapy regimen for advanced pancreatic cancer. We used the random-model generic inverse variance method to analyse the binary data with 95% confidence intervals (CIs). Eleven studies were included in the meta-analysis with 563 total patients. The 6-month and 1-year overall survival (OS) rates of locally advanced pancreatic cancer (LAPC) were 90.9% and 76.2%. The 6-month and 1-year progression-free survival (PFS) rates of LAPC were 81.5% and 48.5%. The 6-month and 1-year OS rates of metastatic pancreatic cancer (MPC) were 79.7% and 47.6%. The 6-month and 1-year PFS rates of MPC were 56.3% and 20.6%. The following rates were also calculated: complete response rate (CR): 2.9%; partial response rate (PR): 35.9%; stable disease rate (SD): 41.2%; overall response rate (OR): 34.6%; disease control rate (DCR): 76.7%; progressive disease: 23.1%; and grade III/IV adverse events (AEs): neutropenia 23.1%, febrile neutropenia 4.8%, thrombocytopenia 4.8%, anaemia 5.7%, fatigue 11.5%, nausea 9.1%, diarrhoea 10.1%, vomiting 5.7%, neuropathy 3.8%, and increased ALT 5.7%. In conclusion, modified FOLFIRINOX could provide comparative survival benefits with fewer adverse events compared to the conventional dosage.

Observational study of patients with gastroenteropancreatic and bronchial neuroendocrine tumors in Argentina: Results from the large database of a multidisciplinary group clinical multicenter study

PubMed Central

O’CONNOR, JUAN MANUEL; MARMISSOLLE, FABIANA; BESTANI, CLAUDIA; PESCE, VERONICA; BELLI, SUSANA; DOMINICHINI, ENZO; MENDEZ, GUILLERMO; PRICE, PAOLA; GIACOMI, NORA; PAIROLA, ALEJANDRO; LORIA, FERNANDO SÁNCHEZ; HUERTAS, EDUARDO; MARTIN, CLAUDIO; PATANE, KARINA; POLERI, CLAUDIA; ROSENBERG, MOISES; CABANNE, ANA; KUJARUK, MIRTA; CAINO, ANALIA; ZAMORA, VICTOR; MARIANI, JAVIER; DIOCA, MARIANO; PARMA, PATRICIA; PODESTA, GUSTAVO; ANDRIANI, OSCAR; GONDOLESI, GABRIEL; ROCA, ENRIQUE

2014-01-01

Neuroendocrine tumors (NET) include a spectrum of malignancies arising from neuroendocrine cells throughout the body. The objective of this clinical investigation of retrospectively and prospectively collected data was to describe the prevalence, demographic data, clinical symptoms and methods of diagnosis of NET and the treatment and long-term follow-up of patients with NET. Data were provided by the participating centers and assessed for consistency by internal reviewers. All the cases were centrally evaluated (when necessary) by the pathologists in our group. The tissue samples were reviewed by hematoxylin and eosin and immunohistochemical staining techniques to confirm the diagnosis of NET. In total, 532 cases were documented: 461 gastroenteropancreatic-NET (GEP-NET) and 71 bronchial NET (BNET). All the tumors were immunohistochemically defined according to the World Health Organization (WHO) and European Neuroendocrine Tumor Society criteria. The most common initial symptoms in GEP-NET were abdominal pain, diarrhea, bowel obstruction, flushing, gastrointestinal bleeding and weight loss. The most common tumor types were carcinoid (58.0%), non-functional pancreatic tumor (23.0%), metastatic NET of unknown primary (16.0%) and functional pancreatic tumor (3.0%). Of the BNET, 89.0% were typical and 11.0% atypical carcinoids. Of the patients with GEP-NET, 59.2% had distant metastasis at diagnosis. The locations of the primary tumors in GEP-NET were the small bowel (26.9%), pancreas (25.2%), colon-rectum (12.4%), appendix (7.6%), stomach (6.9%), esophagus (2.8%), duodenum (2.0%) and unknown primary (16.3%). The histological subtypes based on the WHO classification were well-differentiated NET (20.1%), well-differentiated neuroendocrine carcinomas (66.5%) and poorly differentiated neuroendocrine carcinomas (10.3%). Overall, 67.3% of the patients underwent surgery, 41.2% with curative intent and 26.1% for palliative purposes. The 5-year survival rates were 65.1% (95

Veliparib, Cisplatin, and Gemcitabine Hydrochloride in Treating Patients With Advanced Biliary, Pancreatic, Urothelial, or Non-Small Cell Lung Cancer

ClinicalTrials.gov

2013-07-01

Advanced Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Regional Transitional Cell Cancer of the Renal Pelvis and Ureter; Stage III Bladder Cancer; Stage III Pancreatic Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Bladder Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Pancreatic Cancer; Transitional Cell Carcinoma of the Bladder; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

Chronic pancreatitis: diagnosis, classification, and new genetic developments.

PubMed

Etemad, B; Whitcomb, D C

2001-02-01

The utilization of recent advances in molecular and genomic technologies and progress in pancreatic imaging techniques provided remarkable insight into genetic, environmental, immunologic, and pathobiological factors leading to chronic pancreatitis. Translation of these advances into clinical practice demands a reassessment of current approaches to diagnosis, classification, and staging. We conclude that an adequate pancreatic biopsy must be the gold standard against which all diagnostic approaches are judged. Although computed tomography remains the initial test of choice for the diagnosis of chronic pancreatitis, the roles of endoscopic retrograde pancreatography, endoscopic ultrasonography, and magnetic resonance imaging are considered. Once chronic pancreatitis is diagnosed, proper classification becomes important. Major predisposing risk factors to chronic pancreatitis may be categorized as either (1) toxic-metabolic, (2) idiopathic, (3) genetic, (4) autoimmune, (5) recurrent and severe acute pancreatitis, or (6) obstructive (TIGAR-O system). After classification, staging of pancreatic function, injury, and fibrosis becomes the next major concern. Further research is needed to determine the clinical and natural history of chronic pancreatitis developing in the context of various risk factors. New methods are needed for early diagnosis of chronic pancreatitis, and new therapies are needed to determine whether interventions will delay or prevent the progression of the irreversible damage characterizing end-stage chronic pancreatitis.

Phase I study of oral S-1 and concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sudo, Kentaro; Yamaguchi, Taketo; Ishihara, Takeshi

Purpose: The primary objective of this study was to determine the maximum-tolerated dose (MTD) of S-1, an oral fluoropyrimidine derivative, with concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer. Methods and Materials: Patients with histopathologically proven, unresectable, locally advanced pancreatic cancer were eligible. Radiotherapy was delivered in 1.8 Gy daily fractions to a total dose of 50.4 Gy over 5.5 weeks. S-1 was administered orally twice a day from Day 1 to 14 and 22 to 35 at escalating doses from 60 to 80 mg/m{sup 2}/day. Results: Sixteen patients were enrolled in this study. Three patients received S-1more » at 60 mg/m{sup 2}/day, 3 at 70 mg/m{sup 2}/day, and 10 at 80 mg/m{sup 2}/day. Though 1 patient at the final dose level (80 mg/m{sup 2}/day) experienced a dose limiting toxicity (biliary infection with Grade 3 neutropenia), the MTD was not reached in this study. The most common toxicities were anorexia and leukocytopenia, with Grade 3 toxicity occurring in 31% and 6.3% of the patients, respectively. Conclusions: The recommended dose of S-1 with concurrent radiotherapy was determined to be 80 mg/m{sup 2}/day from Day 1 to 14 and 22 to 35 in patients with locally advanced pancreatic cancer. Oral S-1 and radiotherapy is well tolerated and feasible and should be further investigated.« less

Neuroendocrine Tumors in the Stomach, Duodenum, and Pancreas Accompanied by Novel MEN1 Gene Mutation.

PubMed

Yang, Min A; Lee, Woong Ki; Shin, Hong Shik; Park, Sung Hyun; Kim, Byung Sun; Kim, Ji Woong; Cho, Jin Woong; Yun, So Hee

2017-03-25

Multiple endocrine neoplasia type 1 (MEN1) syndrome is a relatively rare disease, characterized by the occurrence of multiple endocrine tumors in the parathyroid and pituitary glands as well as the pancreas. Here, we report a case of MEN1 with neuroendocrine tumors (NETs) in the stomach, duodenum, and pancreas. A 53-year-old man visited our hospital to manage gastric NET. Five years prior to his visit, he had undergone surgery for incidental meningioma. His brother had pancreatic nodules and a history of surgery for adrenal adenoma. His brother's daughter also had pancreatic nodules, but had not undergone surgery. The lesion was treated by endoscopic submucosal dissection and diagnosed as a grade 1 NET. Another small NET was detected in the second duodenal portion, resected by endoscopic submucosal dissection, which was also diagnosed as a grade 1 NET. During evaluation, three nodules were detected in the pancreas, and no evidence of pituitary, parathyroid tumors, or metastasis was observed. After surgery, the pancreatic lesions were diagnosed as NETs, with the same immunohistochemical patterns as those of the stomach and duodenum. Genetic testing was performed, and a heterozygous mutation was detected in the MEN1 gene, which is located on 11q13.

Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors.

PubMed

Strosberg, Jonathan; El-Haddad, Ghassan; Wolin, Edward; Hendifar, Andrew; Yao, James; Chasen, Beth; Mittra, Erik; Kunz, Pamela L; Kulke, Matthew H; Jacene, Heather; Bushnell, David; O'Dorisio, Thomas M; Baum, Richard P; Kulkarni, Harshad R; Caplin, Martyn; Lebtahi, Rachida; Hobday, Timothy; Delpassand, Ebrahim; Van Cutsem, Eric; Benson, Al; Srirajaskanthan, Rajaventhan; Pavel, Marianne; Mora, Jaime; Berlin, Jordan; Grande, Enrique; Reed, Nicholas; Seregni, Ettore; Öberg, Kjell; Lopera Sierra, Maribel; Santoro, Paola; Thevenet, Thomas; Erion, Jack L; Ruszniewski, Philippe; Kwekkeboom, Dik; Krenning, Eric

2017-01-12

Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 ( 177 Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177 Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) ( 177 Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177 Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177 Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177 Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177 Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. Treatment with 177 Lu

Recent advances in 3D computed tomography techniques for simulation and navigation in hepatobiliary pancreatic surgery.

PubMed

Uchida, Masafumi

2014-04-01

A few years ago it could take several hours to complete a 3D image using a 3D workstation. Thanks to advances in computer science, obtaining results of interest now requires only a few minutes. Many recent 3D workstations or multimedia computers are equipped with onboard 3D virtual patient modeling software, which enables patient-specific preoperative assessment and virtual planning, navigation, and tool positioning. Although medical 3D imaging can now be conducted using various modalities, including computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and ultrasonography (US) among others, the highest quality images are obtained using CT data, and CT images are now the most commonly used source of data for 3D simulation and navigation image. If the 2D source image is bad, no amount of 3D image manipulation in software will provide a quality 3D image. In this exhibition, the recent advances in CT imaging technique and 3D visualization of the hepatobiliary and pancreatic abnormalities are featured, including scan and image reconstruction technique, contrast-enhanced techniques, new application of advanced CT scan techniques, and new virtual reality simulation and navigation imaging. © 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

Association between protein C levels and mortality in patients with advanced prostate, lung and pancreatic cancer.

PubMed

Wilts, I T; Hutten, B A; Meijers, J C M; Spek, C A; Büller, H R; Kamphuisen, P W

2017-06-01

Procoagulant factors promote cancer progression and metastasis. Protein C is involved in hemostasis, inflammation and signal transduction, and has a protective effect on the endothelial barrier. In mice, administration of activated protein C reduced experimental metastasis. We assessed the association between protein C and mortality in patients with three types of cancer. The study population consisted of patients with advanced prostate, non-small cell lung or pancreatic cancer, who participated in the INPACT trial (NCT00312013). The trial evaluated the addition of nadroparin to chemotherapy in patients with advanced malignancy. Patients were divided into tertiles based on protein C at baseline. The association between protein C levels and mortality was evaluated with Cox proportional hazard models. We analysed 477 patients (protein C tertiles: <97, 97-121 and ≥121%). Mean age was 65±9years; 390 (82%) were male; 191 patients (40%) had prostate cancer, 161 (34%) had lung cancer, and 125 (26%) pancreatic cancer. During a median follow-up of 10.4months, 291 patients (61%) died. Median protein C level was 107% (IQR 92-129). In the lowest tertile, 75 patients per 100 patient-years died, as compared to 60 and 54 in the middle and high tertile, respectively. Lower levels of protein C were associated with increased mortality (in tertiles: HR for trend 1.18, 95%CI 1.02-1.36, adjusted for age, sex and nadroparin use; as a continuous variable: HR 1.004, 95%CI 1.00-1.008, p=0.07). Protein C seems inversely associated with mortality in patients with advanced prostate, lung and pancreatic cancer. Further research should validate protein C as a biomarker for mortality, and explore the effects of protein C on progression of cancer. Copyright © 2017 Elsevier Ltd. All rights reserved.

Efficacy and Factors Affecting Outcome of Gemcitabine Concurrent Chemoradiotherapy in Patients With Locally Advanced Pancreatic Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, P.-I.; National Yang-Ming University School of Medicine, Taipei, Taiwan; Chao, Yee

Purpose: To evaluate the efficacy and prognostic factors of gemcitabine (GEM) concurrent chemoradiotherapy (CCRT) in patients with locally advanced pancreatic cancer. Methods and Materials: Between January 2002 and December 2005, 55 patients with locally advanced pancreatic cancer treated with GEM (400 mg/m{sup 2}/wk) concurrently with radiotherapy (median dose, 50.4 Gy; range, 26-61.2) at Taipei Veterans General Hospital were enrolled. GEM (1,000 mg/m{sup 2}) was continued after CCRT as maintenance therapy once weekly for 3 weeks and repeated every 4 weeks. The response, survival, toxicity, and prognostic factors were evaluated. Results: With a median follow-up of 10.8 months, the 1- andmore » 2-year survival rate was 52% and 19%, respectively. The median overall survival (OS) and median time to progression (TTP) was 12.4 and 5.9 months, respectively. The response rate was 42% (2 complete responses and 21 partial responses). The major Grade 3-4 toxicities were neutropenia (22%) and anorexia (19%). The median OS and TTP was 15.8 and 9.5 months in the GEM CCRT responders compared with 7.5 and 3.5 months in the nonresponders, respectively (both p < 0.001). The responders had a better Karnofsky performance status (KPS) (86 {+-} 2 vs. 77 {+-} 2, p = 0.002) and had received a greater GEM dose intensity (347 {+-} 13 mg/m{sup 2}/wk vs. 296 {+-} 15 mg/m{sup 2}/wk, p = 0.02) than the nonresponders. KPS and serum carbohydrate antigen 19-9 were the most significant prognostic factors of OS and TTP. Conclusion: The results of our study have shown that GEM CCRT is effective and tolerable for patients with locally advanced pancreatic cancer. The KPS and GEM dose correlated with response. Also, the KPS and CA 19-9 level were the most important factors affecting OS and TTP.« less

Middle-preserving pancreatectomy for advanced transverse colon cancer invading the duodenun and non-functioning endocrine tumor in the pancreatic tail.

PubMed

Noda, Hiroshi; Kato, Takaharu; Kamiyama, Hidenori; Toyama, Nobuyuki; Konishi, Fumio

2011-02-01

A 73-year-old female was referred to our hospital with a diagnosis of advanced transverse colon cancer with severe anemia and body weight loss. Preoperative evaluations, including colonoscopy, gastroduodenoscopy, and computed tomography, revealed not only a transverse colon cancer massively invading the duodenum, but also a non-functioning endocrine tumor in the pancreatic tail. We performed middle-preserving pancreatectomy (MPP) with right hemicolectomy for these tumors with a curative intent. After the resection, about 6 cm of the body of the pancreas was preserved, and signs of diabetes mellitus have not appeared. The postoperative course was complicated by a grade B pancreatic fistula, but this was successfully treated with conservative management. After a 33-day hospital stay, the patient returned to daily life without signs of pancreatic exocrine insufficiency. Although the long-term follow-up of the patient is indispensable, in this case, MPP might be able to lead to the curative resection of transverse colon cancer massively invading the duodenum and non-functioning endocrine tumor in the pancreatic tail with preservation of pancreatic function.

Chemical strategies for pancreatic β cell differentiation, reprogramming, and regeneration.

PubMed

Ma, Xiaojie; Zhu, Saiyong

2017-04-01

Generation of unlimited functional pancreatic β cells is critical for the study of pancreatic biology and treatment of diabetes mellitus. Recent advances have suggested several promising directions, including directed differentiation of pancreatic β cells from pluripotent stem cells, reprogramming of pancreatic β cells from other types of somatic cells, and stimulated proliferation and enhanced functions of existing pancreatic β cells. Small molecules are useful in generating unlimited numbers of functional pancreatic cells in vitro and could be further developed as drugs to stimulate endogenous pancreatic regeneration. Here, we provide an updated summary of recent major achievements in pancreatic β cell differentiation, reprogramming, proliferation, and function. These studies will eventually lead to significant advances in the field of pancreatic biology and regeneration. © The Author 2017. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Advances of high intensity focused ultrasound (HIFU) for pancreatic cancer.

PubMed

Xiaoping, Li; Leizhen, Zheng

2013-11-01

High intensity focused ultrasound (HIFU) is a novel therapeutic modality. Several preclinical and clinical studies have investigated the safety and efficacy of HIFU for treating solid tumours, including pancreatic cancer. Preliminary studies suggest that HIFU may be useful for the palliative therapy of cancer-related pain in patients with unresectable pancreatic cancer. This review provides a brief overview of HIFU, describes current clinical applications of HIFU for pancreatic cancer, and discusses future applications and challenges.

Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs)

PubMed Central

Ahmed, A; Ardill, J; Bax, N; Breen, D J; Caplin, M E; Corrie, P; Davar, J; Davies, A H; Lewington, V; Meyer, T; Newell-Price, J; Poston, G; Reed, N; Rockall, A; Steward, W; Thakker, R V; Toubanakis, C; Valle, J; Verbeke, C; Grossman, A B

2011-01-01

These guidelines update previous guidance published in 2005. They have been revised by a group who are members of the UK and Ireland Neuroendocrine Tumour Society with endorsement from the clinical committees of the British Society of Gastroenterology, the Society for Endocrinology, the Association of Surgeons of Great Britain and Ireland (and its Surgical Specialty Associations), the British Society of Gastrointestinal and Abdominal Radiology and others. The authorship represents leaders of the various groups in the UK and Ireland Neuroendocrine Tumour Society, but a large amount of work has been carried out by other specialists, many of whom attended a guidelines conference in May 2009. We have attempted to represent this work in the acknowledgements section. Over the past few years, there have been advances in the management of neuroendocrine tumours, which have included clearer characterisation, more specific and therapeutically relevant diagnosis, and improved treatments. However, there remain few randomised trials in the field and the disease is uncommon, hence all evidence must be considered weak in comparison with other more common cancers. PMID:22052063

Combining neuroendocrine inhibitors in heart failure: reflections on safety and efficacy.

PubMed

Jneid, Hani; Moukarbel, George V; Dawson, Bart; Hajjar, Roger J; Francis, Gary S

2007-12-01

Neuroendocrine activation in heart failure has become the major target of pharmacotherapy for this growing epidemic. Agents targeting the renin-angiotensin-aldosterone and sympathetic nervous systems have shown cardiovascular and survival benefits in clinical trials. Beta-blockers and angiotensin-converting enzyme (ACE) inhibitors remain the mainstream initial therapy. The benefits of aldosterone antagonists have been demonstrated in advanced heart failure (spironolactone) and after myocardial infarction complicated by left ventricular dysfunction and heart failure (eplerenone). Emerging clinical evidence demonstrated that angiotensin receptor blockers may be a reasonable alternative to ACE inhibitors in patients with heart failure (candesartan) and following myocardial infarction complicated by heart failure or left ventricular dysfunction (valsartan). Angiotensin receptor blockers (candesartan) also provided incremental benefits when added to ACE inhibitors in chronic heart failure. Thus, combining neuroendocrine inhibitors in heart failure appears both biologically plausible and evidence-based. However, this approach raised concerns about side effects, such as hypotension, renal insufficiency, hyperkalemia, and others. Close follow-up and implementation of evidence-based medicine (ie, using agents and doses proven beneficial in clinical trials) should therefore be undertaken when combining neuroendocrine inhibitors.

Review article: the investigation and management of gastric neuroendocrine tumours.

PubMed

Basuroy, R; Srirajaskanthan, R; Prachalias, A; Quaglia, A; Ramage, J K

2014-05-01

Gastric carcinoids (GCs) or neuroendocrine tumours (NETs) are increasingly identified at endoscopy, and account for 0.6-2% of all gastric polyps identified. The SEER database in the US has demonstrated a rising incidence of gastric NETs amongst all NETs; from 2.2% between 1950 and 1969 to 6.0% between 2000 and 2007. To review the literature and assist clinicians in managing patients with GCs. A literature search was conducted through MEDLINE using search terms: gastric, carcinoid, neuroendocrine tumour, therapy, endoscopy, mucosal resection, submucosal dissection. Relevant articles were identified through manual review. The reference lists of these articles were reviewed to include further appropriate articles. There are three types of GCs with important epidemiological, pathophysiological, histological and endoscopic differences that affect prognosis and management. Type 1 and 2 GCs develop in the context of hypergastrinaemia that originates from achlorhydria in atrophic gastritis and a gastrinoma, respectively. Type 3 GCs occur sporadically and independent of gastrin. The histological type, grade and Ki67 index are used to determine prognosis and direct clinical management. Type 1 GCs >1 cm in size and type 2 GCs should be assessed for invasion beyond the submucosa with EUS prior to endoscopic resection with EMR or ESD. Type 3 GCs should be managed as per recommendations for gastric adenocarcinoma. The treatment of advanced disease is multimodal. Patients with gastric carcinoids should be discussed in a specialist neuroendocrine tumour multidisciplinary meeting to ensure all treatment options are explored in localised and advanced disease. Areas of controversy exist that need further research. © 2014 John Wiley & Sons Ltd.

Carbon Ion Radiation Therapy With Concurrent Gemcitabine for Patients With Locally Advanced Pancreatic Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shinoto, Makoto, E-mail: shinoto@saga-himat.jp; Ion Beam Therapy Center, SAGA HIMAT Foundation, Tosu; Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka

Purpose: To determine, in the setting of locally advanced pancreatic cancer, the maximum tolerated dose of carbon ion radiation therapy (C-ion RT) and gemcitabine dose delivered concurrently and to estimate local effect and survival. Methods and Materials: Eligibility included pathologic confirmation of pancreatic invasive ductal carcinomas and radiographically unresectable disease without metastasis. Concurrent gemcitabine was administered on days 1, 8, and 15, and the dose levels were escalated from 400 to 1000 mg/m{sup 2} under the starting dose level (43.2 GyE) of C-ion RT. The dose levels of C-ion RT were escalated from 43.2 to 55.2 GyE at 12 fractions undermore » the fixed recommended gemcitabine dose determined. Results: Seventy-six patients were enrolled. Among the 72 treated patients, dose-limiting toxicity was observed in 3 patients: grade 3 infection in 1 patient and grade 4 neutropenia in 2 patients. Only 1 patient experienced a late grade 3 gastric ulcer and bleeding 10 months after C-ion RT. The recommended dose of gemcitabine with C-ion RT was found to be 1000 mg/m{sup 2}. The dose of C-ion RT with the full dose of gemcitabine (1000 mg/m{sup 2}) was safely increased to 55.2 GyE. The freedom from local progression rate was 83% at 2 years using the Response Evaluation Criteria in Solid Tumors. The 2-year overall survival rates in all patients and in the high-dose group with stage III (≥45.6 GyE) were 35% and 48%, respectively. Conclusions: Carbon ion RT with concurrent full-dose gemcitabine was well tolerated and effective in patients with unresectable locally advanced pancreatic cancer.« less

Neuroendocrine-Immune Circuits, Phenotypes, and Interactions

PubMed Central

Ashley, Noah T.; Demas, Gregory E.

2016-01-01

Multidirectional interactions among the immune, endocrine, and nervous systems have been demonstrated in humans and non-human animal models for many decades by the biomedical community, but ecological and evolutionary perspectives are lacking. Neuroendocrine-immune interactions can be conceptualized using a series of feedback loops, which culminate into distinct neuroendocrine-immune phenotypes. Behavior can exert profound influences on these phenotypes, which can in turn reciprocally modulate behavior. For example, the behavioral aspects of reproduction, including courtship, aggression, mate selection and parental behaviors can impinge upon neuroendocrine-immune interactions. One classic example is the immunocompetence handicap hypothesis (ICHH), which proposes that steroid hormones act as mediators of traits important for female choice while suppressing the immune system. Reciprocally, neuroendocrine-immune pathways can promote the development of altered behavioral states, such as sickness behavior. Understanding the energetic signals that mediate neuroendocrine-immune crosstalk is an active area of research. Although the field of psychoneuroimmunology (PNI) has begun to explore this crosstalk from a biomedical standpoint, the neuroendocrine-immune-behavior nexus has been relatively underappreciated in comparative species. The field of ecoimmunology, while traditionally emphasizing the study of non-model systems from an ecological evolutionary perspective, often under natural conditions, has focused less on the physiological mechanisms underlying behavioral responses. This review summarizes neuroendocrine-immune interactions using a comparative framework to understand the ecological and evolutionary forces that shape these complex physiological interactions. PMID:27765499

Neuroendocrine-immune circuits, phenotypes, and interactions.

PubMed

Ashley, Noah T; Demas, Gregory E

2017-01-01

Multidirectional interactions among the immune, endocrine, and nervous systems have been demonstrated in humans and non-human animal models for many decades by the biomedical community, but ecological and evolutionary perspectives are lacking. Neuroendocrine-immune interactions can be conceptualized using a series of feedback loops, which culminate into distinct neuroendocrine-immune phenotypes. Behavior can exert profound influences on these phenotypes, which can in turn reciprocally modulate behavior. For example, the behavioral aspects of reproduction, including courtship, aggression, mate selection and parental behaviors can impinge upon neuroendocrine-immune interactions. One classic example is the immunocompetence handicap hypothesis (ICHH), which proposes that steroid hormones act as mediators of traits important for female choice while suppressing the immune system. Reciprocally, neuroendocrine-immune pathways can promote the development of altered behavioral states, such as sickness behavior. Understanding the energetic signals that mediate neuroendocrine-immune crosstalk is an active area of research. Although the field of psychoneuroimmunology (PNI) has begun to explore this crosstalk from a biomedical standpoint, the neuroendocrine-immune-behavior nexus has been relatively underappreciated in comparative species. The field of ecoimmunology, while traditionally emphasizing the study of non-model systems from an ecological evolutionary perspective, often under natural conditions, has focused less on the physiological mechanisms underlying behavioral responses. This review summarizes neuroendocrine-immune interactions using a comparative framework to understand the ecological and evolutionary forces that shape these complex physiological interactions. Copyright © 2016 Elsevier Inc. All rights reserved.

Wilms tumor gene (WT1) peptide-based cancer vaccine combined with gemcitabine for patients with advanced pancreatic cancer.

PubMed

Nishida, Sumiyuki; Koido, Shigeo; Takeda, Yutaka; Homma, Sadamu; Komita, Hideo; Takahara, Akitaka; Morita, Satoshi; Ito, Toshinori; Morimoto, Soyoko; Hara, Kazuma; Tsuboi, Akihiro; Oka, Yoshihiro; Yanagisawa, Satoru; Toyama, Yoichi; Ikegami, Masahiro; Kitagawa, Toru; Eguchi, Hidetoshi; Wada, Hiroshi; Nagano, Hiroaki; Nakata, Jun; Nakae, Yoshiki; Hosen, Naoki; Oji, Yusuke; Tanaka, Toshio; Kawase, Ichiro; Kumanogoh, Atsushi; Sakamoto, Junichi; Doki, Yuichiro; Mori, Masaki; Ohkusa, Toshifumi; Tajiri, Hisao; Sugiyama, Haruo

2014-01-01

Wilms tumor gene (WT1) protein is an attractive target for cancer immunotherapy. We aimed to investigate the feasibility of a combination therapy consisting of gemcitabine and WT1 peptide-based vaccine for patients with advanced pancreatic cancer and to make initial assessments of its clinical efficacy and immunologic response. Thirty-two HLA-A*24:02 patients with advanced pancreatic cancer were enrolled. Patients received HLA-A*24:02-restricted, modified 9-mer WT1 peptide (3 mg/body) emulsified with Montanide ISA51 adjuvant (WT1 vaccine) intradermally biweekly and gemcitabine (1000 mg/m) on days 1, 8, and 15 of a 28-day cycle. This combination therapy was well tolerated. The frequencies of grade 3-4 adverse events for this combination therapy were similar to those for gemcitabine alone. Objective response rate was 20.0% (6/30 evaluable patients). Median survival time and 1-year survival rate were 8.1 months and 29%, respectively. The association between longer survival and positive delayed-type hypersensitivity to WT1 peptide was statistically significant, and longer survivors featured a higher frequency of memory-phenotype WT1-specific cytotoxic T lymphocytes both before and after treatment. WT1 vaccine in combination with gemcitabine was well tolerated for patients with advanced pancreatic cancer. Delayed-type hypersensitivity-positivity to WT1 peptide and a higher frequency of memory-phenotype WT1-specific cytotoxic T lymphocytes could be useful prognostic markers for survival in the combination therapy with gemcitabine and WT1 vaccine. Further clinical investigation is warranted to determine the effectiveness of this combination therapy.

Radiofrequency assisted pancreaticoduodenectomy for palliative surgical resection of locally advanced pancreatic adenocarcinoma.

PubMed

Kumar, Jayant; Reccia, Isabella; Sodergren, Mikael H; Kusano, Tomokazu; Zanellato, Artur; Pai, Madhava; Spalding, Duncan; Zacharoulis, Dimitris; Habib, Nagy

2018-03-20

Despite careful patient selection and preoperative investigations curative resection rate (R0) in pancreaticoduodenectomy ranges from 15% to 87%. Here we describe a new palliative approach for pancreaticoduodenectomy using a radiofrequency energy device to ablate tumor in situ in patients undergoing R1/R2 resections for locally advanced pancreatic ductal adenocarcinoma where vascular reconstruction was not feasible. There was neither postoperative mortality nor significant morbidity. Each time the ablation lasted less than 15 minutes. Following radiofrequency ablation it was observed that the tumor remnant attached to the vessel had shrunk significantly. In four patients this allowed easier separation and dissection of the ablated tumor from the adherent vessel leading to R1 resection. In the other two patients, the ablated tumor did not separate from vessel due to true tumor invasion and patients had an R2 resection. The ablated remnant part of the tumor was left in situ. Whenever pancreaticoduodenectomy with R0 resection cannot be achieved, this new palliative procedure could be considered in order to facilitate resection and enable maximum destruction in remnant tumors. Six patients with suspected tumor infiltration and where vascular reconstruction was not warranted underwent radiofrequency-assisted pancreaticoduodenectomy for locally advanced pancreatic ductal adenocarcinoma. Radiofrequency was applied across the tumor vertically 5-10 mm from the edge of the mesenteric and portal veins. Following ablation, the duodenum and the head of pancreas were removed after knife excision along the ablated line. The remaining ablated tissue was left in situ attached to the vessel.

Changing the course of pancreatic cancer--Focus on recent translational advances.

PubMed

Javle, Milind; Golan, Talia; Maitra, Anirban

2016-03-01

In the past decade, insightful preclinical research has led to important breakthroughs in our understanding of pancreatic cancer. Even though the vast majority of pancreatic cancers are KRAS mutated, not all pancreatic cancer tumors are "KRAS equal"; there seems to be varying dependencies on the KRAS pathway. While KRAS-targeting therapies have been disappointing in the clinic, 'synthetic lethal' approaches hold promise in this setting. The pancreatic cancer stromal microenvironment appears to have contradictory roles. While there is evidence to suggest that stromal barrier prevents drug delivery, in other circumstances, stroma can play a protective role and its disruption enhances tumor dissemination. Clinical trials aimed at manipulating the various stromal components are in progress. BRCA mutation-related pancreatic tumors illustrate a unique subtype with enhanced susceptibility to DNA damaging agents and PARP-inhibition. DNA repair defects in cancer extend beyond germ line BRCA mutation and may extend the indications for DNA repair-targeting agents. Immune strategies are an area of active investigation in pancreatic cancer. Although the initial trials of single-agent checkpoint inhibitors have been negative, combinational approaches using immune-modifying agents and vaccines appear promising and goal is to identify an 'immune-therapy responsive' profile in pancreatic cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cytologic characteristics of circulating epithelioid cells in pancreatic disease.

PubMed

Rosenbaum, Matthew W; Cauley, Christy E; Kulemann, Birte; Liss, Andrew S; Castillo, Carlos Fernandez-Del; Warshaw, Andrew L; Lillemoe, Keith D; Thayer, Sarah P; Pitman, Martha B

2017-05-01

Circulating epithelioid cells (CECs), also known as circulating tumor, circulating cancer, circulating epithelial, or circulating nonhematologic cells, are a prognostic factor in various malignancies that can be isolated via various protocols. In the current study, the authors analyzed the cytomorphologic characteristics of CECs isolated by size in a cohort of patients with benign and malignant pancreatic diseases to determine whether cytomorphological features could predict CEC origin. Blood samples were collected from 9 healthy controls and 171 patients with pancreatic disease who were presenting for surgical evaluation before treatment. Blood was processed with the ScreenCell size-based filtration device. Evaluable CECs were analyzed in a blinded fashion for cytomorphologic characteristics, including cellularity; nucleoli; nuclear size, irregularity, variability, and hyperchromasia; and nuclear-to-cytoplasmic ratio. Statistical differences between variables were analyzed via the Fisher exact test. No CECs were identified among the 9 normal healthy controls. Of the 115 patients with CECs (positive or suspicious for), 25 had nonmalignant disease and 90 had malignancy. There were no significant differences in any of the cytologic criteria noted between groups divided by benign versus malignant, neoplastic versus nonneoplastic, or pancreatic ductal adenocarcinoma versus neuroendocrine tumor. CECs were observed in patients with malignant and nonmalignant pancreatic disease, but not in healthy controls. There were no morphologic differences observed between cells from different pancreatic diseases, suggesting that numerous conditions may be associated with CECs in the circulation and that care must be taken not to overinterpret cells identified by cytomorphology as indicative of circulating tumor cells of pancreatic cancer. Additional studies are required to determine the origin and clinical significance of these cells. Cancer Cytopathol 2017;125:332-340. © 2017

Management of the hormonal syndrome of neuroendocrine tumors

PubMed Central

Waligórska-Stachura, Joanna; Czarnywojtek, Agata; Sawicka-Gutaj, Nadia; Bączyk, Maciej; Ziemnicka, Katarzyna; Fischbach, Jakub; Woliński, Kosma; Kaznowski, Jarosław; Wrotkowska, Elżbieta; Ruchała, Marek

2016-01-01

Gastroenteropancreatic neuroendocrine tumors (GEP/NET) are unusual and rare neoplasms that present many clinical challenges. They characteristically synthesize store and secrete a variety of peptides and neuroamines which can lead to the development of distinct clinical syndrome, however many are clinically silent until late presentation with mass effects. Management strategies include surgery cure and cytoreduction with the use of somatostatin analogues. Somatostatin have a broad range of biological actions that include inhibition of exocrine and endocrine secretions, gut motility, cell proliferation, cell survival and angiogenesis. Five somatostatin receptors (SSTR1-SSTR5) have been cloned and characterized. Somatostatin analogues include octreotide and lanreotide are effective medical tools in the treatment and present selectivity for SSTR2 and SSTR5. During treatment is seen disapperance of flushing, normalization of bowel movements and reduction of serotonin and 5-hydroxyindole acetic acid (5-HIAA) secretion. Telotristat represents a novel approach by specifically inhibiting serotonin synthesis and as such, is a promising potential new treatment for patients with carcinoid syndrome. To pancreatic functionig neuroendocrine tumors belongs insulinoma, gastrinoma, glucagonoma and VIP-oma. Medical management in patients with insulinoma include diazoxide which suppresses insulin release. Also mTOR inhibitors may inhibit insulin secretion. Treatment of gastrinoma include both proton pump inhibitors (PPIs) and histamine H2 – receptor antagonists. In patients with glucagonomas hyperglycaemia can be controlled using insulin and oral blood glucose lowering drugs. In malignant glucagonomas smatostatin analogues are effective in controlling necrolytic migratory erythemia. Severe cases of the VIP-oma syndrome require supplementation of fluid losses. Octreotide reduce tumoral VIP secretion and control secretory diarrhoea. PMID:28507564

A pilot study of the experience of family caregivers of patients with advanced pancreatic cancer using a mixed methods approach.

PubMed

Sherman, Deborah W; McGuire, Deborah B; Free, David; Cheon, Joo Young

2014-09-01

Pancreatic cancer presents a wide spectrum of significant symptomatology. The high symptom burden, coupled with a rapidly fatal diagnosis, limits preparation or time for adjustment for both patients and their family caregivers. From the initial diagnosis and throughout the illness experience, the physical and emotional demands of caregiving can predispose caregivers themselves to illness and a greater risk of mortality. Understanding the negative and positive aspects of caregiving for patients with advanced pancreatic cancer will inform interventions that promote positive caregiver outcomes and support caregivers in their role. To provide feasibility data for a larger, mixed methods, longitudinal study focused on the experience of family caregivers of patients with advanced pancreatic cancer and preliminary qualitative data to substantiate the significance of studying this caregiver population. This was a mixed methods study guided by the Stress Process Model. Eight family caregivers of patients with advanced pancreatic cancer from oncology practices of a university-affiliated medical center were surveyed. The pilot results supported the ability to recruit and retain participants and informed recruitment and data collection procedures. The qualitative results provided preliminary insights into caregiver experiences during the diagnosis and treatment phases. Key findings that substantiated the significance of studying these caregivers included the caregiving context of the history of sentinel symptoms, the crisis of diagnosis, the violation of assumptions about life and health, recognition of the circle of association, and contextual factors, as well as primary and secondary stressors, coping strategies, resources, discoveries, gains and growth, associated changes/transitions, and unmet caregiver needs. Findings indicated caregivers' willingness to participate in research, highlighted the negative and positive aspects of the caregiver experience, and reinforced the

[Pancreatic ultrasonography].

PubMed

Fernández-Rodríguez, T; Segura-Grau, A; Rodríguez-Lorenzo, A; Segura-Cabral, J M

2015-04-01

Despite the recent technological advances in imaging, abdominal ultrasonography continues to be the first diagnostic test indicated in patients with a suspicion of pancreatic disease, due to its safety, accessibility and low cost. It is an essential technique in the study of inflammatory processes, since it not only assesses changes in pancreatic parenchyma, but also gives an indication of the origin (bile or alcoholic). It is also essential in the detection and tracing of possible complications as well as being used as a guide in diagnostic and therapeutic punctures. It is also the first technique used in the study of pancreatic tumors, detecting them with a sensitivity of around 70% and a specificity of 90%. Copyright © 2014 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España. All rights reserved.

State-of-the-art pancreatic MRI.

PubMed

Sandrasegaran, Kumaresan; Lin, Chen; Akisik, Fatih M; Tann, Mark

2010-07-01

The purpose of this article is to discuss the most current techniques used for pancreatic imaging, highlighting the advantages and disadvantages of state-of-the-art and emerging pulse sequences and their application to pancreatic disease. Given the technologic advances of the past decade, pancreatic MRI protocols have evolved. Most sequences can now be performed in one or a few breath-holds; 3D sequences with thin, contiguous slices offer improved spatial resolution; and better fat and motion suppression allow improved contrast resolution and image quality. The diagnostic potential of MRCP is now almost as good as ERCP, with pancreatic MRI as the main imaging technique to investigate biliopancreatic pain, chronic pancreatitis, and cystic pancreatic tumors at many institutions. In addition, functional information is provided with secretin-enhanced MRCP.

Secretagogin is a novel marker for neuroendocrine differentiation.

PubMed

Birkenkamp-Demtröder, Karin; Wagner, Ludwig; Brandt Sørensen, Flemming; Bording Astrup, Lone; Gartner, Wolfgang; Scherübl, Hans; Heine, Bernhard; Christiansen, Peer; Ørntoft, Torben Falck

2005-01-01

Our previous microarray-based studies identified secretagogin to be highly expressed in normal colon mucosa compared to basal expression in colon adenocarcinomas. The aim of this study was to analyze the differential expression of secretagogin in normal mucosa, adenocarcinomas, and neuroendocrine tumors. Western blotting, immunohistochemistry, immunofluorescence microscopy and ELISA were applied. Western blot analysis detected a 32-kDa secretagogin band in samples from normal mucosa. Immunohistochemical analyses on tissue specimens showed that secretagogin is exclusively expressed in neuroendocrine cells and nerve cells in normal mucosa of the digestive tract. Tissues adjacent to benign hyperplasic polyps and adenomas showed a decreased number of secretagogin-expressing neuroendocrine cells. Secretagogin co-localized with neuroendocrine markers (chromogranin A, neuron-specific enolase, synaptophysin) in neuroendocrine cells in crypts of normal mucosa, and in tumor cells of carcinoids. Secretagogin was strongly expressed in the cytosol and the nucleus of 19 well-differentiated neuroendocrine carcinoids and carcinoid metastases, as well as in neuroendocrine tumors from the lung, pancreas and adrenal gland. Secretagogin was detected in plasma from carcinoid patients with distant metastasis. Combined immunohistochemical analysis of secretagogin and FK506-binding protein 65, a protein de novo synthesized in adenocarcinomas, distinguished well-differentiated carcinoids, adenocarcinoids and undifferentiated carcinomas. We conclude that secretagogin is a novel marker for neuroendocrine differentiation.

Targeted agents for patients with advanced/metastatic pancreatic cancer: A protocol for systematic review and network meta-analysis.

PubMed

Di, Baoshan; Pan, Bei; Ge, Long; Ma, Jichun; Wu, Yiting; Guo, Tiankang

2018-03-01

Pancreatic cancer (PC) is a devastating malignant tumor. Although surgical resection may offer a good prognosis and prolong survival, approximately 80% patients with PC are always diagnosed as unresectable tumor. National Comprehensive Cancer Network's (NCCN) recommended gemcitabine-based chemotherapy as efficient treatment. While, according to recent studies, targeted agents might be a better available option for advanced or metastatic pancreatic cancer patients. The aim of this systematic review and network meta-analysis will be to examine the differences of different targeted interventions for advanced/metastatic PC patients. We will conduct this systematic review and network meta-analysis using Bayesian method and according to Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) statement. To identify relevant studies, 6 electronic databases including PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of science, CNKI (Chinese National Knowledge Infrastructure), and CBM (Chinese Biological Medical Database) will be searched. The risk of bias in included randomized controlled trials (RCTs) will be assessed using the Cochrane Handbook version 5.1.0. And we will use GRADE approach to assess the quality of evidence from network meta-analysis. Data will be analyzed using R 3.4.1 software. To the best of our knowledge, this systematic review and network meta-analysis will firstly use both direct and indirect evidence to compare the differences of different targeted agents and targeted agents plus chemotherapy for advanced/metastatic pancreatic cancer patients. This is a protocol of systematic review and meta-analysis, so the ethical approval and patient consent are not required. We will disseminate the results of this review by submitting to a peer-reviewed journal.

New insights into pancreatic cancer biology.

PubMed

Hidalgo, M

2012-09-01

Pancreatic cancer remains a devastating disease. Over the last few years, there have been important advances in the molecular and biological understanding of pancreatic cancer. This included understanding of the genomic complexity of the disease, the role of pancreatic cancer stem cells, the relevance of the tumor microenvironment, and the unique metabolic adaptation of pancreas cancer cells to obtain nutrients under hypoxic environment. In this paper, we review the most salient developments in these few areas.

Genetic evolution of pancreatic cancer: lessons learnt from the pancreatic cancer genome sequencing project

PubMed Central

Iacobuzio-Donahue, Christine A

2012-01-01

Pancreatic cancer is a disease caused by the accumulation of genetic alterations in specific genes. Elucidation of the human genome sequence, in conjunction with technical advances in the ability to perform whole exome sequencing, have provided new insight into the mutational spectra characteristic of this lethal tumour type. Most recently, exomic sequencing has been used to clarify the clonal evolution of pancreatic cancer as well as provide time estimates of pancreatic carcinogenesis, indicating that a long window of opportunity may exist for early detection of this disease while in the curative stage. Moving forward, these mutational analyses indicate potential targets for personalised diagnostic and therapeutic intervention as well as the optimal timing for intervention based on the natural history of pancreatic carcinogenesis and progression. PMID:21749982

PDX-1 Is a Therapeutic Target for Pancreatic Cancer, Insulinoma and Islet Neoplasia Using a Novel RNA Interference Platform

PubMed Central

Liu, Shi-He; Rao, Donald D.; Nemunaitis, John; Senzer, Neil; Zhou, Guisheng; Dawson, David; Gingras, Marie-Claude; Wang, Zhaohui; Gibbs, Richard; Norman, Michael; Templeton, Nancy S.; DeMayo, Francesco J.; O'Malley, Bert; Sanchez, Robbi; Fisher, William E.; Brunicardi, F. Charles

2012-01-01

Pancreatic and duodenal homeobox-1 (PDX-1) is a transcription factor that regulates insulin expression and islet maintenance in the adult pancreas. Our recent studies demonstrate that PDX-1 is an oncogene for pancreatic cancer and is overexpressed in pancreatic cancer. The purpose of this study was to demonstrate that PDX-1 is a therapeutic target for both hormonal symptoms and tumor volume in mouse models of pancreatic cancer, insulinoma and islet neoplasia. Immunohistochemistry of human pancreatic and islet neoplasia specimens revealed marked PDX-1 overexpression, suggesting PDX-1 as a “drugable” target within these diseases. To do so, a novel RNA interference effector platform, bifunctional shRNAPDX-1, was developed and studied in mouse and human cell lines as well as in mouse models of pancreatic cancer, insulinoma and islet neoplasia. Systemic delivery of bi-shRNAhumanPDX-1 lipoplexes resulted in marked reduction of tumor volume and improved survival in a human pancreatic cancer xenograft mouse model. bi-shRNAmousePDX-1 lipoplexes prevented death from hyperinsulinemia and hypoglycemia in an insulinoma mouse model. shRNAmousePDX-1 lipoplexes reversed hyperinsulinemia and hypoglycemia in an immune-competent mouse model of islet neoplasia. PDX-1 was overexpressed in pancreatic neuroendocrine tumors and nesidioblastosis. These data demonstrate that PDX-1 RNAi therapy controls hormonal symptoms and tumor volume in mouse models of pancreatic cancer, insulinoma and islet neoplasia, therefore, PDX-1 is a potential therapeutic target for these pancreatic diseases. PMID:22905092

Nonfunctional pancreatic neuroendocrine tumors <2 cm on preoperative imaging are associated with a low incidence of nodal metastasis and an excellent overall survival.

PubMed

Toste, Paul A; Kadera, Brian E; Tatishchev, Sergei F; Dawson, David W; Clerkin, Barbara M; Muthusamy, Raman; Watson, Rabindra; Tomlinson, James S; Hines, Oscar J; Reber, Howard A; Donahue, Timothy R

2013-12-01

The optimal surgical management of small nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) remains controversial. We sought to identify (1) clinicopathologic factors associated with survival in NF-PNETs and (2) preoperative tumor characteristics that can be used to determine which lesions require resection and lymph node (LN) harvest. The records of all 116 patients who underwent resection for NF-PNETs between 1989 and 2012 were reviewed retrospectively. Preoperative factors, operative data, pathology, surgical morbidity, and survival were analyzed. The overall 5- and 10-year survival rates were 83.9 and 72.8 %, respectively. Negative LNs (p = 0.005), G1 or G2 histology (p = 0.033), and age <60 years (p = 0.002) correlated with better survival on multivariate analysis. The 10-year survival rate was 86.6 % for LN-negative patients (n = 73) and 34.1 % for LN-positive patients (n = 32). Tumor size ≥2 cm on preoperative imaging predicted nodal positivity with a sensitivity of 93.8 %. Positive LNs were found in 38.5 % of tumors ≥2 cm compared to only 7.4 % of tumors <2 cm. LN status, a marker of systemic disease, was a highly significant predictor of survival in this series. Tumor size on preoperative imaging was predictive of nodal disease. Thus, it is reasonable to consider parenchyma-sparing resection or even close observation for NF-PNETs <2 cm.

Chemoprevention strategies for pancreatic cancer

PubMed Central

Stan, Silvia D.; Singh, Shivendra V.; Brand, Randall E.

2010-01-01

Pancreatic cancer has a poor prognosis and it is often diagnosed at advanced stages, which makes it very difficult to treat. The low survival rate of patients with pancreatic cancer points toward an increased need for novel therapeutic and chemopreventive strategies and early detection. Increased consumption of fruits and vegetables has been associated with a reduced risk of pancreatic cancer. Both synthetic as well as natural, diet-derived bioactive compounds have been evaluated as pancreatic cancer chemopreventive agents and have been shown to have various degrees of efficacy in cellular and in vivo animal models. Some chemopreventive agents (for example curcumin, resveratrol, B-DIM) have also been reported to sensitize pancreatic cancer cells to standard chemotherapeutic drugs (for example gemcitabine or erlotinib), which suggests the potential use of chemopreventive agents as potentiators of standard chemotherapy. Very few clinical trials with pancreatic cancer chemopreventive agents have been completed and some are in early phases. Further development of pancreatic cancer chemopreventive agents may prove to be tremendously valuable for individuals at high-risk of developing pancreatic cancer and patients who present with premalignant lesions. This Review discusses the current state of the pancreatic cancer chemoprevention field and highlights the challenges ahead. PMID:20440279

Dietary consumption of advanced glycation end products and pancreatic cancer in the prospective NIH-AARP Diet and Health Study.

PubMed

Jiao, Li; Stolzenberg-Solomon, Rachael; Zimmerman, Thea Palmer; Duan, Zhigang; Chen, Liang; Kahle, Lisa; Risch, Adam; Subar, Amy F; Cross, Amanda J; Hollenbeck, Albert; Vlassara, Helen; Striker, Gary; Sinha, Rashmi

2015-01-01

Advanced glycation end products (AGEs) are a heterogeneous group of compounds present in uncooked foods as well as in foods cooked at high temperatures. AGEs have been associated with insulin resistance, oxidative stress, and chronic inflammation in patients with diabetes. Dietary AGEs are an important contributor to the AGE pool in the body. N(ϵ)-(carboxymethyl)lysine (CML) AGE is one of the major biologically and chemically well-characterized AGE markers. The consumption of red meat, which is CML-AGE rich, has been positively associated with pancreatic cancer in men. With the use of a published food CML-AGE database, we estimated the consumption of CML AGE in the prospective NIH-AARP Diet and Health Study and evaluated the association between CML-AGE consumption and pancreatic cancer and the mediating effect of CML AGE on the association between red meat consumption and pancreatic cancer. Multivariate Cox proportional hazard regression models were used to estimate HRs and 95% CIs for pancreatic cancer. During an average of 10.5 y of follow-up, we identified 2193 pancreatic cancer cases (1407 men and 786 women) from 528,251 subjects. With the comparison of subjects in the fifth and the first quintiles of CML-AGE consumption, we observed increased pancreatic cancer risk in men (HR: 1.43; 95% CI: 1.06, 1.93, P-trend = 0.003) but not women (HR: 1.14; 95% CI: 0.76, 1.72, P-trend = 0.42). Men in the highest quintile of red meat consumption had higher risk of pancreatic cancer (HR: 1.35; 95% CI: 1.07, 1.70), which attenuated after adjustment for CML-AGE consumption (HR: 1.20; 95% CI: 0.95, 1.53). Dietary CML-AGE consumption was associated with modestly increased risk of pancreatic cancer in men and may partially explain the positive association between red meat and pancreatic cancer. © 2015 American Society for Nutrition.

Plastic biliary stent patency in patients with locally advanced pancreatic adenocarcinoma receiving downstaging chemotherapy.

PubMed

Ge, Phillip S; Hamerski, Christopher M; Watson, Rabindra R; Komanduri, Srinadh; Cinnor, Birtukan B; Bidari, Kiran; Klapman, Jason B; Lin, Cui L; Shah, Janak N; Wani, Sachin; Donahue, Timothy R; Muthusamy, V Raman

2015-02-01

Plastic stents in patients with biliary obstruction caused by pancreatic adenocarcinoma are typically exchanged at 3-month intervals. Plastic stents may have reduced durability in patients receiving chemotherapy. To determine the duration of plastic biliary stent patency in patients undergoing chemotherapy for pancreatic adenocarcinoma. Retrospective, multicenter cohort study. Three tertiary academic referral centers. A total of 173 patients receiving downstaging chemotherapy for locally advanced or borderline resectable pancreatic adenocarcinoma from 1996 to 2013. Placement of 10F or larger plastic biliary stents. Primary outcome was overall duration of stent patency. Secondary outcomes included the incidence of premature stent exchange (because of cholangitis or jaundice) and hospitalization rates. A total of 233 plastic stents were placed, and the overall median duration of stent patency was 53 days (interquartile range [IQR] 25-99 days). Eighty-seven stents were removed at the time of surgical resection, and 63 stents were exchanged routinely per protocol. The remaining 83 stent exchanges were performed for worsening liver function test results, jaundice, or cholangitis, representing a 35.6% rate of premature stent exchange. The median stent patency duration in the premature stent exchange group was 49 days (IQR 25-91 days) with a 44.6% hospitalization rate. The overall rate of cholangitis was 15.0% of stent exchanges, occurring a median of 56 days after stent placement (IQR 26-89 days). Retrospective study. Plastic biliary stents placed during chemotherapy/chemoradiation for pancreatic adenocarcinoma have a shorter-than-expected patency duration, and a substantial number of patients will require premature stent exchange. Consideration should be given to shortening the interval for plastic biliary stent exchange. Copyright © 2015 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.

Primary neuroendocrine neoplasm of the gallbladder.

PubMed

Kanakala, Venkatesh; Kasaraneni, Ramesh; Smith, David A; Goulbourne, Ian A

2009-01-01

Carcinoid tumours are distinct neuroendocrine tumours with characteristic clinical and histological behavioural properties which arise mainly in the gastrointestinal tract (73.7%) or bronchopulmonary system (25.1%). Neuroendocrine tumours of the gallbladder are rare-to date there have been only 42 cases reported in the literature. This case was an incidental finding which was recognised during routine histopathological examination after laparoscopic cholecystectomy for symptomatic cholelithiasis. The patient recovered well from the operation. There were no concurrent lesions or metastases noted on further investigations, and the final diagnosis was a primary neuroendocrine tumour of the gallbladder.

Programming of neuroendocrine self in the thymus and its defect in the development of neuroendocrine autoimmunity.

PubMed

Geenen, Vincent; Bodart, Gwennaëlle; Henry, Séverine; Michaux, Hélène; Dardenne, Olivier; Charlet-Renard, Chantal; Martens, Henri; Hober, Didier

2013-10-16

For centuries after its first description by Galen, the thymus was considered as only a vestigial endocrine organ until the discovery in 1961 by Jacques FAP Miller of its essential role in the development of T (thymo-dependent) lymphocytes. A unique thymus first appeared in cartilaginous fishes some 500 million years ago, at the same time or shortly after the emergence of the adaptive (acquired) immune system. The thymus may be compared to a small brain or a computer highly specialized in the orchestration of central immunological self-tolerance. This was a necessity for the survival of species, given the potent evolutionary pressure imposed by the high risk of autotoxicity inherent in the stochastic generation of the diversity of immune cell receptors that characterize the adaptive immune response. A new paradigm of "neuroendocrine self-peptides" has been proposed, together with the definition of "neuroendocrine self." Neuroendocrine self-peptides are secreted by thymic epithelial cells (TECs) not according to the classic model of neuroendocrine signaling, but are processed for presentation by, or in association with, the thymic major histocompatibility complex (MHC) proteins. The autoimmune regulator (AIRE) gene/protein controls the transcription of neuroendocrine genes in TECs. The presentation of self-peptides in the thymus is responsible for the clonal deletion of self-reactive T cells, which emerge during the random recombination of gene segments that encode variable parts of the T cell receptor for the antigen (TCR). At the same time, self-antigen presentation in the thymus generates regulatory T (Treg) cells that can inhibit, in the periphery, those self-reactive T cells that escaped negative selection in the thymus. Several arguments indicate that the origin of autoimmunity directed against neuroendocrine glands results primarily from a defect in the intrathymic programming of self-tolerance to neuroendocrine functions. This defect may be genetic or

Gastric neuroendocrine tumours.

PubMed

Crosby, David A; Donohoe, Claire L; Fitzgerald, Louise; Muldoon, Cian; Hayes, Brian; O'Toole, Dermot; Reynolds, John V

2012-01-01

Gastric neuroendocrine tumours (NETs) are increasingly recognised, and management decisions may be difficult due to an incomplete understanding of aetiology, natural history and optimum therapy. This article presents a current understanding based on recent advances in epidemiology, classification, molecular profiling, and treatment. Relevant medical literature was identified from searches of PubMed and references cited in appropriate articles identified. Selection of articles was based on peer review, journal and relevance. Gastric NETs may be divided into three clinical prognostic groups: type I is associated with autoimmune atrophic gastritis and hypergastrinaemia, type II is associated with Zollinger-Ellison syndrome, and type III lesions are gastrin-independent, have the greatest metastatic potential and poorest prognosis. There has been an increased frequency of gastric NETs reported. Management approaches have evolved in parallel with advances in endoscopic staging and surgery, as well as improved understanding of the biology and natural history of NETs. Gastric NETs present a spectrum of activity from indolent tumours to metastatic malignancy. Treatment decisions for patients must be individualised and are best managed by a multidisciplinary team approach. The current evidence base is limited to small series and efforts to treat patients within clinical networks of expertise are warranted. Copyright © 2012 S. Karger AG, Basel.

Important technical remarks on distal pancreatectomy with en-bloc celiac axis resection for locally advanced pancreatic body cancer (with video).

PubMed

Tanaka, Eiichi; Hirano, Satoshi; Tsuchikawa, Takahiro; Kato, Kentaro; Matsumoto, Joe; Shichinohe, Toshiaki

2012-03-01

We have already reported the feasibility, safety, and excellent long-term results of distal pancreatectomy with en-bloc celiac axis resection (DP-CAR) for locally advanced pancreatic body cancer. An international standard for the surgical technique of DP-CAR has yet to be established. DP-CAR was carefully performed in 42 patients in Hokkaido University Hospital from 1998 to July 2007. Arterial blood flow alteration and collateral flow development toward the liver and stomach was obtained following preoperative routine transcatheter arterial embolization of the common hepatic artery. The right-sided approach to the superior mesenteric artery and celiac artery, and the preservation of the inferior pancreatoduodenal artery during the dissection of the plexus around the pancreatic head, are the key techniques in DP-CAR. The operative morbidity and mortality were 43 and 4.8%, respectively. R0 resection could be done in 39 (93%) patients. Median operation time and intraoperative blood loss were 478 min and 1030 ml, respectively. Ischemic gastropathy was complicated in 5 (12%) patients, but liver abscess was found in only one patient and no liver failure was encountered. We emphasize again the feasibility and safety of DP-CAR; it should be a treatment of choice for locally advanced pancreatic body cancer.

Laser Tissue Welding - Distal Pancreatectomy Sealing Study

ClinicalTrials.gov

2018-04-20

Pancreatic Tumor, Benign; Pancreatic Neoplasms; Pancreatic Adenocarcinoma; Pancreatic Pseudocyst; Pancreatic Neuroendocrine Tumor; Pancreas; Insulinoma; Pancreatic Cyst; Pancreatic Teratoma; Pancreatic Polypeptide Tumor; Pancreatic Vipoma; Pancreatic Cystadenoma; Pancreas Injury; Pancreatic Gastrinoma; Pancreatic Glucagonoma

Acute pancreatitis in children and adolescents

PubMed Central

Suzuki, Mitsuyoshi; Sai, Jin Kan; Shimizu, Toshiaki

2014-01-01

In this Topic Highlight, the causes, diagnosis, and treatment of acute pancreatitis in children are discussed. Acute pancreatitis should be considered during the differential diagnosis of abdominal pain in children and requires prompt treatment because it may become life-threatening. The etiology, clinical manifestations, and course of acute pancreatitis in children are often different than in adults. Therefore, the specific features of acute pancreatitis in children must be considered. The etiology of acute pancreatitis in children is often drugs, infections, trauma, or anatomic abnormalities. Diagnosis is based on clinical symptoms (such as abdominal pain and vomiting), serum pancreatic enzyme levels, and imaging studies. Several scoring systems have been proposed for the assessment of severity, which is useful for selecting treatments and predicting prognosis. The basic pathogenesis of acute pancreatitis does not greatly differ between adults and children, and the treatments for adults and children are similar. In large part, our understanding of the pathology, optimal treatment, assessment of severity, and outcome of acute pancreatitis in children is taken from the adult literature. However, we often find that the common management of adult pancreatitis is difficult to apply to children. With advances in diagnostic techniques and treatment methods, severe acute pancreatitis in children is becoming better understood and more controllable. PMID:25400985

PKD signaling and pancreatitis

PubMed Central

Yuan, Jingzhen; Pandol, Stephen J.

2016-01-01

Background Acute pancreatitis is a serious medical disorder with no current therapies directed to the molecular pathogenesis of the disorder. Inflammation, inappropriate intracellular activation of digestive enzymes, and parenchymal acinar cell death by necrosis are the critical pathophysiologic processes of acute pancreatitis. Thus, it is necessary to elucidate the key molecular signals that mediate these pathobiologic processes and develop new therapeutic strategies to attenuate the appropriate signaling pathways in order to improve outcomes for this disease. A novel serine/threonine protein kinase D (PKD) family has emerged as key participants in signal transduction, and this family is increasingly being implicated in the regulation of multiple cellular functions and diseases. Methods This review summarizes recent findings of our group and others regarding the signaling pathway and the biological roles of the PKD family in pancreatic acinar cells. In particular, we highlight our studies of the functions of PKD in several key pathobiologic processes associated with acute pancreatitis in experimental models. Results Our findings reveal that PKD signaling is required for NF-κB activation/inflammation, intracellular zymogen activation, and acinar cell necrosis in rodent experimental pancreatitis. Novel small-molecule PKD inhibitors attenuate the severity of pancreatitis in both in vitro and in vivo experimental models. Further, this review emphasizes our latest advances in the therapeutic application of PKD inhibitors to experimental pancreatitis after the initiation of pancreatitis. Conclusions These novel findings suggest that PKD signaling is a necessary modulator in key initiating pathobiologic processes of pancreatitis, and that it constitutes a novel therapeutic target for treatments of this disorder. PMID:26879861

Primary neuroendocrine neoplasm of the gallbladder

PubMed Central

Kanakala, Venkatesh; Kasaraneni, Ramesh; Smith, David A; Goulbourne, Ian A

2009-01-01

Carcinoid tumours are distinct neuroendocrine tumours with characteristic clinical and histological behavioural properties which arise mainly in the gastrointestinal tract (73.7%) or bronchopulmonary system (25.1%). Neuroendocrine tumours of the gallbladder are rare—to date there have been only 42 cases reported in the literature. This case was an incidental finding which was recognised during routine histopathological examination after laparoscopic cholecystectomy for symptomatic cholelithiasis. The patient recovered well from the operation. There were no concurrent lesions or metastases noted on further investigations, and the final diagnosis was a primary neuroendocrine tumour of the gallbladder. PMID:21686357

A bipartite graph of Neuroendocrine System

NASA Astrophysics Data System (ADS)

Guo, Zhong-Wei; Zou, Sheng-Rong; Peng, Yu-Jing; Zhou, Ta; Gu, Chang-Gui; He, Da-Ren

2008-03-01

We present an empirical investigation on the neuroendocrine system and suggest describe it by a bipartite graph. In the net the cells can be regarded as collaboration acts and the mediators can be regarded as collaboration actors. The act degree stands for the number of the cells that secrete a single mediator. Among them bFGF (the basic fibroblast growth factor) has the largest node act degree. It is the most important mitogenic cytokine, followed by TGF-beta, IL-6, IL1-beta, VEGF, IGF-1and so on. They are critical in neuroendocrine system to maintain bodily healthiness, emotional stabilization and endocrine harmony. The act degree distribution shows a shifted power law (SPL) function forms [1]. The average act degree of neuroendocrine network is h=3.01, It means that each mediator is secreted by three cells on average. The similarity, which stands for the average probability of secreting the same mediators by all neuroendocrine cells, is observed as s=0.14. Our results may be used in the research of the medical treatment of neuroendocrine diseases. [1] Assortativity and act degree distribution of some collaboration networks, Hui Chang, Bei-Bei Su, Yue-Ping Zhou, Daren He, Physica A, 383 (2007) 687-702

Immune-Neuroendocrine Interactions and Autoimmune Diseases

PubMed Central

Jara, Luis J.; Navarro, Carmen; Medina, Gabriela; Vera-Lastra, Olga; Blanco, Francisco

2006-01-01

The relationship between immune-neuroendocrine system is firmly established. The messengers of this connection are hormones, neuropeptides, neurotransmitters and cytokines. The immune-neuroendocrine system have the capacity to synthesize and release these molecules, which, in turn, can stimulate or suppress the activity of immune or neuroendocrine cells by binding to receptors. In fact, hormones, neuropeptides and neurotransmitters participate in innate and adaptive immune response.Autoimmune rheumatic diseases (ARD) are characterized by aberrant production of pro-inflammatory cytokines, which are a potent activator of the HPA axis. In consequence, high levels of pro-inflammatory hormones such as estrogens and prolactin, and low levels of glucocorticoids, an anti-inflammatory hormone, have been described in the active phase of ARD. In addition, high levels of pro-inflammatory hormones and cytokines have also been frequently detected in organ involvement of patients with ARD, suggesting an abnormal local neuroendocrine immune interaction. There is evidence that hormonal changes may appear before the symptomatic phase of the disease. Therefore, it is possible that a pro-inflammatory hormone favors the rupture of tolerance, which is a key feature of autoimmune diseases. The interactions between the immune-neuroendocrine system have a major impact on our understanding of the pathogenic mechanisms, diagnosis and therapy of ARD. PMID:17162354

Translating Discovery in Zebrafish Pancreatic Development to Human Pancreatic Cancer: Biomarkers, Targets, Pathogenesis, and Therapeutics

PubMed Central

Kazi, Abid A.; Yee, Rosemary K.

2013-01-01

Abstract Experimental studies in the zebrafish have greatly facilitated understanding of genetic regulation of the early developmental events in the pancreas. Various approaches using forward and reverse genetics, chemical genetics, and transgenesis in zebrafish have demonstrated generally conserved regulatory roles of mammalian genes and discovered novel genetic pathways in exocrine pancreatic development. Accumulating evidence has supported the use of zebrafish as a model of human malignant diseases, including pancreatic cancer. Studies have shown that the genetic regulators of exocrine pancreatic development in zebrafish can be translated into potential clinical biomarkers and therapeutic targets in human pancreatic adenocarcinoma. Transgenic zebrafish expressing oncogenic K-ras and zebrafish tumor xenograft model have emerged as valuable tools for dissecting the pathogenetic mechanisms of pancreatic cancer and for drug discovery and toxicology. Future analysis of the pancreas in zebrafish will continue to advance understanding of the genetic regulation and biological mechanisms during organogenesis. Results of those studies are expected to provide new insights into how aberrant developmental pathways contribute to formation and growth of pancreatic neoplasia, and hopefully generate valid biomarkers and targets as well as effective and safe therapeutics in pancreatic cancer. PMID:23682805

Translating discovery in zebrafish pancreatic development to human pancreatic cancer: biomarkers, targets, pathogenesis, and therapeutics.

PubMed

Yee, Nelson S; Kazi, Abid A; Yee, Rosemary K

2013-06-01

Abstract Experimental studies in the zebrafish have greatly facilitated understanding of genetic regulation of the early developmental events in the pancreas. Various approaches using forward and reverse genetics, chemical genetics, and transgenesis in zebrafish have demonstrated generally conserved regulatory roles of mammalian genes and discovered novel genetic pathways in exocrine pancreatic development. Accumulating evidence has supported the use of zebrafish as a model of human malignant diseases, including pancreatic cancer. Studies have shown that the genetic regulators of exocrine pancreatic development in zebrafish can be translated into potential clinical biomarkers and therapeutic targets in human pancreatic adenocarcinoma. Transgenic zebrafish expressing oncogenic K-ras and zebrafish tumor xenograft model have emerged as valuable tools for dissecting the pathogenetic mechanisms of pancreatic cancer and for drug discovery and toxicology. Future analysis of the pancreas in zebrafish will continue to advance understanding of the genetic regulation and biological mechanisms during organogenesis. Results of those studies are expected to provide new insights into how aberrant developmental pathways contribute to formation and growth of pancreatic neoplasia, and hopefully generate valid biomarkers and targets as well as effective and safe therapeutics in pancreatic cancer.

[Latest advances in acute pancreatitis].

PubMed

de-Madaria, Enrique

2013-10-01

The present article analyzes the main presentations on acute pancreatitis (AP) in Digestive Disease Week 2013. Perfusion computed tomography allows early diagnosis of pancreatic necrosis. Neutrophil gelatinase-associated lipocalin predicts the development of acute renal failure, severe AP and death. Factors associated with greater fluid sequestration in AP are alcoholic etiology, an elevated hematocrit, and the presence of criteria of systemic inflammatory response syndrome; fluid sequestration is associated with a worse outcome. True pseudocysts (fluid collections without necrosis for more than 4 weeks) are a highly infrequent complication in AP. Patients with necrotic collections have a poor prognosis, especially if associated with infection. A meta-analysis on fluid therapy suggests that early aggressive fluid administration is associated with higher mortality and more frequent respiratory complications. According to a meta-analysis, enteral nutrition initiated within 24 hours of admission improves the outcome of AP compared with later initiation of enteral nutrition. Pentoxifylline could be a promising alternative in AP; a double-blind randomized study showed that this drug reduced the length of hospital and intensive care unit stay, as well as the need for intensive care unit admission. The association of octreotide and celecoxib seems to reduce the frequency of organ damage compared with octreotide alone. Mild AP can be managed in the ambulatory setting through hospital-at-home units after a short, 24-hour admission. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Neuroendocrine Differentiation in Sporadic CRC and Hereditary Nonpolyosis Colorectal Cancer

PubMed Central

Sun, M. H.

2004-01-01

Extent neuroendocrine differentiation can be encountered in many human neoplasm derived from different organs and systems using immunohistochemistry and ultrastructural techniques. The tumor cells' behaviors resemble those of neurons and neuroendocrine cells. The presence of neuroendocrine differentiation reputedly appears to be associated with a poorer prognosis than the adenocarcinoma counterparts in sporadic human neoplasm. In this review the neuroendocrine carcinoma and the adenocarcinoma with neuroendocrine differentiation of colon and rectum both in sporadic colorectal carcinoma and the hereditary nonpolyposis colorectal cancer, the relationship of neuroendocrine differentiation and some possible molecular pathways in tumorogenesis of colorectal cancer will be discussed. Possible treatment strategy will also be addressed. PMID:15528794

Small amounts of tissue preserve pancreatic function

PubMed Central

Lu, Zipeng; Yin, Jie; Wei, Jishu; Dai, Cuncai; Wu, Junli; Gao, Wentao; Xu, Qing; Dai, Hao; Li, Qiang; Guo, Feng; Chen, Jianmin; Xi, Chunhua; Wu, Pengfei; Zhang, Kai; Jiang, Kuirong; Miao, Yi

2016-01-01

Abstract Middle-segment preserving pancreatectomy (MPP) is a novel procedure for treating multifocal lesions of the pancreas while preserving pancreatic function. However, long-term pancreatic function after this procedure remains unclear. The aims of this current study are to investigate short- and long-term outcomes, especially long-term pancreatic endocrine function, after MPP. From September 2011 to December 2015, 7 patients underwent MPP in our institution, and 5 cases with long-term outcomes were further analyzed in a retrospective manner. Percentage of tissue preservation was calculated using computed tomography volumetry. Serum insulin and C-peptide levels after oral glucose challenge were evaluated in 5 patients. Beta-cell secreting function including modified homeostasis model assessment of beta-cell function (HOMA2-beta), area under the curve (AUC) for C-peptide, and C-peptide index were evaluated and compared with those after pancreaticoduodenectomy (PD) and total pancreatectomy. Exocrine function was assessed based on questionnaires. Our case series included 3 women and 2 men, with median age of 50 (37–81) years. Four patients underwent pylorus-preserving PD together with distal pancreatectomy (DP), including 1 with spleen preserved. The remaining patient underwent Beger procedure and spleen-preserving DP. Median operation time and estimated intraoperative blood loss were 330 (250–615) min and 800 (400–5500) mL, respectively. Histological examination revealed 3 cases of metastatic lesion to the pancreas, 1 case of chronic pancreatitis, and 1 neuroendocrine tumor. Major postoperative complications included 3 cases of delayed gastric emptying and 2 cases of postoperative pancreatic fistula. Imaging studies showed that segments representing 18.2% to 39.5% of the pancreas with good blood supply had been preserved. With a median 35.0 months of follow-ups on pancreatic functions, only 1 patient developed new-onset diabetes mellitus of the 4

Practical management of everolimus-related toxicities in patients with advanced solid tumors.

PubMed

Grünwald, Viktor; Weikert, Steffen; Pavel, Marianne E; Hörsch, Dieter; Lüftner, Diana; Janni, Wolfgang; Geberth, Matthias; Weber, Matthias M

2013-01-01

Everolimus is an orally administered inhibitor of the mammalian target of rapamycin (mTOR), an intracellular protein kinase downstream of the phosphatidylinositol 3-kinase/AKT pathway involved in key components of tumorigenesis, including cell growth, proliferation, and angiogenesis. In the advanced cancer setting, based on favorable results from phase III trials, everolimus is indicated for the treatment of advanced renal cell carcinoma, advanced neuroendocrine tumors of pancreatic origin, and advanced hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. Additional oncology indications for everolimus include renal angiomyolipoma with tuberous sclerosis complex and subependymal giant-cell astrocytoma. Although it is generally well tolerated, with most adverse events of mild to moderate severity and manageable, everolimus exhibits a distinct adverse event profile that warrants guidance for proper diagnostic and medical management. This guidance is particularly important given the potential for widespread long-term use of everolimus. This review will focus on the most relevant toxicities associated with mTOR inhibitors and on their management. Practical treatment recommendations are presented for stomatitis, noninfectious pneumonitis, rash, selected metabolic abnormalities, and infections. Provided these events are rapidly identified and treated, the vast majority should resolve with minimal effect on treatment outcomes and patients' quality of life. Copyright © 2013 S. Karger AG, Basel.

Pancreatic enucleation using the da Vinci robotic surgical system: a report of 26 cases.

PubMed

Shi, Yusheng; Peng, Chenghong; Shen, Baiyong; Deng, Xiaxing; Jin, Jiabin; Wu, Zhichong; Zhan, Qian; Li, Hongwei

2016-12-01

As a tissue-sparing procedure, pancreatic enucleation has become an alternative for benign or borderline pancreatic tumours; it has been proved to be safe and feasible. To date, a large sample size of robotic pancreatic enucleation has not been reported. This study aimed to discuss the clinical evaluation and postoperative complications after robotic pancreatic enucleation and compare it with open surgery. Patients who underwent robotic or open pancreatic enucleation during December 2010-December 2014 at Shanghai Ruijin Hospital, affiliated with the Shanghai Jiaotong University School of Medicine in China, were included. Clinical data were collected and analysed. Patients were divided into an open group and a robotic group: 26 patients underwent robotic pancreatic enucleation, of whom 13 patients were female. The mean age was 51.7 years, the operation time was 125.7 ± 58.8 min, blood loss was 49.4 ± 33.4 ml and mean tumour size was 18.8 ± 7.9 mm; 17 patients underwent open pancreatic enucleation, of whom 11 were female. The mean age was 54.6 ± 17.2 min, blood loss was 198.5 ± 70.7 ml and mean tumour size was 3.5 ± 1.9 cm. Pathology included insulinomas, intrapancreatic mucinous neoplasmas (IPMNs), pancreatic neuro-endocrine tumours (PNETs), solid pseudopapillary tumours (SPTs) and serous cystadenomas (SCAs). Robotic pancreatic enucleations were associated with less trauma, shorter operation time, less blood loss and faster wound recovery compared with open pancreatic enucleation. Pancreatic fistulas (PFs) were the main complication that occurred in the robotic group; infection also occurred in the open group. All patients recovered after effective drainage and the use of somatostatin. The mean follow-up time was 25 months. No recurrence was discovered, and one patient in the open group suffered endocrine insufficiency. Robotic pancreatic enucleation is a safe and effective surgical procedure for pancreatic benign and borderline tumours. It produces less

Overcoming Drug Resistance in Pancreatic Cancer

PubMed Central

Long, Jiang; Zhang, Yuqing; Yu, Xianjun; Yang, Jingxuan; LeBrun, Drake; Chen, Changyi; Yao, Qizhi; Li, Min

2011-01-01

Introduction Pancreatic cancer has the worst survival rate of all cancers. The current standard care for metastatic pancreatic cancer is gemcitabine, however, the success of this treatment is poor and overall survival has not improved for decades. Drug resistance (both intrinsic and acquired) is thought to be a major reason for the limited benefit of most pancreatic cancer therapies. Areas covered Previous studies have indicated various mechanisms of drug resistance in pancreatic cancer, including changes in individual genes or signaling pathways, the influence of the tumor microenvironment, and the presence of highly resistant stem cells. This review summarizes recent advances in the mechanisms of drug resistance in pancreatic cancer, and potential strategies to overcome this. Expert Opinion Increasing drug delivery efficiency and decreasing drug resistance is the current aim in pancreatic cancer treatment, and will also benefit the treatment of other cancers. Understanding the molecular and cellular basis of drug resistance in pancreatic cancer will lead to the development of novel therapeutic strategies with the potential to sensitize pancreatic cancer to chemotherapy, and to increase the efficacy of current treatments in a wide variety of human cancers. PMID:21391891

Animal models for investigating chronic pancreatitis

PubMed Central

2011-01-01

Chronic pancreatitis is defined as a continuous or recurrent inflammatory disease of the pancreas characterized by progressive and irreversible morphological changes. It typically causes pain and permanent impairment of pancreatic function. In chronic pancreatitis areas of focal necrosis are followed by perilobular and intralobular fibrosis of the parenchyma, by stone formation in the pancreatic duct, calcifications in the parenchyma as well as the formation of pseudocysts. Late in the course of the disease a progressive loss of endocrine and exocrine function occurs. Despite advances in understanding the pathogenesis no causal treatment for chronic pancreatitis is presently available. Thus, there is a need for well characterized animal models for further investigations that allow translation to the human situation. This review summarizes existing experimental models and distinguishes them according to the type of pathological stimulus used for induction of pancreatitis. There is a special focus on pancreatic duct ligation, repetitive overstimulation with caerulein and chronic alcohol feeding. Secondly, attention is drawn to genetic models that have recently been generated and which mimic features of chronic pancreatitis in man. Each technique will be supplemented with data on the pathophysiological background of the model and their limitations will be discussed. PMID:22133269

Programming of neuroendocrine self in the thymus and its defect in the development of neuroendocrine autoimmunity

PubMed Central

Geenen, Vincent; Bodart, Gwennaëlle; Henry, Séverine; Michaux, Hélène; Dardenne, Olivier; Charlet-Renard, Chantal; Martens, Henri; Hober, Didier

2013-01-01

For centuries after its first description by Galen, the thymus was considered as only a vestigial endocrine organ until the discovery in 1961 by Jacques FAP Miller of its essential role in the development of T (thymo-dependent) lymphocytes. A unique thymus first appeared in cartilaginous fishes some 500 million years ago, at the same time or shortly after the emergence of the adaptive (acquired) immune system. The thymus may be compared to a small brain or a computer highly specialized in the orchestration of central immunological self-tolerance. This was a necessity for the survival of species, given the potent evolutionary pressure imposed by the high risk of autotoxicity inherent in the stochastic generation of the diversity of immune cell receptors that characterize the adaptive immune response. A new paradigm of “neuroendocrine self-peptides” has been proposed, together with the definition of “neuroendocrine self.” Neuroendocrine self-peptides are secreted by thymic epithelial cells (TECs) not according to the classic model of neuroendocrine signaling, but are processed for presentation by, or in association with, the thymic major histocompatibility complex (MHC) proteins. The autoimmune regulator (AIRE) gene/protein controls the transcription of neuroendocrine genes in TECs. The presentation of self-peptides in the thymus is responsible for the clonal deletion of self-reactive T cells, which emerge during the random recombination of gene segments that encode variable parts of the T cell receptor for the antigen (TCR). At the same time, self-antigen presentation in the thymus generates regulatory T (Treg) cells that can inhibit, in the periphery, those self-reactive T cells that escaped negative selection in the thymus. Several arguments indicate that the origin of autoimmunity directed against neuroendocrine glands results primarily from a defect in the intrathymic programming of self-tolerance to neuroendocrine functions. This defect may be genetic

Pathology of Neuroendocrine Tumours of the Female Genital Tract.

PubMed

Howitt, Brooke E; Kelly, Paul; McCluggage, W Glenn

2017-09-01

Neuroendocrine tumours are uncommon or rare at all sites in the female genital tract. The 2014 World Health Organisation (WHO) Classification of neuroendocrine tumours of the endometrium, cervix, vagina and vulva has been updated with adoption of the terms low-grade neuroendocrine tumour and high-grade neuroendocrine carcinoma. In the endometrium and cervix, high-grade neoplasms are much more prevalent than low-grade and are more common in the cervix than the corpus. In the ovary, low-grade tumours are more common than high-grade carcinomas and the term carcinoid tumour is still used in WHO 2014. The term ovarian small-cell carcinoma of pulmonary type is included in WHO 2014 for a tumour which in other organs is termed high small-cell neuroendocrine carcinoma. Neuroendocrine tumours at various sites within the female genital tract often occur in association with other neoplasms and more uncommonly in pure form.

Gemcitabine Chemotherapy and Single-Fraction Stereotactic Body Radiotherapy for Locally Advanced Pancreatic Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schellenberg, Devin; Goodman, Karyn A.; Lee, Florence

2008-11-01

Purpose: Fractionated radiotherapy and chemotherapy for locally advanced pancreatic cancer achieves only modest local control. This prospective trial evaluated the efficacy of a single fraction of 25 Gy stereotactic body radiotherapy (SBRT) delivered between Cycle 1 and 2 of gemcitabine chemotherapy. Methods and Materials: A total of 16 patients with locally advanced, nonmetastatic, pancreatic adenocarcinoma received gemcitabine with SBRT delivered 2 weeks after completion of the first cycle. Gemcitabine was resumed 2 weeks after SBRT and was continued until progression or dose-limiting toxicity. The gross tumor volume, with a 2-3-mm margin, was treated in a single 25-Gy fraction by Cyberknife.more » Patients were evaluated at 4-6 weeks, 10-12 weeks, and every 3 months after SBRT. Results: All 16 patients completed SBRT. A median of four cycles (range one to nine) of chemotherapy was delivered. Three patients (19%) developed local disease progression at 14, 16, and 21 months after SBRT. The median survival was 11.4 months, with 50% of patients alive at 1 year. Patients with normal carbohydrate antigen (CA)19-9 levels either at diagnosis or after Cyberknife SBRT had longer survival (p <0.01). Acute gastrointestinal toxicity was mild, with 2 cases of Grade 2 (13%) and 1 of Grade 3 (6%) toxicity. Late gastrointestinal toxicity was more common, with five ulcers (Grade 2), one duodenal stenosis (Grade 3), and one duodenal perforation (Grade 4). A trend toward increased duodenal volumes radiated was observed in those experiencing late effects (p = 0.13). Conclusion: SBRT with gemcitabine resulted in comparable survival to conventional chemoradiotherapy and good local control. However, the rate of duodenal ulcer development was significant.« less

Safety and Immune Response to a Multi-component Immune Based Therapy (MKC1106-PP) for Patients With Advanced Cancer.

ClinicalTrials.gov

2010-08-02

Ovarian; Melanoma; Renal; Prostate; Colorectal; Endometrial Carcinoma; Cervical Carcinoma; Testicular Cancer; Thyroid Cancer; Small Cell Lung Carcinoma; Mesothelioma; Breast Carcinoma; Esophageal Carcinoma; Gastric Cancer; Pancreatic Carcinoma; Neuroendocrine Cancer; Liver Cancer; Gallbladder Cancer; Biliary Tract Cancer; Anal Carcinoma; Bone Sarcomas; Soft Tissue Sarcomas; Carcinoma of Unknown Origin, Primary

Icotinib plus gemcitabine for metastatic pancreatic cancer: A case report

PubMed Central

Zhao, Jing; Shen, Hong; Hu, Han-Guang; Huang, Jian-Jin

2015-01-01

A large majority of patients diagnosed with pancreatic cancer have advanced metastatic disease with unresectable malignancies. Despite treatment advances, the survival benefit from chemotherapeutic regimens and targeted drugs is limited. Moreover, their application is limited in China because of high toxicity and cost. Recently, inhibitors of epidermal growth factor receptor activity have shown promise for the treatment of solid cancers when used in combination with standard therapy. However, these drugs have not been evaluated extensively for the treatment of pancreatic cancer. Here, we report the treatment of a 64-year-old male with metastatic pancreatic cancer using a novel regimen of icotinib with gemcitabine. Marked shrinkage of the mass was observed after two treatment cycles, and partial remission was achieved. The abdominal pain was relieved. The adverse effects were tolerable and treatment cost was acceptable. This is the first reported case for the treatment of advanced pancreatic cancer with icotinib plus gemcitabine and demonstrates a promising therapeutic alternative. PMID:25805958

Icotinib plus gemcitabine for metastatic pancreatic cancer: a case report.

PubMed

Zhao, Jing; Shen, Hong; Hu, Han-Guang; Huang, Jian-Jin

2015-03-21

A large majority of patients diagnosed with pancreatic cancer have advanced metastatic disease with unresectable malignancies. Despite treatment advances, the survival benefit from chemotherapeutic regimens and targeted drugs is limited. Moreover, their application is limited in China because of high toxicity and cost. Recently, inhibitors of epidermal growth factor receptor activity have shown promise for the treatment of solid cancers when used in combination with standard therapy. However, these drugs have not been evaluated extensively for the treatment of pancreatic cancer. Here, we report the treatment of a 64-year-old male with metastatic pancreatic cancer using a novel regimen of icotinib with gemcitabine. Marked shrinkage of the mass was observed after two treatment cycles, and partial remission was achieved. The abdominal pain was relieved. The adverse effects were tolerable and treatment cost was acceptable. This is the first reported case for the treatment of advanced pancreatic cancer with icotinib plus gemcitabine and demonstrates a promising therapeutic alternative.

Inaugural Meeting of North American Pancreatic Cancer Organizations: Advancing Collaboration and Communication.

PubMed

Kenner, Barbara J; Fleshman, Julie M; Goldberg, Ann E; Rothschild, Laura J

2015-11-01

A meeting of North American Pancreatic Cancer Organizations planned by Kenner Family Research Fund and Pancreatic Cancer Action Network was held on July 15-16, 2015, in New York City. The meeting was attended by 32 individuals from 20 nonprofit groups from the United States and Canada. The objectives of this inaugural convening were to share mission goals and initiatives, engage as leaders, cultivate potential partnerships, and increase participation in World Pancreatic Cancer Day. The program was designed to provide opportunities for informal conversations, as well as facilitated discussions to meet the stated objectives. At the conclusion of the meeting, the group agreed that enhancing collaboration and communication will result in a more unified approach within the field and will benefit individuals diagnosed with pancreatic cancer. As a first step, the group will actively collaborate to participate in World Pancreatic Cancer Day, which is planned for November 13, 2015, and seeks to raise the level of visibility about the disease globally.

Gastroduodenal neuroendocrine neoplasms, including gastrinoma - management guidelines (recommended by the Polish Network of Neuroendocrine Tumours).

PubMed

Lipiński, Michał; Rydzewska, Grażyna; Foltyn, Wanda; Andrysiak-Mamos, Elżbieta; Bałdys-Waligórska, Agata; Bednarczuk, Tomasz; Blicharz-Dorniak, Jolanta; Bolanowski, Marek; Boratyn-Nowicka, Agnieszka; Borowska, Małgorzata; Cichocki, Andrzej; Ćwikła, Jarosław B; Falconi, Massimo; Handkiewicz-Junak, Daria; Hubalewska-Dydejczyk, Alicja; Jarząb, Barbara; Junik, Roman; Kajdaniuk, Dariusz; Kamiński, Grzegorz; Kolasińska-Ćwikła, Agnieszka; Kowalska, Aldona; Król, Robert; Królicki, Leszek; Kunikowska, Jolanta; Kuśnierz, Katarzyna; Lampe, Paweł; Lange, Dariusz; Lewczuk-Myślicka, Anna; Lewiński, Andrzej; Londzin-Olesik, Magdalena; Marek, Bogdan; Nasierowska-Guttmejer, Anna; Nowakowska-Duława, Ewa; Pilch-Kowalczyk, Joanna; Poczkaj, Karolina; Rosiek, Violetta; Ruchała, Marek; Siemińska, Lucyna; Sowa-Staszczak, Anna; Starzyńska, Teresa; Steinhof-Radwańska, Katarzyna; Strzelczyk, Janusz; Sworczak, Krzysztof; Syrenicz, Anhelli; Szawłowski, Andrzej; Szczepkowski, Marek; Wachuła, Ewa; Zajęcki, Wojciech; Zemczak, Anna; Zgliczyński, Wojciech; Kos-Kudła, Beata

2017-01-01

This paper presents the updated Polish Neuroendocrine Tumour Network expert panel recommendations on the management of neuroendocrine neoplasms (NENs) of the stomach and duodenum, including gastrinoma. The recommendations discuss the epidemiology, pathogenesis, and clinical presentation of these tumours as well as their diagnosis, including biochemical, histopathological, and localisation diagnoses. The principles of treatment are discussed, including endoscopic, surgical, pharmacological, and radionuclide treatments. Finally, there are also recommendations on patient monitoring.

Validation of a Cytotechnologist Manual Counting Service for the Ki67 Index in Neuroendocrine Tumors of the Pancreas and Gastrointestinal Tract.

PubMed

Cottenden, Jennielee; Filter, Emily R; Cottreau, Jon; Moore, David; Bullock, Martin; Huang, Weei-Yuarn; Arnason, Thomas

2018-03-01

- Pathologists routinely assess Ki67 immunohistochemistry to grade gastrointestinal and pancreatic neuroendocrine tumors. Unfortunately, manual counts of the Ki67 index are very time consuming and eyeball estimation has been criticized as unreliable. Manual Ki67 counts performed by cytotechnologists could potentially save pathologist time and improve accuracy. - To assess the concordance between manual Ki67 index counts performed by cytotechnologists versus eyeball estimates and manual Ki67 counts by pathologists. - One Ki67 immunohistochemical stain was retrieved from each of 18 archived gastrointestinal or pancreatic neuroendocrine tumor resections. We compared pathologists' Ki67 eyeball estimates on glass slides and printed color images with manual counts performed by 3 cytotechnologists and gold standard manual Ki67 index counts by 3 pathologists. - Tumor grade agreement between pathologist image eyeball estimate and gold standard pathologist manual count was fair (κ = 0.31; 95% CI, 0.030-0.60). In 9 of 20 cases (45%), the mean pathologist eyeball estimate was 1 grade higher than the mean pathologist manual count. There was almost perfect agreement in classifying tumor grade between the mean cytotechnologist manual count and the mean pathologist manual count (κ = 0.910; 95% CI, 0.697-1.00). In 20 cases, there was only 1 grade disagreement between the 2 methods. Eyeball estimation by pathologists required less than 1 minute, whereas manual counts by pathologists required a mean of 17 minutes per case. - Eyeball estimation of the Ki67 index has a high rate of tumor grade misclassification compared with manual counting. Cytotechnologist manual counts are accurate and save pathologist time.

Molecular biology of pancreatic cancer.

PubMed

Zavoral, Miroslav; Minarikova, Petra; Zavada, Filip; Salek, Cyril; Minarik, Marek

2011-06-28

In spite of continuous research efforts directed at early detection and treatment of pancreatic cancer, the outlook for patients affected by the disease remains dismal. With most cases still being diagnosed at advanced stages, no improvement in survival prognosis is achieved with current diagnostic imaging approaches. In the absence of a dominant precancerous condition, several risk factors have been identified including family history, chronic pancreatitis, smoking, diabetes mellitus, as well as certain genetic disorders such as hereditary pancreatitis, cystic fibrosis, familial atypical multiple mole melanoma, and Peutz-Jeghers and Lynch syndromes. Most pancreatic carcinomas, however, remain sporadic. Current progress in experimental molecular techniques has enabled detailed understanding of the molecular processes of pancreatic cancer development. According to the latest information, malignant pancreatic transformation involves multiple oncogenes and tumor-suppressor genes that are involved in a variety of signaling pathways. The most characteristic aberrations (somatic point mutations and allelic losses) affect oncogenes and tumor-suppressor genes within RAS, AKT and Wnt signaling, and have a key role in transcription and proliferation, as well as systems that regulate the cell cycle (SMAD/DPC, CDKN2A/p16) and apoptosis (TP53). Understanding of the underlying molecular mechanisms should promote development of new methodology for early diagnosis and facilitate improvement in current approaches for pancreatic cancer treatment.

The side effects and complications of percutaneous iodine-125 seeds implantation under CT-guide for patients with advanced pancreatic cancer.

PubMed

Lv, Wei-Fu; Lu, Dong; Xiao, Jing-Kun; Mukhiya, Gauri; Tan, Zhong-Xiao; Cheng, De-Lei; Zhou, Chun-Ze; Zhang, Xing-Min; Zhang, Zheng-Feng; Hou, Chang-Long

2017-12-01

The present study investigates the side effects and complications of computed tomography (CT)-guided percutaneous iodine-125 (I-125) seeds implantation for advanced pancreatic cancer. The clinical data were retrospectively analyzed for patients treated with implantation of I-125 seeds under CT-guide in our hospital from May 2010 to April 2015. The side effects and complications were collected and their possible reasons were analyzed. A total of 78 patients were enrolled. The side effects were categorized as fever in 29 cases (37.18%), abdominal pain in 26 cases (33.33%), nausea and vomiting in 9 cases (11.54%), diarrhea in 5 cases (6.41%), and constipation in 4 cases (5.13%). Complications were composed of pancreatitis in 9 cases (11.54%), infection in 5 cases (6.41%), seed migration in 2 cases (2.56%), intestinal perforation in 1 case (1.28%), and intestinal obstruction in 1 case. The incidence of complication was 23.08% (18/78). The difference in incidence of complication was statistically significant between patients implanted with ≤27 seeds and those with >27 seeds (P = .032). The side effects and complications frequently occur in implantation of I-125 seeds for patients with advanced pancreatic cancer. More concern should be given to the patients treated by this technique. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

Pharmacokinetically Guided Everolimus in Patients With Breast Cancer, Pancreatic Neuroendocrine Tumors, or Kidney Cancer

ClinicalTrials.gov

2016-12-09

Estrogen Receptor-positive Breast Cancer; Gastrinoma; Glucagonoma; HER2-negative Breast Cancer; Insulinoma; Mucositis; Oral Complications; Pancreatic Polypeptide Tumor; Progesterone Receptor-positive Breast Cancer; Recurrent Breast Cancer; Recurrent Islet Cell Carcinoma; Recurrent Renal Cell Cancer; Somatostatinoma; Stage III Renal Cell Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Stage IV Renal Cell Cancer

Well-differentiated neuroendocrine tumor of the stomach

PubMed Central

Gumuscu, Burak; Norwood, Kevin; Parker, George A.; Bridges, C. Lee; Rountree, Carl B.

2016-01-01

Abstract Introduction: A 13-year-old African–American female presented to her primary care physician's office with fatigue, syncope, and hematemesis. After initial evaluation, the patient was referred to pediatric gastroenterology clinic for further evaluation. Main concerns, important findings: An upper gastrointestinal endoscopy was performed to evaluate the source of her bleeding. Endoscopy revealed a 3-cm mass in the lesser curvature of the stomach, and a biopsy of the mass revealed a concern for carcinoid (neuroendocrine) features. Diagnosis: She underwent an open gastrectomy. Post-surgical pathology reports confirmed a well-differentiated neuroendocrine tumor of the stomach. Conclusion: Neuroendocrine tumors of the stomach in children are rare and we presently do not have pediatric-specific diagnostic and treatment guidelines. Although adult-based The North American Neuroendocrine Tumor Society (NANETS) guidelines are helpful, they are clearly not geared toward pediatric patients. To establish pediatric guidelines and to assess effectiveness of treatments, multicenter data collection is essential. In the long run, accumulation of clinically useful treatment information and long-term follow-up guidelines should enable clinicians to improve standard of care given to children with neuroendocrine tumors. PMID:27442656

Secretin-stimulated MRI characterization of pancreatic morphology and function in patients with chronic pancreatitis.

PubMed

Madzak, Adnan; Olesen, Søren Schou; Haldorsen, Ingfrid Salvesen; Drewes, Asbjørn Mohr; Frøkjær, Jens Brøndum

Chronic pancreatitis (CP) is characterized by abnormal pancreatic morphology and impaired endocrine and exocrine function. However, little is known about the relationship between pancreatic morphology and function, and also the association with the etiology and clinical manifestations of CP. The aim was to explore pancreatic morphology and function with advanced MRI in patients with CP and healthy controls (HC) METHODS: Eighty-two patients with CP and 22 HC were enrolled in the study. Morphological imaging parameters included pancreatic main duct diameter, gland volume, fat signal fraction and apparent diffusion coefficient (ADC) values. Functional secretin-stimulated MRI (s-MRI) parameters included pancreatic secretion (bowel fluid volume) and changes in pancreatic ADC value before and after secretin stimulation. Patients were classified according to the modified Cambridge and M-ANNHEIM classification system and fecal elastase was collected. All imaging parameters differentiated CP patients from HC; however, correlations between morphological and functional parameters in CP were weak. Patients with alcoholic and non-alcoholic etiology had comparable s-MRI findings. Fecal elastase was positively correlated to pancreatic gland volume (r = 0.68, P = 0.0016) and negatively correlated to Cambridge classification (r = -0.35, P < 0.001). Additionally, gland volume was negatively correlated to the duration of CP (r = -0.39, P < 0.001) and baseline ADC (r = -0.35, P = 0.027). When stratified by clinical stage (M-ANNHEIM), the pancreatic gland volume was significantly decreased in the severe stages of CP (P = 0.001). S-MRI provides detailed information about pancreatic morphology and function and represents a promising non-invasive imaging method to characterize pancreatic pathophysiology and may enable monitoring of disease progression in patients with CP. Copyright © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.

Pancreatic carcinogenesis: apoptosis and angiogenesis.

PubMed

Onizuka, Shinya; Kawakami, Shunsuke; Taniguchi, Ken; Fujioka, Hikaru; Miyashita, Kosei

2004-04-01

Apoptosis and angiogenesis are critical biologic processes that are altered during carcinogenesis. Both apoptosis and angiogenesis may play an important role in pancreatic carcinogenesis. Despite numerous advances in the diagnosis and treatment of pancreatic cancer, its prognosis remains dismal and a new therapeutic approach is much needed. Recent research has revealed that apoptosis and angiogenesis are closely interrelated. Several reports show that a tumor suppresser gene that is expressed in pancreatic carcinoma and related to malignant potential can induce apoptosis and also inhibit angiogenesis. At present, it is generally accepted that tumor growth in cancers, including pancreatic cancer, depends on angiogenesis. We have identified 2 new angiogenesis inhibitors from a conditioned medium of human pancreatic carcinoma cell line (BxPC-3): antiangiogenic antithrombin III (aaAT-III) and vitamin D binding protein-macrophage activating factor (DBP-maf). These molecules were able to regress tumors in severe combined immunodeficiency disease (SCID) mice, demonstrating potent inhibition of endothelial cell proliferation. Moreover, the angiogenesis inhibitors induced tumor dormancy in the animal model. These results suggest that antiangiogenic therapy using angiogenesis inhibitors may become a new strategy for treatment of pancreatic cancer in the near future.

[A Case of Von Hippel-Lindau Disease with Nonfunctioning Pancreatic Neuroendocrine Tumors Treated by Duodenum-Preserving Resection of the Head of the Pancreas and Spleen-Preserving Resection of the Tail of the Pancreas].

PubMed

Umehara, Yutaka; Umehara, Minoru; Tokura, Tomohisa; Yachi, Takafumi; Takahashi, Kenichi; Morita, Takayuki; Hakamada, Kenichi

2015-10-01

A 26-year-old woman presented to our department with a diagnosis of multiple nonfunctioning pancreatic neuroendocrine tumors. She had a family history of pheochromocytoma and a medical history of bilateral adrenalectomy for pheochromocytoma at the age of 25 years. During follow-up treatment for adrenal insufficiency after the surgery, highly enhanced tumors in the pancreas were detected on contrast-enhanced CT. Other examinations found that the patient did not satisfy the clinical criteria for von Hippel-Lindau (VHL) disease. Considering her age and risk of developing multiple heterotopic and heterochronous tumors, we performed a duodenum-preserving resection of the head of the pancreas and spleen-preserving resection of the tail of the pancreas with informed consent. The histopathological findings revealed that all of the tumors were NET G1. She underwent genetic testing postoperatively and was diagnosed with VHL disease. This diagnosis meant that we were able to create an optimal treatment plan for the patient. If a tumor predisposition syndrome is suspected, VHL disease should be borne in mind and genetic testing after genetic counseling should be duly considered.

Long-Term Natural Course of Small Nonfunctional Pancreatic Neuroendocrine Tumors in MEN1-Results From the Dutch MEN1 Study Group.

PubMed

Pieterman, Carolina R C; de Laat, Joanne M; Twisk, Jos W R; van Leeuwaarde, Rachel S; de Herder, Wouter W; Dreijerink, Koen M A; Hermus, Ad R M M; Dekkers, Olaf M; van der Horst-Schrivers, Anouk N A; Drent, Madeleine L; Bisschop, Peter H; Havekes, Bastiaan; Borel Rinkes, Inne H M; Vriens, Menno R; Valk, Gerlof D

2017-10-01

Pancreatic neuroendocrine tumors (pNETs) are highly prevalent in patients with multiple endocrine neoplasia type 1 (MEN1), and metastatic disease is an important cause of MEN1-related mortality. Especially small nonfunctional (NF) pNETs pose a challenge to the treating physician and more information is needed regarding their natural course. We assessed long-term natural history of small NF-pNETs and its modifiers in the Dutch MEN1 population. Retrospective longitudinal observational cohort study of patients with small (<2 cm) NF-pNETs from the Dutch national MEN1 database, which includes >90% of the Dutch MEN1 population. Modifiers of long-term natural course were analyzed using linear mixed-models analysis. Growth rate of the 115 included small NF-pNETs from 99 patients was slow (0.4 mm/y; 95% confidence interval, 0.15 to 0.59). Seventy percent of the tumors was stable and a subgroup of 30% of the tumors was growing (1.6 mm/y; 95% confidence interval, 1.1 to 2.0). No differences in clinical characteristics were identified between growing and stable tumors. Within the subgroup of growing tumors, germline missense mutations were significantly associated with accelerated growth compared with nonsense and frameshift mutations. The majority of small NF-pNETs are stable at long-term follow-up, irrespective of the underlying MEN1 genotype. A subgroup of tumors is slowly growing but cannot be identified on clinical grounds. In this subgroup, tumors with missense mutations exhibited faster growth. Additional events appear necessary for pNETs to progress. Future studies should be aimed at identifying these molecular driving events, which could be used as potential biomarkers. Copyright © 2017 Endocrine Society

Consuming a Ketogenic Diet while Receiving Radiation and Chemotherapy for Locally Advanced Lung Cancer and Pancreatic Cancer: The University of Iowa Experience of Two Phase 1 Clinical Trials.

PubMed

Zahra, Amir; Fath, Melissa A; Opat, Emyleigh; Mapuskar, Kranti A; Bhatia, Sudershan K; Ma, Daniel C; Rodman, Samuel N; Snyders, Travis P; Chenard, Catherine A; Eichenberger-Gilmore, Julie M; Bodeker, Kellie L; Ahmann, Logan; Smith, Brian J; Vollstedt, Sandy A; Brown, Heather A; Hejleh, Taher Abu; Clamon, Gerald H; Berg, Daniel J; Szweda, Luke I; Spitz, Douglas R; Buatti, John M; Allen, Bryan G

2017-06-01

Ketogenic diets are low in carbohydrates and high in fat, which forces cells to rely more heavily upon mitochondrial oxidation of fatty acids for energy. Relative to normal cells, cancer cells are believed to exist under a condition of chronic mitochondrial oxidative stress that is compensated for by increases in glucose metabolism to generate reducing equivalents. In this study we tested the hypothesis that a ketogenic diet concurrent with radiation and chemotherapy would be clinically tolerable in locally advanced non-small cell lung cancer (NSCLC) and pancreatic cancer and could potentially exploit cancer cell oxidative metabolism to improve therapeutic outcomes. Mice bearing MIA PaCa-2 pancreatic cancer xenografts were fed either a ketogenic diet or standard rodent chow, treated with conventionally fractionated radiation (2 Gy/fraction), and tumor growth rates were assessed daily. Tumors were assessed for immunoreactive 4-hydroxy-2-nonenal-(4HNE)-modfied proteins as a marker of oxidative stress. Based on this and another previously published preclinical study, phase 1 clinical trials in locally advanced NSCLC and pancreatic cancer were initiated, combining standard radiation and chemotherapy with a ketogenic diet for six weeks (NSCLC) or five weeks (pancreatic cancer). The xenograft experiments demonstrated prolonged survival and increased 4HNE-modfied proteins in animals consuming a ketogenic diet combined with radiation compared to radiation alone. In the phase 1 clinical trial, over a period of three years, seven NSCLC patients enrolled in the study. Of these, four were unable to comply with the diet and withdrew, two completed the study and one was withdrawn due to a dose-limiting toxicity. Over the same time period, two pancreatic cancer patients enrolled in the trial. Of these, one completed the study and the other was withdrawn due to a dose-limiting toxicity. The preclinical experiments demonstrate that a ketogenic diet increases radiation sensitivity

Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors.

PubMed

George, Julie; Walter, Vonn; Peifer, Martin; Alexandrov, Ludmil B; Seidel, Danila; Leenders, Frauke; Maas, Lukas; Müller, Christian; Dahmen, Ilona; Delhomme, Tiffany M; Ardin, Maude; Leblay, Noemie; Byrnes, Graham; Sun, Ruping; De Reynies, Aurélien; McLeer-Florin, Anne; Bosco, Graziella; Malchers, Florian; Menon, Roopika; Altmüller, Janine; Becker, Christian; Nürnberg, Peter; Achter, Viktor; Lang, Ulrich; Schneider, Peter M; Bogus, Magdalena; Soloway, Matthew G; Wilkerson, Matthew D; Cun, Yupeng; McKay, James D; Moro-Sibilot, Denis; Brambilla, Christian G; Lantuejoul, Sylvie; Lemaitre, Nicolas; Soltermann, Alex; Weder, Walter; Tischler, Verena; Brustugun, Odd Terje; Lund-Iversen, Marius; Helland, Åslaug; Solberg, Steinar; Ansén, Sascha; Wright, Gavin; Solomon, Benjamin; Roz, Luca; Pastorino, Ugo; Petersen, Iver; Clement, Joachim H; Sänger, Jörg; Wolf, Jürgen; Vingron, Martin; Zander, Thomas; Perner, Sven; Travis, William D; Haas, Stefan A; Olivier, Magali; Foll, Matthieu; Büttner, Reinhard; Hayes, David Neil; Brambilla, Elisabeth; Fernandez-Cuesta, Lynnette; Thomas, Roman K

2018-03-13

Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: "type I LCNECs" with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and "type II LCNECs" enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1 high /DLL3 high /NOTCH low , type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1 low /DLL3 low /NOTCH high , and an upregulation of immune-related pathways. In conclusion, LCNECs comprise two molecularly defined subgroups, and distinguishing them from SCLC may allow stratified targeted treatment of high-grade neuroendocrine lung tumors.

The pancreatic niche inhibits the effectiveness of sunitinib treatment of pancreatic cancer

PubMed Central

Martínez-Bosch, Neus; Guerrero, Pedro Enrique; Moreno, Mireia; José, Anabel; Iglesias, Mar; Munné-Collado, Jessica; Anta, Héctor; Gibert, Joan; Orozco, Carlos Alberto; Vinaixa, Judith; Fillat, Cristina; Viñals, Francesc; Navarro, Pilar

2016-01-01

Current treatments for pancreatic ductal adenocarcinoma (PDA) are ineffective, making this the 4th leading cause of cancer deaths. Sunitinib is a broad-spectrum inhibitor of tyrosine kinase receptors mostly known for its anti-angiogenic effects. We tested the therapeutic effects of sunitinib in pancreatic cancer using the Ela-myc transgenic mouse model. We showed that Ela-myc pancreatic tumors express PDGFR and VEGFR in blood vessels and epithelial cells, rendering these tumors sensitive to sunitinib by more than only its anti-angiogenic activity. However, sunitinib treatment of Ela-myc mice with either early or advanced tumor progression had no impact on either survival or tumor burden. Further histopathological characterization of these tumors did not reveal differences in necrosis, cell differentiation, angiogenesis, apoptosis or proliferation. In stark contrast, in vitro sunitinib treatment of Ela-myc– derived cell lines showed high sensitivity to the drug, with increased apoptosis and reduced proliferation. Correspondingly, subcutaneous tumors generated from these cell lines completely regressed in vivo after sunitinib treatments. These data point at the pancreatic tumor microenvironment as the most likely barrier preventing sunitinib treatment efficiency in vivo. Combined treatments with drugs that disrupt tumor fibrosis may enhance sunitinib therapeutic effectiveness in pancreatic cancer treatment. PMID:27374084

Bevacizumab plus capecitabine in patients with progressive advanced well-differentiated neuroendocrine tumors of the gastro-intestinal (GI-NETs) tract (BETTER trial)--a phase II non-randomised trial.

PubMed

Mitry, Emmanuel; Walter, Thomas; Baudin, Eric; Kurtz, Jean-Emmanuel; Ruszniewski, Philippe; Dominguez-Tinajero, Sophie; Bengrine-Lefevre, Leïla; Cadiot, Guillaume; Dromain, Clarisse; Farace, Françoise; Rougier, Philippe; Ducreux, Michel

2014-12-01

Gastro-intestinal neuroendocrine tumours (GI-NETs) are chemotherapy-resistant tumours. Bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF), has shown promising results in several phase II trials of gastro-entero-pancreatic-NETs. We assessed bevacizumab combined with capecitabine, specifically in GI-NET patients. BEvacizumab in The Treament of neuroEndocrine tumoRs (BETTER) was a multicentre, open-label, non-randomised, two-group phase II trial. Here we present the group of patients with progressive, metastatic, well-differentiated GI-NETs. Patients Eastern Cooperative Oncology Group-performance status (ECOG-PS)⩽2, Ki-67 proliferation rate <15% and no prior systemic chemotherapy were treated with bevacizumab (7.5 mg/kg/q3w) and capecitabine (1000 mg/m2 twice daily, orally d1-14, resumed on d22) for 6-24 months. The primary end-point was progression-free survival (PFS); secondary end-points included overall survival (OS), response rate, safety and quality of life. Of the 49 patients included, 53% were men, median age was 60 years (41-82), primary tumour site was ileal in 82% patients and Ki-67 was <15% in 48 patients and not available for one patient. After a maximum of 24 month follow-up per patient, the median PFS by investigator assessment was 23.4 months [95% confidence interval (CI): 13.2; not reached] and the overall disease control rate was 88% (18% partial response, 70% stable disease). The 2-year survival rate was 85%. Median OS was not reached. The most frequent grade 3-4 adverse events were hypertension (31%), diarrhoea (14%) and hand-foot syndrome (10%). The combination of bevacizumab and capecitabine showed clinical activity and a manageable safety profile in the treatment of GI-NETs that warrant confirmation in a randomised phase III trial. Copyright © 2014 Elsevier Ltd. All rights reserved.

Grade Assignment by Ki-67 Proliferative Index, Mitotic Count, and Phosphohistone H3 Count in Surgically Resected Gastrointestinal and Pancreatic Neuroendocrine Tumors.

PubMed

Murphy, Claire E; McCormick, Kinsey A; Shankaran, Veena; Reddi, Deepti M; Swanson, Paul E; Upton, Melissa P; Papanicolau-Sengos, Antonios; Khor, Sara; Westerhoff, Maria

The aim of this study was to evaluate the concordance in grade assignment for gastroenteropancreatic neuroendocrine tumors using mitotic count (MC), Ki-67 proliferative index (KPI), and phosphohistone H3 count (PHH3C). Resected gastroenteropancreatic neuroendocrine tumors were graded based on MC, KPI, and PHH3C. Concordance was determined using a weighted κ statistic. Median survival across each grade category was determined using Kaplan-Meier methods. Of the 110 patients, the majority had gastrointestinal primaries and grade 1 or 2 tumors. Rates of discordance in grade assignment were 29% of cases for KPI versus MC (κW = 0.26), 32% for PHH3C versus MC (κW = 0.34), and 32% for PHH3C versus KPI (κW = 0.37). There was fair agreement between grading by KPI and MC. Relative to grade by KPI and MC, PHH3C tended to upgrade tumors. The proportion alive at 3 and 5 years was not significantly different for patients with grade 1 versus grade 2 tumors. The concordance between KPI and MC was fair. Phosphohistone H3 count tended to upgrade tumors using the cutoffs established by MC. Grade 1 and grade 2 tumors were associated with similar survival regardless of grading method. The overall relevance of the current cutoff values used in grading neuroendocrine tumors may need to be revisited.

Detection of Somatic Mutations in Gastroenteropancreatic Neuroendocrine Tumors Using Targeted Deep Sequencing.

PubMed

Backman, Samuel; Norlén, Olov; Eriksson, Barbro; Skogseid, Britt; Stålberg, Peter; Crona, Joakim

2017-02-01

Mutations affecting the mechanistic target of rapamycin (MTOR) signalling pathway are frequent in human cancer and have been identified in up to 15% of pancreatic neuroendocrine tumours (NETs). Grade A evidence supports the efficacy of MTOR inhibition with everolimus in pancreatic NETs. Although a significant proportion of patients experience disease stabilization, only a minority will show objective tumour responses. It has been proposed that genomic mutations resulting in activation of MTOR signalling could be used to predict sensitivity to everolimus. Patients with NETs that underwent treatment with everolimus at our Institution were identified and those with available tumour tissue were selected for further analysis. Targeted next-generation sequencing (NGS) was used to re-sequence 22 genes that were selected on the basis of documented involvement in the MTOR signalling pathway or in the tumourigenesis of gastroenterpancreatic NETs. Radiological responses were documented using Response Evaluation Criteria in Solid Tumours. Six patients were identified, one had a partial response and four had stable disease. Sequencing of tumour tissue resulted in a median sequence depth of 667.1 (range=404-1301) with 1-fold coverage of 95.9-96.5% and 10-fold coverage of 87.6-92.2%. A total of 494 genetic variants were discovered, four of which were identified as pathogenic. All pathogenic variants were validated using Sanger sequencing and were found exclusively in menin 1 (MEN1) and death domain associated protein (DAXX) genes. No mutations in the MTOR pathway-related genes were observed. Targeted NGS is a feasible method with high diagnostic yield for genetic characterization of pancreatic NETs. A potential association between mutations in NETs and response to everolimus should be investigated by future studies. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Advances in surgical treatment of chronic pancreatitis.

PubMed

Ni, Qingqiang; Yun, Lin; Roy, Manish; Shang, Dong

2015-02-08

The incidence of chronic pancreatitis (CP) is between 2 and 200 per 100,000 persons and shows an increasing trend year by year. India has the highest incidence of CP in the world at approximately 114 to 200 per 100,000 persons. The incidence of CP in China is approximately 13 per 100,000 persons. The aim of this review is to assist surgeons in managing patients with CP in surgical treatment. We conducted a PubMed search for "chronic pancreatitis" and "surgical treatment" and reviewed relevant articles. On the basis of our review of the literature, we found that CP cannot be completely cured. The purpose of surgical therapy for CP is to relieve symptoms, especially pain; to improve the patient's quality of life; and to treat complications. Decompression (drainage), resection, neuroablation and decompression combined with resection are commonly used methods for the surgical treatment of CP. Before developing a surgical regimen, surgeons should comprehensively evaluate the patient's clinical manifestations, auxiliary examination results and medical history to develop an individualized surgical treatment regimen.

Reanalysis of study of pancreatic effects of incretin therapy: methodological deficiencies.

PubMed

Bonner-Weir, S; In't Veld, P A; Weir, G C

2014-07-01

A recently published study by Butler et al. concluded that incretin treatment had adverse effects on the human type 2 diabetic pancreas including 'a marked expansion of the exocrine and endocrine pancreatic compartments, the former being accompanied by increased proliferation and dysplasia and the latter by α-cell hyperplasia with the potential for evolution into neuroendocrine tumours'. Incretin therapy has become widely used for type 2 diabetes, so these conclusions have instigated major concerns with regard to patient safety. We reassessed both the clinical case information and virtual microscopy images of the same 34 cases that were used in the Butler study as well as Network for Pancreatic Organ Donation (nPOD) cases that were not included. Whereas we would like to stress that it is important to investigate in depth any indication that incretin treatment may lead to inflammation or dysplasia in the pancreas, we find that the data presented in the Butler paper have serious methodological deficiencies that preclude any meaningful conclusions. © 2014 John Wiley & Sons Ltd.

Neuroendocrine Disorders in Pediatric Craniopharyngioma Patients

PubMed Central

Daubenbüchel, Anna M. M.; Müller, Hermann L.

2015-01-01

Childhood-onset craniopharyngiomas are partly cystic embryonic malformations of the sellar/parasellar region. The therapy of choice in patients with favorable tumor localization is complete resection with a specific focus on maintaining optical and hypothalamic neuroendocrine functions. In patients with unfavorable tumor localization (i.e., hypothalamic involvement), a limited hypothalamus-sparing surgical strategy followed by local irradiation is recommended. Involvement and/or surgical lesions of posterior hypothalamic areas cause major neuroendocrine sequelae. The overall survival rates are high (92%) but neuroendocrine disorders such as obesity and metabolic syndrome due to involvement and/or treatment-related hypothalamic lesions have major negative impact on survival and quality of life. Recurrences and progressions are frequent post-surgical events. Because irradiation is efficient in preventing tumor progression, appropriate timing of post-surgical irradiation is currently under investigation in a randomized multinational trial (KRANIOPHARYNGEOM 2007). Childhood-onset craniopharyngioma should be recognized as a chronic disease requiring treatment and constant monitoring of the clinical and quality of life consequences, frequently impaired due to neuroendocrine disorders, by experienced multidisciplinary teams in order to provide optimal care of surviving patients. PMID:26239246

Long-term outcomes of endoscopic vs surgical drainage of the pancreatic duct in patients with chronic pancreatitis.

PubMed

Cahen, Djuna L; Gouma, Dirk J; Laramée, Philippe; Nio, Yung; Rauws, Erik A J; Boermeester, Marja A; Busch, Olivier R; Fockens, Paul; Kuipers, Ernst J; Pereira, Stephen P; Wonderling, David; Dijkgraaf, Marcel G W; Bruno, Marco J

2011-11-01

A randomized trial that compared endoscopic and surgical drainage of the pancreatic duct in patients with advanced chronic pancreatitis reported a significant benefit of surgery after a 2-year follow-up period. We evaluated the long-term outcome of these patients after 5 years. Between 2000 and 2004, 39 symptomatic patients were randomly assigned to groups that underwent endoscopic drainage or operative pancreaticojejunostomy. In 2009, information was collected regarding pain, quality of life, morbidity, mortality, length of hospital stay, number of procedures undergone, changes in pancreatic function, and costs. Analysis was performed according to an intention-to-treat principle. During the 79-month follow-up period, one patient was lost and 7 died from unrelated causes. Of the patients treated by endoscopy, 68% required additional drainage compared with 5% in the surgery group (P = .001). Hospital stay and costs were comparable, but overall, patients assigned to endoscopy underwent more procedures (median, 12 vs 4; P = .001). Moreover, 47% of the patients in the endoscopy group eventually underwent surgery. Although the mean difference in Izbicki pain scores was no longer significant (39 vs 22; P = .12), surgery was still superior in terms of pain relief (80% vs 38%; P = .042). Levels of quality of life and pancreatic function were comparable. In the long term, symptomatic patients with advanced chronic pancreatitis who underwent surgery as the initial treatment for pancreatic duct obstruction had more relief from pain, with fewer procedures, than patients who were treated endoscopically. Importantly, almost half of the patients who were treated with endoscopy eventually underwent surgery. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

AAVP displaying octreotide for ligand-directed therapeutic transgene delivery in neuroendocrine tumors of the pancreas.

PubMed

Smith, Tracey L; Yuan, Ziqiang; Cardó-Vila, Marina; Sanchez Claros, Carmen; Adem, Asha; Cui, Min-Hui; Branch, Craig A; Gelovani, Juri G; Libutti, Steven K; Sidman, Richard L; Pasqualini, Renata; Arap, Wadih

2016-03-01

Patients with inoperable or unresectable pancreatic neuroendocrine tumors (NETs) have limited treatment options. These rare human tumors often express somatostatin receptors (SSTRs) and thus are clinically responsive to certain relatively stable somatostatin analogs, such as octreotide. Unfortunately, however, this tumor response is generally short-lived. Here we designed a hybrid adeno-associated virus and phage (AAVP) vector displaying biologically active octreotide on the viral surface for ligand-directed delivery, cell internalization, and transduction of an apoptosis-promoting tumor necrosis factor (TNF) transgene specifically to NETs. These functional attributes of AAVP-TNF particles displaying the octreotide peptide motif (termed Oct-AAVP-TNF) were confirmed in vitro, in SSTR type 2-expressing NET cells, and in vivo using cohorts of pancreatic NET-bearing Men1 tumor-suppressor gene KO mice, a transgenic model of functioning (i.e., insulin-secreting) tumors that genetically and clinically recapitulates the human disease. Finally, preclinical imaging and therapeutic experiments with pancreatic NET-bearing mice demonstrated that Oct-AAVP-TNF lowered tumor metabolism and insulin secretion, reduced tumor size, and improved mouse survival. Taken together, these proof-of-concept results establish Oct-AAVP-TNF as a strong therapeutic candidate for patients with NETs of the pancreas. More broadly, the demonstration that a known, short, biologically active motif can direct tumor targeting and receptor-mediated internalization of AAVP particles may streamline the potential utility of myriad other short peptide motifs and provide a blueprint for therapeutic applications in a variety of cancers and perhaps many nonmalignant diseases as well.

Cost-effectiveness analysis of gemcitabine, S-1 and gemcitabine plus S-1 for treatment of advanced pancreatic cancer based on GEST study.

PubMed

Zhou, Jing; Zhao, Rongce; Wen, Feng; Zhang, Pengfei; Tang, Ruilei; Du, Zedong; He, Xiaofeng; Zhang, Jian; Li, Qiu

2015-04-01

Gemcitabine (GEM) alone, S-1 alone and gemcitabine plus S-1 (GS) have shown a marginal clinical benefit for the treatment of advanced pancreatic cancer. However, there is no clearly defined optimal cost-effectiveness treatment. The objective of this study was to assess the cost-effectiveness of GEM alone, S-1 alone and GS for the treatment of advanced pancreatic cancer based on GEST study for public payers. A decision model compared GEM alone, S-1 alone and GS. Primary base case data were identified using the GEST study and the literatures. Costs were estimated from West China Hospital, Sichuan University, China, and incremental cost-effectiveness ratios (ICERs) were calculated. Survival benefits were reported in quality-adjusted life-months (QALMs). Sensitive analyses were performed by varying potentially modifiable parameters of the model. The base case analysis showed that the GEM cost $21,912 and yielded survival of 6.93 QALMs, S-1 cost $19,371 and yielded survival of 7.90 QALMs and GS cost $22,943 and yielded survival of 7.46 QALMs in the entire treatment. The one-way sensitivity analyses showed that the ICER of S-1 was driven mostly by the S-1 group utility score of stable state compared with GEM, and the GEM group utility score of progressed state played a key role on the ICER of GS compared with GEM. S-1 represents an attractive cost-effective treatment for advanced pancreatic cancer, given the favorable cost per QALM and improvement in clinical efficacy, especially the limited available treatment options.

Percutaneous ablation of pancreatic cancer

PubMed Central

D’Onofrio, Mirko; Ciaravino, Valentina; De Robertis, Riccardo; Barbi, Emilio; Salvia, Roberto; Girelli, Roberto; Paiella, Salvatore; Gasparini, Camilla; Cardobi, Nicolò; Bassi, Claudio

2016-01-01

Pancreatic ductal adenocarcinoma is a highly aggressive tumor with an overall 5-year survival rate of less than 5%. Prognosis and treatment depend on whether the tumor is resectable or not, which mostly depends on how quickly the diagnosis is made. Chemotherapy and radiotherapy can be both used in cases of non-resectable pancreatic cancer. In cases of pancreatic neoplasm that is locally advanced, non-resectable, but non-metastatic, it is possible to apply percutaneous treatments that are able to induce tumor cytoreduction. The aim of this article will be to describe the multiple currently available treatment techniques (radiofrequency ablation, microwave ablation, cryoablation, and irreversible electroporation), their results, and their possible complications, with the aid of a literature review. PMID:27956791

Neuroendocrine Disruption: More than Hormones are Upset

PubMed Central

Waye, Andrew; Trudeau, Vance L.

2011-01-01

Only a small proportion of the published research on endocrine-disrupting chemicals (EDC) directly examined effects on neuroendocrine processes. There is an expanding body of evidence that anthropogenic chemicals exert effects on neuroendocrine systems and that these changes might impact peripheral organ systems and physiological processes. Neuroendocrine disruption extends the concept of endocrine disruption to include the full breadth of integrative physiology (i.e., more than hormones are upset). Pollutants may also disrupt numerous other neurochemical pathways to affect an animal's capacity to reproduce, develop and grow, or deal with stress and other challenges. Several examples are presented in this review, from both vertebrates and invertebrates, illustrating that diverse environmental pollutants including pharmaceuticals, organochlorine pesticides, and industrial contaminants have the potential to disrupt neuroendocrine control mechanisms. While most investigations on EDC are carried out with vertebrate models, an attempt is also made to highlight the importance of research on invertebrate neuroendocrine disruption. The neurophysiology of many invertebrates is well described and many of their neurotransmitters are similar or identical to those in vertebrates; therefore, lessons learned from one group of organisms may help us understand potential adverse effects in others. This review argues for the adoption of systems biology and integrative physiology to address the effects of EDC. Effects of pulp and paper mill effluents on fish reproduction are a good example of where relatively narrow hypothesis testing strategies (e.g., whether or not pollutants are sex steroid mimics) have only partially solved a major problem in environmental biology. It is clear that a global, integrative physiological approach, including improved understanding of neuroendocrine control mechanisms, is warranted to fully understand the impacts of pulp and paper mill effluents

First-line erlotinib and fixed dose-rate gemcitabine for advanced pancreatic cancer.

PubMed

Vaccaro, Vanja; Bria, Emilio; Sperduti, Isabella; Gelibter, Alain; Moscetti, Luca; Mansueto, Giovanni; Ruggeri, Enzo Maria; Gamucci, Teresa; Cognetti, Francesco; Milella, Michele

2013-07-28

To investigate activity, toxicity, and prognostic factors for survival of erlotinib and fixed dose-rate gemcitabine (FDR-Gem) in advanced pancreatic cancer. We designed a single-arm prospective, multicentre, open-label phase II study to evaluate the combination of erlotinib (100 mg/d, orally) and weekly FDR-Gem (1000 mg/m(2), infused at 10 mg/m(2) per minute) in a population of previously untreated patients with locally advanced, inoperable, or metastatic pancreatic cancer. Primary endpoint was the rate of progression-free survival at 6 mo (PFS-6); secondary endpoints were overall response rate (ORR), response duration, tolerability, overall survival (OS), and clinical benefit. Treatment was not considered to be of further interest if the PFS-6 was < 20% (p0 = 20%), while a PFS-6 > 40% would be of considerable interest (p1 = 40%); with a 5% rejection error (α = 5%) and a power of 80%, 35 fully evaluable patients with metastatic disease were required to be enrolled in order to complete the study. Analysis of prognostic factors for survival was also carried out. From May 2007 to September 2009, 46 patients were enrolled (male/female: 25/21; median age: 64 years; median baseline carbohydrate antigen 19-9 (CA 19-9): 897 U/mL; locally advanced/metastatic disease: 5/41). PFS-6 and median PFS were 30.4% and 14 wk (95%CI: 10-19), respectively; 1-year and median OS were 20.2% and 26 wk (95%CI: 8-43). Five patients achieved an objective response (ORR: 10.9%, 95%CI: 1.9-19.9); disease control rate was 56.5% (95%CI: 42.2-70.8); clinical benefit rate was 43.5% (95%CI: 29.1-57.8). CA 19-9 serum levels were decreased by > 25% as compared to baseline in 14/23 evaluable patients (63.6%). Treatment was well-tolerated, with skin rash being the most powerful predictor of both longer PFS (P < 0.0001) and OS (P = 0.01) at multivariate analysis (median OS for patients with or without rash: 42 wk vs 15 wk, respectively, Log-rank P = 0.03). Additional predictors of better outcome were: CA

First-line erlotinib and fixed dose-rate gemcitabine for advanced pancreatic cancer

PubMed Central

Vaccaro, Vanja; Bria, Emilio; Sperduti, Isabella; Gelibter, Alain; Moscetti, Luca; Mansueto, Giovanni; Ruggeri, Enzo Maria; Gamucci, Teresa; Cognetti, Francesco; Milella, Michele

2013-01-01

AIM: To investigate activity, toxicity, and prognostic factors for survival of erlotinib and fixed dose-rate gemcitabine (FDR-Gem) in advanced pancreatic cancer. METHODS: We designed a single-arm prospective, multicentre, open-label phase II study to evaluate the combination of erlotinib (100 mg/d, orally) and weekly FDR-Gem (1000 mg/m2, infused at 10 mg/m2 per minute) in a population of previously untreated patients with locally advanced, inoperable, or metastatic pancreatic cancer. Primary endpoint was the rate of progression-free survival at 6 mo (PFS-6); secondary endpoints were overall response rate (ORR), response duration, tolerability, overall survival (OS), and clinical benefit. Treatment was not considered to be of further interest if the PFS-6 was < 20% (p0 = 20%), while a PFS-6 > 40% would be of considerable interest (p1 = 40%); with a 5% rejection error (α = 5%) and a power of 80%, 35 fully evaluable patients with metastatic disease were required to be enrolled in order to complete the study. Analysis of prognostic factors for survival was also carried out. RESULTS: From May 2007 to September 2009, 46 patients were enrolled (male/female: 25/21; median age: 64 years; median baseline carbohydrate antigen 19-9 (CA 19-9): 897 U/mL; locally advanced/metastatic disease: 5/41). PFS-6 and median PFS were 30.4% and 14 wk (95%CI: 10-19), respectively; 1-year and median OS were 20.2% and 26 wk (95%CI: 8-43). Five patients achieved an objective response (ORR: 10.9%, 95%CI: 1.9-19.9); disease control rate was 56.5% (95%CI: 42.2-70.8); clinical benefit rate was 43.5% (95%CI: 29.1-57.8). CA 19-9 serum levels were decreased by > 25% as compared to baseline in 14/23 evaluable patients (63.6%). Treatment was well-tolerated, with skin rash being the most powerful predictor of both longer PFS (P < 0.0001) and OS (P = 0.01) at multivariate analysis (median OS for patients with or without rash: 42 wk vs 15 wk, respectively, Log-rank P = 0.03). Additional predictors of

Alternative Lengthening of Telomeres and Loss of DAXX/ATRX Expression Predicts Metastatic Disease and Poor Survival in Patients with Pancreatic Neuroendocrine Tumors.

PubMed

Singhi, Aatur D; Liu, Ta-Chiang; Roncaioli, Justin L; Cao, Dengfeng; Zeh, Herbert J; Zureikat, Amer H; Tsung, Allan; Marsh, J Wallis; Lee, Kenneth K; Hogg, Melissa E; Bahary, Nathan; Brand, Randall E; McGrath, Kevin M; Slivka, Adam; Cressman, Kristi L; Fuhrer, Kimberly; O'Sullivan, Roderick J

2017-01-15

Pancreatic neuroendocrine tumors (PanNET) are a heterogeneous group of neoplasms with increasing incidence and unpredictable behavior. Whole-exome sequencing has identified recurrent mutations in the genes DAXX and ATRX, which correlate with loss of protein expression and alternative lengthening of telomeres (ALT). Both ALT and DAXX/ATRX loss were initially reported to be associated with a favorable prognosis; however, recent studies suggest the contrary. Our aims were to assess the prevalence and prognostic significance of ALT and DAXX/ATRX in both primary and metastatic PanNETs. Telomere-specific FISH and DAXX/ATRX IHC was performed on a multi-institutional cohort of 321 patients with resected PanNET and 191 distant metastases from 52 patients. These results were correlated with clinicopathologic features, including disease-free survival (DFS) and disease-specific survival (DSS). The prevalence of ALT and DAXX/ATRX loss in resected PanNETs was 31% and 26%, respectively, and associated with larger tumor size, higher WHO grade, lymph node metastasis, and distant metastasis (P < 0.001). The 5-year DFS and 10-year DSS of patients with ALT-positive and DAXX/ATRX-negative PanNETs were 40% and 50%, respectively, as compared with 96% and 89%, respectively, for wild-type PanNETs. Among distant metastases, ALT and DAXX/ATRX loss was 67% and 52%, respectively, and only occurred in the setting of an ALT-positive and DAXX/ATRX-negative primary PanNET. By multivariate analysis, both ALT and DAXX/ATRX loss were negative, independent prognostic factors for DFS. ALT and DAXX/ATRX loss in PanNETs was associated with shorter DFS and DSS and likely plays a significant role in driving metastatic disease. Clin Cancer Res; 23(2); 600-9. ©2016 AACR. ©2016 American Association for Cancer Research.

Developmental Programming: Postnatal Estradiol Modulation of Prenatally Organized Reproductive Neuroendocrine Function in Sheep

PubMed Central

Puttabyatappa, Muraly; Cardoso, Rodolfo C.; Herkimer, Carol; Veiga-Lopez, Almudena; Padmanabhan, Vasantha

2016-01-01

Gestational testosterone (T) excess, acting via both the androgenic and estrogenic pathways, advances puberty and disrupts the neuroendocrine estradiol (E) feedback and periovulatory hormonal dynamics in female sheep. These prenatally programmed defects may be subject to postnatal modifications by continued organizational and/or activational effects of steroids. The present study investigated 1) the organizational contribution of prenatal estrogen excess and 2) the impact of postnatal exposure to E in modulating the effects of prenatal androgen excess (T and dihydrotestosterone [DHT]) on puberty, neuroendocrine feedback mechanisms, and periovulatory hormonal dynamics in sheep. Pregnant Suffolk sheep were treated with T, DHT, E, or E plus DHT (ED) from days 30 to 90 of gestation. A subset of the control (C), T, and DHT female offspring received a constant-release E implant postnatally. Findings revealed that 1) prenatal E-treatment failed to reproduce the neuroendocrine disruptions predicted to be programmed by the estrogenic pathway and 2) prenatal ED-treatment did not adequately replicate the reproductive neuroendocrine defects induced by prenatal T excess. More importantly, continuous postnatal E-treatment, while delaying the onset of puberty and reducing the inhibitory effects of E on tonic luteinizing hormone (LH) release, failed to amplify the E positive feedback and periovulatory defects induced by prenatal T-treatment. Our results indicate that disruptions in E positive feedback mechanisms and periovulatory gonadotropin secretion induced by prenatal T-treatment are programmed predominantly during the prenatal life with postnatal exposure to E excess not contributing further to these disruptions. PMID:27222598

Stereotactic Body Radiation Therapy for Locally Advanced and Borderline Resectable Pancreatic Cancer Is Effective and Well Tolerated

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chuong, Michael D.; Springett, Gregory M.; Freilich, Jessica M.

Purpose: Stereotactic body radiation therapy (SBRT) provides high rates of local control (LC) and margin-negative (R0) resections for locally advanced pancreatic cancer (LAPC) and borderline resectable pancreatic cancer (BRPC), respectively, with minimal toxicity. Methods and Materials: A single-institution retrospective review was performed for patients with nonmetastatic pancreatic cancer treated with induction chemotherapy followed by SBRT. SBRT was delivered over 5 consecutive fractions using a dose painting technique including 7-10 Gy/fraction to the region of vessel abutment or encasement and 5-6 Gy/fraction to the remainder of the tumor. Restaging scans were performed at 4 weeks, and resectable patients were considered formore » resection. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Results: Seventy-three patients were evaluated, with a median follow-up time of 10.5 months. Median doses of 35 Gy and 25 Gy were delivered to the region of vessel involvement and the remainder of the tumor, respectively. Thirty-two BRPC patients (56.1%) underwent surgery, with 31 undergoing an R0 resection (96.9%). The median OS, 1-year OS, median PFS, and 1-year PFS for BRPC versus LAPC patients was 16.4 months versus 15 months, 72.2% versus 68.1%, 9.7 versus 9.8 months, and 42.8% versus 41%, respectively (all P>.10). BRPC patients who underwent R0 resection had improved median OS (19.3 vs 12.3 months; P=.03), 1-year OS (84.2% vs 58.3%; P=.03), and 1-year PFS (56.5% vs 25.0%; P<.0001), respectively, compared with all nonsurgical patients. The 1-year LC in nonsurgical patients was 81%. We did not observe acute grade ≥3 toxicity, and late grade ≥3 toxicity was minimal (5.3%). Conclusions: SBRT safely facilitates margin-negative resection in patients with BRPC pancreatic cancer while maintaining a high rate of LC in unresectable patients. These data support the expanded implementation of SBRT for pancreatic cancer.« less

Radiofrequency ablation for locally advanced pancreatic cancer: SMAD4 analysis segregates a responsive subgroup of patients.

PubMed

Paiella, Salvatore; Malleo, Giuseppe; Cataldo, Ivana; Gasparini, Clizia; De Pastena, Matteo; De Marchi, Giulia; Marchegiani, Giovanni; Rusev, Borislav; Scarpa, Aldo; Girelli, Roberto; Giardino, Alessandro; Frigerio, Isabella; D'Onofrio, Mirko; Secchettin, Erica; Bassi, Claudio; Salvia, Roberto

2018-03-01

SMAD4 mutational status correlates with pancreatic ductal adenocarcinoma (PDAC) failure pattern. We investigated in a subset of locally advanced patients submitted to radiofrequency ablation (RFA) whether the assessment of SMAD4 status is a useful way to select the patients. Clinical, radiological, and follow-up details of patients submitted to RFA for locally advanced pancreatic cancer (LAPC), in whom cytohistological material was available at our institution, were retrospectively retrieved. SMAD4 expression was evaluated by immunohistochemistry (IHC) and considered "negative" or "positive." The survival analysis was conducted using Kaplan-Meier and Cox proportional hazards models. The study population consisted of 30 patients. Thirteen patients (43.3%) received RFA upfront, whereas 17 (56.7%) after induction treatments. SMAD4 was mutant in 18 out of 30 patients (60%). The overall estimated post-RFA disease-specific survival (DSS) was 15 months (95% CI 11.64-18.35). The estimated post-RFA DSS of patients with wild-type and mutant SMAD4 was 22 and 12 months, respectively (log-rank p < 0.05). At the multivariate analysis, SMAD4 was the only independent predictor of survival (p = 0.05). The pattern of failure was not associated with SMAD4 status (p = 0.4). Within patients undergoing RFA for LAPC, SMAD4 analysis could segregate a subgroup of subjects with improved survival, who likely benefited from tumor ablation.

Phenome-genome association studies of pancreatic cancer: new targets for therapy and diagnosis.

PubMed

Narayanan, Ramaswamy

2015-01-01

Pancreatic cancer, has a very high mortality rate and requires novel molecular targets for diagnosis and therapy. Genetic association studies over databases offer an attractive starting point for gene discovery. The National Center for Biotechnology Information (NCBI) Phenome Genome Integrator (PheGenI) tool was enriched for pancreatic cancer-associated traits. The genes associated with the trait were characterized using diverse bioinformatics tools for Genome-Wide Association (GWA), transcriptome and proteome profile and protein classes for motif and domain. Two hundred twenty-six genes were identified that had a genetic association with pancreatic cancer in the human genome. This included 25 uncharacterized open reading frames (ORFs). Bioinformatics analysis of these ORFs identified putative druggable proteins and biomarkers including enzymes, transporters and G-protein-coupled receptor signaling proteins. Secreted proteins including a neuroendocrine factor and a chemokine were identified. Five out of these ORFs encompassed non coding RNAs. The ORF protein expression was detected in numerous body fluids, such as ascites, bile, pancreatic juice, milk, plasma, serum and saliva. Transcriptome and proteome analyses showed a correlation of mRNA and protein expression for nine ORFs. Analysis of the Catalogue of Somatic Mutations in Cancer (COSMIC) database revealed a strong correlation across copy number variations and mRNA over-expression for four ORFs. Mining of the International Cancer Gene Consortium (ICGC) database identified somatic mutations in a significant number of pancreatic patients' tumors for most of these ORFs. The pancreatic cancer-associated ORFs were also found to be genetically associated with other neoplasms, including leukemia, malignant melanoma, neuroblastoma and prostate carcinomas, as well as other unrelated diseases and disorders, such as Alzheimer's disease, Crohn's disease, coronary diseases, attention deficit disorder and addiction. Based

MRI assessed pancreatic morphology and exocrine function are associated with disease burden in chronic pancreatitis.

PubMed

Madzak, Adnan; Olesen, Søren Schou; Lykke Poulsen, Jakob; Bolvig Mark, Esben; Mohr Drewes, Asbjørn; Frøkjær, Jens Brøndum

2017-11-01

The aim of this study was to explore the association between morphological and functional secretin-stimulated MRI parameters with hospitalization, quality of life (QOL), and pain in patients with chronic pancreatitis (CP). This prospective cohort study included 82 patients with CP. Data were obtained from clinical information, QOL, and pain as assessed by questionnaires (The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and modified Brief Pain Inventory short form). Secretin-stimulated MRI morphological parameters included pancreatic gland volume, main pancreatic duct diameter, the modified Cambridge Classification of Duct Abnormality, apparent diffusion coefficient, fat signal fraction, and the pancreatic secretion volume as a functional parameter. The primary outcomes were time to first hospitalization related to the CP, as well as annual hospitalization frequency and duration. The secondary outcomes were pain severity, QOL, and pain interference scores. A main pancreatic duct diameter below 5 mm was associated with reduced time to first hospitalization (hazard ratio=2.06; 95% confidence interval: 1.02-4.17; P=0.043). Pancreatic secretion volume was correlated with QOL (r=0.31; P=0.0072) and pain interference score (r=-0.27; P=0.032), and fecal elastase was also correlated with QOL (r=0.28; P=0.017). However, functional and morphological findings were not related to pain intensity. Advanced pancreatic imaging techniques may be a highly sensitive tool for prognostication and monitoring of disease activity and its consequences.

Stent selection for both biliary and pancreatic strictures caused by chronic pancreatitis: multiple plastic stents or metallic stents?

PubMed

Gupta, Rajesh; Reddy, D Nageshwar

2011-09-01

Endoscopic stenting is an effective treatment option in the management of both benign biliary strictures and pancreatic ductal strictures. Plastic stents and self-expandable metal stents have been used with variable success for the management of both benign biliary strictures and pancreatic ductal strictures caused by chronic pancreatitis. Fully covered self-expandable metal stents of improved design represent a major technological advance which has added to the endoscopic armamentarium. Both multiple plastic stents and covered self-expandable metal stents have shown promising results. However, data to support the use of self-expandable metal stents over multiple plastic stents or vice versa are still lacking.

Small-cell neuroendocrine carcinoma as a variant form of prostate cancer recurrence: a case report and short literature review.

PubMed

Yashi, Masahiro; Terauchi, Fumihito; Nukui, Akinori; Ochi, Masanori; Yuzawa, Masayuki; Hara, Yosuke; Morita, Tatsuo

2006-01-01

Small-cell neuroendocrine carcinoma has been recognized as a rare histologic variant occurring in only 0.5% to 2% of prostatic primary tumors. However, recent autopsy studies suggest development to this phenotype in up to 10% to 20% of the cases with hormone-refractory disease. A case of conventional adenocarcinoma before androgen-ablation therapy but showing progression to small-cell neuroendocrine carcinoma at the recurrence. The immunohistochemistry of the tumor showed strong positive staining for progastrin-releasing peptide (ProGRP), a carboxy terminal region common to 3 precursors for gastrin-releasing peptide, but almost negative staining for chromogranin-A and prostate-specific antigen. Combination chemotherapy based on cisplatin and etoposide was effective for controlling the tumor progression for 7 months, and the serum ProGRP level correlated well to the clinical course. Neither objective nor subjective responses were observed to somatostatin analogue therapy performed in the late stage of disease. The present case reminds the urologist that small-cell neuroendocrine carcinoma may be a variant form of disease recurrence during androgen ablation in advanced prostate cancer. A strategic approach for this phenotype evaluating serum neuroendocrine markers, such as ProGRP, should be taken when serum prostate-specific antigen does not reflect the disease state. This approach would allow one to choose alternative therapies targeting neuroendocrine cells other than androgen ablation.

Health-Related Quality of Life in SCALOP, a Randomized Phase 2 Trial Comparing Chemoradiation Therapy Regimens in Locally Advanced Pancreatic Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hurt, Christopher N., E-mail: hurtcn@cardiff.ac.uk; Mukherjee, Somnath; Bridgewater, John

Purpose: Chemoradiation therapy (CRT) for patients with locally advanced pancreatic cancer (LAPC) provides survival benefits but may result in considerable toxicity. Health-related quality of life (HRQL) measurements during CRT have not been widely reported. This paper reports HRQL data from the Selective Chemoradiation in Advanced Localised Pancreatic Cancer (SCALOP) trial, including validation of the QLQ-PAN26 tool in CRT. Methods and Materials: Patients with locally advanced, inoperable, nonmetastatic carcinoma of the pancreas were eligible. Following 12 weeks of induction gemcitabine plus capecitabine (GEMCAP) chemotherapy, patients with stable and responding disease were randomized to a further cycle of GEMCAP followed by capecitabine- or gemcitabine-basedmore » CRT. HRQL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the EORTC Pancreatic Cancer module (PAN26). Results: A total of 114 patients from 28 UK centers were registered and 74 patients randomized. There was improvement in the majority of HRQL scales during induction chemotherapy. Patients with significant deterioration in fatigue, appetite loss, and gastrointestinal symptoms during CRT recovered within 3 weeks following CRT. Differences in changes in HRQL scores between trial arms rarely reached statistical significance; however, where they did, they favored capecitabine therapy. PAN26 scales had good internal consistency and were able to distinguish between subgroups of patients experiencing toxicity. Conclusions: Although there is deterioration in HRQL following CRT, this resolves within 3 weeks. HRQL data support the use of capecitabine- over gemcitabine-based chemoradiation. The QLQ-PAN26 is a reliable and valid tool for use in patients receiving CRT.« less

Management of unresectable, locally advanced pancreatic adenocarcinoma.

PubMed

Salgado, M; Arévalo, S; Hernando, O; Martínez, A; Yaya, R; Hidalgo, M

2018-02-01

The diagnosis of unresectable locally advanced pancreatic adenocarcinoma (LAPC) requires confirmation, through imaging tests, of the unfeasibility of achieving a complete surgical resection, in the absence of metastatic spread. The increase in overall survival (OS), together with an appropriate symptom management is the therapeutic target in LAPC, maintaining an acceptable quality of life and, if possible, increasing the time until the appearance of metastasis. Chemoradiation (CRT) improves OS compared to best support treatment or radiotherapy (RT) but with greater toxicity. No significant increase in OS has been achieved with CRT when compared to chemotherapy (QT) alone in patients without disease progression after four months of treatment with QT. However, a significantly better local control, that is, a significant increase in the time to disease progression was associated with this approach. The greater effectiveness of the schemes FOLFIRINOX and gemcitabine (Gem) + Nab-paclitaxel compared to gemcitabine alone, has been extrapolated from metastatic disease to LAPC, representing a possible alternative for patients with good performance status (ECOG 0-1). In the absence of randomized clinical trials, Gem is the standard treatment in LAPC. If disease control is achieved after 4-6 cycles of QT, the use of CRT for consolidation can be considered an option vs QT treatment maintenance. Capecitabine has a better toxicity profile and effectiveness compared to gemcitabine as a radiosensitizer. After local progression, and without evidence of metastases, treatment with RT or CRT, in selected patients, can support to maintain the regional disease control.

Chemotherapy Regimen Extends Survival in Advanced Pancreatic Cancer Patients

Cancer.gov

A four-drug chemotherapy regimen has produced the longest improvement in survival ever seen in a phase III clinical trial of patients with metastatic pancreatic cancer, one of the deadliest types of cancer.

Pancreatic stellate cell: physiologic role, role in fibrosis and cancer.

PubMed

Apte, Minote; Pirola, Romano C; Wilson, Jeremy S

2015-09-01

Ever since the first descriptions of methods to isolate pancreatic stellate cells (PSCs) from rodent and human pancreas 17 years ago, rapid advances have been made in our understanding of the biology of these cells and their functions in health and disease. This review updates recent literature in the field, which indicates an increasingly complex role for the cells in normal pancreas, pancreatitis and pancreatic cancer. Work reported over the past 12 months includes improved methods of PSC immortalization, a role for PSCs in islet fibrosis, novel factors causing PSC activation as well as those inducing quiescence, and translational research aimed at inhibiting the facilitatory effects of PSCs on disease progression in chronic pancreatitis as well as pancreatic cancer. Improved understanding of the role of PSCs in pancreatic pathophysiology has prompted a focus on translational studies aimed at developing novel approaches to modulate PSC function in a bid to improve clinical outcomes of two major fibrotic diseases of the pancreas: chronic pancreatitis and pancreatic cancer.

Gastrointestinal neuroendocrine (carcinoid) tumours: current diagnosis and management.

PubMed

Modlin, Irvin M; Moss, Steven F; Oberg, Kjell; Padbury, Robert; Hicks, Rodney J; Gustafsson, Bjorn I; Wright, Nicholas A; Kidd, Mark

2010-07-05

Neuroendocrine tumours (NETs) are increasing in both incidence and prevalence and, as a group, are more prevalent than either gastric, pancreatic, oesophageal or hepatobiliary adenocarcinomas, or any two of these cancers combined. Clinical awareness of the protean and intermittent symptoms of NETs (eg, sweating, flushing, diarrhoea, and bronchospasm) is critical for timely diagnosis; however, the classical carcinoid syndrome is relatively uncommon. The most useful diagnostic test for gastrointestinal NETs is measurement of plasma chromogranin A (CgA) levels. Disease extent is assessed by both anatomical imaging, and nuclear imaging with radiolabelled somatostatin analogues. Pathological evaluation comprises tumour-node-metastasis classification, a minimum pathological dataset, CgA and synaptophysin immunostaining, as well as mitotic count or Ki-67 index (a marker of cell proliferation) to define grading. Resection of the primary lesion and as much metastatic disease as possible increases the efficacy of medical therapy. Other management strategies include hepatic embolisation and peptide receptor radionuclide therapy. Patients with tumours expressing somatostatin receptors should be treated with somatostatin analogues. Depending on the tumour grade, other effective agents include cytotoxics, tyrosine kinase inhibitors, and antiangiogenics. The overarching requirement for best management of patients with NETs is to ensure that they have ready access to experienced multidisciplinary clinician groups located within centres of appropriate subspecialty expertise.

Pancreatic resection for renal cell carcinoma metastasis: An exceptionally rare coexistence.

PubMed

Boussios, Stergios; Zerdes, Ioannis; Batsi, Ourania; Papakostas, Vasilios P; Seraj, Esmeralda; Pentheroudakis, George; Glantzounis, George K

2016-01-01

Pancreatic metastases are uncommon and only found in a minority of patients with widespread metastatic disease at autopsy. The most common primary cancer site resulting in pancreatic metastases is the kidney, followed by colorectal cancer, melanoma, breast cancer, lung carcinoma and sarcoma. Herein, we report a 63-year-old male patient who presented -3.5 years after radical nephrectomy performed for renal cell carcinoma (RCC)-with a well-defined lobular, round mass at the body of the pancreas demonstrated by abdominal Magnetic Resonance Imaging (MRI). The patient underwent distal pancreatectomy combined with splenectomy and cholecystectomy. Histopathological examination revealed clusters of epithelial clear cells, immunohistochemically positive for RCC marker, and negative for CD10 and CA19-9. A final diagnosis of clear RCC metastasizing to pancreas was obtained in view of the past history of RCC, microscopy and the immunoprofile. This was the second metachronous disease recurrence after a previous metastatic involvement of the liver, developed 19 months from the initial diagnosis. The patient has remained well at a 6 month follow up post-resection. Solitary pancreatic metastases may be misdiagnosed as primary pancreatic cancer. However, imaging including computed tomography (CT) and MRI, may discriminate between them. Surgical procedures could differentiate solitary metastasis from neuroendocrine neoplasms. The optimal resection strategy involves adequate resection margins and maximal tissue preservation of the pancreas. Recently, an increasing number of surgical resections have been performed in selected patients with limited metastatic disease to the pancreas. In addition, a rigid follow-up scheme, including endoscopic ultrasound (EUS) and CT is essential give patients a chance for a prolonged life. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

The Epidemiology of Pancreatitis and Pancreatic Cancer

PubMed Central

Yadav, Dhiraj; Lowenfels, Albert B.

2013-01-01

Acute pancreatitis is one of the most frequent gastrointestinal causes for hospital admission in the US. Chronic pancreatitis, although lower in incidence, significantly reduces patients’ quality of life. Pancreatic cancer has high mortality and is 1 of the top 5 causes of death from cancer. The burden of pancreatic disorders is expected to increase over time. The risk and etiology of pancreatitis differ with age and sex, and all pancreatic disorders affect Blacks more than any other race. Gallstones are the most common cause of acute pancreatitis, and early cholecystectomy eliminates the risk of future attacks. Alcohol continues to be the single most important risk factor for chronic pancreatitis. Smoking is an independent risk factor for acute and chronic pancreatitis, and its effects could synergize with those of alcohol. Significant risk factors for pancreatic cancer include smoking and non-O blood groups. Alcohol abstinence and smoking cessation can alter progression of pancreatitis and reduce recurrence; smoking cessation is the most effective strategy to reduce the risk of pancreatic cancer. PMID:23622135

Neoadjuvant therapy in pancreatic cancer: an emerging strategy.

PubMed

Bittoni, Alessandro; Santoni, Matteo; Lanese, Andrea; Pellei, Chiara; Andrikou, Kalliopi; Stefano, Cascinu

2014-01-01

Pancreatic adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths among men and women, being responsible for 6% of all cancer-related deaths. Surgical resection offers the only chance of cure, but only 15 to 20 percent of cases are potentially resectable at presentation. In recent years, increasing evidences support the use of neoadjuvant strategies in pancreatic cancer in patients with resectable pancreatic cancer as well as in patients with borderline resectable or locally advanced PDAC in order to allow early treatment of micrometastatic disease, tumour regression, and reduced risk of peritoneal tumour implantation during surgery. Furthermore, neoadjuvant treatment allows evaluation of tumour response and increases patient's compliance. However, most evidences in this setting come from retrospective analysis or small case series and in many studies chemotherapy or chemoradiation therapies used were suboptimal. Currently, prospective randomized trials using the most active chemotherapy regimens available are trying to define the real benefit of neoadjuvant strategies compared to conventional adjuvant strategies. In this review, the authors examined available data on neoadjuvant treatment in patients with resectable pancreatic cancer as well as in patients with borderline resectable or locally advanced PDAC and the future directions in this peculiar setting.

[The role of endoscopy in gastroenteropancreatic neuroendocrine tumors].

PubMed

Magno, L; Sivero, L; Napolitano, V; Ruggiero, S; Fontanarosa, G; Massa, S

2010-01-01

Versione italiana Riassunto: Il ruolo dell'endoscopia nei tumori neuroendocrini gastroenteropancreatici. L. Magno, L. Sivero, V. Napolitano, S. Ruggiero, G. Fontanarosa, S. Massa I tumori neuroendocrini (NET) gastro-entero-pancreatici (GEP) sono neoplasie rare che originano dalle cellule neuroendocrine del tubo digerente e del pancreas. L'endoscopia digestiva e l'ecoendoscopia rivestono un ruolo importante nella diagnosi, stadiazione e sorveglianza dei pazienti con NET. Inoltre, in casi selezionati, le tecniche endoscopiche operative consentono il trattamento di queste neoplasie in fase precoce. English version Summary: The role of endoscopy in gastroenteropancreatic neuroendocrine tumors. L. Magno, L. Sivero, V. Napolitano, S. Ruggiero, G. Fontanarosa, S. Massa Gastroenteropancreatic (GEP) neuroendocrine tumors (NET) are rare neoplasia arisen from neuroendocrine cells present in the gut mucosa and pancreas. Digestive endoscopy and endoscopic ultrasonography play a relevant role in NET diagnosis, stadiation and surveillance. Moreover, in selected patients, surgical endoscopy allows the tratment of these cancers at an early stage.

A prospective study of soluble receptor for advanced glycation end products and adipokines in association with pancreatic cancer in postmenopausal women.

PubMed

White, Donna L; Hoogeveen, Ron C; Chen, Liang; Richardson, Peter; Ravishankar, Milan; Shah, Preksha; Tinker, Lesley; Rohan, Thomas; Whitsel, Eric A; El-Serag, Hashem B; Jiao, Li

2018-05-01

Advanced glycation end products (AGEs) dysregulate adipokines and induce inflammation by binding to their adipocyte receptor (RAGE). Soluble RAGE (sRAGE) prevents AGEs/RAGE signaling. We performed a nested case-control study of the association between sRAGE, adipokines, and incident pancreatic cancer risk in the prospective Women's Health Initiative Study. We individually matched controls (n = 802) to cases (n = 472) on age, race, and blood draw date. We evaluated serum concentrations of sRAGE, adiponectin, leptin, monocyte chemotactic protein 1 (MCP1), and plasminogen activator inhibitor-1 (PAI1) using immunoassay. We used conditional logistic regression model to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for pancreatic cancer over biomarker quartiles (Q1-Q4). We used principal component analysis to create two composite biomarkers and performed a confirmatory factor analysis to examine the association between composite biomarker scores (CBS) and pancreatic cancer risk. Baseline serum sRAGE concentrations were inversely associated with pancreatic cancer risk (aOR Q4 vs. Q1  = 0.70, 95% CI: 0.50-0.99). High MCP1 (aOR Q4 vs. Q1  = 2.55, 95% CI: 1.41-4.61) and the higher CBS including MCP1, PAI1, and leptin (aOR Q4 vs. Q1  = 1.82, 95% CI = 1.04-3.18) were also associated with increased pancreatic cancer risk among women with BMI <25 kg/m 2 (P values for interaction <0.05). We found an inverse association between prediagnostic sRAGE concentrations and risk of incident pancreatic cancer in postmenopausal women. A proinflammatory CBS was associated with increased risk only in women with normal BMI. MCP1 was not modulated by sRAGE. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Expression of VGF mRNA in developing neuroendocrine and endocrine tissues.

PubMed

Snyder, S E; Peng, B; Pintar, J E; Salton, S R J

2003-11-01

Analysis of knockout mice suggests that the neurotropin-inducible secreted polypeptide VGF (non-acronymic) plays an important role in the regulation of energy balance. VGF is synthesized by neurons in the central and peripheral nervous systems (CNS, PNS), as well as in the adult pituitary, adrenal medulla, endocrine cells of the stomach and pancreatic beta cells. Thus VGF, like cholecystokinin, leptin, ghrelin and other peptide hormones that have been shown to regulate feeding and energy expenditure, is synthesized in both the gut and the brain. Although detailed developmental studies of VGF localization in the CNS and PNS have been completed, little is known about the ontogeny of VGF expression in endocrine and neuroendocrine tIssues. Here, we report that VGF mRNA is detectable as early as embryonic day 15.5 in the developing rat gastrointestinal and esophageal lumen, pancreas, adrenal, and pituitary, and we further demonstrate that VGF mRNA is synthesized in the gravid rat uterus, together supporting possible functional roles for this polypeptide outside the nervous system and in the enteric plexus.

Developmental programming: postnatal estradiol modulation of prenatally organized reproductive neuroendocrine function in sheep.

PubMed

Puttabyatappa, Muraly; Cardoso, Rodolfo C; Herkimer, Carol; Veiga-Lopez, Almudena; Padmanabhan, Vasantha

2016-08-01

Gestational testosterone (TS) excess, acting via both the androgenic and estrogenic pathways, advances puberty and disrupts the neuroendocrine estradiol (E2) feedback and periovulatory hormonal dynamics in female sheep. These prenatally programmed defects may be subject to postnatal modifications by continued organizational and/or activational effects of steroids. This study investigated (1) the organizational contribution of prenatal estrogen excess and (2) the impact of postnatal exposure to E2 in modulating the effects of prenatal androgen excess (TS and dihydrotestosterone (DHT)) on puberty, neuroendocrine feedback mechanisms, and periovulatory hormonal dynamics in sheep. Pregnant Suffolk sheep were treated with TS, DHT, E2, or E2 plus DHT (ED) from days 30 to 90 of gestation. A subset of the control (C), TS, and DHT female offspring received a constant-release E2 implant postnatally. Findings revealed that (1) prenatal E2-treatment failed to reproduce the neuroendocrine disruptions predicted to be programmed by the estrogenic pathway and (2) prenatal E2D-treatment did not adequately replicate the reproductive neuroendocrine defects induced by prenatal TS excess. More importantly, continuous postnatal E2-treatment, while delaying the onset of puberty and reducing the inhibitory effects of E2 on tonic luteinizing hormone (LH) release, failed to amplify the E2-positive feedback and periovulatory defects induced by prenatal TS-treatment. Our results indicate that disruptions in E2-positive feedback mechanisms and periovulatory gonadotropin secretion induced by prenatal TS-treatment are programmed predominantly during the prenatal life with postnatal exposure to E2 excess not contributing further to these disruptions. © 2016 Society for Reproduction and Fertility.

[Management of localized, locally advanced and metastatic pancreatic adenocarcinoma].

PubMed

Delpero, Jean-Robert; Turrini, Olivier; Raoul, Jean-Luc

2015-03-01

Pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of all pancreatic tumours, is a devastating malignancy. The prognosis is extremely poor because PDAC is usually a systemic disease at diagnosis. All stages, the survival does not exceed 5% at 5 years. However 15% of PDAC can be resected and today a margin-negative resection followed by adjuvant chemotherapy remains the only potential for a prolonged survival. Postoperative mortality had significantly decreased and the benefit of postoperative adjuvant chemotherapy has been clearly shown. Substantial progress has been made in the field of palliative chemotherapy by introducing new chemotherapy regimens (FOLFIRINOX [folinic acid, 5-fluorouracil, irinotecan and oxaliplatin] and gemcitabine/nab-paclitaxel), when the patient's performance status allows the use of these drugs. The role of radiation therapy remains controversial.

Neuroendocrine host factors and inflammatory disease susceptibility.

PubMed Central

Ligier, S; Sternberg, E M

1999-01-01

The etiology of autoimmune diseases is multifactorial, resulting from a combination of genetically predetermined host characteristics and environmental exposures. As the term autoimmune implies, immune dysfunction and dysregulated self-tolerance are key elements in the pathophysiology of all these diseases. The neuroendocrine and sympathetic nervous systems are increasingly recognized as modulators of the immune response at the levels of both early inflammation and specific immunity. As such, alterations in their response represent a potential mechanism by which pathologic autoimmunity may develop. Animal models of autoimmune diseases show pre-existing changes in neuroendocrine responses to a variety of stimuli, and both animal and human studies have shown altered stress responses in the setting of active immune activation. The potential role of the neuroendocrine system in linking environmental exposures and autoimmune diseases is 2-fold. First, it may represent a direct target for toxic compounds. Second, its inadequate function may result in the inappropriate response of the immune system to an environmental agent with immunogenic properties. This article reviews the relationship between autoimmune diseases and the neuroendocrine system and discusses the difficulties and pitfalls of investigating a physiologic response that is sensitive to such a multiplicity of environmental exposures. PMID:10502534

Management strategies in pancreatic cancer.

PubMed

Campen, Christopher J; Dragovich, Tomislav; Baker, Amanda F

2011-04-01

Current first-line and adjuvant chemotherapeutic strategies for management of patients with pancreatic cancer are reviewed. Pancreatic adenocarcinoma is the 10th most prevalent cancer and the fourth most common cause of cancer deaths in the United States. More than 80% of patients with pancreatic cancer are diagnosed with locally advanced or metastatic disease and are not candidates for surgery; these patients often require multimodal treatment. The most widely used chemotherapy for such patients, as well as patients requiring adjuvant therapy after surgery, is gemcitabine or gemcitabine-based chemotherapy. All current chemotherapies for pancreatic cancer are associated with dose-limiting hematologic toxicity and other adverse effects that require ongoing monitoring and dosage adjustment to balance the benefits and risks of treatment. Pharmacists can play an important role in monitoring and providing drug information and guidance to patients and oncologists. Current investigational strategies include efforts to improve chemotherapy response rates and outcomes through modulation of cell signaling pathways and use of nanotechnology to improve drug delivery. Current management of pancreatic cancer is multifaceted, involving anticancer therapy, supportive care, and toxicity management. Standard systemic therapy with gemcitabine as a single agent or in combination with other cytotoxic agents provides modest benefits in terms of response and symptom control.

The epidemiology of pancreatitis and pancreatic cancer.

PubMed

Yadav, Dhiraj; Lowenfels, Albert B

2013-06-01

Acute pancreatitis is one of the most frequent gastrointestinal causes of hospital admission in the United States. Chronic pancreatitis, although lower in incidence, significantly reduces patients' quality of life. Pancreatic cancer is associated with a high mortality rate and is one of the top 5 causes of death from cancer. The burden of pancreatic disorders is expected to increase over time. The risk and etiology of pancreatitis differ with age and sex, and all pancreatic disorders affect the black population more than any other race. Gallstones are the most common cause of acute pancreatitis, and early cholecystectomy eliminates the risk of future attacks. Alcohol continues to be the single most important risk factor for chronic pancreatitis. Smoking is an independent risk factor for acute and chronic pancreatitis, and its effects could synergize with those of alcohol. Significant risk factors for pancreatic cancer include smoking and non-O blood groups. Alcohol abstinence and smoking cessation can alter the progression of pancreatitis and reduce recurrence; smoking cessation is the most effective strategy to reduce the risk of pancreatic cancer. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Neuroendocrine activity of the melanocyte

PubMed Central

Slominski, Andrzej

2009-01-01

More than 15 years ago, we have proposed that melanocytes are sensory and regulatory cells with computing capability, which transform external and/or internal signals/energy into organized regulatory network(s) for the maintenance of the cutaneous homeostasis. This concept is substantiated by accumulating evidence that melanocytes produce classical stress neurotransmitters, neuropeptides and hormones, express corresponding receptors and these processes are modified and/or regulated by ultraviolet radiation, biological factors or stress. Examples of the above are catecholamines, serotonin, N-acetyl-serotonin, melatonin, proopiomelanocortin-derived adrenocorticotropic hormone, β-endorphin or melanocyte-stimulating hormone peptides, corticotropin releasing factor, related urocortins and corticosteroids including cortisol and corticosterone as well as their precursors. Furthermore, their production is not random, but hierarchical and follows the structures of classical neuroendocrine organizations such as hypothalamic-pituitary-adrenal axis, serotoninergic, melatoninergic and catecholaminergic systems. An example of an intrinsic but overlooked neuroendocrine activity is production and secretion of melanogenesis intermediates including L-DOPA or its derivatives that could enter circulation and act on distant sites. Such capabilities have defined melanocytes as neuroendocrine cells that not only coordinate cutaneous but also can affect a global homeostasis. PMID:19558501

A phase I study evaluating the role of the anti-epidermal growth factor receptor (EGFR) antibody cetuximab as a radiosensitizer with chemoradiation for locally advanced pancreatic cancer

PubMed Central

Arnoletti, J. P.; Frolov, A.; Eloubeidi, M.; Keene, K.; Posey, J.; Wood, T.; Greeno, Edward; Jhala, N.; Varadarajulu, S.; Russo, S.; Christein, J.; Oster, R.; Buchsbaum, D. J.; Vickers, S. M.

2012-01-01

Purpose (1) To determine the safety of the epidermal growth factor receptor (EGFR) antibody cetuximab with concurrent gemcitabine and abdominal radiation in the treatment of patients with locally advanced adenocarcinoma of the pancreas. (2) To evaluate the feasibility of pancreatic cancer cell epithelial–mesenchymal transition (EMT) molecular profiling as a potential predictor of response to anti-EGFR treatment. Methods Patients with non-metastatic, locally advanced pancreatic cancer were treated in this dose escalation study with gemcitabine (0–300 mg/m2/week) given concurrently with cetuximab (400 mg/m2 loading dose, 250 mg/m2 weekly maintenance dose) and abdominal irradiation (50.4 Gy). Expression of E-cadherin and vimentin was assessed by immunohistochemistry in diagnostic endoscopic ultrasound fine-needle aspiration (EUS-FNA) specimens. Results Sixteen patients were enrolled in 4 treatment cohorts with escalating doses of gemcitabine. Incidence of grade 1–2 adverse events was 96%, and incidence of 3–4 adverse events was 9%. There were no treatment-related mortalities. Two patients who exhibited favorable treatment response underwent surgical exploration and were intraoperatively confirmed to have unresectable tumors. Median overall survival was 10.5 months. Pancreatic cancer cell expression of E-cadherin and vimentin was successfully determined in EUS-FNA specimens from 4 patients. Conclusions Cetuximab can be safely administered with abdominal radiation and concurrent gemcitabine (up to 300 mg/m2/week) in patients with locally advanced adenocarcinoma of the pancreas. This combined therapy modality exhibited limited activity. Diagnostic EUS-FNA specimens could be analyzed for molecular markers of EMT in a minority of patients with pancreatic cancer. PMID:20589377

Neuroendocrine carcinoma of the larynx with metastasis to the eyelid.

PubMed

Assi, Hussein A; Patel, Raina; Mehdi, Syed

2015-10-01

Neuroendocrine tumors are a rare type of neoplasms that comprise only 0.5% of all malignancies.¹ They usually arise from the gastrointestinal tract and the lung.¹,² Neuroendocrine carcinoma of the head and neck is a relatively rare malignancy described in the literature. The larynx is the most commonly affected region of the head and neck.³,⁴ Nevertheless, small-cell carcinoma comprises only 0.5% of all laryngeal cancers.⁵ Neuroendocrine carcinoma of the larynx carries variable prognosis depending on the histological subtype.⁶ Typical carcinoid rarely metastasizes, but atypical carcinoid and small-cell carcinoma have high rates of metastasis, usually in the lung and liver.² Cutaneous metastasis from neuroendocrine carcinoma is an extremely rare entity, with only few cases reported in the English literature.⁷,⁸ We report the case of an elderly man with recurrent laryngeal neuroendocrine carcinoma with metastasis to the eyelid. ©2015 Frontline Medical Communications.

Spectrum of magnetic resonance imaging findings in pancreatic and other abdominal manifestations of Von Hippel-Lindau disease in a series of 23 patients: a pictorial review.

PubMed

Graziani, Rossella; Mautone, Simona; Vigo, Mario; Manfredi, Riccardo; Opocher, Giuseppe; Falconi, Massimo

2014-01-10

Von Hippel Lindau disease is a rare autosomal dominantly inherited multisystem disorder characterized by development of benign and malignant tumors. The abdominal manifestation of the syndrome are protean. Magnetic resonance plays an important role in identification of abdominal abnormalities and follow-up of lesions. To describe magnetic resonance imaging findings and patterns of pancreatic and other principal abdominal manifestations in a series of von Hippel-Lindau (VHL) disease patients and to review literature. We retrospectively reviewed abdominal magnetic resonance studies performed in 23 patients (10 males, 13 females) diagnosed of VHL. In all examined patients abdominal involvement was present. The pancreatic imaging findings detected were: unilocular cystic lesions (6/23: 26.1%); serous cystadenomas (11/23: 47.8%), including diffuse lesions (8/23: 34.8%); solid neuroendocrine tumors (8/23: 34.8%); cystic neuroendocrine tumors (1/23: 4.3%). The renal findings detected were: simple renal cysts (18/23: 78.3%); complex renal cysts (13/23: 56.5%), including benign lesions (10/23: 43.5%) and malignant lesions (3/23: 13.0%); renal carcinomas (11/23: 47.8%) and 5 of these (45.5%) were multiple and bilateral. Five patients (21.7%) presented pheochromocytoma (4 of these were bilateral; 80.0%) and 1 patient (4.3%) presented cystadenoma of the epididymis. In VHL disease patients, magnetic resonance imaging plays an essential role in the identification of pancreatic and other abdominal lesions, in their follow-up, in the screening of asymptomatic gene carriers, and in their long-term surveillance.

[Diagnosis and surgical management in gastrointestinal neuroendocrine tumors].

PubMed

Tomulescu, V; Stănciulea, O; Dima, S; Herlea, V; Stoica Mustafa, E; Dumitraşcu, T; Pechianu, C; Popescu, I

2011-01-01

Neuroendocrine tumors, known as carcinoid tumors constitute a heterogeneous group of neoplasms that present many clinical challenges. They secrete peptides and neuroamines that cause specific clinical syndromes. Assessment of specific or general tumors markers offers high sensitivity in establishing the diagnosis and they also have prognostic significance. Management strategies include curative surgery, whenever possible-that can be rarely achieved, palliative surgery, chemotherapy, radiologic therapy, such as radiofrequency ablation and chemoembolisations and somatostatin analogues therapy in order to control the symptoms. The aim of this paper is to review recent publications in this field and to give recommendations that take into account current advances in order to facilitate improvement in management and outcome.

Molecular Targeted Intervention for Pancreatic Cancer

PubMed Central

Mohammed, Altaf; Janakiram, Naveena B.; Pant, Shubham; Rao, Chinthalapally V.

2015-01-01

Pancreatic cancer (PC) remains one of the worst cancers, with almost uniform lethality. PC risk is associated with westernized diet, tobacco, alcohol, obesity, chronic pancreatitis, and family history of pancreatic cancer. New targeted agents and the use of various therapeutic combinations have yet to provide adequate treatments for patients with advanced cancer. To design better preventive and/or treatment strategies against PC, knowledge of PC pathogenesis at the molecular level is vital. With the advent of genetically modified animals, significant advances have been made in understanding the molecular biology and pathogenesis of PC. Currently, several clinical trials and preclinical evaluations are underway to investigate novel agents that target signaling defects in PC. An important consideration in evaluating novel drugs is determining whether an agent can reach the target in concentrations effective to treat the disease. Recently, we have reported evidence for chemoprevention of PC. Here, we provide a comprehensive review of current updates on molecularly targeted interventions, as well as dietary, phytochemical, immunoregulatory, and microenvironment-based approaches for the development of novel therapeutic and preventive regimens. Special attention is given to prevention and treatment in preclinical genetically engineered mouse studies and human clinical studies. PMID:26266422

Molecular Endoscopic Ultrasound for Diagnosis of Pancreatic Cancer

PubMed Central

Bournet, Barbara; Pointreau, Adeline; Delpu, Yannick; Selves, Janick; Torrisani, Jerome; Buscail, Louis; Cordelier, Pierre

2011-01-01

Endoscopic ultrasound-guided fine needle aspiration-biopsy is a safe and effective technique in diagnosing and staging of pancreatic ductal adenocarcinoma. However its predictive negative value does not exceed 50% to 60%. Unfortunately, the majority of pancreatic cancer patients have a metastatic and/or a locally advanced disease (i.e., not eligible for curative resection) which explains the limited access to pancreatic tissue specimens. Endoscopic ultrasound-guided fine needle aspiration-biopsy is the most widely used approach for cytological and histological material sampling in these situations used in up to two thirds of patients with pancreatic cancer. Based on this unique material, we and others developed strategies to improve the differential diagnosis between carcinoma and inflammatory pancreatic lesions by analysis of KRAS oncogene mutation, microRNA expression and methylation, as well as mRNA expression using both qRT-PCR and Low Density Array Taqman analysis. Indeed, differentiating pancreatic cancer from pseudotumoral chronic pancreatitis remains very difficult in current clinical practice, and endoscopic ultrasound-guided fine needle aspiration-biopsy analysis proved to be very helpful. In this review, we will compile the clinical and molecular advantages of using endoscopic ultrasound-guided fine needle aspiration-biopsy in managing pancreatic cancer. PMID:24212643

Molecular biology of pancreatic cancer: how useful is it in clinical practice?

PubMed

Sakorafas, George H; Smyrniotis, Vasileios

2012-07-10

During the recent two decades dramatic advances of molecular biology allowed an in-depth understanding of pancreatic carcinogenesis. It is currently accepted that pancreatic cancer has a genetic component. The real challenge is now how these impressive advances could be used in clinical practice. To critically present currently available data regarding clinical application of molecular biology in pancreatic cancer. Reports about clinical implications of molecular biology in patients with pancreatic cancer were retrieved from PubMed. These reports were selected on the basis of their clinical relevance, and the data of their publication (preferentially within the last 5 years). Emphasis was placed on reports investigating diagnostic, prognostic, and therapeutic implications. Molecular biology can be used to identify individuals at high-risk for pancreatic cancer development. Intensive surveillance is indicated in these patients to detect pancreatic neoplasia ideally at a preinvasive stage, when curative resection is still possible. Molecular biology can also be used in the diagnosis of pancreatic cancer, with molecular analysis on samples of biologic material, such as serum or plasma, duodenal fluid or preferentially pure pancreatic juice, pancreatic cells or tissue, and stools. Molecular indices have also prognostic significance. Finally, molecular biology may have therapeutic implications by using various therapeutic approaches, such as antiangiogenic factors, purine synthesis inhibitors, matrix metalloproteinase inhibitors, factors modulating tumor-stroma interaction, inactivation of the hedgehog pathway, gene therapy, oncolytic viral therapy, immunotherapy (both passive as well as active) etc. Molecular biology may have important clinical implications in patients with pancreatic cancer and represents one of the most active areas on cancer research. Hopefully clinical applications of molecular biology in pancreatic cancer will expand in the future, improving the

Quantitative Proteomic Analysis of Serum Exosomes from Patients with Locally Advanced Pancreatic Cancer Undergoing Chemoradiotherapy.

PubMed

An, Mingrui; Lohse, Ines; Tan, Zhijing; Zhu, Jianhui; Wu, Jing; Kurapati, Himabindu; Morgan, Meredith A; Lawrence, Theodore S; Cuneo, Kyle C; Lubman, David M

2017-04-07

Pancreatic cancer is the third leading cause of cancer-related death in the USA. Despite extensive research, minimal improvements in patient outcomes have been achieved. Early identification of treatment response and metastasis would be valuable to determine the appropriate therapeutic course for patients. In this work, we isolated exosomes from the serum of 10 patients with locally advanced pancreatic cancer at serial time points over a course of therapy, and quantitative analysis was performed using the iTRAQ method. We detected approximately 700-800 exosomal proteins per sample, several of which have been implicated in metastasis and treatment resistance. We compared the exosomal proteome of patients at different time points during treatment to healthy controls and identified eight proteins that show global treatment-specific changes. We then tested the effect of patient-derived exosomes on the migration of tumor cells and found that patient-derived exosomes, but not healthy controls, induce cell migration, supporting their role in metastasis. Our data show that exosomes can be reliably extracted from patient serum and analyzed for protein content. The differential loading of exosomes during a course of therapy suggests that exosomes may provide novel insights into the development of treatment resistance and metastasis.

Chronic pancreatitis

MedlinePlus

Chronic pancreatitis - chronic; Pancreatitis - chronic - discharge; Pancreatic insufficiency - chronic; Acute pancreatitis - chronic ... abuse over many years. Repeated episodes of acute pancreatitis can lead to chronic pancreatitis. Genetics may be ...

The evolution of the surgical treatment of chronic pancreatitis.

PubMed

Andersen, Dana K; Frey, Charles F

2010-01-01

To establish the current status of surgical therapy for chronic pancreatitis, recent published reports are examined in the context of the historical advances in the field. The basis for decompression (drainage), denervation, and resection strategies for the treatment of pain caused by chronic pancreatitis is reviewed. These divergent approaches have finally coalesced as the head of the pancreas has become apparent as the nidus of chronic inflammation. The recent developments in surgical methods to treat the complications of chronic pancreatitis and the results of recent prospective randomized trials of operative approaches were reviewed to establish the current best practices. Local resection of the pancreatic head, with or without duct drainage, and duodenum-preserving pancreatic head resection offer outcomes as effective as pancreaticoduodenectomy, with lowered morbidity and mortality. Local resection or excavation of the pancreatic head offers the advantage of lowest cost and morbidity and early prevention of postoperative diabetes. The late incidences of recurrent pain, diabetes, and exocrine insufficiency are equivalent for all 3 surgical approaches. Local resection of the pancreatic head appears to offer best outcomes and lowest risk for the management of the pain of chronic pancreatitis.

Hedgehog Signaling in Pancreatic Fibrosis and Cancer

PubMed Central

Bai, Yongyu; Bai, Yongheng; Dong, Jiaojiao; Li, Qiang; Jin, Yuepeng; Chen, Bicheng; Zhou, Mengtao

2016-01-01

Abstract The hedgehog signaling pathway was first discovered in the 1980s. It is a stem cell-related pathway that plays a crucial role in embryonic development, tissue regeneration, and organogenesis. Aberrant activation of hedgehog signaling leads to pathological consequences, including a variety of human tumors such as pancreatic cancer. Multiple lines of evidence indicate that blockade of this pathway with several small-molecule inhibitors can inhibit the development of pancreatic neoplasm. In addition, activated hedgehog signaling has been reported to be involved in fibrogenesis in many tissues, including the pancreas. Therefore, new therapeutic targets based on hedgehog signaling have attracted a great deal of attention to alleviate pancreatic diseases. In this review, we briefly discuss the recent advances in hedgehog signaling in pancreatic fibrogenesis and carcinogenesis and highlight new insights on their potential relationship with respect to the development of novel targeted therapies. PMID:26962810

Neuroendocrine small cell carcinoma of the uterine cervix.

PubMed

Reig Castillejo, Anna; Membrive Conejo, Ismael; Foro Arnalot, Palmira; Rodríguez de Dios, Nuria; Algara López, Manuel

2010-07-01

Neuroendocrine small cell carcinoma of the uterine cervix (SCC) is a rare disease that mixes clinical and biological characteristics of both cervical neoplasms and neuroendocrine small cell cancer. The prognosis is poor and the optimal treatment has not yet been clarified. Multimodality treatment, with surgery and concurrent chemoradiation has recently been shown to improve local control and survival rates.

Benign gastric neuroendocrine tumors in three snow leopards (Panthera uncia).

PubMed

Dobson, Elizabeth C; Naydan, Dianne K; Raphael, Bonnie L; McAloose, Denise

2013-06-01

Neuroendocrine tumors are relatively rare neoplasms arising from neuroendocrine cells that are distributed throughout the body and are predominant in the gastrointestinal tract. This report describes benign, well-differentiated gastric neuroendocrine tumors in three captive snow leopards (Panthera uncia). All tumors were well circumscribed, were within the gastric mucosa or submucosa, and had histologic and immunohistochemical features of neuroendocrine tumors. Histologic features included packeted cuboidal to columnar epithelial cells that were arranged in palisades or pseudorosettes and contained finely granular cellular cytoplasm with centrally placed, round nuclei. Cytoplasmic granules of neoplastic cells strongly expressed chromogranin A, variably expressed neuron-specific enolase, and did not express synaptophysin or gastrin. Each leopard died or was euthanatized for reasons unrelated to its tumor.

Premenstrual dysphoric disorder: neuroendocrine interferences.

PubMed

Poiană, Cătălina; Muşat, Mădălina; Carsote, Mara; Chiriţă, Corina

2009-01-01

Premenstrual dysphoric disorder (PMDD) consists in severe cognitive and mood changes, more aggressive as seen in premenstrual syndrome (PMS). These two syndromes are situated at the border between gynecology and psychiatry but the link between the two domains remains the neuroendocrine underlying mechanisms. In present, there are some molecular systems certainly proved as being involved, like estrogens. The hormonal pattern consists not in different levels of the hormones but different response to normal hormonal levels. The cyclical biochemical triggers are related to neurotransmitters as serotonin, endorphin and gamma-amino butyric acid (GABA). The heritability of the syndrome is sustained by genetic polymorphism in ESR1 gene. Thus, the PMDD is the result of multiple disturbances regarding neuroendocrine systems.

Chronic Pancreatitis.

PubMed

Stram, Michelle; Liu, Shu; Singhi, Aatur D

2016-12-01

Chronic pancreatitis is a debilitating condition often associated with severe abdominal pain and exocrine and endocrine dysfunction. The underlying cause is multifactorial and involves complex interaction of environmental, genetic, and/or other risk factors. The pathology is dependent on the underlying pathogenesis of the disease. This review describes the clinical, gross, and microscopic findings of the main subtypes of chronic pancreatitis: alcoholic chronic pancreatitis, obstructive chronic pancreatitis, paraduodenal ("groove") pancreatitis, pancreatic divisum, autoimmune pancreatitis, and genetic factors associated with chronic pancreatitis. As pancreatic ductal adenocarcinoma may be confused with chronic pancreatitis, the main distinguishing features between these 2 diseases are discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

Outcomes after extended pancreatectomy in patients with borderline resectable and locally advanced pancreatic cancer.

PubMed

Hartwig, W; Gluth, A; Hinz, U; Koliogiannis, D; Strobel, O; Hackert, T; Werner, J; Büchler, M W

2016-11-01

In the recent International Study Group of Pancreatic Surgery (ISGPS) consensus on extended pancreatectomy, several issues on perioperative outcome and long-term survival remained unclear. Robust data on outcomes are sparse. The present study aimed to assess the outcome of extended pancreatectomy for borderline resectable and locally advanced pancreatic cancer. A consecutive series of patients with primary pancreatic adenocarcinoma undergoing extended pancreatectomies, as defined by the new ISGPS consensus, were compared with patients who had a standard pancreatectomy. Univariable and multivariable analysis was performed to identify risk factors for perioperative mortality and characteristics associated with survival. Long-term outcome was assessed by means of Kaplan-Meier analysis. The 611 patients who had an extended pancreatectomy had significantly greater surgical morbidity than the 1217 patients who underwent a standard resection (42·7 versus 34·2 per cent respectively), and higher 30-day mortality (4·3 versus 1·8 per cent) and in-hospital mortality (7·5 versus 3·6 per cent) rates. Operating time of 300 min or more, extended total pancreatectomy, and ASA fitness grade of III or IV were associated with increased in-hospital mortality in multivariable analysis, whereas resections involving the colon, portal vein or arteries were not. Median survival and 5-year overall survival rate were reduced in patients having extended pancreatectomy compared with those undergoing a standard resection (16·1 versus 23·6 months, and 11·3 versus 20·6 per cent, respectively). Older age, G3/4 tumours, two or more positive lymph nodes, macroscopic positive resection margins, duration of surgery of 420 min or above, and blood loss of 1000 ml or more were independently associated with decreased overall survival. Extended resections are associated with increased perioperative morbidity and mortality, particularly when extended total pancreatectomy is performed. Favourable

Pancreatic fibrosis correlates with exocrine pancreatic insufficiency after pancreatoduodenectomy.

PubMed

Tran, T C K; van 't Hof, G; Kazemier, G; Hop, W C; Pek, C; van Toorenenbergen, A W; van Dekken, H; van Eijck, C H J

2008-01-01

Obstruction of the pancreatic duct can lead to pancreatic fibrosis. We investigated the correlation between the extent of pancreatic fibrosis and the postoperative exocrine and endocrine pancreatic function. Fifty-five patients who were treated for pancreatic and periampullary carcinoma and 19 patients with chronic pancreatitis were evaluated. Exocrine pancreatic function was evaluated by fecal elastase-1 test, while endocrine pancreatic function was assessed by plasma glucose level. The extent of fibrosis, duct dilation and endocrine tissue loss was examined histopathologically. A strong correlation was found between pancreatic fibrosis and elastase-1 level less than 100 microg/g (p < 0.0001), reflecting severe exocrine pancreatic insufficiency. A strong correlation was found between pancreatic fibrosis and endocrine tissue loss (p < 0.0001). Neither pancreatic fibrosis nor endocrine tissue loss were correlated with the development of postoperative diabetes mellitus. Duct dilation alone was neither correlated with exocrine nor with endocrine function loss. The majority of patients develop severe exocrine pancreatic insufficiency after pancreatoduodenectomy. The extent of exocrine pancreatic insufficiency is strongly correlated with preoperative fibrosis. The loss of endocrine tissue does not correlate with postoperative diabetes mellitus. Preoperative dilation of the pancreatic duct per se does not predict exocrine or endocrine pancreatic insufficiency postoperatively. Copyright 2008 S. Karger AG, Basel.

High incidence of coagualopathy in phase II studies of recombinant tumor necrosis factor in advanced pancreatic and gastric cancers.

PubMed

Muggia, F M; Brown, T D; Goodman, P J; Macdonald, J S; Hersh, E M; Fleming, T R; Leichman, L

1992-06-01

This multi-center trial was carried out to assess the therapeutic potential of recombinant tumor necrosis factor (rTNF) as the first form of systemic therapy for advanced carcinomas of gastric and pancreatic origin. To be eligible patients were required to have no overt sign of coagulopathy and hepatic function studies with enzymes less than two times beyond the normal range. Twenty nine patients with gastric cancer and 26 with pancreatic cancer were entered from various institutions in the Southwest Oncology Group with 27 and 22, respectively, meeting eligibility criteria. Drug treatment consisted of rTNF (Genentech) given at a dose of 150 micrograms intravenously for five consecutive days every 3 weeks; 50% dose reduction was made for acute intolerance such as hypotension or severe fever and chills. Although eight patients with gastric cancer and five patients with pancreatic cancer received four or more courses of treatment, no objective antitumor responses were recorded. As in other trials common toxicities of rTNF included nausea and vomiting, chills and fever, hypotension, headache, myalgias, fatigue and malaise. However, in this trial, other toxicities became prominent: four episodes of symptomatic disseminated intravascular clotting occurred among patients with pancreatic cancer. Eleven with this disease and five with gastric cancer manifested laboratory findings of abnormal amounts of fibrin split products, and/or hypofibrinogenemia, and/or thrombocytopenia after treatment began. Other laboratory abnormalities that were commonly encountered included hyperglycemia, hypertriglyceridemia, anemia, neutropenia and an elevation in liver enzymes. We conclude that rTNF does not demonstrate antitumor efficacy against adenocarcinomas of the stomach and the pancreas.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatocellular carcinoma with neuroendocrine differentiation: a case report.

PubMed

Lu, Jiajie G; Farukhi, M Aabid; Mayeda, Donna; French, Samuel W

2017-10-01

Hepatocellular carcinoma with neuroendocrine differentiation, where tumor cells stain for both hepatocellular and neuroendocrine markers, is extremely rare. We report a case of a 65-year-old man who presented with a 14-cm rapidly growing mass in the right lobe of his liver with local extension into the gallbladder and portal vein. Serum AFP was 4625ng/mL. Liver biopsy showed a poorly differentiated neoplasm with cells showing nuclear pleomorphism, high nuclear/cytoplasmic ratio, and numerous mitoses. The tumor cells stain for AFP, glutamine synthase, arginase, and glypican-3. The same tumor regions also stain positively for synaptophysin, chromogranin, and CD56. Given this histological pattern, this tumor was ultimately diagnosed as hepatocellular carcinoma with neuroendocrine differentiation. Published by Elsevier Inc.

Early Detection of Sporadic Pancreatic Cancer

PubMed Central

Kenner, Barbara J.; Chari, Suresh T.; Cleeter, Deborah F.; Go, Vay Liang W.

2015-01-01

Abstract Innovation leading to significant advances in research and subsequent translation to clinical practice is urgently necessary in early detection of sporadic pancreatic cancer. Addressing this need, the Early Detection of Sporadic Pancreatic Cancer Summit Conference was conducted by Kenner Family Research Fund in conjunction with the 2014 American Pancreatic Association and Japan Pancreas Society Meeting. International interdisciplinary scientific representatives engaged in strategic facilitated conversations based on distinct areas of inquiry: Case for Early Detection: Definitions, Detection, Survival, and Challenges; Biomarkers for Early Detection; Imaging; and Collaborative Studies. Ideas generated from the summit have led to the development of a Strategic Map for Innovation built upon 3 components: formation of an international collaborative effort, design of an actionable strategic plan, and implementation of operational standards, research priorities, and first-phase initiatives. Through invested and committed efforts of leading researchers and institutions, philanthropic partners, government agencies, and supportive business entities, this endeavor will change the future of the field and consequently the survival rate of those diagnosed with pancreatic cancer. PMID:25938853

Pancreatic cancer surgery: past, present, and future

PubMed Central

Poruk, Katherine E.

2015-01-01

The history of pancreatic cancer surgery, though fraught with failure and setbacks, is punctuated by periods of incremental progress dependent upon the state of the art and the mettle of the surgeons daring enough to attempt it. Surgical anesthesia and the aseptic techniques developed during the latter half of the 19th century were instrumental in establishing a viable setting for pancreatic surgery to develop. Together, they allowed for bolder interventions and improved survival through the post-operative period. Surgical management began with palliative procedures to address biliary obstruction in advanced disease. By the turn of the century, surgical pioneers such as Alessandro Codivilla and Walther Kausch were demonstrating the technical feasibility of pancreatic head resections and applying principles learned from palliation to perform complicated anatomical reconstructions. Allen O. Whipple, the namesake of the pancreaticoduodenectomy (PD), was the first to take a systematic approach to refining the procedure. Perhaps his greatest contribution was sparking a renewed interest in the surgical management of periampullary cancers and engendering a community of surgeons who advanced the field through their collective efforts. Though the work of Whipple and his contemporaries legitimized PD as an accepted surgical option, it was the establishment of high-volume centers of excellence and a multidisciplinary approach in the later decades of the 20th century that made it a viable surgical option. Today, pancreatic surgeons are experimenting with minimally invasive surgical techniques, expanding indications for resection, and investigating new methods for screening and early detection. In the future, the effective management of pancreatic cancer will depend upon our ability to reliably detect the earliest cancers and precursor lesions to allow for truly curative resections. PMID:26361403

Pancreatic cancer surgery: past, present, and future.

PubMed

Griffin, James F; Poruk, Katherine E; Wolfgang, Christopher L

2015-08-01

The history of pancreatic cancer surgery, though fraught with failure and setbacks, is punctuated by periods of incremental progress dependent upon the state of the art and the mettle of the surgeons daring enough to attempt it. Surgical anesthesia and the aseptic techniques developed during the latter half of the 19(th) century were instrumental in establishing a viable setting for pancreatic surgery to develop. Together, they allowed for bolder interventions and improved survival through the post-operative period. Surgical management began with palliative procedures to address biliary obstruction in advanced disease. By the turn of the century, surgical pioneers such as Alessandro Codivilla and Walther Kausch were demonstrating the technical feasibility of pancreatic head resections and applying principles learned from palliation to perform complicated anatomical reconstructions. Allen O. Whipple, the namesake of the pancreaticoduodenectomy (PD), was the first to take a systematic approach to refining the procedure. Perhaps his greatest contribution was sparking a renewed interest in the surgical management of periampullary cancers and engendering a community of surgeons who advanced the field through their collective efforts. Though the work of Whipple and his contemporaries legitimized PD as an accepted surgical option, it was the establishment of high-volume centers of excellence and a multidisciplinary approach in the later decades of the 20(th) century that made it a viable surgical option. Today, pancreatic surgeons are experimenting with minimally invasive surgical techniques, expanding indications for resection, and investigating new methods for screening and early detection. In the future, the effective management of pancreatic cancer will depend upon our ability to reliably detect the earliest cancers and precursor lesions to allow for truly curative resections.

[Mediastinal Pancreatic Pseudocyst with Pancreatic Pleural Effusion].

PubMed

Sasajima, Motoko; Kawai, Hideki; Suzuki, Yohei; Saito, Yoshitaro; Eto, Takeshi

2017-06-01

A 72-year-old man with chronic alcohol related pancreatitis was admitted for dyspnea and pain at the upper body. Chest X-ray showed right massive pleural effusion. Chest and abdominal contrast enhanced thin slice computed tomography revealed the route from the pancreatic head reaching the right thoracic cavity via the esophagus hiatus and the communication between the cystic lesion and main pancreatic duct. We drained the pleural effusion that showed abnormally high amylase activity. We diagnosed his illness as mediastinal pancreatic pseudocyst with pancreatic pleural effusion. Endoscopic Nasopancreatic Drainage catheter was placed in the main pancreatic duct, and the pleural effusion disappeared.

A novel monoclonal antibody targeting carboxymethyllysine, an advanced glycation end product in atherosclerosis and pancreatic cancer.

PubMed

Wendel, Ulrika; Persson, Nina; Risinger, Christian; Bengtsson, Eva; Nodin, Björn; Danielsson, Lena; Welinder, Charlotte; Nordin Fredrikson, Gunilla; Jansson, Bo; Blixt, Ola

2018-01-01

Advanced glycation end products are formed by non-enzymatic reactions between proteins and carbohydrates, causing irreversible lysine and arginine alterations that severely affect protein structure and function. The resulting modifications induce inflammation by binding to scavenger receptors. An increase in advanced glycation end products is observed in a number of diseases e.g. atherosclerosis and cancer. Since advanced glycation end products also are present in healthy individuals, their detection and quantification are of great importance for usage as potential biomarkers. Current methods for advanced glycation end product detection are though limited and solely measure total glycation. This study describes a new epitope-mapped single chain variable fragment, D1-B2, against carboxymethyllysine, produced from a phage library that was constructed from mouse immunizations. The phage library was selected against advanced glycation end product targets using a phage display platform. Characterization of its binding pattern was performed using large synthetic glycated peptide and protein libraries displayed on microarray slides. D1-B2 showed a preference for an aspartic acid, three positions N-terminally from a carboxymethyllysine residue and also bound to a broad collection of glycated proteins. Positive immunohistochemical staining of mouse atherosclerotic plaques and of a tissue microarray of human pancreatic tumors confirmed the usability of the new scFv for advanced glycation end product detection in tissues. This study demonstrates a promising methodology for high-throughput generation of epitope-mapped monoclonal antibodies against AGE.

A novel monoclonal antibody targeting carboxymethyllysine, an advanced glycation end product in atherosclerosis and pancreatic cancer

PubMed Central

Wendel, Ulrika; Persson, Nina; Risinger, Christian; Bengtsson, Eva; Nodin, Björn; Danielsson, Lena; Welinder, Charlotte; Nordin Fredrikson, Gunilla

2018-01-01

Advanced glycation end products are formed by non-enzymatic reactions between proteins and carbohydrates, causing irreversible lysine and arginine alterations that severely affect protein structure and function. The resulting modifications induce inflammation by binding to scavenger receptors. An increase in advanced glycation end products is observed in a number of diseases e.g. atherosclerosis and cancer. Since advanced glycation end products also are present in healthy individuals, their detection and quantification are of great importance for usage as potential biomarkers. Current methods for advanced glycation end product detection are though limited and solely measure total glycation. This study describes a new epitope-mapped single chain variable fragment, D1-B2, against carboxymethyllysine, produced from a phage library that was constructed from mouse immunizations. The phage library was selected against advanced glycation end product targets using a phage display platform. Characterization of its binding pattern was performed using large synthetic glycated peptide and protein libraries displayed on microarray slides. D1-B2 showed a preference for an aspartic acid, three positions N-terminally from a carboxymethyllysine residue and also bound to a broad collection of glycated proteins. Positive immunohistochemical staining of mouse atherosclerotic plaques and of a tissue microarray of human pancreatic tumors confirmed the usability of the new scFv for advanced glycation end product detection in tissues. This study demonstrates a promising methodology for high-throughput generation of epitope-mapped monoclonal antibodies against AGE. PMID:29420566

The role of intraoperative radiation therapy in patients with pancreatic cancer.

PubMed

Palta, Manisha; Willett, Christopher; Czito, Brian

2014-04-01

Intraoperative radiation therapy (IORT) techniques allow for the delivery of high doses of radiation therapy while excluding part or all of the nearby dose-limiting sensitive structures. Therefore, the effective radiation dose is increased and local tumor control potentially improved. This is pertinent in the case of pancreatic cancer because local failure rates are as high as 50%-80% in patients with resected and locally advanced disease. Available data in patients receiving IORT after pancreaticoduodenectomy reveal an improvement in local control, though overall survival benefit is unclear. Series of patients with locally advanced pancreatic cancer also suggest pain relief, and in select studies, improved survival associated with the inclusion of IORT. At present, no phase III data clearly supports the use of IORT in the management of pancreatic cancer. © 2013 Published by Elsevier Inc.

CFTR: A new horizon in the pathomechanism and treatment of pancreatitis

PubMed Central

Hegyi, Péter; Wilschanski, Michael; Muallem, Shmuel; Lukacs, Gergely; Sahin-Tóth, Miklós; Uc, Aliye; Gray, Michael A.; Rakonczay, Zoltán; Maléth, József

2017-01-01

Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel that conducts chloride and bicarbonate ions across epithelial cell membranes. Mutations in the CFTR gene diminish the ion channel function and lead to impaired epithelial fluid transport in multiple organs such as the lung and the pancreas resulting in cystic fibrosis. Heterozygous carriers of CFTR mutations do not develop cystic fibrosis but exhibit increased risk for pancreatitis and associated pancreatic damage characterized by elevated mucus levels, fibrosis and cyst formation. Importantly, recent studies demonstrated that pancreatitis causing insults, such as alcohol, smoking or bile acids strongly inhibit CFTR function. Furthermore, human studies showed reduced levels of CFTR expression and function in all forms of pancreatitis. These findings indicate that impairment of CFTR is critical in the development of pancreatitis; therefore, correcting CFTR function could be the first specific therapy in pancreatitis. In this review, we summarize recent advances in the field and discuss new possibilities for the treatment of pancreatitis. PMID:26856995

Primary hepatic neuroendocrine tumor after 4 years tumor-free follow-up.

PubMed

Lambrescu, Ioana Maria; Martin, Sorina; Cima, Luminita; Herlea, Vlad; Badiu, Corin; Fica, Simona

2015-06-01

A primary hepatic neuroendocrine tumour (PHNET) is a very rare disease. The liver represents the preferential site for neuroendocrine tumors' metastases. A 45-year old Caucasian female who presented with nausea, vomiting, diarrhea, accompanied by diffuse abdominal pain was found to have on contrast-enhanced computer tomography an encapsulated, partially cystic liver mass. The patient underwent an uneventful left atypical hepatic resection. Histopatological and immunohistochemical examination revealed a slowly growing (G1) hepatic neuroendocrine tumour. Post surgery, the specific neuroendocrine markers (serum Chromogranin A and 24h urinary 5 hydroxy-indolacetic acid) were within normal range. Further functional imaging investigations were performed. No other lesions were found making probable the diagnosis of PHNET. The patient is presently after 4 years of follow-up with no local recurrence or distant metastases. The diagnosis of PHNET is a medical challenge that requires a thorough long term follow-up in order to exclude an occult primary neuroendocrine tumour.

Clinical benefit of systemic treatment in patients with advanced pancreatic and gastrointestinal neuroendocrine tumours according to ESMO-MCBS and ASCO framework.

PubMed

de Hosson, L D; van Veenendaal, L M; Schuller, Y; Zandee, W T; de Herder, W W; Tesselaar, M E T; Klümpen, H J; Walenkamp, A M E

2017-12-01

Assessment of clinical benefit of systemic treatments of rare diseases including gastroenteropancreatic neuroendocrine tumours (GEP-NET) is challenging. Recently several tools have been developed to grade the clinical benefit of cancer drugs. The European Society for Medical Oncology (ESMO) has developed the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS). The American Society of Clinical Oncology (ASCO) has developed and revised the ASCO framework consisting of the Net Health Benefit (NHB) score juxtaposed against the costs of the treatment. In this review, we graded systemic treatments for GEP-NET patients with both frameworks. The electronic databases (PubMed and EMBASE) were searched for papers reporting comparative trials, conducted in adult GEP-NET patients in the English language. Papers were assessed according to the ESMO-MCBS and the NHB part of the ASCO revised Framework (NHB-ASCO-F) by four independent assessors, and discrepancies were discussed. The search yielded 32 trials of which 6 were eligible for grading with the ESMO-MCBS resulting in scores of 2 or 3. Eight trials were eligible for grading with the NHB-ASCO-F, resulting in scores between 37.6 and 57.4. Trials that were not primary assessable by the tools were analysed separately. Consensus between assessors was reached in 68% of trials with the ESMO-MCBS and in 23% of trials with the NHB-ASCO-F. The currently used systemic treatments for GEP-NET patients had low scores according to the NHB-ASCO-F and none could be graded as meaningful clinical beneficial according to the ESMO-MCBS. Despite the low incidence, the heterogeneous patient population and relatively long natural course of NET, future studies on new treatment modalities should aim for high clinical benefit outcomes. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

68Ga-DOTATATE PET/CT in Primary Hepatic Neuroendocrine Tumor.

PubMed

Gorla, Arun Kumar Reddy; Basher, Rajender Kumar; Kaman, Lileshwar; Bal, Amanjit; Bhattacharya, Anish; Mittal, Bhagwant Rai

2017-02-01

Primary neuroendocrine tumors of the liver are a diagnostic challenge. We present a rare case of primary hepatic neuroendocrine tumor in which Ga-DOTATATE PET/CT imaging played an important role in the diagnosis and follow-up.

Guadecitabine and Durvalumab in Treating Patients With Advanced Liver, Pancreatic, Bile Duct, or Gallbladder Cancer

ClinicalTrials.gov

2018-04-27

Extrahepatic Bile Duct Adenocarcinoma, Biliary Type; Gallbladder Adenocarcinoma, Biliary Type; Metastatic Pancreatic Adenocarcinoma; Recurrent Cholangiocarcinoma; Recurrent Gallbladder Carcinoma; Recurrent Hepatocellular Carcinoma; Recurrent Intrahepatic Cholangiocarcinoma; Recurrent Pancreatic Carcinoma; Stage III Gallbladder Cancer AJCC V7; Stage III Hepatocellular Carcinoma AJCC v7; Stage III Intrahepatic Cholangiocarcinoma AJCC v7; Stage III Pancreatic Cancer AJCC v6 and v7; Stage IIIA Gallbladder Cancer AJCC v7; Stage IIIA Hepatocellular Carcinoma AJCC v7; Stage IIIB Gallbladder Cancer AJCC v7; Stage IIIB Hepatocellular Carcinoma AJCC v7; Stage IIIC Hepatocellular Carcinoma AJCC v7; Stage IV Gallbladder Cancer AJCC v7; Stage IV Hepatocellular Carcinoma AJCC v7; Stage IV Pancreatic Cancer AJCC v6 and v7; Stage IVA Gallbladder Cancer AJCC v7; Stage IVA Hepatocellular Carcinoma AJCC v7; Stage IVA Intrahepatic Cholangiocarcinoma AJCC v7; Stage IVB Gallbladder Cancer AJCC v7; Stage IVB Hepatocellular Carcinoma AJCC v7; Stage IVB Intrahepatic Cholangiocarcinoma AJCC v7; Unresectable Gallbladder Carcinoma; Unresectable Pancreatic Carcinoma

Management of pancreatic cancer in the elderly.

PubMed

Higuera, Oliver; Ghanem, Ismael; Nasimi, Rula; Prieto, Isabel; Koren, Laura; Feliu, Jaime

2016-01-14

Currently, pancreatic adenocarcinoma mainly occurs after 60 years of age, and its prognosis remains poor despite modest improvements in recent decades. The aging of the population will result in a rise in the incidence of pancreatic adenocarcinoma within the next years. Thus, the management of pancreatic cancer in the elderly population is gaining increasing relevance. Older cancer patients represent a heterogeneous group with different biological, functional and psychosocial characteristics that can modify the usual management of this disease, including pharmacokinetic and pharmacodynamic changes, polypharmacy, performance status, comorbidities and organ dysfunction. However, the biological age, not the chronological age, of the patient should be the limiting factor in determining the most appropriate treatment for these patients. Unfortunately, despite the increased incidence of this pathology in older patients, there is an underrepresentation of these patients in clinical trials, and the management of older patients is thus determined by extrapolation from the results of studies performed in younger patients. In this review, the special characteristics of the elderly, the multidisciplinary management of localized and advanced ductal adenocarcinoma of the pancreas and the most recent advances in the management of this condition will be discussed, focusing on surgery, chemotherapy, radiation and palliative care.

Management of Inflammatory Fluid Collections and Walled-Off Pancreatic Necrosis.

PubMed

Shah, Apeksha; Denicola, Richard; Edirisuriya, Cynthia; Siddiqui, Ali A

2017-12-01

Pancreatic fluid collections are a frequent complication of acute pancreatitis. The revised Atlanta criterion classifies chronic fluid collections into pseudocysts and walled-off pancreatic necrosis (WON). Symptomatic PFCs require drainage options that include surgical, percutaneous, or endoscopic approaches. With the advent of newer and more advanced endoscopic tools and expertise, minimally invasive endoscopic drainage has now become the preferred approach. An endoscopic ultrasonography (EUS)-guided approach for pancreatic fluid collection drainage is now the preferred endoscopic approach. Both plastic stents and metal stents are efficacious and safe; however, metal stents may offer an advantage, especially in infected pseudocysts and in WON. Direct endoscopic necrosectomy is often required in WON. Lumen apposing metal stents allow for direct endoscopic necrosectomy and debridement through the stent lumen and are now preferred in these patients. Endoscopic retrograde cholangiopancreatography with pancreatic duct exploration should be performed concurrent to PFC drainage in patients with suspected PD disruption. PD disruption is associated with an increased severity of pancreatitis, an increased risk of recurrent attacks of pancreatitis and long-term complications, and a decreased rate of PFC resolution after drainage. Ideally, pancreatic ductal disruption should be bridged with endoscopic stenting.

Out-FOXing Pancreatic Cancer | Center for Cancer Research

Cancer.gov

Pancreatic cancer is one of the most lethal cancer types worldwide with increasing incidence and mortality rates in the United States. Consequently, it is projected to become the second leading cause of cancer death by 2020. Poor patient outcomes are due to a combination of diagnosis at an advanced stage and a lack of effective treatments. However, a better understanding of the molecular pathways at work in pancreatic cancers may lead to the identification of novel therapeutic targets.

Nutritional status of patients with locally advanced pancreatic cancer: a pilot study.

PubMed

Ferrucci, Leah M; Bell, Diana; Thornton, Jennifer; Black, Glenda; McCorkle, Ruth; Heimburger, Douglas C; Saif, Muhammad Wasif

2011-11-01

Nutritional status may influence quality of life and prognosis among pancreatic cancer patients, yet few studies describe measures of nutritional status during treatment. We evaluated the nutritional status of locally advanced pancreatic cancer (LAPC) patients undergoing chemoradiotherapy who received baseline nutritional assessment and counseling. Fourteen newly diagnosed LAPC patients enrolled in phase I/II trials of capecitabine with concomitant radiotherapy were assessed for baseline clinical nutrition measures (body mass index, albumin, weight loss, total energy, and protein intake). Participants completed the Anorexia/Cachexia Subscale (A/CS) questionnaire at baseline and during the 6 weeks of treatment. We evaluated associations between baseline characteristics and subsequent A/CS scores with linear regression and changes in A/CS were assessed with the paired t test. We observed a statistically significant increase in mean A/CS between baseline [24.9, standard deviation (SD) = 9.7] and end of treatment (29.9, SD = 6.2). Controlling for baseline A/CS score, only weight loss greater than 5% of body weight over 1 month was associated with A/CS scores at 6 weeks (β = 10.558, standard error = 3.307, p value = 0.009) and mean A/CS scores during the last 3 weeks of treatment (β = 12.739, standard error = 2.251, p value = 0.001). After 6 weeks of chemoradiotherapy, LAPC patients reported a statistically significant improvement in appetite and weight concerns. Increases in AC/S scores were associated with higher baseline A/CS scores and weight loss of 5% or more during 1 month. Further research is needed to determine the impact of nutritional support during treatment, as improvements in this domain may impact LAPC patients' overall quality of life.

[High dosage therapy with stem cell transplantation in neuroendocrine carcinoma].

PubMed

Buxhofer, V; Ruckser, R; Kier, P; Habertheuer, K H; Zelenka, P; Tatzreiter, G; Dorner, S; Vedovelli, H; Sebesta, C; Hinterberger, W

2000-01-01

Neuroendocrine carcinoma and small-cell lung cancer (SCLC) are highly responsive to chemo- and radiotherapy. Nevertheless, most patients (pts.) experience relapse. At the 2nd department of medicine in the Donauspital, 4 pts. with neuroendocrine carcinomas of different primary sites underwent high-dose chemotherapy with autologous stem-cell transplantation (ASTx). Pt. 1 suffered from neuroendocrine lung cancer, pt. 2 from a small-cell carcinoma of the pancreas. Pt. 3 had a metastatic small-cell abdominal bulky tumor and pt. 4 presented with neuroendocrine carcinoma of the prostate. After 4-6 cycles induction chemotherapy pts. were consolidated with 1 cycle of HDCht and ASTx. Prior to HDCht pt. 1 and pt. 2 were in complete remission (CR) and pt. 3 and pt. 4 in partial remission. Pt. 3 converted in CR after HDCht. He is still in CR with a disease-free survival of 23 month after ASTx and 30 month after diagnosis. Pt. 1, 2 and 4 died from relapse 10, 16 and 5 month after ASTx and 16, 22 and 9 month after diagnosis. Pts. with neuroendocrine carcinomas might be suitable candidates for HDCht and ASTx.

Immunohistochemical characterization of neuroendocrine differentiation of canine anal sac glandular tumours.

PubMed

Suzuki, K; Morita, R; Hojo, Y; Nomura, K; Shibutani, M; Mitsumori, K

2013-01-01

Histological features and expression of neuroendocrine markers were examined in 69 samples of canine anal sac glandular carcinomas (ASGCs). The tumours were classified into solid, rosette and tubular types and mixtures of these types. Tumour-associated death in dogs with solid tumours and mixed tumours with solid components was higher than in dogs with rosette and tubular type tumours. Chromogranin A immunoreactivity was observed in 28 of 69 samples (40.6%) irrespective of histological type and was localized to the marginal areas of the tumour nest and the basal areas of the tubular and rosette structures. Neuron-specific enolase immunoreactivity in neoplastic epithelial cells was observed in 32 cases (46.4%) and was less frequently observed in the tubular type (14.3%). Synaptophysin expression was present in 15.9% of cases and was least frequent in the tubular type. Twenty-one of the 69 samples expressed more than two neuroendocrine markers and were classified as carcinomas with neuroendocrine differentiation. There was no relationship between neuroendocrine differentiation and clinical outcome. These results suggest that some ASGCs have neuroendocrine differentiation regardless of histological pattern, but clinical outcome is more related to the histological pattern than to neuroendocrine differentiation. Copyright © 2013 Elsevier Ltd. All rights reserved.

The serum miR-21 level serves as a predictor for the chemosensitivity of advanced pancreatic cancer, and miR-21 expression confers chemoresistance by targeting FasL.

PubMed

Wang, Peng; Zhuang, Liping; Zhang, Juan; Fan, Jie; Luo, Jianmin; Chen, Hao; Wang, Kun; Liu, Luming; Chen, Zhen; Meng, Zhiqiang

2013-06-01

miR-21 expression in cancer tissue has been reported to be associated with the clinical outcome and activity of gemcitabine in pancreatic cancer. However, resection is possible in only a minority of patients due to the advanced stages often present at the time of diagnosis, and safely obtaining sufficient quantities of pancreatic tumor tissue for molecular analysis is difficult at the unresectable stages. In this study, we investigated whether the serum level of miR-21 could be used as a predictor of chemosensitivity. We tested the levels of serum miR-21 in a cohort of 177 cases of advanced pancreatic cancer who received gemcitabine-based palliative chemotherapy. We found that a high level of miR-21 in the serum was significantly correlated with a shortened time-to-progression (TTP) and a lower overall survival (OS). The serum miR-21 level was an independent prognostic factor for both the TTP and the OS (HR 1.920; 95% CI, 1.274-2.903, p = 0.002 for TTP and HR 1.705; 95% CI, 1.147-2.535, p = 0.008 for OS). The results from a functional study showed that gemcitabine exposure down-regulated miR-21 expression and up-regulated FasL expression. The increased FasL expression following gemcitabine treatment induced cancer cell apoptosis, whereas the ectopic expression of miR-21 partially protected the cancer cells from gemcitabine-induced apoptosis. Additionally, we confirmed that FasL was a direct target of miR-21. Therefore, the serum level of miR-21 may serve as a predictor of chemosensitivity in advanced pancreatic cancer. Additionally, we identified a new mechanism of chemoresistance mediated by the effects of miR-21 on the FasL/Fas pathway. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Budget impact of somatostatin analogs as treatment for metastatic gastroenteropancreatic neuroendocrine tumors in US hospitals.

PubMed

Ortendahl, Jesse D; Pulgar, Sonia J; Mirakhur, Beloo; Cox, David; Bentley, Tanya Gk; Phan, Alexandria T

2017-01-01

With the introduction of new therapies, hospitals have to plan spending limited resources in a cost-effective manner. To assist in identifying the optimal treatment for patients with locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors, budget impact modeling was used to estimate the financial implications of adoption and diffusion of somatostatin analogs (SSAs). A hypothetical cohort of 500 gastroenteropancreatic neuroendocrine tumor patients was assessed in an economic model, with the proportion with metastatic disease treated with an SSA estimated using published data. Drug acquisition, preparation, and administration costs were based on national pricing databases and published literature. Octreotide dosing was based on published estimates of real-world data, whereas for lanreotide, real-world dosing was unavailable and we therefore used the highest indicated dosing. Alternative scenarios reflecting the proportion of patients receiving lanreotide or octreotide were considered to estimate the incremental budget impact to the hospital. In the base case, 313 of the initial 500 gastroenteropancreatic neuroendocrine tumor patients were treated with an SSA. The model-predicted per-patient cost was US$83,473 for lanreotide and US$89,673 for octreotide. With a hypothetical increase in lanreotide utilization from 5% to 30% of this population, the annual model-projected hospital costs decreased by US$488,615. When varying the inputs in one-way sensitivity analyses, the results were most sensitive to changes in dosing assumptions. Results suggest that factors beyond drug acquisition cost can influence the budget impact to a hospital. When considering preparation and administration time, and real-world dosing, use of lanreotide has the potential to reduce health care expenditures associated with metastatic gastroenteropancreatic neuroendocrine tumor treatments.

Circulating tumor DNA as a liquid biopsy target for detection of pancreatic cancer.

PubMed

Takai, Erina; Yachida, Shinichi

2016-10-14

Most pancreatic cancer patients present with advanced metastatic disease, resulting in extremely poor 5-year survival, mainly because of the lack of a reliable modality for early detection and limited therapeutic options for advanced disease. Therefore, there is a need for minimally-invasive diagnostic tools for detecting pancreatic cancer at an early stage, when curative surgery and also novel therapeutic approaches including precision medicine may be feasible. The "liquid biopsy" addresses these unmet clinical needs based on the concept that simple peripheral blood sampling and detection of circulating tumor DNA (ctDNA) could provide diagnostic information. In this review, we provide an overview of the current status of blood-based tests for diagnosis of pancreatic cancer and the potential utility of ctDNA for precision medicine. We also discuss challenges that remain to be addressed in developing practical ctDNA-based liquid biopsy approaches for early diagnosis of pancreatic cancer.

Depletion of neuroendocrine cells in rectal biopsy specimens from HIV positive patients.

PubMed Central

McCullough, J. B.; Batman, P. A.; Miller, A. R.; Sedgwick, P. M.; Griffin, G. E.

1992-01-01

AIMS: To compare the density of neuroendocrine cells in rectal biopsy specimens from human immunodeficiency virus (HIV) infected individuals with that of a control group. METHODS: Neuroendocrine cells in rectal biopsies were identified using an immunohistochemical stain for chromogranin and subsequently quantified using a method of linear intercept. RESULTS: Neuroendocrine cells were found to be significantly decreased in the HIV positive group. CONCLUSIONS: Loss of neuroendocrine cells may contribute to apoptotic bodies seen in this condition. This could be related to infection of these cells with HIV and could contribute to diarrhoeal disease in HIV infection. Images PMID:1624601

Validation of full-field optical coherence tomography in distinguishing malignant and benign tissue in resected pancreatic cancer specimens

PubMed Central

Fariña-Sarasqueta, Arantza; de Haan, Lorraine M.; Eggermont, Jeroen; Bonsing, Bert A.; Morreau, Hans; Lelieveldt, Boudewijn P. F.; van de Velde, Cornelis J. H.; Vahrmeijer, Alexander L.; Dijkstra, Jouke

2017-01-01

Background Pancreatic cancer is the fourth leading cause of cancer-related mortality in the United States. The minority of patients can undergo curative-intended surgical therapy due to progressive disease stage at time of diagnosis. Nonetheless, tumor involvement of surgical margins is seen in up to 70% of resections, being a strong negative prognostic factor. Real-time intraoperative imaging modalities may aid surgeons to obtain tumor-free resection margins. Full-field optical coherence tomography (FF-OCT) is a promising diagnostic tool using high-resolution white-light interference microscopy without tissue processing. Therefore, we composed an atlas of FF-OCT images of malignant and benign pancreatic tissue, and investigated the accuracy with which the pathologists could distinguish these. Materials and methods One hundred FF-OCT images were collected from specimens of 29 patients who underwent pancreatic resection for various indications between 2014 and 2016. One experienced gastrointestinal pathologist and one pathologist in training scored independently the FF-OCT images as malignant or benign blinded to the final pathology conclusion. Results were compared to those obtained with standard hematoxylin and eosin (H&E) slides. Results Overall, combined test characteristics of both pathologists showed a sensitivity of 72%, specificity of 74%, positive predictive value of 69%, negative predictive value of 79% and an overall accuracy of 73%. In the subset of pancreatic ductal adenocarcinoma patients, 97% of the FF-OCT images (n = 35) were interpreted as tumor by at least one pathologist. Moreover, normal pancreatic tissue was recognised in all cases by at least one pathologist. However, atrophy and fibrosis, serous cystadenoma and neuroendocrine tumors were more often wrongly scored, in 63%, 100% and 25% respectively. Conclusion FF-OCT could distinguish normal pancreatic tissue from pathologic pancreatic tissue in both processed as non-processed specimens using

Targeting Epidermal Growth Factor Receptor-Related Signaling Pathways in Pancreatic Cancer.

PubMed

Philip, Philip A; Lutz, Manfred P

2015-10-01

Pancreatic cancer is aggressive, chemoresistant, and characterized by complex and poorly understood molecular biology. The epidermal growth factor receptor (EGFR) pathway is frequently activated in pancreatic cancer; therefore, it is a rational target for new treatments. However, the EGFR tyrosine kinase inhibitor erlotinib is currently the only targeted therapy to demonstrate a very modest survival benefit when added to gemcitabine in the treatment of patients with advanced pancreatic cancer. There is no molecular biomarker to predict the outcome of erlotinib treatment, although rash may be predictive of improved survival; EGFR expression does not predict the biologic activity of anti-EGFR drugs in pancreatic cancer, and no EGFR mutations are identified as enabling the selection of patients likely to benefit from treatment. Here, we review clinical studies of EGFR-targeted therapies in combination with conventional cytotoxic regimens or multitargeted strategies in advanced pancreatic cancer, as well as research directed at molecules downstream of EGFR as alternatives or adjuncts to receptor targeting. Limitations of preclinical models, patient selection, and trial design, as well as the complex mechanisms underlying resistance to EGFR-targeted agents, are discussed. Future clinical trials must incorporate translational research end points to aid patient selection and circumvent resistance to EGFR inhibitors.

Imaging of Chemokine Receptor 4 Expression in Neuroendocrine Tumors - a Triple Tracer Comparative Approach.

PubMed

Werner, Rudolf A; Weich, Alexander; Higuchi, Takahiro; Schmid, Jan S; Schirbel, Andreas; Lassmann, Michael; Wild, Vanessa; Rudelius, Martina; Kudlich, Theodor; Herrmann, Ken; Scheurlen, Michael; Buck, Andreas K; Kropf, Saskia; Wester, Hans-Jürgen; Lapa, Constantin

2017-01-01

C-X-C motif chemokine receptor 4 (CXCR4) and somatostatin receptors (SSTR) are overexpressed in gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). In this study, we aimed to elucidate the feasibility of non-invasive CXCR4 positron emission tomography/computed tomography (PET/CT) imaging in GEP-NET patients using [ 68 Ga]Pentixafor in comparison to 68 Ga-DOTA-D-Phe-Tyr3-octreotide ([ 68 Ga]DOTATOC) and 18 F-fluorodeoxyglucose ([ 18 F]FDG). Twelve patients with histologically proven GEP-NET (3xG1, 4xG2, 5xG3) underwent [ 68 Ga]DOTATOC, [ 18 F]FDG, and [ 68 Ga]Pentixafor PET/CT for staging and planning of the therapeutic management. Scans were analyzed on a patient as well as on a lesion basis and compared to immunohistochemical staining patterns of CXCR4 and somatostatin receptors SSTR2a and SSTR5. [ 68 Ga]Pentixafor visualized tumor lesions in 6/12 subjects, whereas [ 18 F]FDG revealed sites of disease in 10/12 and [ 68 Ga]DOTATOC in 11/12 patients, respectively. Regarding sensitivity, SSTR-directed PET was the superior imaging modality in all G1 and G2 NET. CXCR4-directed PET was negative in all G1 NET. In contrast, 50% of G2 and 80% of G3 patients exhibited [ 68 Ga]Pentixafor-positive tumor lesions. Whereas CXCR4 seems to play only a limited role in detecting well-differentiated NET, increasing receptor expression could be non-invasively observed with increasing tumor grade. Thus, [ 68 Ga]Pentixafor PET/CT might serve as non-invasive read-out for evaluating the possibility of CXCR4-directed endoradiotherapy in advanced dedifferentiated SSTR-negative tumors.

Prkar1a gene knockout in the pancreas leads to neuroendocrine tumorigenesis.

PubMed

Saloustros, Emmanouil; Salpea, Paraskevi; Starost, Matthew; Liu, Sissi; Faucz, Fabio R; London, Edra; Szarek, Eva; Song, Woo-Jin; Hussain, Mehboob; Stratakis, Constantine A

2017-01-01

Carney complex (CNC) is a rare disease associated with multiple neoplasias, including a predisposition to pancreatic tumors; it is caused most frequently by the inactivation of the PRKAR1A gene, a regulator of the cyclic AMP (cAMP)-dependent kinase (PKA). The method used was to create null alleles of prkar1a in mouse cells expressing pdx1 (Δ-Prkar1a). We found that these mice developed endocrine or mixed endocrine/acinar cell carcinomas with 100% penetrance by the age of 4-5 months. Malignant behavior of the tumors was seen as evidenced by stromal invasion and metastasis to locoregional lymph nodes. Histologically, most tumors exhibited an organoid pattern as seen in the islet-cell tumors. Biochemically, the lesions exhibited high PKA activity, as one would expect from deleting prkar1a The primary neuroendocrine nature of these tumor cells was confirmed by immunohistochemical staining and electron microscopy, the latter revealing the characteristic granules. Although the Δ-Prkar1a mice developed hypoglycemia after overnight fasting, insulin and glucagon levels in the plasma were normal. Negative immunohistochemical staining for the most commonly produced peptides (insulin, c-peptide, glucagon, gastrin and somatostatin) suggested that these tumors were non-functioning. We hypothesize that the recently identified multipotent pdx1+/insulin- cell in adult pancreas, gives rise to endocrine or mixed endocrine/acinar pancreatic malignancies with complete prkar1a deficiency. In conclusion, this mouse model supports the role of prkar1a as a tumor suppressor gene in the pancreas and points to the PKA pathway as a possible therapeutic target for these lesions. © 2017 Society for Endocrinology.

Singapore Cancer Network (SCAN) Guidelines for Systemic Therapy of Pancreatic Adenocarcinoma.

PubMed

2015-10-01

The SCAN pancreatic cancer workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for systemic therapy for pancreatic adenocarcinoma in Singapore. The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting. Five international guidelines were evaluated- those developed by the National Cancer Comprehensive Network (2014), the European Society of Medical Oncology (2012), Cancer Care Ontario (2013), the Japan Pancreas Society (2013) and the British Society of Gastroenterology, Pancreatic Society of Great Britain and Ireland, and the Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland (2005). Recommendations on the management of resected, borderline resectable, locally advanced and metastatic pancreatic adenocarcinoma were developed. These adapted guidelines form the SCAN Guidelines for systemic therapy for pancreatic adenocarcinoma in Singapore.

New insights into the pathways initiating and driving pancreatitis

PubMed Central

Gukovskaya, Anna S.; Pandol, Stephen J.; Gukovsky, Ilya

2016-01-01

Purpose of review In this article, we discuss recent studies that advance our understanding of molecular and cellular factors initiating and driving pancreatitis, with the emphasis on the role of acinar cell organelle disorders. Recent findings The central physiologic function of the pancreatic acinar cell – to synthesize, store, and secrete digestive enzymes – critically relies on coordinated actions of the endoplasmic reticulum (ER), the endolysosomal system, mitochondria, and autophagy. Recent studies begin to unravel the roles of these organelles’ disordering in the mechanism of pancreatitis. Mice deficient in key autophagy mediators Atg5 or Atg7, or lysosome-associated membrane protein-2, exhibit dysregulation of multiple signaling and metabolic pathways in pancreatic acinar cells and develop spontaneous pancreatitis. Mitochondrial dysfunction caused by sustained opening of the permeability transition pore is shown to mediate pancreatitis in several clinically relevant experimental models, and its inhibition by pharmacologic or genetic means greatly reduces local and systemic pathologic responses. Experimental pancreatitis is also alleviated with inhibitors of ORAI1, a key component of the plasma membrane channel mediating pathologic rise in acinar cell cytosolic Ca2+. Pancreatitis-promoting mutations are increasingly associated with the ER stress. These findings suggest novel pathways and drug targets for pancreatitis treatment. In addition, the recent studies identify new mediators (e.g., neutrophil extracellular traps) of the inflammatory and other responses of pancreatitis. Summary The recent findings illuminate a critical role of organelles regulating the autophagic, endolysosomal, mitochondrial, and ER pathways in maintaining pancreatic acinar cell homeostasis and secretory function; provide compelling evidence that organelle disordering is a key pathogenic mechanism initiating and driving pancreatitis; and identify molecular and cellular factors

Molecular and genetic bases of pancreatic cancer.

PubMed

Vaccaro, Vanja; Gelibter, Alain; Bria, Emilio; Iapicca, Pierluigi; Cappello, Paola; Di Modugno, Francesca; Pino, Maria Simona; Nuzzo, Carmen; Cognetti, Francesco; Novelli, Francesco; Nistico, Paola; Milella, Michele

2012-06-01

Pancreatic cancer remains a formidable challenge for oncologists and patients alike. Despite intensive efforts, attempts at improving survival in the past 15 years, particularly in advanced disease, have failed. This is true even with the introduction of molecularly targeted agents, chosen on the basis of their action on pathways that were supposedly important in pancreatic cancer development and progression: indeed, with the notable exception of the epidermal growth factor receptor (EGFR) inhibitor erlotinib, that has provided a minimal survival improvement when added to gemcitabine, other agents targeting EGFR, matrix metallo-proteases, farnesyl transferase, or vascular endothelial growth factor have not succeeded in improving outcomes over standard gemcitabine monotherapy for a variety of different reasons. However, recent developments in the molecular epidemiology of pancreatic cancer and an ever evolving understanding of the molecular mechanisms underlying pancreatic cancer initiation and progression raise renewed hope to find novel, relevant therapeutic targets that could be pursued in the clinical setting. In this review we focus on molecular epidemiology of pancreatic cancer, epithelial-to-mesenchymal transition and its influence on sensitivity to EGFR-targeted approaches, apoptotic pathways, hypoxia-related pathways, developmental pathways (such as the hedgehog and Notch pathways), and proteomic analysis as keys to a better understanding of pancreatic cancer biology and, most importantly, as a source of novel molecular targets to be exploited therapeutically.

Genetic and molecular alterations in pancreatic cancer: implications for personalized medicine.

PubMed

Fang, Yantian; Yao, Qizhi; Chen, Zongyou; Xiang, Jianbin; William, Fisher E; Gibbs, Richard A; Chen, Changyi

2013-10-31

Recent advances in human genomics and biotechnologies have profound impacts on medical research and clinical practice. Individual genomic information, including DNA sequences and gene expression profiles, can be used for prediction, prevention, diagnosis, and treatment for many complex diseases. Personalized medicine attempts to tailor medical care to individual patients by incorporating their genomic information. In a case of pancreatic cancer, the fourth leading cause of cancer death in the United States, alteration in many genes as well as molecular profiles in blood, pancreas tissue, and pancreas juice has recently been discovered to be closely associated with tumorigenesis or prognosis of the cancer. This review aims to summarize recent advances of important genes, proteins, and microRNAs that play a critical role in the pathogenesis of pancreatic cancer, and to provide implications for personalized medicine in pancreatic cancer.

Tumors of the endocrine/neuroendocrine system: an overview.

PubMed

Erlandson, R A; Nesland, J M

1994-01-01

For the sake of discussion, the markedly diversified tumors of the endocrine/neuroendocrine system are classified as those originating in classic epithelial endocrine organs (eg, adrenal cortical adenomas), from the diffuse endocrine cells (eg, jejunal carcinoid tumors), or from clusters of these cells (eg, islet cell tumors); and those arising from neurosecretory neurons (eg, neuroblastoma) or paraganglia (eg, carotid body tumor). Although traditional transmission electron microscopy is useful for identifying neurosecretory or endosecretory granules as such, with few exceptions (eg, insulin-containing granules with a complex paracrystalline core) it is not possible to ascribe a granule type (size, shape, or ultrastructure) to a distinct nosologic entity or secretory product because of their overlapping fine structures in different cell types. Immunoelectron microscopy methods utilizing colloidal gold-labeled secondary antibodies can be used to localize virtually any antigen (peptide or neuroamine) to a specific neurosecretory or endosecretory granule or other cell structure. General endocrine/neuroendocrine cell markers such as neuron-specific enolase, the chromogranins, and synaptophysin are useful in identifying neuroendocrine differentiation in a neoplasm using routine immunohistochemical procedures. The current relevance of the APUD concept of Pearse as well as the biologic importance of endocrine/neuroendocrine secretory products such as bombesin and insulinlike growth factors also are discussed.

[Chronic pancreatitis diagnosed after the first attack of acute pancreatitis].

PubMed

Bojková, Martina; Dítě, Petr; Uvírová, Magdalena; Dvořáčková, Nina; Kianička, Bohuslav; Kupka, Tomáš; Svoboda, Pavel; Klvaňa, Pavel; Martínek, Arnošt

2016-02-01

One of the diseases involving a potential risk of developing chronic pancreatitis is acute pancreatitis. Of the overall number of 231 individuals followed with a diagnosis of chronic pancreatitis, 56 patients were initially treated for acute pancreatitis (24.2 %). Within an interval of 12- 24 months from the first attack of acute pancreatitis, their condition gradually progressed to reached the picture of chronic pancreatitis. The individuals included in the study abstained (from alcohol) following the first attack of acute pancreatitis and no relapse of acute pancreatitis was proven during the period of their monitoring. The etiology of acute pancreatitis identified alcohol as the predominant cause (55.3 %), biliary etiology was proven in 35.7 %. According to the revised Atlanta classification, severe pancreatitis was established in 69.6 % of the patients, the others met the criterion for intermediate form, those with the light form were not included. Significant risk factors present among the patients were smoking, obesity and 18 %, resp. 25.8 % had pancreatogenous diabetes mellitus identified. 88.1 % of the patients with acute pancreatitis were smokers. The majority of individuals with chronic pancreatitis following an attack of acute pancreatitis were of a productive age from 25 to 50 years. It is not only acute alcoholic pancreatitis which evolves into chronic pancreatitis, we have also identified this transition for pancreatitis of biliary etiology.

Colorectal neuroendocrine neoplasms - management guidelines (recommended by the Polish Network of Neuroendocrine Tumours).

PubMed

Starzyńska, Teresa; Londzin-Olesik, Magdalena; Bałdys-Waligórska, Agata; Bednarczuk, Tomasz; Blicharz-Dorniak, Jolanta; Bolanowski, Marek; Boratyn-Nowicka, Agnieszka; Borowska, Małgorzata; Cichocki, Andrzej; Ćwikła, Jarosław B; Deptała, Andrzej; Falconi, Massimo; Foltyn, Wanda; Handkiewicz-Junak, Daria; Hubalewska-Dydejczyk, Alicja; Jarząb, Barbara; Junik, Roman; Kajdaniuk, Dariusz; Kamiński, Grzegorz; Kolasińska-Ćwikła, Agnieszka; Kowalska, Aldona; Król, Robert; Królicki, Leszek; Kunikowska, Jolanta; Kuśnierz, Katarzyna; Lampe, Paweł; Lange, Dariusz; Lewczuk-Myślicka, Anna; Lewiński, Andrzej; Lipiński, Michał; Marek, Bogdan; Nasierowska-Guttmejer, Anna; Nowakowska-Duława, Ewa; Pilch-Kowalczyk, Joanna; Remiszewski, Piotr; Rosiek, Violetta; Ruchała, Marek; Siemińska, Lucyna; Sowa-Staszczak, Anna; Steinhof-Radwańska, Katarzyna; Strzelczyk, Janusz; Sworczak, Krzysztof; Syrenicz, Anhelli; Szawłowski, Andrzej; Szczepkowski, Marek; Wachuła, Ewa; Zajęcki, Wojciech; Zemczak, Anna; Zgliczyński, Wojciech; Kos-Kudła, Beata

2017-01-01

Neuroendocrine neoplasms/tumours (NENs/NETs) of the large intestine are detected increasingly often, especially rectal tumours, which is probably associated with the widespread use of screening colonoscopy. There is a growing body of evidence supporting the thesis that the NENs of the rectum and the NENs of the colon are two different diseases. Rectal NENs are usually small lesions, of low to moderate histological malignancy, associated with good prognosis, and most may be treated endoscopically. NENs of the colon, however, are often aggressive, poorly differentiated, associated with a poor or uncer-tain prognosis, and require surgical treatment. The management guidelines regarding these groups of patients are constantly changing. On the basis of the recent literature data and conclusions reached by the working meeting of the Polish Network of Neuroendocrine Tumours (December 2016), this study completes and updates the data and management guidelines regarding colorectal NENs published in Endokrynologia Polska 2013; 64: 358-368.

Prospective evaluation of 68 Ga-DOTATATE PET/CT in limited disease neuroendocrine tumors and/or elevated serum neuroendocrine biomarkers.

PubMed

Gabriel, Sophie; Garrigue, Philippe; Dahan, Laetitia; Castinetti, Frédéric; Sebag, Frédéric; Baumstark, Karine; Archange, Cendrine; Abhishek, Jha; Pacak, Karel; Guillet, Benjamin; Taïeb, David

2018-05-22

The 68 Ga-labelled somatostatin analogues ( 68 Ga-DOTA-SSAs) is becoming popular as an important diagnostic tool in neuroendocrine tumors as evidenced by a growing number of reports detailing institutional experience with various DOTA peptides. However, only few prospective studies have compared 68 Ga-DOTA-SSAs and somatostatin receptor scintigraphy (SRS) in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and pulmonary neuroendocrine tumors. The aim of our prospective study was to perform head-to-head comparison between 68 Ga-DOTATATE PET/CT and standard imaging work-up (SI) that included multiphasic CT, liver MRI, and SRS using single photon emission computed tomography. In this prospective study, the patients were enrolled only if they met any of the following inclusion criteria were: i- initial staging of a NETs without distant metastases on SI or neuroendocrine tumor with unknown primary on SI; ii-restaging of NETs that could be treated by focused therapeutic interventions; iii- elevated serum neuroendocrine hormones or peptides. The exclusion criteria was grade 3 GEP-NETs. Thirty-two patients were enrolled in the study. Eleven patients (6 pancreas, 4 ileum, 1 duodenal) were included for initial evaluation and staging of NETs, 8 patients (5 pancreas, 1 ileal, 1 lung, 1 duodenal gastrinoma) for restaging, and 13 patients for elevated serum neuroendocrine biomarkers (5 ectopic Cushing's syndrome, 5 organic hypoglycemia, 1 patient each with elevated vasoactive inhibitory peptide, chromogranin A, and neuron-specific enolase). 68 Ga-DOTATATE PET/CT detected more primary tumors than SRS (15/18 vs 10/18: p=0.074). The missed tumors on 68 Ga-DOTATATE PET/CT were located in the lung in 2 cases and duodenum in 1 case. For other anatomical regions (nodal and distant metastasis), no statistical difference was observed between imaging modalities using 68 Ga-DOTATATE PET/CT and SRS. Overall, 68 Ga-DOTATATE PET/CT+CT+MRI detected 31/33 of the involved regions

Characterization of three peptides derived from prosomatostatin [prosomatostatin-(1-63)-, -(65-76)- and -(79-92)-peptides] in a human pancreatic tumour.

PubMed

Conlon, J M; Eriksson, B; Grimelius, L; Oberg, K; Thim, L

1987-11-15

By using only reverse-phase h.p.l.c., three fragments of prosomatostatin were isolated from an extract of a human pancreatic neuroendocrine tumour that produced somatostatin, vasoactive intestinal polypeptide and gastrin-releasing peptide. The amino acid composition of the peptides indicated that they represented prosomatostatin-(1-63)-peptide, prosomatostain-(65-76)-peptide and prosomatostatin-(79-92)-peptide (somatostatin-14). The identity of prosomatostatin-(1-63)-peptide was confirmed by characterization of the products of digestion with Armillaria mellea (honey fungus) proteinase. Partial micro-sequencing of prosomatostatin-(1-63)-peptide showed that the Gly24-Ala25 bond of preprosomatostatin was the site of cleavage of the signal peptide. Thus human prosomatostatin is a protein of 92 amino acid residues that is proteolytically cleaved in a pancreatic tumour at the site of a dibasic-residue (arginine-lysine) processing site and at a single-monobasic-residue (arginine) processing site.

Cost-effectiveness of everolimus for the treatment of advanced neuroendocrine tumours of gastrointestinal or lung origin in Canada.

PubMed

Chua, A; Perrin, A; Ricci, J F; Neary, M P; Thabane, M

2018-02-01

In 2016, everolimus was approved by Health Canada for the treatment of unresectable, locally advanced or metastatic, well-differentiated, non-functional, neuroendocrine tumours (NET) of gastrointestinal (GI) or lung origin in adult patients with progressive disease. This analysis evaluated the cost-effectiveness of everolimus in this setting from a Canadian societal perspective. A partitioned survival model was developed to compare the cost per life-year (LY) gained and cost per quality-adjusted life-year (QALY) gained of everolimus plus best supportive care (BSC) versus BSC alone in patients with advanced or metastatic NET of GI or lung origin. Model health states included stable disease, disease progression, and death. Efficacy inputs were based on the RADIANT-4 trial and utilities were mapped from quality-of-life data retrieved from RADIANT-4. Resource utilization inputs were derived from a Canadian physician survey, while cost inputs were obtained from official reimbursement lists from Ontario and other published sources. Costs and efficacy outcomes were discounted 5% annually over a 10-year time horizon, and sensitivity analyses were conducted to test the robustness of the base case results. Everolimus had an incremental gain of 0.616 QALYs (0.823 LYs) and CA$89,795 resulting in an incremental cost-effectiveness ratio of CA$145,670 per QALY gained (CA$109,166 per LY gained). The probability of cost-effectiveness was 52.1% at a willingness to pay (WTP) threshold of CA$150,000 per QALY. Results of the probabilistic sensitivity analysis indicate that everolimus has a 52.1% probability of being cost-effective at a WTP threshold of CA$150,000 per QALY gained in Canada.

Synchronous occurrence of neuroendocrine colon carcinoma and hairy cell leukemia.

PubMed

Salemis, Nikolaos S; Pinialidis, Dionisios; Tsiambas, Evangelos; Gakis, Christos; Nakos, Georgios; Sambaziotis, Dimitrios; Christofyllakis, Charalambos

2011-09-01

BACKGROUND-PURPOSE: The risk of secondary malignancy development in patients with hairy cell leukemia has been evaluated in several studies with varying results. The aim of this study is to describe a case of synchronous occurrence of neuroendocrine colon carcinoma and hairy cell leukemia. A 69-year-old man presented with rectal bleeding. Colonoscopy revealed a rectal tumor, whereas biopsy specimens revealed a poorly differentiated carcinoma. During the preoperative evaluation, pancytopenia was detected. At laparotomy, a mass was detected 16 cm from the anal verge and an anterior resection of the rectum was performed. Detailed histological and immunohistochemical analyses revealed a poorly differentiated neuroendocrine carcinoma of the rectum. Postoperative evaluation of pancytopenia revealed hairy cell leukemia. The patient was initially treated with chemotherapy for hairy cell leukemia followed by chemotherapy for neuroendocrine colon carcinoma. Survival was 44 months. To our knowledge, synchronous occurrence of neuroendocrine colon carcinoma and hairy cell leukemia has not been previously reported in the literature. Given the rare incidence of both entities in the general population, it is highly unlikely that they occurred together by chance. Further research is needed to determine what would be the optimal management options of patients with simultaneous hairy cell leukemia and a neuroendocrine colon cancer.

Robotic transgastric cystgastrostomy and pancreatic debridement in the management of pancreatic fluid collections following acute pancreatitis.

PubMed

Kirks, Russell C; Sola, Richard; Iannitti, David A; Martinie, John B; Vrochides, Dionisios

2016-01-01

Pancreatic and peripancreatic fluid collections may develop after severe acute pancreatitis. Organized fluid collections such as pancreatic pseudocyst and walled-off pancreatic necrosis (WOPN) that mature over time may require intervention to treat obstructive or constitutional symptoms related to the size and location of the collection as well as possible infection. Endoscopic, open surgical and minimally invasive techniques are described to treat post-inflammatory pancreatic fluid collections. Surgical intervention may be required to treat collections containing necrotic pancreatic parenchyma or in locations not immediately apposed to the stomach or duodenum. Comprising a blend of the surgical approach and the clinical benefits of minimally invasive surgery, the robot-assisted technique of pancreatic cystgastrostomy with pancreatic debridement is described.

Circulating tumor DNA as a liquid biopsy target for detection of pancreatic cancer

PubMed Central

Takai, Erina; Yachida, Shinichi

2016-01-01

Most pancreatic cancer patients present with advanced metastatic disease, resulting in extremely poor 5-year survival, mainly because of the lack of a reliable modality for early detection and limited therapeutic options for advanced disease. Therefore, there is a need for minimally-invasive diagnostic tools for detecting pancreatic cancer at an early stage, when curative surgery and also novel therapeutic approaches including precision medicine may be feasible. The “liquid biopsy” addresses these unmet clinical needs based on the concept that simple peripheral blood sampling and detection of circulating tumor DNA (ctDNA) could provide diagnostic information. In this review, we provide an overview of the current status of blood-based tests for diagnosis of pancreatic cancer and the potential utility of ctDNA for precision medicine. We also discuss challenges that remain to be addressed in developing practical ctDNA-based liquid biopsy approaches for early diagnosis of pancreatic cancer. PMID:27784960

Generation of glyceraldehyde-derived advanced glycation end-products in pancreatic cancer cells and the potential of tumor promotion

PubMed Central

Takata, Takanobu; Ueda, Tadashi; Sakasai-Sakai, Akiko; Takeuchi, Masayoshi

2017-01-01

AIM To determine the possibility that diabetes mellitus promotes pancreatic ductal adenocarcinoma via glyceraldehyde (GA)-derived advanced glycation-end products (GA-AGEs). METHODS PANC-1, a human pancreatic cancer cell line, was treated with 1-4 mmol/L GA for 24 h. The cell viability and intracellular GA-AGEs were measured by WST-8 assay and slot blotting. Moreover, immunostaining of PANC-1 cells with an anti-GA-AGE antibody was performed. Western blotting (WB) was used to analyze the molecular weight of GA-AGEs. Heat shock proteins 90α, 90β, 70, 27 and cleaved caspase-3 were analyzed by WB. In addition, PANC-1 cells were treated with GA-AGEs-bovine serum albumin (GA-AGEs-BSA), as a model of extracellular GA-AGEs, and proliferation of PANC-1 cells was measured. RESULTS In PANC-1 cells, GA induced the production of GA-AGEs and cell death in a dose-dependent manner. PANC-1 cell viability was approximately 40% with a 2 mmol/L GA treatment and decreased to almost 0% with a 4 mmol/L GA treatment (each significant difference was P < 0.01). Cells treated with 2 and 4 mmol/L GA produced 6.4 and 21.2 μg/mg protein of GA-AGEs, respectively (P < 0.05 and P < 0.01). The dose-dependent production of some high-molecular-weight (HMW) complexes of HSP90β, HSP70, and HSP27 was observed following administration of GA. We considered HMW complexes to be dimers and trimers with GA-AGEs-mediated aggregation. Cleaved caspase-3 could not be detected with WB. Furthermore, 10 and 20 μg/mL GA-AGEs-BSA was 27% and 34% greater than that of control cells, respectively (P < 0.05 and P < 0.01). CONCLUSION Although intracellular GA-AGEs induce pancreatic cancer cell death, their secretion and release may promote the proliferation of other pancreatic cancer cells. PMID:28785145

Advanced glycation end products impair glucose-induced insulin secretion from rat pancreatic β-cells.

PubMed

Hachiya, Hiroyuki; Miura, Yoshikazu; Inoue, Ken-Ichi; Park, Kyung Hwa; Takeuchi, Masayoshi; Kubota, Keiichi

2014-02-01

Advanced glycation end products (AGEs) are derivative compounds generated from non-enzymatic glycosylation and oxidation. In comparison with glucose-derived AGEs (Glu-AGEs), glyceraldehyde-derived AGEs (Glycer-AGEs) have stronger toxicity to living systems. In this study, we compared the effects of Glu-AGE and Glycer-AGE on insulin secretion. Rat pancreatic islets were isolated by collagenase digestion and primary-cultured in the presence of 0.1 mg/ml bovine serum albumin (BSA) or 0.1 mg/ml Glu-AGE or Glycer-AGE-albumin. After 48 h of culture, we performed an insulin secretion test and identified the defects by a battery of rescue experiments [corrected]. Also, mRNA expression of genes associated with insulin secretion was measured. Insulin secretion induced by a high glucose concentration was 164.1 ± 6.0, 124.4 ± 4.4 (P < 0.05) and 119.8 ± 7.1 (P < 0.05) μU/3 islets/h in the presence of BSA, Glu-AGE, and Glycer-AGE, respectively. Inhibition of insulin secretion by Glu-AGE or Glycer-AGE was rescued by a high extracellular potassium concentration, tolbutamide and α-ketoisocaproic acid, but not by glyceraldehyde, dihydroxacetone, methylpyruvate, glucagon-like peptide-1 and acetylcholine. Glu-AGE or Glycer-AGE reduced the expression of the malate dehydrogenase (Mdh1/2) gene, which plays a critical role in the nicotinamide adenine dinucleotide (NADH) shuttle. Despite its reported cytotoxicity, the effects of Glycer-AGE on insulin secretion are similar to those of Glu-AGE. © 2013 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

Neoadjuvant radiotherapeutic strategies in pancreatic cancer

PubMed Central

Roeder, Falk

2016-01-01

This review summarizes the current status of neoadjuvant radiation approaches in the treatment of pancreatic cancer, including a description of modern radiation techniques, and an overview on the literature regarding neoadjuvant radio- or radiochemotherapeutic strategies both for resectable and irresectable pancreatic cancer. Neoadjuvant chemoradiation for locally-advanced, primarily non- or borderline resectable pancreas cancer results in secondary resectability in a substantial proportion of patients with consecutively markedly improved overall prognosis and should be considered as possible alternative in pretreatment multidisciplinary evaluations. In resectable pancreatic cancer, outstanding results in terms of response, local control and overall survival have been observed with neoadjuvant radio- or radiochemotherapy in several phase I/II trials, which justify further evaluation of this strategy. Further investigation of neoadjuvant chemoradiation strategies should be performed preferentially in randomized trials in order to improve comparability of the current results with other treatment modalities. This should include the evaluation of optimal sequencing with newer and more potent systemic induction therapy approaches. Advances in patient selection based on new molecular markers might be of crucial interest in this context. Finally modern external beam radiation techniques (intensity-modulated radiation therapy, image-guided radiation therapy and stereotactic body radiation therapy), new radiation qualities (protons, heavy ions) or combinations with alternative boosting techniques widen the therapeutic window and contribute to the reduction of toxicity. PMID:26909133

Nasal and paranasal adenocarcinomas with neuroendocrine differentiation in dogs.

PubMed

Ninomiya, F; Suzuki, S; Tanaka, H; Hayashi, S; Ozaki, K; Narama, I

2008-03-01

Tumors of the nasal cavity or paranasal sinuses of 18 dogs were examined histopathologically, immunohistochemically, and histochemically. The tumors were classified histologically as 13 adenocarcinomas, 3 transitional carcinomas, 1 squamous cell carcinoma, and 1 adenosquamous carcinoma. Tumor cells were strongly immunoreactive for broad-spectrum cytokeratins in all cases, for cytokeratin 8/18 in 16 cases, and for cytokeratin 19 in 17 cases. None of the 18 carcinomas had cytologic or histologic features indicative of neuroendocrine differentiation, yet tumor cells in 5 of the 13 adenocarcinomas were argyrophilic and immunohistochemically positive for synaptophysin and chromogranin A. Results of this study indicate that neuroendocrine markers may be detected immunohistochemically and histochemically in canine nasal or paranasal adenocarcinomas despite the lack of typical histologic features of neuroendocrine differentiation.

Pancreatic trauma.

PubMed

Lahiri, R; Bhattacharya, S

2013-05-01

Pancreatic trauma occurs in approximately 4% of all patients sustaining abdominal injuries. The pancreas has an intimate relationship with the major upper abdominal vessels, and there is significant morbidity and mortality associated with severe pancreatic injury. Immediate resuscitation and investigations are essential to delineate the nature of the injury, and to plan further management. If main pancreatic duct injuries are identified, specialised input from a tertiary hepatopancreaticobiliary (HPB) team is advised. A comprehensive online literature search was performed using PubMed. Relevant articles from international journals were selected. The search terms used were: 'pancreatic trauma', 'pancreatic duct injury', 'radiology AND pancreas injury', 'diagnosis of pancreatic trauma', and 'management AND surgery'. Articles that were not published in English were excluded. All articles used were selected on relevance to this review and read by both authors. Pancreatic trauma is rare and associated with injury to other upper abdominal viscera. Patients present with non-specific abdominal findings and serum amylase is of little use in diagnosis. Computed tomography is effective in diagnosing pancreatic injury but not duct disruption, which is most easily seen on endoscopic retrograde cholangiopancreaticography or operative pancreatography. If pancreatic injury is suspected, inspection of the entire pancreas and duodenum is required to ensure full evaluation at laparotomy. The operative management of pancreatic injury depends on the grade of injury found at laparotomy. The most important prognostic factor is main duct disruption and, if found, reconstructive options should be determined by an experienced HPB surgeon. The diagnosis of pancreatic trauma requires a high index of suspicion and detailed imaging studies. Grading pancreatic injury is important to guide operative management. The most important prognostic factor is pancreatic duct disruption and in these cases

Molecular Imaging of Pancreatic Cancer with Antibodies

PubMed Central

2015-01-01

Development of novel imaging probes for cancer diagnostics remains critical for early detection of disease, yet most imaging agents are hindered by suboptimal tumor accumulation. To overcome these limitations, researchers have adapted antibodies for imaging purposes. As cancerous malignancies express atypical patterns of cell surface proteins in comparison to noncancerous tissues, novel antibody-based imaging agents can be constructed to target individual cancer cells or surrounding vasculature. Using molecular imaging techniques, these agents may be utilized for detection of malignancies and monitoring of therapeutic response. Currently, there are several imaging modalities commonly employed for molecular imaging. These imaging modalities include positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance (MR) imaging, optical imaging (fluorescence and bioluminescence), and photoacoustic (PA) imaging. While antibody-based imaging agents may be employed for a broad range of diseases, this review focuses on the molecular imaging of pancreatic cancer, as there are limited resources for imaging and treatment of pancreatic malignancies. Additionally, pancreatic cancer remains the most lethal cancer with an overall 5-year survival rate of approximately 7%, despite significant advances in the imaging and treatment of many other cancers. In this review, we discuss recent advances in molecular imaging of pancreatic cancer using antibody-based imaging agents. This task is accomplished by summarizing the current progress in each type of molecular imaging modality described above. Also, several considerations for designing and synthesizing novel antibody-based imaging agents are discussed. Lastly, the future directions of antibody-based imaging agents are discussed, emphasizing the potential applications for personalized medicine. PMID:26620581

Pancreatitis in Children.

PubMed

Sathiyasekaran, Malathi; Biradar, Vishnu; Ramaswamy, Ganesh; Srinivas, S; Ashish, B; Sumathi, B; Nirmala, D; Geetha, M

2016-11-01

Pancreatic disease in children has a wide clinical spectrum and may present as Acute pancreatitis (AP), Acute recurrent pancreatitis (ARP), Chronic pancreatitis (CP) and Pancreatic disease without pancreatitis. This article highlights the etiopathogenesis and management of pancreatitis in children along with clinical data from five tertiary care hospitals in south India [Chennai (3), Cochin and Pune].

Course of alcoholic chronic pancreatitis: a prospective clinicomorphological long-term study.

PubMed

Ammann, R W; Heitz, P U; Klöppel, G

1996-07-01

The pathogenesis of alcoholic chronic pancreatitis and its relationship to alcoholic acute pancreatitis are debated. According to our recent clinical long-term study, alcoholic chronic pancreatitis seems to evolve from severe acute pancreatits. The aim of this study was to correlate clinical findings to the pancreatic histopathology at early and advanced stages of the disease. Morphological changes (pseudocysts, autodigestive necrosis, calcification, and perilobular and intralobular fibrosis) were recorded in 37 surgical and 46 postmortem pancreas specimens of 73 patients from our long-term series, who progressed from clinically acute to chronic pancreatitis (mean follow-up, 12 years). Pancreatic function was monitored at yearly intervals. Surgical interventions were performed at a mean of 4.1 years from onset. Histologically, focal necrosis (49%) and mild perilobular fibrosis (54%) predominated, Pseudocysts (n = 41, mostly postnecrotic) occurred in 88% within 6 years from onset. Autopsy specimens were obtained at a mean of 12 years. These pancreata often showed severe perilobular and intralobular fibrosis (85%) and calcifications (74%), but rarely necrosis (4%). Fibrosis correlated with progressive pancreatic dysfunction (P < 0.001), particularly in the 10 patients with two histological assessments (mean interval between biopsy and autopsy, 8 years). The data support an evolution from severe alcoholic acute pancreatitis to chronic pancreatitis.

Pathology and Molecular Genetics of Pancreatic Neoplasms

PubMed Central

Wood, Laura D.; Hruban, Ralph H.

2014-01-01

Cancer is fundamentally a genetic disease caused by the ac cumulation of somatic mutations in oncogenes and tumor suppressor genes. In the last decade, rapid advances in sequencing and bioinformatic technology led to an explosion in sequencing studies of cancer genomes, greatly expanding our knowledge of the genetic changes underlying a variety of tumor types. Several of these studies of cancer genomes have focused on pancreatic neoplasms, and cancers from the pancreas are some of the best characterized tumors at the genetic level. Pancreatic neoplasms encompass a wide array of clinical diseases, from benign cysts to deadly cancers, and the genetic alterations underlying neoplasms of the pancreas are similarly diverse. This new knowledge of pancreatic cancer genomes has deepened our understanding of tumorigenesis in the pancreas and has opened several promising new avenues for novel diagnostics and therapeutics. PMID:23187835

MIA PaCa-2 and PANC-1 - pancreas ductal adenocarcinoma cell lines with neuroendocrine differentiation and somatostatin receptors.

PubMed

Gradiz, Rui; Silva, Henriqueta C; Carvalho, Lina; Botelho, Maria Filomena; Mota-Pinto, Anabela

2016-02-17

Studies using cell lines should always characterize these cells to ensure that the results are not distorted by unexpected morphological or genetic changes possibly due to culture time or passage number. Thus, the aim of this study was to describe those MIA PaCa-2 and PANC-1 cell line phenotype and genotype characteristics that may play a crucial role in pancreatic cancer therapeutic assays, namely neuroendocrine chemotherapy and peptide receptor radionuclide therapy. Epithelial, mesenchymal, endocrine and stem cell marker characterization was performed by immunohistochemistry and flow cytometry, and genotyping by PCR, gene sequencing and capillary electrophoresis. MIA PaCa-2 (polymorphism) expresses CK5.6, AE1/AE3, E-cadherin, vimentin, chromogranin A, synaptophysin, SSTR2 and NTR1 but not CD56. PANC-1 (pleomorphism) expresses CK5.6, MNF-116, vimentin, chromogranin A, CD56 and SSTR2 but not E-cadherin, synaptophysin or NTR1. MIA PaCA-1 is CD24(-), CD44(+/++), CD326(-/+) and CD133/1(-), while PANC-1 is CD24(-/+), CD44(+), CD326(-/+) and CD133/1(-). Both cell lines have KRAS and TP53 mutations and homozygous deletions including the first 3 exons of CDKN2A/p16(INK4A), but no SMAD4/DPC4 mutations or microsatellite instability. Both have neuroendocrine differentiation and SSTR2 receptors, precisely the features making them suitable for the therapies we propose to assay in future studies.

Lanreotide in metastatic enteropancreatic neuroendocrine tumors.

PubMed

Caplin, Martyn E; Pavel, Marianne; Ćwikła, Jarosław B; Phan, Alexandria T; Raderer, Markus; Sedláčková, Eva; Cadiot, Guillaume; Wolin, Edward M; Capdevila, Jaume; Wall, Lucy; Rindi, Guido; Langley, Alison; Martinez, Séverine; Blumberg, Joëlle; Ruszniewski, Philippe

2014-07-17

Somatostatin analogues are commonly used to treat symptoms associated with hormone hypersecretion in neuroendocrine tumors; however, data on their antitumor effects are limited. We conducted a randomized, double-blind, placebo-controlled, multinational study of the somatostatin analogue lanreotide in patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptor-positive neuroendocrine tumors of grade 1 or 2 (a tumor proliferation index [on staining for the Ki-67 antigen] of <10%) and documented disease-progression status. The tumors originated in the pancreas, midgut, or hindgut or were of unknown origin. Patients were randomly assigned to receive an extended-release aqueous-gel formulation of lanreotide (Autogel [known in the United States as Depot], Ipsen) at a dose of 120 mg (101 patients) or placebo (103 patients) once every 28 days for 96 weeks. The primary end point was progression-free survival, defined as the time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.0) or death. Secondary end points included overall survival, quality of life (assessed with the European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-GI.NET21), and safety. Most patients (96%) had no tumor progression in the 3 to 6 months before randomization, and 33% had hepatic tumor volumes greater than 25%. Lanreotide, as compared with placebo, was associated with significantly prolonged progression-free survival (median not reached vs. median of 18.0 months, P<0.001 by the stratified log-rank test; hazard ratio for progression or death, 0.47; 95% confidence interval [CI], 0.30 to 0.73). The estimated rates of progression-free survival at 24 months were 65.1% (95% CI, 54.0 to 74.1) in the lanreotide group and 33.0% (95% CI, 23.0 to 43.3) in the placebo group. The therapeutic effect in predefined subgroups was generally consistent with that in the overall

Role of Vitamin D in the Prevention of Pancreatic Cancer

PubMed Central

Bulathsinghala, Pubudu; Syrigos, Kostas N.; Saif, Muhammad W.

2010-01-01

Pancreatic cancer is a malignancy of poor prognosis which is mostly diagnosed at advanced stages. Current treatment modalities are very limited creating great interest for novel preventive and therapeutic options. Vitamin D seems to have a protective effect against pancreatic cancer by participating in numerous proapoptotic, antiangiogenic, anti-inflammatory, prodifferentiating, and immunomodulating mechanisms. 25-hydroxyvitamin D [25(OH)D] serum concentrations are currently the best indicator of vitamin D status. There are three main sources of vitamin D: sun exposure, diet,and dietary supplements. Sun exposure has been associated with lower incidence of pancreatic cancer in ecological studies. Increased vitamin D levels seem to protect against pancreatic cancer, but caution is needed as excessive dietary intake may have opposite results. Future studies will verify the role of vitamin D in the prevention and therapy of pancreatic cancer and will lead to guidelines on adequate sun exposure and vitamin D dietary intake. PMID:21274445

Anaesthetic perioperative management of patients with pancreatic cancer

PubMed Central

De Pietri, Lesley; Montalti, Roberto; Begliomini, Bruno

2014-01-01

Pancreatic cancer remains a significant and unresolved therapeutic challenge. Currently, the only curative treatment for pancreatic cancer is surgical resection. Pancreatic surgery represents a technically demanding major abdominal procedure that can occasionally lead to a number of pathophysiological alterations resulting in increased morbidity and mortality. Systemic, rather than surgical complications, cause the majority of deaths. Because patients are increasingly referred to surgery with at advanced ages and because pancreatic surgery is extremely complex, anaesthesiologists and surgeons play a crucial role in preoperative evaluations and diagnoses for surgical intervention. The anaesthetist plays a key role in perioperative management and can significantly influence patient outcome. To optimise overall care, patients should be appropriately referred to tertiary centres, where multidisciplinary teams (surgical, medical, radiation oncologists, gastroenterologists, interventional radiologists and anaesthetists) work together and where close cooperation between surgeons and anaesthesiologists promotes the safe performance of major gastrointestinal surgeries with acceptable morbidity and mortality rates. In this review, we sought to provide simple daily recommendations to the clinicians who manage pancreatic surgery patients to make their work easier and suggest a joint approach between surgeons and anaesthesiologists in daily decision making. PMID:24605028

Chronic pancreatitis with multiple pseudocysts and pancreatic panniculitis: A case report.

PubMed

Gu, Yuqing; Qian, Zhuyin

2018-06-01

Pancreatic pseudocyst can present single or multiple, inside or outside the pancreas. Pancreatic panniculitis is a rare skin lesion in pancreatic disease patients. The purpose of this study is to report a case of chronic pancreatitis coexisting with multiple pseudocysts and pancreatic panniculitis. A 46-year-old man with chronic pancreatitis presented multiple small cystic lesions inside the head of the pancreas and two large cystic lesions adjacent to the tail of the pancreas. The patient also developed subcutaneous nodules involving upper and lower limbs, hands, and lower abdomen bilaterally. The patient was diagnosed with pancreatic pseudocyst and pancreatic panniculitis resulted from chronic pancreatitis. Bile duct stent and pancreatic duct stent placement was performed endoscopicly. Panniculitis faded three weeks later and the pancreatic pseudocysts disappeared six weeks later. Clinicians should be aware of the manifestation of multiple pancreatic pseudocyst and pancreatic panniculitis, and endoscopic transpapillary drainage may be a effective way in this scenario.

KISS1 over-expression suppresses metastasis of pancreatic adenocarcinoma in a xenograft mouse model

USDA-ARS?s Scientific Manuscript database

Identifying molecular targets for treatment of pancreatic cancer metastasis is critical due to the high frequency of dissemination prior to diagnosis of this lethal disease. Because the KISS1 metastasis suppressor is expressed at reduced levels in advanced pancreatic cancer, we hypothesized that re-...

Primary Pancreatic Head Tuberculosis: Great Masquerader of Pancreatic Adenocarcinoma

PubMed Central

Gupta, Dhaval; Patel, Jatin; Rathi, Chetan; Ingle, Meghraj; Sawant, Prabha

2015-01-01

Isolated pancreatic tuberculosis (TB) is considered an extremely rare condition, even in the developing countries. Most reported cases of pancreatic TB are diagnosed after exploratory laparotomy or autopsy. Pancreatic TB is a potential mimic of invasive pancreatic malignancy and the presence of vascular invasion does not distinguish one condition from the other. Every effort should be made for the earliest diagnosis of this condition as TB is a treatable condition and it avoids unnecessary management of pancreatic carcinoma. Here we report a rare case of primary pancreatic head TB in a 58-year-old male who presented with hypodense lesion in head of pancreas with double duct sign and portal vein invasion mimicking non-resectable pancreatic carcinoma. PMID:27785295

[Chronic pancreatitis: Retrospective review of 121 cases].

PubMed

Berger F, Zoltán; Mancilla A, Carla

2016-12-01

Chronic pancreatitis (CP) is a rare disease in Chile, without a clear explanation for this low prevalence. To analyze the characteristics of our patients with pancreatitis. Retrospective analysis of a database of patients with pancreatitis of a clinical hospital. Morphological proof of diagnosis (calcifications/calculi, alterations of ducts, local complication or histology) was obtained for every patient. History of acute pancreatitis was recorded and exocrine-endocrine function was assessed. We retrieved information of 121 patients with pancreatitis (86 males) in a period of 20 years. The number of cases increased markedly every five years. The calculated incidence and prevalence was 0.8/100,000/year and 6/100,000, respectively. Pancreatic calcifications were initially observed in 93 patients and became evident during the follow-up in another six patients. Severe pain or local complications occurred in 27 patients, requiring surgery in 10 or endoscopic treatment in 15. During the years of follow-up, 55 patients were free of symptoms. Exocrine and endocrine insufficiency was demonstrated and treated in 81 and 67 patients, respectively. Alcoholic etiology was evident in 40% of patients. In 29% no etiology was identified. Mapuche origin was exceptional. Late diagnosis of CP is common, since most of our patients presented with advanced stages. Even though CP is increasingly diagnosed in our hospitals, the number of cases is still far fewer when compared to other countries. Underdiagnosis alone cannot explain this difference and genetic factors might be of importance.

Early diagnosis of chronic pancreatitis: understanding the factors associated with the development of chronic pancreatitis

PubMed Central

Yamabe, Akane; Irisawa, Atsushi; Shibukawa, Goro; Sato, Ai; Fujisawa, Mariko; Arakawa, Noriyuki; Yoshida, Yoshitsugu; Abe, Yoko; Igarashi, Ryo; Maki, Takumi; Yamamoto, Shogo

2017-01-01

Abstract The prognosis of advanced chronic pancreatitis (CP) is poor with the mortality rate approximately two-fold higher than the general population according to a survey of the prognosis of CP. From this standpoint, the concept of early CP was propagated in Japan in 2009 to encourage the medical treatment for the earlier stages of CP. That is, picking up the patients suspicious for early CP and then providing medical treatment for them are very important not only for patients, but also for health care economics. In this review, we described some potential factors associated with the development of CP (alcohol, smoking, past history of acute pancreatitis, aging, gallstone, and gender) that are extremely important to discover patients with early-stage CP. PMID:28450665

Early diagnosis of chronic pancreatitis: understanding the factors associated with the development of chronic pancreatitis.

PubMed

Yamabe, Akane; Irisawa, Atsushi; Shibukawa, Goro; Sato, Ai; Fujisawa, Mariko; Arakawa, Noriyuki; Yoshida, Yoshitsugu; Abe, Yoko; Igarashi, Ryo; Maki, Takumi; Yamamoto, Shogo

2017-04-28

The prognosis of advanced chronic pancreatitis (CP) is poor with the mortality rate approximately two-fold higher than the general population according to a survey of the prognosis of CP.　From this standpoint, the concept of early CP was propagated in Japan in 2009 to encourage the medical treatment for the earlier stages of CP.　That is, picking up the patients suspicious for early CP and then providing medical treatment for them are very important not only for patients, but also for health care economics.　In this review, we described some potential factors associated with the development of CP (alcohol, smoking, past history of acute pancreatitis, aging, gallstone, and gender) that are extremely important to discover patients with early-stage CP.

Specification of Drosophila Corpora Cardiaca Neuroendocrine Cells from Mesoderm Is Regulated by Notch Signaling

PubMed Central

Park, Sangbin; Bustamante, Erika L.; Antonova, Julie; McLean, Graeme W.; Kim, Seung K.

2011-01-01

Drosophila neuroendocrine cells comprising the corpora cardiaca (CC) are essential for systemic glucose regulation and represent functional orthologues of vertebrate pancreatic α-cells. Although Drosophila CC cells have been regarded as developmental orthologues of pituitary gland, the genetic regulation of CC development is poorly understood. From a genetic screen, we identified multiple novel regulators of CC development, including Notch signaling factors. Our studies demonstrate that the disruption of Notch signaling can lead to the expansion of CC cells. Live imaging demonstrates localized emergence of extra precursor cells as the basis of CC expansion in Notch mutants. Contrary to a recent report, we unexpectedly found that CC cells originate from head mesoderm. We show that Tinman expression in head mesoderm is regulated by Notch signaling and that the combination of Daughterless and Tinman is sufficient for ectopic CC specification in mesoderm. Understanding the cellular, genetic, signaling, and transcriptional basis of CC cell specification and expansion should accelerate discovery of molecular mechanisms regulating ontogeny of organs that control metabolism. PMID:21901108

Risk of Pancreatic Cancer After a Primary Episode of Acute Pancreatitis.

PubMed

Rijkers, Anton P; Bakker, Olaf J; Ahmed Ali, Usama; Hagenaars, Julia C J P; van Santvoort, Hjalmar C; Besselink, Marc G; Bollen, Thomas L; van Eijck, Casper H

2017-09-01

Acute pancreatitis may be the first manifestation of pancreatic cancer. The aim of this study was to assess the risk of pancreatic cancer after a first episode of acute pancreatitis. Between March 2004 and March 2007, all consecutive patients with a first episode of acute pancreatitis were prospectively registered. Follow-up was based on hospital records audit, radiological imaging, and patient questionnaires. Outcome was stratified based on the development of chronic pancreatitis. We included 731 patients. The median follow-up time was 55 months. Progression to chronic pancreatitis was diagnosed in 51 patients (7.0%). In this group, the incidence rate per 1000 person-years for developing pancreatic cancer was 9.0 (95% confidence interval, 2.3-35.7). In the group of 680 patients who did not develop chronic pancreatitis, the incidence rate per 1000 person-years for developing pancreatic cancer in this group was 1.1 (95% confidence interval, 0.3-3.3). Hence, the rate ratio of pancreatic cancer was almost 9 times higher in patients who developed chronic pancreatitis compared with those who did not (P = 0.049). Although a first episode of acute pancreatitis may be related to pancreatic cancer, this risk is mainly present in patients who progress to chronic pancreatitis.

Fractionated Radioimmunotherapy With 90Y-Clivatuzumab Tetraxetan and Low-Dose Gemcitabine Is Active in Advanced Pancreatic Cancer

PubMed Central

Ocean, Allyson J.; Pennington, Kenneth L.; Guarino, Michael J.; Sheikh, Arif; Bekaii-Saab, Tanios; Serafini, Aldo N.; Lee, Daniel; Sung, Max W.; Gulec, Seza A.; Goldsmith, Stanley J.; Manzone, Timothy; Holt, Michael; O’Neil, Bert H.; Hall, Nathan; Montero, Alberto J.; Kauh, John; Gold, David V.; Horne, Heather; Wegener, William A.; Goldenberg, David M.

2014-01-01

BACKGROUND It has been demonstrated that the humanized clivatuzumab tetraxetan (hPAM4) antibody targets pancreatic ductal carcinoma selectively. After a trial of radioimmunotherapy that determined the maximum tolerated dose of single-dose yttrium-90-labeled hPAM4 (90Y-hPAM4) and produced objective responses in patients with advanced pancreatic ductal carcinoma, the authors studied fractionated radioimmunotherapy combined with low-dose gemcitabine in this disease. METHODS Thirty-eight previously untreated patients (33 patients with stage IV disease and 5 patients with stage III disease) received gemcitabine 200 mg/m2 weekly for 4 weeks with 90Y-hPAM4 given weekly in Weeks 2, 3, and 4 (cycle 1), and the same cycle was repeated in 13 patients (cycles 2–4). In the first part of the study, 19 patients received escalating weekly 90Y doses of 6.5 mCi/m2, 9.0 mCi/m2, 12.0 mCi/m2, and 15.0 mCi/m2. In the second portion, 19 additional patients received weekly doses of 9.0 mCi/m2 or 12.0 mCi/m2. RESULTS Grade 3/4 thrombocytopenia or neutropenia (according to version 3.0 of the National Cancer Institute’s Common Terminology Criteria for Adverse Events) developed in 28 of 38 patients after cycle 1 and in all retreated patients; no grade >3 nonhematologic toxicities occurred. Fractionated dosing of cycle 1 allowed almost twice the radiation dose compared with single-dose radioimmunotherapy. The maximum tolerated dose of 90Y-hPAM4 was 12.0 mCi/m2 weekly for 3 weeks for cycle 1, with ≤9.0 mCi/m2 weekly for 3 weeks for subsequent cycles, and that dose will be used in future trials. Six patients (16%) had partial responses according to computed tomography-based Response Evaluation Criteria in Solid Tumors, and 16 patients (42%) had stabilization as their best response (58% disease control). The median overall survival was 7.7 months for all 38 patients, including 11.8 months for those who received repeated cycles (46% [6 of 13 patients] ≥1 year), with improved efficacy at

Pancreatic trauma

PubMed Central

Bhattacharya, S

2013-01-01

Introduction Pancreatic trauma occurs in approximately 4% of all patients sustaining abdominal injuries. The pancreas has an intimate relationship with the major upper abdominal vessels, and there is significant morbidity and mortality associated with severe pancreatic injury. Immediate resuscitation and investigations are essential to delineate the nature of the injury, and to plan further management. If main pancreatic duct injuries are identified, specialised input from a tertiary hepatopancreaticobiliary (HPB) team is advised. Methods A comprehensive online literature search was performed using PubMed. Relevant articles from international journals were selected. The search terms used were: ‘pancreatic trauma’, ‘pancreatic duct injury’, ‘radiology AND pancreas injury’, ‘diagnosis of pancreatic trauma’, and ‘management AND surgery’. Articles that were not published in English were excluded. All articles used were selected on relevance to this review and read by both authors. Results Pancreatic trauma is rare and associated with injury to other upper abdominal viscera. Patients present with non-specific abdominal findings and serum amylase is of little use in diagnosis. Computed tomography is effective in diagnosing pancreatic injury but not duct disruption, which is most easily seen on endoscopic retrograde cholangiopancreaticography or operative pancreatography. If pancreatic injury is suspected, inspection of the entire pancreas and duodenum is required to ensure full evaluation at laparotomy. The operative management of pancreatic injury depends on the grade of injury found at laparotomy. The most important prognostic factor is main duct disruption and, if found, reconstructive options should be determined by an experienced HPB surgeon. Conclusions The diagnosis of pancreatic trauma requires a high index of suspicion and detailed imaging studies. Grading pancreatic injury is important to guide operative management. The most important

Irreversible electroporation as treatment of locally advanced and as margin accentuation in borderline resectable pancreatic adenocarcinoma.

PubMed

Marsanic, P; Mellano, A; Sottile, A; De Simone, M

2017-07-01

In recent years, many local ablation technologies based on thermal damage have been used in the treatment of locally advanced pancreatic carcinoma (LAPC) and borderline resectable pancreatic carcinoma (BLRPC). However, they are associated with major complications because of possible vascular and ductal damage. Irreversible electroporation (IRE) is a nonthermal ablation technology that seems safe near vital vascular and ductal structures. IRE could be used as exclusive treatment of LAPC (en situ to IRE) after induction chemotherapy In BLRPC, surgery is not really radical in 6% of patients (microscopic residual) and local recurrences occur in 11-42% of apparent radical resections. IRE could be used as margin accentuation to increase posterior margin during radical surgery in BLRPC. Our outcomes are safety, time to progression. Secondary outcomes are overall survival, pain control and quality of life. We are performing a prospective evaluation of patients undergoing IRE for LAPC or BLRPC since July 2014. We have included patients with non-metastatic LAPC with maximum size ≤4 cm (en situ to IRE) and patients with BLRPC (complementary IRE). We have performed induction chemotherapy in both groups. After treatment, patients were evaluated on days 1, 2, 4, 7, 14, 21, 30, 60 and 90 with amylase and lipase serum and abdominal drainage test. Based on Ethics Committee's request, follow-up imaging was performed at the 10th day for safety evaluation, at 30, 60 and 90 days for response evaluation and then every 3 months. Seven patients (two women and five men) underwent IRE. Two patients had LAPC and received en situ to IRE. In five patients affected by BLRPC we performed IRE and pancreatic head resection. In all patients, intraoperative imaging confirmed that the treatment of the whole tumor volume was complete. All seven patients demonstrated nonclinically relevant elevation of their amylase and lipase, which returned normal at 5 days postprocedure. No patient showed

Regional intra-arterial vs. systemic chemotherapy for advanced pancreatic cancer: a systematic review and meta-analysis of randomized controlled trials.

PubMed

Liu, Fenghua; Tang, Yong; Sun, Junwei; Yuan, Zhanna; Li, Shasha; Sheng, Jun; Ren, He; Hao, Jihui

2012-01-01

To investigate the efficacy and safety of regional intra-arterial chemotherapy (RIAC) versus systemic chemotherapy for stage III/IV pancreatic cancer. Randomized controlled trials of patients with advanced pancreatic cancer treated by regional intra-arterial or systemic chemotherapy were identified using PubMed, ISI, EMBASE, Cochrane Library, Google, Chinese Scientific Journals Database (VIP), and China National Knowledge Infrastructure (CNKI) electronic databases, for all publications dated between 1960 and December 31, 2010. Data was independently extracted by two reviewers. Odds ratios and relative risks were pooled using either fixed- or random-effects models, depending on I(2) statistic and Q test assessments of heterogeneity. Statistical analysis was performed using RevMan 5.0. Six randomized controlled trials comprised of 298 patients met the standards for inclusion in the meta-analysis, among 492 articles that were identified. Eight patients achieved complete remission (CR) with regional intra-arterial chemotherapy (RIAC), whereas no patients achieved CR with systemic chemotherapy. Compared with systemic chemotherapy, patients receiving RIAC had superior partial remissions (RR = 1.99, 95% CI: 1.50, 2.65; 58.06% with RIAC and 29.37% with systemic treatment), clinical benefits (RR = 2.34, 95% CI: 1.84, 2.97; 78.06% with RAIC and 29.37% with systemic treatment), total complication rates (RR = 0.72, 95% CI: 0.60, 0.87; 49.03% with RIAC and 71.33% with systemic treatment), and hematological side effects (RR = 0.76, 95% CI: 0.63, 0.91; 60.87% with RIAC and 85.71% with systemic treatment). The median survival time with RIAC (5-21 months) was longer than for systemic chemotherapy (2.7-14 months). Similarly, one year survival rates with RIAC (28.6%-41.2%) were higher than with systemic chemotherapy (0%-12.9%.). Regional intra-arterial chemotherapy is more effective and has fewer complications than systemic chemotherapy for treating advanced

The Association of Viral Hepatitis and Acute Pancreatitis

PubMed Central

Geokas, Michael C.; Olsen, Harvey; Swanson, Virginia; Rinderknecht, Heinrich

1972-01-01

The histological features of 24 pancreases obtained from patients who died of causes other than hepatitis, pancreatitis or pancreatic tumors, included a variable degree of autolysis, rare foci of inflammatory reaction but no hemorrhagic fat necrosis or destruction of elastic tissue in vessel walls (elastolysis). Assays of elastase in extracts of these pancreases showed no free enzyme, but varying amounts of proelastase. A review of autopsy findings in 33 patients with fatal liver necrosis attributed to halothane anesthesia, demonstrated changes of acute pancreatitis only in two. On the other hand, a review of 16 cases of fulminant viral hepatitis revealed changes characteristic of acute pancreatitis in seven – interstitial edema, hemorrhagic fat necrosis, inflammatory reaction and frequently elastolysis in vessel walls. Determination of elastase in extracts of one pancreas showed the bulk of the enzyme in free form. Furthermore, assays of urinary amylase in 44 patients with viral hepatitis showed increased levels of this enzyme (2583 ± 398 mean value ± standard error, Somogyi units per 100 ml in 13, or 29.5 percent). The evidence suggests that acute pancreatitis may at times complicate viral hepatitis. Although direct proof of viral pancreatic involvement is not feasible at present, a rational hypothesis is advanced which underlines similar mechanisms of tissue involvement in both liver and pancreas that may be brought about by the hepatitis viruses. PMID:5070694

Combination Chemotherapy With or Without Oregovomab Followed by Stereotactic Body Radiation Therapy and Nelfinavir Mesylate in Treating Patients With Locally Advanced Pancreatic Cancer

ClinicalTrials.gov

2018-04-24

Pancreatic Adenocarcinoma; Resectable Pancreatic Carcinoma; Stage I Pancreatic Cancer; Stage IA Pancreatic Cancer; Stage IB Pancreatic Cancer; Stage II Pancreatic Cancer; Stage IIA Pancreatic Cancer; Stage IIB Pancreatic Cancer; Stage III Pancreatic Cancer

Initial Misdiagnosis of Proximal Pancreatic Adenocarcinoma Is Associated with Delay in Diagnosis and Advanced Stage at Presentation.