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Sample records for pancreatic neuroendocrine tumours

  1. p53 tumour suppressor gene expression in pancreatic neuroendocrine tumour cells.

    PubMed Central

    Bartz, C; Ziske, C; Wiedenmann, B; Moelling, K

    1996-01-01

    Neuroendocrine pancreatic tumours grow slower and metastasise later than ductal and acinar carcinomas. The expression of the p53 tumour suppressor gene in pancreatic neuroendocrine tumour cells is unknown. Pancreatic neuroendocrine cell lines (n = 5) and human tumour tissues (n = 19) were studied for changed p53 coding sequence, transcription, and translation. Proliferative activity of tumour cells was determined analysing Ki-67 expression. No mutation in the p53 nucleotide sequence of neuroendocrine tumour cell was found. However, an overexpression of p53 could be detected in neuroendocrine pancreatic tumour cell lines at a protein level. As no p53 mutations were seen, it is suggested that post-translational events can also lead to an overexpression of p53. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 PMID:8675094

  2. Medical treatment for gastro-entero-pancreatic neuroendocrine tumours

    PubMed Central

    Berardi, Rossana; Morgese, Francesca; Torniai, Mariangela; Savini, Agnese; Partelli, Stefano; Rinaldi, Silvia; Caramanti, Miriam; Ferrini, Consuelo; Falconi, Massimo; Cascinu, Stefano

    2016-01-01

    Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) represents a various family of rare tumours. Surgery is the first choice in GEP-NENs patients with localized disease whilst in the metastatic setting many other treatment options are available. Somatostatin analogues are indicated for symptoms control in functioning tumours. Furthermore they may be effective to inhibit tumour progression. GEP-NENs pathogenesis has been extensively studied in the last years therefore several driver mutations pathway genes have been identified as crucial factors in their tumourigenesis. GEP-NENs can over-express vascular endothelial growth factor (VEGF), basic-fibroblastic growth factor, transforming growth factor (TGF-α and -β), platelet derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1) and their receptors PDGF receptor, IGF-1 receptor, epidermal growth factor receptor, VEGF receptor, and c-kit (stem cell factor receptor) that can be considered as potential targets. The availability of new targeted agents, such as everolimus and sunitinib that are effective in advanced and metastatic pancreatic neuroendocrine tumours, has provided new treatment opportunities. Many trials combing new drugs are ongoing. PMID:27096034

  3. Pancreatic neuroendocrine tumours: correlation between MSCT features and pathological classification.

    PubMed

    Luo, Yanji; Dong, Zhi; Chen, Jie; Chan, Tao; Lin, Yuan; Chen, Minhu; Li, Zi-Ping; Feng, Shi-Ting

    2014-11-01

    We aimed to evaluate the multi-slice computed tomography (MSCT) features of pancreatic neuroendocrine neoplasms (P-NENs) and analyse the correlation between the MSCT features and pathological classification of P-NENs. Forty-one patients, preoperatively investigated by MSCT and subsequently operated on with a histological diagnosis of P-NENs, were included. Various MSCT features of the primary tumour, lymph node, and distant metastasis were analysed. The relationship between MSCT features and pathologic classification of P-NENs was analysed with univariate and multivariate models. Contrast-enhanced images showed significant differences among the three grades of tumours in the absolute enhancement (P = 0.013) and relative enhancement (P = 0.025) at the arterial phase. Univariate analysis revealed statistically significant differences among the tumours of different grades (based on World Health Organization [WHO] 2010 classification) in tumour size (P = 0.001), tumour contour (P < 0.001), cystic necrosis (P = 0.001), tumour boundary (P = 0.003), dilatation of the main pancreatic duct (P = 0.001), peripancreatic tissue or vascular invasion (P < 0.001), lymphadenopathy (P = 0.011), and distant metastasis (P = 0.012). Multivariate analysis suggested that only peripancreatic tissue or vascular invasion (HR 3.934, 95 % CI, 0.426-7.442, P = 0.028) was significantly associated with WHO 2010 pathological classification. MSCT is helpful in evaluating the pathological classification of P-NENs. • P-NENs are potentially malignant, and classification of P-NENs carries important prognostic value. • MSCT plays an important role in the diagnosis and staging of P-NENs. • Correlations between classification of P-NENs and imaging findings have not been systematically evaluated. • MSCT could predict P-NENs classification and may be a useful prognostication tool.

  4. 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.

  5. [Pancreatic neuroendocrine tumours. What do we know of their history?].

    PubMed

    Navarro, Salvador

    2016-04-01

    Starting with Paul Langerhans, who first described pancreatic islets in 1869, this article reviews the various protagonists who, in the last century and a half, have contributed to the discovery of the main hormones originating in the pancreas, the analytical methods for their measurement, the imaging techniques for identifying tumoural location, and the various pancreatic neoplasms. Copyright © 2015. Published by Elsevier Espana.

  6. Case report. Peripancreatic intranodal haemangioma mimicking pancreatic neuroendocrine tumour: imaging and pathological findings.

    PubMed

    Karaosmanoglu, A D; Arellano, R; Baker, G

    2011-12-01

    Haemangiomas are common benign tumours that are generally detected within the skin, mucosal surfaces and soft tissues. However, intranodal haemangiomas are extremely rare and are among the benign primary vascular abnormalities of the lymph nodes that include lymphangioma, haemangioendothelioma, angiomyomatous hamartoma and haemangiomas. In this case report, we present the imaging and pathological findings of an intranodal haemangioma in the pancreatic head simulating a pancreatic neuroendocrine tumour. To the best of our knowledge, this is the first report of an intranodal haemangioma in this location.

  7. Diagnostic and therapeutic guidelines for gastro-entero-pancreatic neuroendocrine neoplasms (recommended by the Polish Network of Neuroendocrine Tumours).

    PubMed

    Kos-Kudła, Beata; Blicharz-Dorniak, Jolanta; Handkiewicz-Junak, Daria; Jarząb, Barbara; Jarząb, Michał; Kunikowska, Jolanta; Kuśnierz, Katarzyna; Król, Robert; Królicki, Leszek; Krzakowski, Maciej; Nasierowska-Guttmejer, Anna; Nowakowska-Duława, Ewa; Patkowski, Waldemar; Szawłowski, Andrzej W

    2013-01-01

    An increased interest in gastro-entero-pancreatic neuroendocrine neoplasms (GEP NENs) has recently been observed. These are rare neoplasms and their detection in recent years has improved. Over 50% of GEP NENs are carcinoids, and they are usually found incidentally during surgery in the small intestine and appendix and at diagnosis in distant metastases, mainly to the liver. There is a need for co-operation between specialists in various disciplines of medicine in order to work out the diagnostic and therapeutic guidelines. In this publication, we present general recommendations of the Polish Network of Neuroendocrine Tumours for the management of patients with GEP NENs, developed at the Consensus Conference which took place in Kamień Śląski in April 2013. Members of the guidelines working groups were assigned sections of the 2008 guidance to update. In the subsequent parts of this publication, we present the rules of diagnostic and therapeutic management of: - neuroendocrine neoplasms of the stomach and duodenum (including gastrinoma); - pancreatic neuroendocrine neoplasms; - neuroendocrine neoplasms of the small intestine and the appendix; - colorectal neuroendocrine neoplasms. The proposed recommendations by Polish and foreign experts representing different fields of medicine (endocrinology, gastroenterology, surgery, oncology, nuclear medicine and pathology) will be helpful in the diagnosis and treatment of GEP NENs patients.

  8. Pathogenic PALB2 mutation in metastatic pancreatic adenocarcinoma and neuroendocrine tumour: A case report

    PubMed Central

    CHAN, DAVID; CLARKE, STEPHEN; GILL, ANTHONY J.; CHANTRILL, LORRAINE; SAMRA, JAS; LI, BOB T.; BARNES, TRISTAN; NAHAR, KAZI; PAVLAKIS, NICK

    2015-01-01

    Adenocarcinoma of the pancreas is an aggressive malignancy with poor prognosis. Pancreatic neuroendocrine tumours (PNET) comprise ~3% of primary pancreatic neoplasms and they are more heterogeneous in their histological character and outcome. This is the case report of a 73-year-old female patient with synchronously diagnosed pancreatic adenocarcinoma and PNET, which is likely associated with a pathogenic partner and localizer of breast cancer 2, early onset (PALB2) mutation. The potential pathogenic significance of PALB2 and its association with various malignancies were investigated and the potential role of PALB2 in conferring sensitivity to chemotherapeutic agents, such as mitomycin C and cisplatin, was discussed. This case report highlights the significance of ongoing research into the molecular pathogenesis of pancreatic cancer, which may help guide the selection of optimal treatments for this disease, as well as the need for ongoing study of PALB2 as a possible predictive marker of response to DNA-damaging agents. PMID:26171187

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

    SciTech Connect

    Orgera, Gianluigi; Krokidis, Miltiadis; Monfardini, Lorenzo; Bonomo, Guido; Della Vigna, Paolo; Fazio, Nicola; Orsi, Franco

    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 pancreatic NETs. However, currently the procedure should be reserved for inoperable patients for whom symptoms cannot be controlled by medical therapy.

  10. Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study.

    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; Gomez-Panzani, Edda; Ruszniewski, Philippe

    2016-03-01

    In the CLARINET study, lanreotide Autogel (depot in USA) significantly prolonged progression-free survival (PFS) in patients with metastatic pancreatic/intestinal neuroendocrine tumours (NETs). We report long-term safety and additional efficacy data from the open-label extension (OLE). Patients with metastatic grade 1/2 (Ki-67 ≤ 10%) non-functioning NET and documented baseline tumour-progression status received lanreotide Autogel 120 mg (n = 101) or placebo (n = 103) for 96 weeks or until death/progressive disease (PD) in CLARINET study. Patients with stable disease (SD) at core study end (lanreotide/placebo) or PD (placebo only) continued or switched to lanreotide in the OLE. In total, 88 patients (previously: lanreotide, n = 41; placebo, n = 47) participated: 38% had pancreatic, 39% midgut and 23% other/unknown primary tumours. Patients continuing lanreotide reported fewer adverse events (AEs) (all and treatment-related) during OLE than core study. Placebo-to-lanreotide switch patients reported similar AE rates in OLE and core studies, except more diarrhoea was considered treatment-related in OLE (overall diarrhoea unchanged). Median lanreotide PFS (core study randomisation to PD in core/OLE; n=101) was 32.8 months (95% CI: 30.9, 68.0). A sensitivity analysis, addressing potential selection bias by assuming that patients with SD on lanreotide in the core study and not entering the OLE (n=13) had PD 24 weeks after last core assessment, found median PFS remaining consistent: 30.8 months (95% CI: 30.0, 31.3). Median time to further PD after placebo-to-lanreotide switch (n=32) was 14.0 months (10.1; not reached). This OLE study suggests long-term treatment with lanreotide Autogel 120 mg maintained favourable safety/tolerability. CLARINET OLE data also provide new evidence of lanreotide anti-tumour benefits in indolent and progressive pancreatic/intestinal NETs. © 2016 The authors.

  11. Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study

    PubMed Central

    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; Gomez-Panzani, Edda; Ruszniewski, Philippe

    2016-01-01

    In the CLARINET study, lanreotide Autogel (depot in USA) significantly prolonged progression-free survival (PFS) in patients with metastatic pancreatic/intestinal neuroendocrine tumours (NETs). We report long-term safety and additional efficacy data from the open-label extension (OLE). Patients with metastatic grade 1/2 (Ki-67 ≤10%) non-functioning NET and documented baseline tumour-progression status received lanreotide Autogel 120 mg (n=101) or placebo (n=103) for 96 weeks or until death/progressive disease (PD) in CLARINET study. Patients with stable disease (SD) at core study end (lanreotide/placebo) or PD (placebo only) continued or switched to lanreotide in the OLE. In total, 88 patients (previously: lanreotide, n=41; placebo, n=47) participated: 38% had pancreatic, 39% midgut and 23% other/unknown primary tumours. Patients continuing lanreotide reported fewer adverse events (AEs) (all and treatment-related) during OLE than core study. Placebo-to-lanreotide switch patients reported similar AE rates in OLE and core studies, except more diarrhoea was considered treatment-related in OLE (overall diarrhoea unchanged). Median lanreotide PFS (core study randomisation to PD in core/OLE; n=101) was 32.8 months (95% CI: 30.9, 68.0). A sensitivity analysis, addressing potential selection bias by assuming that patients with SD on lanreotide in the core study and not entering the OLE (n=13) had PD 24 weeks after last core assessment, found median PFS remaining consistent: 30.8 months (95% CI: 30.0, 31.3). Median time to further PD after placebo-to-lanreotide switch (n=32) was 14.0 months (10.1; not reached). This OLE study suggests long-term treatment with lanreotide Autogel 120 mg maintained favourable safety/tolerability. CLARINET OLE data also provide new evidence of lanreotide anti-tumour benefits in indolent and progressive pancreatic/intestinal NETs. PMID:26743120

  12. 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.

  13. TRPV6 modulates proliferation of human pancreatic neuroendocrine BON-1 tumour cells

    PubMed Central

    Skrzypski, Marek; Kołodziejski, Paweł A.; Mergler, Stefan; Khajavi, Noushafarin; Nowak, Krzysztof W.; Strowski, Mathias Z.

    2016-01-01

    Highly Ca2+ permeable receptor potential channel vanilloid type 6 (TRPV6) modulates a variety of biological functions including calcium-dependent cell growth and apoptosis. So far, the role of TRPV6 in controlling growth of pancreatic neuroendocrine tumour (NET) cells is unknown. In the present study, we characterize the expression of TRPV6 in pancreatic BON-1 and QGP-1 NET cells. Furthermore, we evaluate the impact of TRPV6 on intracellular calcium, the activity of nuclear factor of activated T-cells (NFAT) and proliferation of BON-1 cells. TRPV6 expression was assessed by real-time PCR and Western blot. TRPV6 mRNA expression and protein production were down-regulated by siRNA. Changes in intracellular calcium levels were detected by fluorescence calcium imaging (fura-2/AM). NFAT activity was studied by NFAT reporter assay; cell proliferation by bromodeoxyuridine (BrdU), MTT and propidium iodine staining. TRPV6 mRNA and protein are present in BON-1 and QGP-1 NET-cells. Down-regulation of TRPV6 attenuates BON-1 cell proliferation. TRPV6 down-regulation is associated with decreased Ca2+ response pattern and reduced NFAT activity. In conclusion, TRPV6 is expressed in pancreatic NETs and modulates cell proliferation via Ca2+-dependent mechanism, which is accompanied by NFAT activation. PMID:27450545

  14. TRPV6 modulates proliferation of human pancreatic neuroendocrine BON-1 tumour cells.

    PubMed

    Skrzypski, Marek; Kołodziejski, Paweł A; Mergler, Stefan; Khajavi, Noushafarin; Nowak, Krzysztof W; Strowski, Mathias Z

    2016-08-01

    Highly Ca(2+) permeable receptor potential channel vanilloid type 6 (TRPV6) modulates a variety of biological functions including calcium-dependent cell growth and apoptosis. So far, the role of TRPV6 in controlling growth of pancreatic neuroendocrine tumour (NET) cells is unknown. In the present study, we characterize the expression of TRPV6 in pancreatic BON-1 and QGP-1 NET cells. Furthermore, we evaluate the impact of TRPV6 on intracellular calcium, the activity of nuclear factor of activated T-cells (NFAT) and proliferation of BON-1 cells. TRPV6 expression was assessed by real-time PCR and Western blot. TRPV6 mRNA expression and protein production were down-regulated by siRNA. Changes in intracellular calcium levels were detected by fluorescence calcium imaging (fura-2/AM). NFAT activity was studied by NFAT reporter assay; cell proliferation by bromodeoxyuridine (BrdU), MTT and propidium iodine staining. TRPV6 mRNA and protein are present in BON-1 and QGP-1 NET-cells. Down-regulation of TRPV6 attenuates BON-1 cell proliferation. TRPV6 down-regulation is associated with decreased Ca(2+) response pattern and reduced NFAT activity. In conclusion, TRPV6 is expressed in pancreatic NETs and modulates cell proliferation via Ca(2+)-dependent mechanism, which is accompanied by NFAT activation.

  15. CUX1: a modulator of tumour aggressiveness in pancreatic neuroendocrine neoplasms.

    PubMed

    Krug, Sebastian; Kühnemuth, Benjamin; Griesmann, Heidi; Neesse, Albrecht; Mühlberg, Leonie; Boch, Michael; Kortenhaus, Juliane; Fendrich, Volker; Wiese, Dominik; Sipos, Bence; Friemel, Juliane; Gress, Thomas M; Michl, Patrick

    2014-01-01

    Pancreatic neuroendocrine neoplasms (PNENs) constitute a rare tumour entity, and prognosis and treatment options depend on tumour-mediating hallmarks such as angiogenesis, proliferation rate and resistance to apoptosis. The molecular pathways that determine the malignant phenotype are still insufficiently understood and this has limited the use of effective combination therapies in the past. In this study, we aimed to characterise the effect of the oncogenic transcription factor Cut homeobox 1 (CUX1) on proliferation, resistance to apoptosis and angiogenesis in murine and human PNENs. The expression and function of CUX1 were analysed using knockdown and overexpression strategies in Ins-1 and Bon-1 cells, xenograft models and a genetically engineered mouse model of insulinoma (RIP1Tag2). Regulation of angiogenesis was assessed using RNA profiling and functional tube-formation assays in HMEC-1 cells. Finally, CUX1 expression was assessed in a tissue microarray of 59 human insulinomas and correlated with clinicopathological data. CUX1 expression was upregulated during tumour progression in a time- and stage-dependent manner in the RIP1Tag2 model, and associated with pro-invasive and metastatic features of human insulinomas. Endogenous and recombinant CUX1 expression increased tumour cell proliferation, tumour growth, resistance to apoptosis, and angiogenesis in vitro and in vivo. Mechanistically, the pro-angiogenic effect of CUX1 was mediated via upregulation of effectors such as HIF1α and MMP9. CUX1 mediates an invasive pro-angiogenic phenotype and is associated with malignant behaviour in human insulinomas. © 2014 Society for Endocrinology.

  16. Two cases of feline paraneoplastic alopecia associated with a neuroendocrine pancreatic neoplasia and a hepatosplenic plasma cell tumour.

    PubMed

    Caporali, Chiara; Albanese, Francesco; Binanti, Diana; Abramo, Francesca

    2016-12-01

    Feline paraneoplastic alopecia (FPA) is a rare condition listed among the cutaneous paraneoplastic syndromes, which occurs in association with pancreatic carcinoma, cholangiocarcinoma, hepatocellular carcinoma and metastatic intestinal carcinoma. To describe the clinicopathological findings of paraneoplastic alopecia in two cats each with an uncommon tumour not previously reported in association with FPA. Paraneoplastic alopecia was associated with neuroendocrine pancreatic neoplasia in a Persian cat and with a hepatosplenic plasma cell tumour in a domestic short hair cat. FPA was suspected based on age, rapid onset of clinical signs, ventral distribution of alopecia, shiny appearance of the skin and telogenization/miniaturization of the follicles on histopathology. The nature of the tumours was determined through cytology, postmortem, histopathological and immunohistochemical examination, and capillary immunoelectrophoresis. A causative association between the skin lesions and the tumour was suggested by clinical and histopathological features shared with previously published cases. Pancreatic neuroendocrine and plasma cell tumour should be considered as differential diagnoses when evaluating FPA. © 2016 ESVD and ACVD.

  17. Expression of Vascular Endothelial Growth Factor and Epidermal Growth Factor Receptor in Pancreatic Ductal Adenocarcinomas, Neuroendocrine Tumours and Chronic Pancreatitis

    PubMed Central

    Angelescu, Radu; Burada, Florin; Angelescu, Cristina; Gheonea, Dan Ionut; Iordache, Sevastița; Mixich, Francisc; Ioana, Mihai; Săftoiu, Adrian

    2013-01-01

    Objective: Angiogenesis is a crucial event for pancreatic carcinogenesis, and it also plays an important role in chronic pancreatitis. The aim of our study was to evaluate the mRNA expression of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) in chronic inflammatory or malignant pancreatic pathology in order to elucidate the differences in expression patterns and potential clinical implications. Methods: Thirty-five patients who had undergone endoscopic ultrasonography followed by endoscipic ultrasound-guided fine needle aspiration (EUS-FNA) of focal pancreatic masses were included in the study. VEGF and EGFR mRNA expression levels in the samples collected by EUS-FNA were analyzed using quantitative real-time polymerase chain reaction (PCR). Results: VEGF expression was detected in all chronic pancreatitis and adenocarcinoma samples and in only 62.5% of pancreatic neuroendocrine tumors. EGFR expression was detected in only 40% of the chronic pancreatitis cases, 76.9% of adenocarcinomas and in 50% of pancreatic neuroendocrine tumors. Both VEGF and EGFR mRNA levels were significantly higher in pancreatic ductal adenocarcinoma than those in normal tissue. VEGF expression inversely correlated with pancreatic ductal adenocarcinoma size, while EGFR expression was related to local invasiveness of adenocarcinoma. Conclusion: Both VEGF and EGFR mRNA expression in EUS-FNA samples may be used as a diagnostic marker associated with invasiveness in patients with pancreatic adenocarcinoma. PMID:24949370

  18. A systematic review of non-surgical treatments for pancreatic neuroendocrine tumours.

    PubMed

    Valle, Juan W; Eatock, Martin; Clueit, Ben; Gabriel, Zahava; Ferdinand, Roxanne; Mitchell, Stephen

    2014-04-01

    Pancreatic neuroendocrine tumours (pNETs) are rare and the majority of patients present with advanced disease. Such patients have limited treatment options. We conducted a systematic review of published clinical trials of non-surgical interventions in pNET, to understand the efficacy, safety and health related quality of life (HRQoL) outcomes from the current evidence base. Electronic databases and manual bibliographic searches were conducted to identify relevant studies. Data were extracted by two independent reviewers. Forty seven clinical studies met the predefined inclusion criteria. The following interventions were included: targeted therapies (two RCTs and six single-arm studies), chemotherapy (two RCTs, one prospective nonrandomised, comparative study and 14 single-arm studies);somatostatin analogues (SSA) and radiolabeled SSA therapies (nine single-arm studies), liver-directed therapies (six single-arm studies), mixed treatment regimens (one RCT, four single-arm studies) and other interventions such as interferon and recombinant human endostatin (one single-arm study for each). The paucity of RCT data and lack of consistency in reporting validated study outcomes and differing patient inclusion criteria between studies made it difficult to compare the relative efficacy of therapies. The majority of published studies assessing treatment regimens for the management of pNET are single arm, non-randomised studies, often enrolling a small number of patients and not reporting clinically meaningful outcomes. However data from recently conducted studies assessing targeted therapies indicate that it is possible to conduct adequately powered RCTs reporting standardised oncological endpoints in this rare cancer. Further, similarly robust studies should be conducted to define the optimal treatment algorithm. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

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

    SciTech Connect

    Orgera, Gianluigi; Krokidis, Miltiadis; Cappucci, Matteo; Gourtsoyianni, Sofia; Tipaldi, Marcello Andrea; Hatzidakis, Adam; Rebonato, Alberto; Rossi, Michele

    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.

  20. Screening for malnutrition in patients with gastro-entero-pancreatic neuroendocrine tumours: a cross-sectional study

    PubMed Central

    Qureshi, Sheharyar A; Burch, Nicola; Druce, Maralyn; Hattersley, John G; Khan, Saboor; Gopalakrishnan, Kishore; Darby, Catherine; Wong, John L H; Davies, Louise; Fletcher, Simon; Shatwell, William; Sothi, Sharmila; Randeva, Harpal S; Dimitriadis, Georgios K; Weickert, Martin O

    2016-01-01

    Objectives To investigate whether screening for malnutrition using the validated malnutrition universal screening tool (MUST) identifies specific characteristics of patients at risk, in patients with gastro-entero-pancreatic neuroendocrine tumours (GEP-NET). Design Cross-sectional study. Setting University Hospitals Coventry & Warwickshire NHS Trust; European Neuroendocrine Tumour Society Centre of Excellence. Participants Patients with confirmed GEP-NET (n=161) of varying primary tumour sites, functioning status, grading, staging and treatment modalities. Main outcome measure To identify disease and treatment-related characteristics of patients with GEP-NET who score using MUST, and should be directed to detailed nutritional assessment. Results MUST score was positive (≥1) in 14% of outpatients with GEP-NET. MUST-positive patients had lower faecal elastase concentrations compared to MUST-negative patients (244±37 vs 383±20 µg/g stool; p=0.018), and were more likely to be on treatment with long-acting somatostatin analogues (65 vs 38%, p=0.021). MUST-positive patients were also more likely to have rectal or unknown primary NET, whereas, frequencies of other GEP-NET including pancreatic NET were comparable between MUST-positive and MUST-negative patients. Conclusions Given the frequency of patients identified at malnutrition risk using MUST in our relatively large and diverse GEP-NET cohort and the clinical implications of detecting malnutrition early, we recommend routine use of malnutrition screening in all patients with GEP-NET, and particularly in patients who are treated with long-acting somatostatin analogues. PMID:27147385

  1. Prediction of pancreatic neuroendocrine tumour grade with MR imaging features: added value of diffusion-weighted imaging.

    PubMed

    Lotfalizadeh, Emad; Ronot, Maxime; Wagner, Mathilde; Cros, Jérôme; Couvelard, Anne; Vullierme, Marie-Pierre; Allaham, Wassim; Hentic, Olivia; Ruzniewski, Philippe; Vilgrain, Valérie

    2017-04-01

    To evaluate the value of MR imaging including diffusion-weighted imaging (DWI) for the grading of pancreatic neuroendocrine tumours (pNET). Between 2006 and 2014, all resected pNETs with preoperative MR imaging including DWI were included. Tumour grading was based on the 2010 WHO classification. MR imaging features included size, T1-w, and T2-w signal intensity, enhancement pattern, apparent (ADC) and true diffusion (D) coefficients. One hundred and eight pNETs (mean 40 ± 33 mm) were evaluated in 94 patients (48 women, 51 %, mean age 52 ± 12). Fifty-five (51 %), 42 (39 %), and 11 (10 %) tumours were given the following grades (G): G1, G2, and G3. Mean ADC and D values were significantly lower as grade increased (ADC: 2.13 ± 0.70, 1.78 ± 0.72, and 0.86 ± 0.22 10(-3) mm(2)/s, and D: 1.92 ± 0.70, 1.75 ± 0.74, and 0.82 ± 0.19 10(-3) mm(2)/s G1, G2, and G3, all p < 0.001). A higher grade was associated with larger sized tumours (p < 0.001). The AUROC of ADC and D to differentiate G3 and G1-2 were 0.96 ± 0.02 and 0.95 ± 0.02. Optimal cut-off values for the identification of G3 were 1.19 10(-3) mm(2)/s for ADC (sensitivity 100 %, specificity 92 %) and 1.04 10(-3) mm(2)/s for D (sensitivity 82 %, specificity 92 %). Morphological/functional MRI features of pNETS depend on tumour grade. DWI is useful for the identification of high-grade tumours. • Morphological and functional MRI features of pNETs depend on tumour grade. • Their combination has a high predictive value for grade. • All pNETs should be explored by MR imaging including DWI. • DWI is helpful for identification of high-grade and poorly-differentiated tumours.

  2. Pancreatic neuroendocrine tumors

    PubMed Central

    Sun, Jian

    2017-01-01

    Summary Pancreatic neuroendocrine neoplasms (pNENs) are a heterogeneous group of tumors including well differentiated pancreatic neuroendocrine tumors (pNETs) and neuroendocrine carcinomas (pNECs). The incidence of pNENs has increased over the past few decades. Although, the understanding and interest for this tumor have also increased significantly, the debate about classification and diagnosis continues. Although the primary treatment for pNENs is surgical resection, there is still a lack of effective therapeutic options for patients with advanced unresectable pNENs. Although many therapeutic methods have proven effective, the choice of treatment and specific programs are still unclear. Our article presents an overview of pNENs, with a focus on their diagnostic work-up, clinical presentation and treatment options. PMID:28357177

  3. A Phase II Study of BEZ235 in Patients with Everolimus-resistant, Advanced Pancreatic Neuroendocrine Tumours

    PubMed Central

    FAZIO, NICOLA; BUZZONI, ROBERTO; BAUDIN, ERIC; ANTONUZZO, LORENZO; HUBNER, RICHARD A.; LAHNER, HARALD; DE HERDER, WOUTER W.; RADERER, MARKUS; TEULÉ, ALEXANDRE; CAPDEVILA, JAUME; LIBUTTI, STEVEN K.; KULKE, MATTHEW H.; SHAH, MANISHA; DEY, DEBARSHI; TURRI, SABINE; AIMONE, PAOLA; MASSACESI, CRISTIAN; VERSLYPE, CHRIS

    2016-01-01

    Background This was a two-stage, phase II trial of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor BEZ235 in patients with everolimus-resistant pancreatic neuroendocrine tumours (pNETs) (NCT01658436). Patients and Methods In stage 1, 11 patients received 400 mg BEZ235 orally twice daily (bid). Due to tolerability concerns, a further 20 patients received BEZ235 300 mg bid. Stage 2 would be triggered by a 16-week progression-free survival (PFS) rate of ≥60% in stage 1. Results As of 30 June, 2014, 29/31 patients had discontinued treatment. Treatment-related grade 3/4 adverse events were reported in eight (72.7%) patients at 400 mg and eight (40.0%) patients at 300 mg, including hyperglycaemia, diarrhoea, nausea, and vomiting. The estimated 16-week PFS rate was 51.6% (90% confidence interval=35.7–67.3%). Conclusion BEZ235 was poorly tolerated by patients with everolimus-resistant pNETs at 400 and 300 mg bid doses. Although evidence of disease stability was observed, the study did not proceed to stage 2. PMID:26851029

  4. Diagnostics of neuroendocrine tumours.

    PubMed

    Hodolic, M; Fettich, J; Banti, E; Chondrogiannis, S; Al-Nahhas, A; Rubello, D

    2010-01-01

    Neuroendocrine tumours (NETs) are rare pathologies which origin from neuroectodermic and endodermic cells and that can produce peptides and amino acids. About 70% of NETs derive from gastroenterohepatic (GEP) system and the other 30% from the different sites through the body. They are distinguished into single and multiple localizations and also into sporadic, familial multiple endocrine-related forms and recurrent forms. Moreover, when they produce hormones they usually are symptomatic; yet, they are characterized by the synthesis and secretion in the blood stream of several tumor-specific markers or can express somatostatin receptors in their cellular surface. The diagnosis and follow-up of NETs rely on laboratory studies, histopathology and the combination of anatomical and functional imaging, with the latter being the main method for monitoring response to therapy. In recent years, nuclear medicine has contributed to the impressive development of the knowledge of NETs in terms of biology (receptor scintigraphy), pharmacology (development of new tracers) and therapy (radiometabolic therapy). Nuclear medicine procedures for diagnosis and treatment of NETs are based on the biological properties of these tumours: the expression of somatostatin receptors. Somatostatin receptor scintigraphy not only has a crucial role in diagnosis and staging of NETs, but also in assessing suitability for treatment with cold and radiolabelled somatostatin analogues, as well as in monitoring response to treatment and detecting recurrent disease. In conventional nuclear medicine, the two most important functional imaging modalities are ¹¹¹In-octrescan and ¹²³I-MIBG. Over the last 5 years, due to the development of new tracers, such as ⁶⁸Ga labelled-DOTA-peptides PET and ¹⁸F-DOPA, PET has also been employed with significant benefits in the diagnosis and management of NETs.

  5. Pancreatic neuroendocrine tumors.

    PubMed

    Varas Lorenzo, Modesto; Cugat Andorra, Esteban; Capdevila Castillón, Jaume

    2017-06-01

    Endocrine or pancreatic neuroendocrine tumors (PNET) were first cited in the 1950s; they may be sporadic or associated with hereditary syndromes, benign or malignant, functioning or non-functioning. Nowadays, NF-PNETs are the most frequent and their prevalence ranges from 50% to 91%. In our current series (including 70 cases, 33% malignant, 52 operated) the frequency was 72% as compared to 37% in the historical series.

  6. Symptomatic Control of Neuroendocrine Tumours with Everolimus.

    PubMed

    Bainbridge, Hannah E; Larbi, Emmanuel; Middleton, Gary

    2015-12-01

    Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, increases progression-free survival in patients with advanced neuroendocrine tumours. Patients with neuroendocrine tumours and symptomatic carcinoid have inferior health-related quality of life than those without symptoms. We aimed to evaluate the effect of everolimus on symptomatic control of neuroendocrine tumours. Fifteen patients with metastatic neuroendocrine disease pre-treated with depot octreotide received combination everolimus and octreotide (midgut = 8, pancreatic = 3, other = 4). Reasons for initiation of everolimus were progressive disease (PD) by response evaluation criteria in solid tumours (n = 5), worsening syndromic symptomology (n = 5), or both (n = 5). Symptomatic and objective response and toxicity were evaluated using standard criteria. 7/10 patients who were syndromic had improvements in symptomology, with a mean duration of symptom control 13.9 months (range 1-39). All 10 symptomatic patients had non pancreatic neuroendocrine (pNET) primaries, and with everolimus, 6/10 had reduced stool frequency, 3/7 had a reduction of asthenia, and 5/7 had reduced frequency and severity of flushing. Sixty percent of patients experienced any grade toxicities, including the following: 40% grade 1/2 stomatitis, 7% grade 3/4 stomatitis, 20% grade 1/2 rash, 13% diarrhoea, and one case of pneumonitis. In this cohort of 15 patients, we demonstrated that 70% of non pNET individuals with common carcinoid syndrome symptoms resistant to depot octreotide had improvement in these symptoms on institution of everolimus, with meaningful durations of symptom control. Although this data is observational, to our knowledge, this represents the largest analysis of carcinoid syndrome control with combined everolimus and octreotide.

  7. Differentiation between pancreatic metastases from renal cell carcinoma and hypervascular neuroendocrine tumour: Use of relative percentage washout value and its clinical implication.

    PubMed

    Kang, Tae Wook; Kim, Seong Hyun; Lee, Jisun; Kim, Ah Yeong; Jang, Kyung Mi; Choi, Dongil; Kim, Min Ji

    2015-11-01

    To compare computed tomography (CT) findings in patients with pancreatic metastasis from renal cell carcinoma (pRCC) and patients with hypervascular pancreatic neuroendocrine tumour (pNET) with a focus on the relative percentage washout (RPW). We evaluated 16 patients with 37 pRCCs and 28 patients with 31 hypervascular pNETs using a protocol consisting of arterial and portal phase CT. Imaging findings were analyzed for comparison between the two groups. The RPW of each tumour using biphasic CT was obtained by two observers for evaluation of diagnostic performance. Interobserver agreement of each value and optimal cut-off level of RPW for discrimination between groups were evaluated. Tumour multiplicity showed significant difference in both groups. The mean RPW of the pRCC group (observer 1, 27.0%; observer 2, 29.4%) was significantly higher than that of the pNET group (observer 1, 0.5%; observer 2, 3.2%) (p<0.001 for each observer). Interobserver agreement for both attenuation values and RPWs was excellent. A RPW value of 19% was selected as the optimal cut-off for pRCC determination, and showed good performance (accuracy 83.8%, sensitivity 83.8%, and specificity 83.9%). With multiplicity, RPW of the tumour on CT could be helpful for differentiating pRCCs from hypervascular pNETs. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  8. The use of biomarkers in neuroendocrine tumours

    PubMed Central

    Khan, Mohid Shakil; Caplin, Martyn E

    2013-01-01

    The incidence and prevalence of neuroendocrine tumours (NETs) arising from the gastrointestinal tract are increasing. At the time of diagnosis, histological grade, based on Ki-67 proliferation index on a tumour biopsy or specimen, offers prognostication but with often lengthy survival, this may not reflect current tumour biology later in the disease course. Biomarkers, including plasma chromogranin A, urinary 5-hydroxyindole acetic acid and pancreatic specific hormones (insulin, gastrin, vasoactive intestinal peptide), have a role in diagnosis but despite being incorporated into routine clinical practice, there is a lack of robust prospectively collected data investigating their prognostic and predictive value. Given the increasing number of treatment options available for NETs and prolonged survival, there is no agreement on the order of treatment for individual NET patients but the emergence of novel biomarkers and validation of existing ones, in addition to better understanding of the molecular biology, may help solve this clinical problem. PMID:28839724

  9. Molecular radiotheranostics for neuroendocrine tumours.

    PubMed

    Navalkissoor, Shaunak; Flux, Glenn; Bomanji, Jamshed

    2017-10-01

    This article discusses the important role of nuclear medicine imaging and therapy in the management of neuroendocrine tumours (NETs). Somatostatin receptor scintigraphy has a high impact on patient management versus conventional imaging. Molecular radiotherapy is an important part of the management of patients with NETs. Selection of patients for molecular radiotherapy in NETs is based on uptake on their radionuclide imaging study. The imaging agent has the same mechanism of uptake as the therapeutic agent. Thus, the imaging study preselects patients that are likely to concentrate radiation within their tumours. © Royal College of Physicians 2017. All rights reserved.

  10. [Radionuclide therapy for neuroendocrine tumours].

    PubMed

    Mortensen, Jann; Oturai, Peter; Højgaard, Liselotte; Knigge, Ulrich; Hansen, Carsten Palnaes; Martiný, Lars; Rasmussen, Palle; Kjaer, Andreas

    2010-10-25

    Peptide receptor radionuclide therapy using somatostatin analogues labelled with beta-emitting isotopes can be given to patients with metastasized or inoperable neuroendocrine tumours provided these have increased uptake on octreotide scintigraphy. This is a brief review of the treatment principle, indications and contraindications and practices with (177)Lu-DOTATATE treatment used at Rigshospitalet. Side effects are generally mild and reversible. Severe long-term side effects are rare. The majority of patients will experience increased quality of life and partial tumour reduction or stabilization for a period of time. However, up to 20% will experience no treatment effect.

  11. Neuroendocrine tumours: cracking the epigenetic code.

    PubMed

    Karpathakis, A; Dibra, H; Thirlwell, C

    2013-06-01

    The field of epigenetics has evolved rapidly over recent years providing insight into the tumorigenesis of many solid and haematological malignancies. Determination of epigenetic modifications in neuroendocrine tumour (NET) development is imperative if we are to improve our understanding of the biology of this heterogenous group of tumours. Epigenetic marks such as DNA methylation at RASSF1A are frequent findings in NETs of all origins and may be associated with worse prognosis. MicroRNA signatures and histone modifications have been identified which can differentiate subtypes of NET and distinguish NET from adenocarcinoma in cases of diagnostic uncertainty. Historically, candidate gene-driven approaches have yielded limited insight into the epigenetics of NET. Recent progress has been facilitated by development of high-throughput tools including second-generation sequencing and arrays for analysis of the 'epigenome' of tumour and normal tissue, permitting unbiased approaches such as exome sequencing that identified mutations of chromatin-remodelling genes ATRX/DAXX in 44% of pancreatic NETs. Epigenetic changes are reversible and therefore represent an attractive therapeutic target; to date, clinical outcomes of epigenetic therapies in solid tumours have been disappointing; however, in vitro studies on NETs are promising and further clinical trials are required to determine utility of this class of novel agents. In this review, we perform a comprehensive evaluation of epigenetic changes found in NETs to date, including rare NETs such as phaeochromocytoma and adrenocortical tumours. We suggest priorities for future research and discuss potential clinical applications and novel therapies.

  12. A short history of neuroendocrine tumours and their peptide hormones.

    PubMed

    de Herder, Wouter W; Rehfeld, Jens F; Kidd, Mark; Modlin, Irvin M

    2016-01-01

    The discovery of neuroendocrine tumours of the gastrointestinal tract and pancreas started in 1870, when Rudolf Heidenhain discovered the neuroendocrine cells, which can lead to the development of these tumours. Siegfried Oberndorfer was the first to introduce the term carcinoid in 1907. The pancreatic islet cells were first described in 1869 by Paul Langerhans. In 1924, Seale Harris was the first to describe endogenous hyperinsulinism/insulinoma. In 1942 William Becker and colleagues were the first to describe the glucagonoma syndrome. The first description of gastrinoma by Robert Zollinger and Edwin Ellison dates from 1955. The first description of the VIPoma syndrome by John Verner and Ashton Morrison dates from 1958. In 1977, the groups of Lars-Inge Larsson and Jens Rehfeld, and of Om Ganda reported the first cases of somatostatinoma. But only in 2013, Jens Rehfeld and colleagues described the CCK-oma syndrome. The most recently updated WHO classification for gastrointestinal neuroendocrine tumours dates from 2010.

  13. Long-term acquired everolimus resistance in pancreatic neuroendocrine tumours can be overcome with novel PI3K-AKT-mTOR inhibitors

    PubMed Central

    Vandamme, Timon; Beyens, Matthias; de Beeck, Ken Op; Dogan, Fadime; van Koetsveld, Peter M; Pauwels, Patrick; Mortier, Geert; Vangestel, Christel; de Herder, Wouter; Van Camp, Guy; Peeters, Marc; Hofland, Leo J

    2016-01-01

    Background: The mTOR-inhibitor everolimus improves progression-free survival in advanced pancreatic neuroendocrine tumours (PNETs). However, adaptive resistance to mTOR inhibition is described. Methods: QGP-1 and BON-1, two human PNET cell lines, were cultured with increasing concentrations of everolimus up to 22 weeks to reach a dose of 1 μM everolimus, respectively, 1000-fold and 250-fold initial IC50. Using total DNA content as a measure of cell number, growth inhibitory dose–response curves of everolimus were determined at the end of resistance induction and over time after everolimus withdrawal. Response to ATP-competitive mTOR inhibitors OSI-027 and AZD2014, and PI3K-mTOR inhibitor NVP-BEZ235 was studied. Gene expression of 10 PI3K-Akt-mTOR pathway-related genes was evaluated using quantitative real-time PCR (RT–qPCR). Results: Long-term everolimus-treated BON-1/R and QGP-1/R showed a significant reduction in everolimus sensitivity. During a drug holiday, gradual return of everolimus sensitivity in BON-1/R and QGP-1/R led to complete reversal of resistance after 10–12 weeks. Treatment with AZD2014, OSI-027 and NVP-BEZ235 had an inhibitory effect on cell proliferation in both sensitive and resistant cell lines. Gene expression in BON-1/R revealed downregulation of MTOR, RICTOR, RAPTOR, AKT and HIF1A, whereas 4EBP1 was upregulated. In QGP-1/R, a downregulation of HIF1A and an upregulation of ERK2 were observed. Conclusions: Long-term everolimus resistance was induced in two human PNET cell lines. Novel PI3K-AKT-mTOR pathway-targeting drugs can overcome everolimus resistance. Differential gene expression profiles suggest different mechanisms of everolimus resistance in BON-1 and QGP-1. PMID:26978006

  14. 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.

  15. Systemic Therapies for Advanced Pancreatic Neuroendocrine Tumors

    PubMed Central

    Raj, Nitya; Reidy-Lagunes, Diane

    2016-01-01

    SYNOPSIS Pancreatic neuroendocrine tumors are a rare tumor type, and comprise 1-2% of all pancreatic neoplasms. When nonfunctional (i.e. nonhormone secreting), these tumors generally cause few symptoms and often go unnoticed for several years; for this reason, they are rarely localized at presentation, and are typically diagnosed in the presence of metastatic disease, most commonly to the liver. Although pancreatic neuroendocrine tumors can be less aggressive than other tumor types, the management poses a significant challenge because of the heterogeneous clinical presentations and varying degrees of aggressiveness. The therapy of pancreatic neuroendocrine tumors includes a multimodality approach and can often include surgery, liver-directed therapies (i.e. embolization), as well as targeted and cytotoxic systemic treatments. A variety of systemic therapies have been developed for the management of pancreatic neuroendocrine tumors. These therapies include somatostatin analogs (octreotide or lanreotide), a select group of cytotoxic chemotherapy agents (alkylating, fluorouracil and platinum drugs), as well as targeted or biologic agents (everolimus and sunitinib). This chapter will review the available systemic therapy options for advanced pancreatic neuroendocrine tumors. PMID:26614372

  16. Radiotherapy for Pancreatic Neuroendocrine Tumors

    SciTech Connect

    Contessa, Joseph N.; Griffith, Kent A.; Wolff, Elizabeth; Ensminger, William; Zalupski, Mark; Ben-Josef, Edgar

    2009-11-15

    Purpose: Pancreatic neuroendocrine tumors (PNTs) are rare malignant neoplasms considered to be resistant to radiotherapy (RT), although data on efficacy are scarce. We reviewed our institutional experience to further delineate the role of RT for patients with PNTs. Methods and Materials: Between 1986 and 2006, 36 patients with PNTs were treated with RT to 49 sites. Of these 36 patients, 23 had radiographic follow-up data, which were used to determine the tumor response rate and freedom from local progression. Long-term toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events. Results: The overall response rate to RT was 39% (13% complete response, 26% partial response, 56% stable disease, and 4% progressive disease). A significant difference in the freedom from local progression between the groups receiving either greater than or less than the median 2 Gy/fraction biologically equivalent dose of 49.6 Gy was found, with all radiographic progression occurring in patients who had received <=32 Gy. The actuarial 3-year local freedom from progression rate was 49%. Palliation was achieved in 90% of patients, with either improvement or resolution of symptoms after RT. Of 35 patients, 33 had metastatic disease at their referral for RT, and the median overall survival for this patient population was 2 years. Three long-term Grade 3 or greater toxicities were recorded. Conclusion: RT is an effective modality for achieving local control in patients with PNTs. RT produces high rates of symptomatic palliation and freedom from local progression. Prospective trials of radiotherapy for PNTs are warranted.

  17. Everolimus in the management of metastatic neuroendocrine tumours

    PubMed Central

    Chan, David L.; Segelov, Eva; Singh, Simron

    2016-01-01

    Neuroendocrine tumours are increasing in incidence and cause a variety of symptoms. The mammalian target of rapamycin (mTOR) pathway plays a key role in neuroendocrine tumour (NET) pathogenesis, leading to increased lipid synthesis, protein synthesis and cellular growth. Upregulation of this pathway is noted in both hereditary and sporadic NETs. This understanding has led to investigations of mTOR inhibitors as therapy for metastatic NETs. After promising preclinical findings, everolimus, an mTOR inhibitor, was trialled in the RADIANT-1−4 studies on patients with advanced, well differentiated NETs. RADIANT-3 and RADIANT-4 established the efficacy of everolimus in improving progression-free survival (PFS) for metastatic NET of pancreatic, lung and gastrointestinal origin, leading to the US Food and Drug Administration (FDA) approval for its use in tumour control in those settings. Everolimus treatment is generally well tolerated; common adverse events include stomatitis, diarrhoea, rash and hyperglycaemia. Although discontinuation rates are low, many patients may require dose modification to successfully continue therapy. The combination of everolimus with somatostatin analogues (SSAs) (such as octreotide or pasireotide) or other targeted agents such as bevacizumab has not produced additional incremental benefit, and dual biologic therapy is not used widely. Ongoing trials are investigating everolimus compared with chemotherapy, optimal sequencing of therapy and combination of everolimus with radiotherapy. Future research should concentrate on identification of predictive biomarkers for benefit from mTOR therapy and include quality of life as a measure. PMID:28286565

  18. Cytomorphology of neuroendocrine tumours of the gallbladder.

    PubMed

    Yadav, R; Jain, D; Mathur, S R; Iyer, V K

    2016-04-01

    Gallbladder neuroendocrine tumours (GB-NETs) are rare and account for 0.5% of all NETs. GB-NETs have an aggressive behaviour, which depends on the tumour grade. The cytomorphological spectrum of these tumours has never been described in detail. The present study evaluates the cytological features of GB-NETs and grades them according to the World Health Organization (WHO) classification. Furthermore, the expression of thyroid transcription factor-1 (TTF-1) has not been investigated previously in GB-NETs, although found in a subset of extrapulmonary NETs. Twenty cases of GB-NET among 875 gallbladder carcinomas diagnosed by ultrasound-guided fine needle aspiration cytology (FNAC) over a period of nearly 4 years were studied. The following parameters were evaluated: architectural pattern, nuclear chromatin, nucleoli, mitoses, necrosis, moulding, apoptosis and smudge cells. Cases were categorized into well-differentiated (grades 1 and 2), small cell carcinoma (SCC) (grade 3) and mixed adenoneuroendocrine carcinoma. Nuclear positivity for TTF-1 was considered as positive. Morphologically, tumour cells were mainly arranged in rosettes in the well-differentiated category; sudden anisonucleosis and rare nuclear moulding with or without mitotic figures were other features. Eleven cases of SCC showed prominent nuclear moulding with frequent smudge cells, mitoses, apoptosis and necrosis. Three mixed adenoneuroendocrine carcinomas showed papillary fragments and an acinar arrangement of tumour cells. Four of the nine SCCs in which TTF-1 was evaluated on de-stained smears showed nuclear positivity. Histopathology was available in two SCCs and showed morphology similar to FNAC. Cytology plays an important role in the diagnosis of GB-NETs for appropriate subtype characterization, which is necessary for the prognostication of these tumours. TTF-1 may not be used for the differentiation of gallbladder SCCs from pulmonary SCCs. © 2015 John Wiley & Sons Ltd.

  19. Pancreatic neuroendocrine tumors: biology, diagnosis, and treatment

    PubMed Central

    Ro, Cynthia; Chai, Wanxing; Yu, Victoria E.; Yu, Run

    2013-01-01

    Pancreatic neuroendocrine tumors (PNETs), a group of endocrine tumors arising in the pancreas, are among the most common neuroendocrine tumors. The genetic causes of familial and sporadic PNETs are somewhat understood, but their molecular pathogenesis remains unknown. Most PNETs are indolent but have malignant potential. The biological behavior of an individual PNET is unpredictable; higher tumor grade, lymph node and liver metastasis, and larger tumor size generally indicate a less favorable prognosis. Endocrine testing, imaging, and histological evidence are necessary to accurately diagnose PNETs. A 4-pronged aggressive treatment approach consisting of surgery, locoregional therapy, systemic therapy, and complication control has become popular in academic centers around the world. The optimal application of the multiple systemic therapeutic modalities is under development; efficacy, safety, availability, and cost should be considered when treating a specific patient. The clinical presentation, diagnosis, and treatment of specific types of PNETs and familial PNET syndromes, including the novel Mahvash disease, are summarized. PMID:23237225

  20. 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.

  1. Evaluating lanreotide as maintenance therapy after first-line treatment in patients with non-resectable duodeno-pancreatic neuroendocrine tumours.

    PubMed

    Lepage, Côme; Dahan, Laetitia; Bouarioua, Nadia; Toumpanakis, Christos; Legoux, Jean-Louis; Le Malicot, Karine; Guimbaud, Rosine; Smith, Denis; Tougeron, David; Lievre, Astrid; Cadiot, Guillaume; Di Fiore, Frédéric; Bouhier-Leporrier, Karine; Hentic, Olivia; Faroux, Roger; Pavel, Marianne; Borbath, Ivan; Valle, Juan W; Rinke, Anja; Scoazec, Jean-Yves; Ducreux, Michel; Walter, Thomas

    2017-05-01

    Patients with metastatic or locally advanced, non-resectable, grade 1 or 2 well-differentiated duodeno-pancreatic (WDDP) NETs are treated following European guidelines. Patients (Pts) with aggressive disease, i.e. progressive and/or symptomatic metastases and/or with significant hepatic invasion (>30-50%), and/or bone metastases, anti-tumour therapy should receive systemic combination of chemotherapy once disease control is obtained. The aim is to stop chemotherapy until progression. REMINET is an academic randomized, double-blind, placebo-controlled, phase II/III study designed to evaluate lanreotide (LAN) as maintenance treatment after L1 chemotherapy in G1-G2 WDDP NET. Main eligibility criteria: adults pts with a metastatic (synchronous or metachronous) or locally advanced, non-resectable, grade 1 or 2 WDDP NETs and documented control disease after L1 therapy at least 4 weeks prior to randomization. 222 patients will be randomly assigned in a 1:1 ratio to receive 120mg LAN or placebo, every 28 days, until disease progression or unacceptable toxicity. The aim of the phase II part is to demonstrate a 6-months PFS >45% in LAN arm. Secondary endpoints are PFS according to central review, overall survival, safety and quality of life. A bio-bank of frozen blood will be constituted. The study is currently open in France, Germany, Belgium, United Kingdom and Ireland. A total of 25 patients are randomized (NCT02288377). Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  2. Latest advances in pancreatic tumours.

    PubMed

    Lariño Noia, José

    2016-09-01

    Pancreatic cancer continues to have a bleak prognosis. Hardly any therapeutic advances have been made in the last few years and consequently most efforts have focused on preventing its development and on diagnosing precursor lesions. In this regard, the use of statins as a preventive factor and the implementation of screening programmes in high-risk patients are gaining ground. In the field of treatment, there is greater focus on the role of neoadjuvant therapy in pancreatic cancer and on a multimodal approach to the disease, with few advances in effective novel therapies. Most studies concerned cystic tumours of the pancreas, especially intraductal mucinous papillary tumour, with its known potential for malignant transformation. Multiple studies were devoted to validation of the 2012 Fukuoka international guidelines and the highly controversial 2015 AGA guidelines. Notable among these studies were those demonstrating the suboptimal positive predictive value and questioning important aspects of the guidelines, such as discontinuation of follow-up or the criteria for surgical referral. Notable among diagnostic procedures were cystoscopy and endoscopic ultrasound-guided needle-based confocal laser endomicroscopy as the most promising techniques due to their high efficacy and negative predictive value in detecting mucinous cystic lesions. There were also a large number of studies on the natural history of intraductal papillary mucinous tumours, which help deepen knowledge of these entities and the search for predictive factors of cancer development. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  3. [Multifocal Pulmonary Neuroendocrine Tumours: Genesis, Diagnostics and Treatment].

    PubMed

    Kirschbaum, A; Beutel, B; Rinke, A; Rexin, P; Fink, L; Koczulla, R; Bartsch, D K

    2016-02-01

    Multifocal neuroendocrine lung tumour is a rare diagnosis. Multiple lung foci of different sizes are usually apparent on chest CT scans. It is assumed that multifocal neuroendocrine lung tumours originally develop from diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). This results in cell aggregations formed by proliferation of neuroendocrine cells that are already physiologically present in the bronchial system. If these cell proliferations break through the bronchial basement membrane, they are considered to constitute tumourlets if they measure ≤ 5 mm and carcinoid tumours if they are larger than 5 mm. The speed of proliferation of the cell hyperplasias appears to vary. Many of the patients are completely asymptomatic, the multifocal neuroendocrine lung tumours being diagnosed by chance. However, other patients complain of breathlessness, reduced physical capacity and cough. There may also be reduction of lung function. In these cases, chest HRCT often reveals peribronchial fibrosis or bronchiectasis in addition to the lung foci. Bronchoscopy is usually not helpful. Surgical lung biopsy is considered to be the diagnostic gold standard. Histological examination typically shows a mixture of cell hyperplasias, tumourlets and carcinoid tumours. There is no consensus on the treatment of multifocal neuroendocrine tumours. Taking the clinical situation and the chest HRCT findings as our starting point, we developed a stepwise approach that is guided by the success of the individual therapeutic procedures. The most favourable prognosis is found in affected people without clinical symptoms whose lung foci all measure less than 5 mm. In these cases the 5-year survival rate is over 90%. © Georg Thieme Verlag KG Stuttgart · New York.

  4. How reliable is the Ki-67 cytological index in grading pancreatic neuroendocrine tumors? A meta-analysis.

    PubMed

    Li, Jun; Lin, Jin Ping; Shi, Liu Hong; Wang, Wei Jia; Li, Ai Qing; Si, Jian Min; Chen, Shu Jie

    2016-02-01

    To investigate the accuracy of the cytological Ki-67 index in distinguishing intermediate and high-grade (G2 + G3) from low-grade (G1) pancreatic neuroendocrine tumors (PNETs). Two investigators independently searched databases to identify eligible studies using the following term: ('Ki-67') AND ('pancreatic endocrine tumor' OR 'pancreatic neuroendocrine tumor' OR 'pancreatic endocrine tumour' OR 'pancreatic neuroendocrine tumour' OR 'pancreatic endocrine tumors' OR 'pancreatic neuroendocrine tumors' OR 'pancreatic endocrine tumours' OR 'pancreatic neuroendocrine tumours'), and meta-analysis was performed to calculate the pooled sensitivity, specificity, positive (PLR) and negative likelihood ratio (NLR), and diagnostic odds ratio (DOR). A total of 263 lesions from 13 studies were included in the study. The pooled sensitivity and specificity of Ki-67 (cut-off value: 2%) in the differential diagnosis of G2 + G3 from G1 PNETs were 64% and 87%, respectively. The pooled PLR, NLR and DOR were 3.96, 0.42 and 11.21, respectively. The area under the summary receiver operating characteristic curve (AUROC) was 0.8397. While the cut-off value of Ki-67 index was set as 5%, the sensitivity and specificity were increased up to 69% and 93%, respectively, and the AUROC was increased to 0.955. The cytological Ki-67 index is very useful in distinguishing intermediate and high-grade from low-grade PNETs, and a cut-off value of 5% had a better predictive value compared with that of 2%. © 2016 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

  5. Pancreatic neuroendocrine tumors: does chemotherapy work?

    PubMed

    Tejani, Mohamedtaki Abdulaziz; Saif, Muhammad Wasif

    2014-03-10

    Pancreatic neuroendocrine tumors (pNETs) are rare well-differentiated neoplasms which can be functional or non-functional. They tend to have a worse prognosis than their counterpart carcinoid tumors. Current systemic treatment options for advanced, unresectable disease include somatostatin analogs, everolimus and sunitinib. Low response rates and toxicity profiles have, thus far, limited the widespread use of cytotoxic chemotherapy in this setting. In this update, we review three abstracts from the 2014 ASCO Gastrointestinal Cancers Symposium that present outcomes of the use of combination capecitabine and temozolomide in patients with advanced pNET. We summarize their results and discuss the role of this regimen in treatment algorithms for metastatic pNET.

  6. Targeted Therapies Improve Survival for Patients with Pancreatic Neuroendocrine Tumors

    Cancer.gov

    In 2011, based on initial findings from two clinical trials, the Food and Drug Administration approved sunitinib and everolimus for patients with pancreatic neuroendocrine tumors. Updated results from the everolimus trial were published in September 2016.

  7. Expression of somatostatin receptors 2 and 5 in circulating tumour cells from patients with neuroendocrine tumours.

    PubMed

    Childs, Alexa; Vesely, Clare; Ensell, Leah; Lowe, Helen; Luong, Tu Vinh; Caplin, Martyn E; Toumpanakis, Christos; Thirlwell, Christina; Hartley, John A; Meyer, Tim

    2016-12-06

    Neuroendocrine tumours (NET) overexpress somatostatin receptors (SSTR) that can be targeted for therapy. Somatostatin receptor expression is routinely measured by molecular imaging but the resolution is insufficient to define heterogeneity. We hypothesised that SSTR expression could be measured on circulating tumour cells (CTCs) and used to investigate heterogeneity of expression and track changes during therapy. MCF-7 cells were transfected with SSTR2 or 5 and spiked into donor blood for analysis by CellSearch. Optimum anti-SSTR antibody concentration and exposure time were determined, and flow cytometry was used to evaluate assay sensitivity. For clinical evaluation, blood was analysed by CellSearch, and SSTR2/5 immunohistochemistry was performed on matched tissue samples. Flow cytometry confirmed CellSearch was sensitive and that detection of SSTR was unaffected by the presence of somatostatin analogue up to a concentration of 100 ng ml(-l). Thirty-one NET patients were recruited: grade; G1 (29%), G2 (45%), G3 (13%), primary site; midgut (58%), pancreatic (39%). Overall, 87% had SSTR-positive tumours according to somatostatin receptor scintigraphy or 68-Ga-DOTATE PET/CT. Circulating tumour cells were detected in 21 out of 31 patients (68%), of which 33% had evidence of heterogeneous expression of either SSTR2 (n=5) or SSTR5 (n=2). Somatostatin receptors 2 and 5 are detectable on CTCs from NET patients and may be a useful biomarker for evaluating SSTR-targeted therapies and this is being prospectively evaluated in the Phase IV CALMNET trial (NCT02075606).

  8. Contrast‐enhanced ultrasound of pancreatic tumours

    PubMed Central

    D'Onofrio, Mirko; Crosara, Stefano; Dal Corso, Flavia; Barbi, Emilio; Canestrini, Stefano; Mucelli, Roberto Pozzi

    2015-01-01

    Abstract Indication/purpose: To review contrast‐enhanced ultrasound features of the most common pancreatic tumours. Methods: Contrast‐enhanced ultrasound (CEUS) can provide distinctive features of pancreatic tumours that are reported in the present paper, providing radiologic‐pathological correlations and clarifying the main differential diagnosis. Conclusion: Contrast‐enhanced ultrasound plays a well‐established role in the evaluation of pancreatic tumours. When possible, CEUS should be always performed after the initial US diagnosis, in order to improve the accuracy of the first line examination. PMID:28191218

  9. Immunohistochemical study of pancreatic neuroendocrine tumor in Panthera tigris tigris.

    PubMed

    Nyska, A; Goldstein, J; Eshkar, G; Klein, B

    1996-07-01

    The histological and immunohistochemical characteristics of a case of pancreatic neuroendocrine tumor are described in a 14-yr-old female Bengal tiger (Panthera tigris tigris) housed at the New Biblical Zoo of Jerusalem, Jerusalem, Israel, 1994. The neoplastic cells were immunohistochemically negative for insulin and glucagon, slightly positive for neuron-specific enolase, moderately positive for serotonin and somatostatin, and markedly positive for chromogranine A and gastrin. This is the first documentation of a pancreatic neuroendocrine tumor in the tiger.

  10. Childhood neuroendocrine tumours: a descriptive study revealing clues for genetic predisposition.

    PubMed

    Diets, I J; Nagtegaal, I D; Loeffen, J; de Blaauw, I; Waanders, E; Hoogerbrugge, N; Jongmans, M C J

    2017-01-17

    Neuroendocrine tumours (NETs) are rare in children and limited data are available. We aimed to specify tumour and patient characteristics and to investigate the role of genetic predisposition in the aetiology of paediatric NETs. Using the Dutch Pathology Registry PALGA, we collected patient- and tumour data of paediatric NETs in the Netherlands between 1991 and 2013 (N=483). The incidence of paediatric NETs in the Netherlands is 5.40 per one million per year. The majority of NETs were appendiceal tumours (N=441;91.3%). Additional surgery in appendiceal NETs was indicated in 89 patients, but performed in only 27 of these patients. Four out of five patients with pancreatic NETs were diagnosed with Von Hippel-Lindau disease (N=2) and Multiple Endocrine Neoplasia type 1 (N=2). In one patient with an appendiceal NET Familial Adenomatous Polyposis was diagnosed. On the basis of second primary tumours or other additional diagnoses, involvement of genetic predisposition was suggestive in several others. We identified a significant number of patients with a confirmed or suspected tumour predisposition syndrome and show that paediatric pancreatic NETs in particular are associated with genetic syndromes. In addition, we conclude that treatment guidelines for appendiceal paediatric NETs need revision and improved implementation.

  11. ENETS TNM Staging Predicts Prognosis in Small Bowel Neuroendocrine Tumours

    PubMed Central

    Srirajaskanthan, Rajaventhan; Ahmed, A.; Prachialias, A.; Srinivasan, P.; Heaton, N.; Jervis, N.; Quaglia, A.; Vivian, G.; Ramage, J. K.

    2013-01-01

    Introduction. Small bowel neuroendocrine tumours (NETs) are the most common type of gastrointestinal neuroendocrine tumours. The incidence and prevalence of these tumours are on the rise. The aims of this study were to determine prognostic clinicopathological features and whether the ENETS TNM staging system predicts prognosis and also. Method. Clinical data was collected retrospectively from 138 patients with histologically proven small bowel NETs managed at King's College Hospital. Histology was reviewed and small bowels tumours, were staged according to the ENETS TNM staging system. Results. Median age was 65 years (range 29–87). The 5-year survival was 79.5% and the 10-year survival was 48.5%. Resection of the primary tumour was associated with improved survival (120 versus 56 months, P < 0.05). On multivariate analysis prognostic factors were primary tumour resection and not having a carcinoid heart disease. TNM staging significantly separated survival of stage 2 and stage 3 from stage 4 NETs. Conclusion. Small bowel primary tumour resection and not having carcinoid heart disease are prognostic factors. The ENETS TNM staging and grading system appears to be of prognostic relevance to small bowel NETs. PMID:23533809

  12. A retroperitoneal neuroendocrine tumor in ectopic pancreatic tissue.

    PubMed

    Okasha, Hussein Hassan; Al-Bassiouni, Fahim; El-Ela, Monir Abo; Al-Gemeie, Emad Hamza; Ezzat, Reem

    2013-07-01

    Ectopic pancreas is the relatively uncommon presence of pancreatic tissue outside the normal location of the pancreas. We report a case of abdominal pain due to retroperitoneal neuroendocrine tumor arising from heterotopic pancreatic tissue between the duodenal wall and the head of the pancreas. Patient underwent surgical enucleation of the tumor.

  13. Renal neuroendocrine tumour and synchronous pancreas metastasis: histopathological diagnosis using prostatic acid phosphatase.

    PubMed

    Kawasaki, Keishi; Kawaguchi, Yoshikuni; Suzuki, Yoshio; Tanaka, Nobutaka

    2016-11-01

    A woman aged 56 years developed 2 synchronous tumours: one, 1.2 cm in diameter at the head of the pancreas; and the other, 4.0 cm in diameter, at the left side of her horseshoe kidney. Preoperative differential diagnosis of these hypovascular lesions included pancreatic ductal carcinoma (PDC) with renal metastasis, PDC with renal angiomyolipoma, renal cell carcinoma with pancreatic metastasis or PDC and renal cell carcinoma. Following pancreaticoduodenectomy and left nephrectomy, both specimens were diagnosed as grade 2 neuroendocrine tumours (NETs). Immunohistochemistry revealed that both were positive for prostatic acid phosphatase (PAP), which is specific to hindgut-derived NET, including renal NET. Accordingly, the renal tumour was diagnosed as the primary lesion, and the pancreatic tumour as a metastasis. To the best of our knowledge, this is the first report of a renal NET with a synchronous pancreas metastasis. Immunohistochemical staining for PAP was a useful diagnostic marker for synchronous NETs in the kidney and pancreas. 2016 BMJ Publishing Group Ltd.

  14. Current medical treatment of pancreatic neuroendocrine tumors.

    PubMed

    Yalcin, Suayib; Oyan, Basak; Bayraktar, Yusuf

    2007-01-01

    Pancreatic neuroendocrine tumors (NETs) consist of a wide group of neoplasms, with different biological behaviors in terms of aggressiveness and hormone production. In the last two decades, significant progress has been observed in our understanding of their biology, diagnosis and treatment. Surgery remains to be the only curative approach, but unfortunately the diagnosis is often delayed due to the slow growth of these tumors and the difficulty in identifying the symptoms related to the tumor-released hormones. In addition to surgery, other approaches to control the disease are biological therapy consisting of somatostatin analogs and interferon (IFN), systemic chemotherapy, radioligand therapy and local therapy with chemoembolization. Several newer cytotoxic agents, including irinotecan, gemcitabine, taxanes, oxaliplatin, capecitabine and PS-341 have been studied in metastatic patients. Considering the high vascularity of these tumors, antiangiogenic agents like endostatin and thalidomide have also been evaluated in advanced NETs. Although these agents seem to have potential activity in NETs and may increase progression free survival, none of these currently available medical therapeutic options are curative. While more efficient novel strategies are to be developed, the rationale use of the current therapeutic options may improve quality of life, control the symptoms related to the hypersecretion of hormones and/or peptides, control tumor proliferation and prolong survival in patients suffering from NETs.

  15. Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin

    PubMed Central

    Mitry, E; Baudin, E; Ducreux, M; Sabourin, J-C; Rufié, P; Aparicio, T; Lasser, P; Elias, D; Duvillard, P; Schlumberger, M; Rougier, P

    1999-01-01

    The purpose of this study was to evaluate by a retrospective analysis of 53 patients the efficacy of chemotherapy combining etoposide and cisplatin in the treatment of neuroendocrine tumours. The regimen was a combination of etoposide 100 mg m–2 day–1 for 3 days and cisplatin 100 mg m–2 on day 1, given by 2-h intravenous infusion, administered every 21 days. Twelve patients had a well-differentiated and 41 a poorly differentiated neuroendocrine tumour. Toxicity of treatment was assessed in 50 patients and efficacy in 52 patients. Among the 11 patients with a well-differentiated tumour evaluable for tumoural response, only one (9.4%) had a partial response for 8.5 months. Forty-one patients with a poorly differentiated tumour showed an objective response rate of 41.5% (four complete and 13 partial responses); the median duration of response was 9.2 months, the median overall survival 15 months and the median progression-free survival 8.9 months. Haematological grade 3–4 toxicity was observed in 60% of the cases with one treatment-related death, digestive grade 3–4 toxicity in 40% and grade 3 alopecia was constant. No severe renal, hearing and neurological toxicities were observed (grade 1 in 6%, 14%, 72% respectively and no grade >1). We confirm that poorly differentiated neuroendocrine tumours are chemosensitive to the etoposide plus cisplatin combination. However, the prognosis remains poor with a 2-year survival lower than 20% confirming that new therapeutic strategies have to be developed. © 1999 Cancer Research Campaign PMID:10604732

  16. Pregnant with metastatic neuroendocrine tumour of the ovary: what now?

    PubMed Central

    Pistilli, B; Grana, CM; Fazio, N; Cavaliere, A; Ferrari, ME; Bodei, L; Baio, SM; Scambia, G; Paganelli, G; Peccatori, FA

    2012-01-01

    Neuroendocrine tumours (NET) are a heterogeneous group of neoplasms commonly occurring in the gastrointestinal tract or lungs but can occur in other regions. Primary ovarian NET account for 5% of all NET and 0.1% of all ovarian malignancies. In metastatic disease, the therapeutic goal is to extend survival and to improve quality of life. As these tumours express somatostatin receptors, somatostatin analogues are frequently used to control symptoms. Here we present a case of a pregnant woman with an ovarian NET with liver metastases and carcinoid syndrome who was treated with the somatostatin analogue, Octreotide LAR. We also summarize reported data of the use of somatostatin analogues during pregnancy. PMID:22331988

  17. Role of positron emission tomography in thyroid and neuroendocrine tumours.

    PubMed

    Treglia, Giorgio; Kroiss, Alexander S; Piccardo, Arnoldo; Lococo, Filippo; Santhanam, Prasanna; Imperiale, Alessio

    2017-09-25

    Positron emission tomography (PET) is an established imaging method in oncology. PET/computed tomography (PET/CT) and PET/magnetic resonance imaging (PET/MRI) are hybrid techniques which combine morphological information obtained by CT and MRI with functional data provided by PET. Several radiotracers evaluating different metabolic pathways or receptor status can be used as PET radiotracers to assess endocrine tumours such as thyroid tumours or neuroendocrine neoplasms (NENs). This review is focused to describe the role of PET imaging using different radiotracers in patients with thyroid tumours and NENs. The role of PET imaging with different radiotracers in several endocrine tumours including thyroid tumours, gastroenteropancreatic neoplasms (GEP-NENs), lung neuroendocrine neoplasms (LNENs), pheochromocytomas (PCC) and paragangliomas (PGL), and multiple endocrine neoplasia (MEN) syndromes has been described. Fluorine-18 fluorodeoxyglucose (18F-FDG) PET evaluating the glucose metabolism provides useful diagnostic and prognostic information in patients with thyroid tumours. Iodine-124 (124I) assessing the iodine metabolism (124I) PET may be used for dosimetry and diagnostic purposes in thyroid tumours. In patients with NENs specific radiotracers can be used for diagnostic purposes such as somatostatin analogues labeled with gallium-68 (68Ga-DOTA-peptides) evaluating somatostatin receptor expression and fluorine-18 fluorodihydroxyphenylalanine (18F- FDOPA) assessing the uptake, decarboxylation and storage of amine precursors. One advantage of 68Ga-DOTA-peptides PET is to select patients with well-differentiated and inoperable NENs for peptide receptor radionuclide therapy (PRRT). 18F-FDG PET may provide useful prognostic information in patients with high-grade NENs. PET imaging with different radiotracers is a useful functional imaging technique in the work-up of several endocrine tumours.

  18. [Neuroendocrine pancreatic tumors and helpfulness of targeted therapies].

    PubMed

    Vaysse, Thibaut; Coriat, Romain; Perkins, Géraldine; Dhooge, Marion; Brezault, Catherine; Chaussade, Stanislas

    2013-06-01

    The neuroendocrine pancreatic tumors are rare tumors, but their incidence is constantly rising. Even if the management of these tumors has to be surgical as soon as possible, the disease is most often metastatic at the stage of the diagnostic. The prognostic and the therapeutic options differ from pancreatic adenocarcinoma. Available treatments have evolved over the last years with recent publications of studies that bring to light the benefits of targeted therapies in this pathology. This has resulted in modifications of both practices and either French and international guidelines. Therefore, we focus on the management of the grade 1 and grade 2 well-differentiated neuroendocrine pancreatic tumors as classified in new WHO classification of neuroendocrine neoplasms published in 2010.

  19. Biochemical prognostic indicators for pancreatic neuroendocrine tumors and small bowel neuroendocrine tumors

    PubMed Central

    Cavaness, Keith; Celinski, Scott; Preskitt, John

    2014-01-01

    Pancreatic neuroendocrine tumors (PNETs) and small bowel neuroendocrine tumors (SBNETs) are rare tumors that are frequently diagnosed late in the course of the disease. Several biomarkers have been proposed in the literature as prognostic factors for patients with these tumors. This article discusses a recent publication in Annals of Surgical Oncology from the University of Iowa analyzing the effect of different biomarkers on survival in patients with PNETs and SBNETs. PMID:25493250

  20. IGF-1 drives chromogranin A secretion via activation of Arf1 in human neuroendocrine tumour cells

    PubMed Central

    Münzberg, Christin; Höhn, Katharina; Krndija, Denis; Maaß, Ulrike; Bartsch, Detlef K; Slater, Emily P; Oswald, Franz; Walther, Paul; Seufferlein, Thomas; von Wichert, Götz

    2015-01-01

    Hypersecretion is the major symptom of functional neuroendocrine tumours. The mechanisms that contribute to this excessive secretion of hormones are still elusive. A key event in secretion is the exit of secretory products from the Golgi apparatus. ADP-ribosylation factor (Arf) GTPases are known to control vesicle budding and trafficking, and have a leading function in the regulation of formation of secretory granula at the Golgi. Here, we show that Arf1 is the predominant Arf protein family member expressed in the neuroendocrine pancreatic tumour cell lines BON and QGP-1. In BON cells Arf1 colocalizes with Golgi markers as well as chromogranin A, and shows significant basal activity. The inhibition of Arf1 activity or expression significantly impaired secretion of chromogranin A. Furthermore, we show that the insulin-like growth factor 1 (IGF-1), a major regulator of growth and secretion in BON cells, induces Arf1 activity. We found that activation of Arf1 upon IGF-1 receptor stimulation is mediated by MEK/ERK signalling pathway in BON and QGP-1 cells. Moreover, the activity of Arf1 in BON cells is mediated by autocrinely secreted IGF-1, and concomitantly, autocrine IGF1 secretion is maintained by Arf1 activity. In summary, our data indicate an important regulatory role for Arf1 at the Golgi in hypersecretion in neuroendocrine cancer cells. PMID:25754106

  1. IGF-1 drives chromogranin A secretion via activation of Arf1 in human neuroendocrine tumour cells.

    PubMed

    Münzberg, Christin; Höhn, Katharina; Krndija, Denis; Maaß, Ulrike; Bartsch, Detlef K; Slater, Emily P; Oswald, Franz; Walther, Paul; Seufferlein, Thomas; von Wichert, Götz

    2015-05-01

    Hypersecretion is the major symptom of functional neuroendocrine tumours. The mechanisms that contribute to this excessive secretion of hormones are still elusive. A key event in secretion is the exit of secretory products from the Golgi apparatus. ADP-ribosylation factor (Arf) GTPases are known to control vesicle budding and trafficking, and have a leading function in the regulation of formation of secretory granula at the Golgi. Here, we show that Arf1 is the predominant Arf protein family member expressed in the neuroendocrine pancreatic tumour cell lines BON and QGP-1. In BON cells Arf1 colocalizes with Golgi markers as well as chromogranin A, and shows significant basal activity. The inhibition of Arf1 activity or expression significantly impaired secretion of chromogranin A. Furthermore, we show that the insulin-like growth factor 1 (IGF-1), a major regulator of growth and secretion in BON cells, induces Arf1 activity. We found that activation of Arf1 upon IGF-1 receptor stimulation is mediated by MEK/ERK signalling pathway in BON and QGP-1 cells. Moreover, the activity of Arf1 in BON cells is mediated by autocrinely secreted IGF-1, and concomitantly, autocrine IGF1 secretion is maintained by Arf1 activity. In summary, our data indicate an important regulatory role for Arf1 at the Golgi in hypersecretion in neuroendocrine cancer cells.

  2. Lutetium-labelled peptides for therapy of neuroendocrine tumours.

    PubMed

    Kam, B L R; Teunissen, J J M; Krenning, E P; de Herder, W W; Khan, S; van Vliet, E I; Kwekkeboom, D J

    2012-02-01

    Treatment with radiolabelled somatostatin analogues is a promising new tool in the management of patients with inoperable or metastasized neuroendocrine tumours. Symptomatic improvement may occur with (177)Lu-labelled somatostatin analogues that have been used for peptide receptor radionuclide therapy (PRRT). The results obtained with (177)Lu-[DOTA(0),Tyr(3)]octreotate (DOTATATE) are very encouraging in terms of tumour regression. Dosimetry studies with (177)Lu-DOTATATE as well as the limited side effects with additional cycles of (177)Lu-DOTATATE suggest that more cycles of (177)Lu-DOTATATE can be safely given. Also, if kidney-protective agents are used, the side effects of this therapy are few and mild and less than those from the use of (90)Y-[DOTA(0),Tyr(3)]octreotide (DOTATOC). Besides objective tumour responses, the median progression-free survival is more than 40 months. The patients' self-assessed quality of life increases significantly after treatment with (177)Lu-DOTATATE. Lastly, compared to historical controls, there is a benefit in overall survival of several years from the time of diagnosis in patients treated with (177)Lu-DOTATATE. These findings compare favourably with the limited number of alternative therapeutic approaches. If more widespread use of PRRT can be guaranteed, such therapy may well become the therapy of first choice in patients with metastasized or inoperable neuroendocrine tumours.

  3. The novel WHO 2010 classification for gastrointestinal neuroendocrine tumours correlates well with the metastatic potential of rectal neuroendocrine tumours.

    PubMed

    Jernman, Juha; Välimäki, Matti J; Louhimo, Johanna; Haglund, Caj; Arola, Johanna

    2012-01-01

    Approximately 10-15% of gastroenteropancreatic neuroendocrine tumours (NETs, carcinoids) occur in the rectum, some of which are potentially able to metastasize. The new WHO 2010 classification of NETs applies to all gastroenteropancreatic NETs, but no reports have studied its correlation with the prognosis of rectal NETs. We retrospectively classified 73 rectal NETs according to the novel WHO 2010 and the previous WHO 2000 classifications. The aim was to assess the validity of the classifications in distinguishing indolent rectal NETs from metastasising tumours. Using the WHO 2010 criteria, we identified 61 G1 tumours, none of which had metastasised during follow-up. Of 11 G2 tumours, 9 had shown distant metastases. The only G3 neuroendocrine carcinoma that occurred had been disseminated at initial presentation. Our results show that rectal NETs classified as G1 according to the WHO 2010 classification have an indolent clinical course, whereas G2 NETs often metastasise. The WHO 2010 classification of NETs predicts the metastatic potential of rectal NETs better than the WHO 2000 classification. Copyright © 2011 S. Karger AG, Basel.

  4. Is visual radiological evaluation of liver tumour burden in patients with neuroendocrine tumours reproducible?

    PubMed Central

    Hentic, Olivia; Vullierme, Marie-Pierre; Lagadec, Matthieu; Ronot, Maxime; Ruszniewski, Philippe; Vilgrain, Valérie

    2017-01-01

    Background Visual semi-quantitative assessment of liver tumour burden for neuroendocrine tumour liver metastases is often used in patient management and outcome. However, published data on the reproducibility of these evaluations are lacking. Objective The aim of this study was to evaluate the interobserver and intraobserver agreement of a visual semi-quantitative assessment of liver tumour burden using CT scan. Methods Fifty consecutive patients (24 men and 26 women, mean aged 54 years) were retrospectively reviewed by four readers (two senior radiologists, one junior radiologist and one gastroenterologist) who assessed the liver tumour burden based on a visual semi-quantitative method with four classes (0–10, 11–25, 26–50 and ≥50%). Interobserver and intraobserver agreement were assessed by weighted kappa coefficient and percentage of agreement. The intraclass correlation was calculated. Results Agreement among the four observers for the evaluation of liver tumour burden was substantial, ranging from 0.62 to 0.73 (P < 0.0001). The intraclass coefficient was 0.977 (P < 0.0001). Intraobserver agreement was 0.78 and ICC was 0.97. Conclusion Reproducibility of the visual semi-quantitative evaluation of liver tumour burden is good and is independent of the level of experience of the readers. We therefore suggest that clinical studies in patients with neuroendocrine liver metastases use this method to categorise liver tumour burden. PMID:28069898

  5. Melatonin Immunoreactivity in Malignant Small Intestinal Neuroendocrine Tumours

    PubMed Central

    Söderquist, Fanny; Janson, Eva Tiensuu; Rasmusson, Annica J.; Ali, Abir; Stridsberg, Mats; Cunningham, Janet L.

    2016-01-01

    Background/Aims Small intestinal neuroendocrine tumours (SI-NETs) are derived from enterochromaffin cells. After demonstrating melatonin in enterochromaffin cells, we hypothesized that SI-NETs may express and secrete melatonin, which may have an impact on clinical factors and treatment response. Methods Tumour tissue from 26 patients with SI-NETs, representing paired sections of primary tumour and metastasis, were immunohistochemically stained for melatonin and its receptors, MT1 and MT2. Plasma melatonin and immunoreactivity (IR) for melatonin, MT1 and MT2 in tumour cells were compared to other tumour markers and clinical parameters. Melatonin was measured at two time points in fasting morning plasma from 43 patients with SI-NETs. Results Melatonin IR was found in all SI-NETS. Melatonin IR intensity in primary tumours correlated inversely to proliferation index (p = 0.022) and patients reported less diarrhoea when melatonin IR was high (p = 0.012). MT1 IR was low or absent in tumours. MT2 expression was medium to high in primary tumours and generally reduced in metastases (p = 0.007). Plasma-melatonin ranged from 4.5 to 220.0 pg/L. Higher levels were associated with nausea at both time points (p = 0.027 and p = 0.006) and flush at the second sampling. In cases with disease stabilization or remission (n = 34), circulating melatonin levels were reduced in the second sample (p = 0.038). Conclusion Immunoreactive melatonin is present in SI-NETs. Circulating levels of melatonin in patients with SI-NETs are reduced after treatment. Our results are congruent with recent understanding of melatonin’s endocrine and paracrine functions and SI-NETs may provide a model for further studies of melatonin function. PMID:27736994

  6. Cystic pancreatic neuroendocrine tumors: To date a diagnostic challenge.

    PubMed

    Caglià, Pietro; Cannizzaro, Maria Teresa; Tracia, Angelo; Amodeo, Luca; Tracia, Luciano; Buffone, Antonino; Amodeo, Corrado; Cannizzaro, Matteo Angelo

    2015-09-01

    Cystic PNETs are an uncommon neoplasms increasingly detected in current clinical practice which often present a diagnostic challenges to both the experienced radiologist and pathologist. The aim of this study was to review the available literature to summarize current data that compare and evaluate both the clinical and pathologic features of cystic pancreatic neuroendocrine tumors. A systematic review of the current literature was performed using the search engines EMBASE and PubMed to identify all studies reporting on cystic pancreatic neuroendocrine tumors. The MeSH search terms used were "cystic pancreatic neuroendocrine tumors", "endocrine neoplasms", and "pancreatic cysts". Multiple combinations of the keywords and MeSH terms were used. The clinical evaluation of cystic pancreatic lesions appears to suffer from same limitations despite the improvement in the diagnostic tools. Subsequently, we highlight diagnostic pitfalls and differential diagnosis of these cystic tumors. In this review we discuss current advances in the application of the imaging modalities and characteristics features with special emphasize on endoscopic ultrasound (EUS), and EUS guide fine needle aspiration (EUS-FNA). Cystic neuroendocrine tumor in the pancreas underlines the clinical impact of endoscopic ultrasound in the work-up of patients with unclear lesions in the pancreas. EUS-FNA cytology and cyst fluid analysis is a useful adjunct to abdominal imaging for the diagnosis of pancreatic cystic lesions. Due to the evident diagnostic difficulties, we hypothesize that cyst fluid characteristics, including cytomorphological features, is the most accurate test to achieve a preoperative diagnosis and to provide a basis for prognostic prediction. Copyright © 2015 IJS Publishing Group Limited. Published by Elsevier Ltd. All rights reserved.

  7. Disseminated Pancreatic Neuroendocrine Neoplasm (NEN) with an Uncommon Localisation in the Central Nervous System. A Case Report

    PubMed Central

    Białkowska, Joanna; Kolasińska-Ćwikła, Agnieszka; Mroczkowska, Dorota; Sowa, Mariusz; Grabarczyk, Łukasz; Maksymowicz, Wojciech; Cichocki, Andrzej; Ćwikła, Jarosław B.

    2017-01-01

    Summary Background Neuroendocrine neoplasms (NEN) are rare neoplasms that originate from neuroendocrine cells and are characterized by the potential of hormonal activity. Approximately 70% of these tumours are located in the gastrointestinal system (GI), followed by the bronchi, endocrine glands-like C cells of the thyroid (medullary carcinoma), the parasympathetic and sympathetic system (paragangliomas, pheochromocytoma) and other very rare locations. The prevalence of cerebral metastases in neuroendocrine tumours is estimated by various authors to be approximately 1.5–5%. When the primary tumour is located in the pancreas, it is associated with a risk of cerebral metastases lower than 2%. Case Report We describe a patient with a disseminated pancreatic NEN that presented with an isolated lesion in the brain. We gathered the important data via medical history,, observation, analysis of medical records, imaging and others diagnostic tests. Despite the fairly rare prevalence of cerebral metastases in NENs, a neurological work-up should be performed. This should include neuroimaging of the brain, preferably with MR, together with the somatostatin receptor scintigraphy (SRS), in each clinically suspicious case. A histopathological examination of the CNS tumour can confirm a dedifferentiation of NEN in the direction of a neuroendocrine carcinoma (NEC – neuroednocrine carcinoma) with a poor prognosis. Conclusions Cerebral metastases are diagnosed in 1.5–5% of patients with a neuroendocrine neoplasm. In each case suggestive of a dissemination into the central nervous system, MRI of the brain should be performed. PMID:28344687

  8. [Classification of gastro-entero-pancreatic neuroendocrine tumors].

    PubMed

    Perren, A; Schmitt, A; Komminoth, P; Pavel, M

    2009-03-01

    Tumors of the disseminated/diffuse neuroendocrine system (NET) are characterized by a common phenotype. However, the biology varies according to histomorphology, endocrine symptoms and organ of origin. The WHO classification takes these differences into account and uses a common framework, where the parameters size and extent of invasion vary according to the organ of origin. In order to achieve a further standardization of reporting the European Neuroendocrine Tumor Society (ENETS) recently proposed a tumor-node-metastasis (TNM) staging and grading system for gastro-entero-pancreatic NET.

  9. Guidelines for the management of neuroendocrine tumours by the Brazilian gastrointestinal tumour group

    PubMed Central

    Riechelmann, Rachel P; Weschenfelder, Rui F; Costa, Frederico P; Andrade, Aline Chaves; Osvaldt, Alessandro Bersch; Quidute, Ana Rosa P; dos Santos, Allan; Hoff, Ana Amélia O; Gumz, Brenda; Buchpiguel, Carlos; Vilhena Pereira, Bruno S; Lourenço Junior, Delmar Muniz; da Rocha Filho, Duilio Reis; Fonseca, Eduardo Antunes; Riello Mello, Eduardo Linhares; Makdissi, Fabio Ferrari; Waechter, Fabio Luiz; Carnevale, Francisco Cesar; Coura-Filho, George B; de Paulo, Gustavo Andrade; Girotto, Gustavo Colagiovanni; Neto, João Evangelista Bezerra; Glasberg, João; Casali-da-Rocha, Jose Claudio; Rego, Juliana Florinda M; de Meirelles, Luciana Rodrigues; Hajjar, Ludhmila; Menezes, Marcos; Bronstein, Marcello D; Sapienza, Marcelo Tatit; Fragoso, Maria Candida Barisson Villares; Pereira, Maria Adelaide Albergaria; Barros, Milton; Forones, Nora Manoukian; do Amaral, Paulo Cezar Galvão; de Medeiros, Raphael Salles Scortegagna; Araujo, Raphael L C; Bezerra, Regis Otaviano França; Peixoto, Renata D’Alpino; Aguiar, Samuel; Ribeiro, Ulysses; Pfiffer, Tulio; Hoff, Paulo M; Coutinho, Anelisa K

    2017-01-01

    Neuroendocrine tumours are a heterogeneous group of diseases with a significant variety of diagnostic tests and treatment modalities. Guidelines were developed by North American and European groups to recommend their best management. However, local particularities and relativisms found worldwide led us to create Brazilian guidelines. Our consensus considered the best feasible strategies in an environment involving more limited resources. We believe that our recommendations may be extended to other countries with similar economic standards. PMID:28194228

  10. Guidelines for the management of neuroendocrine tumours by the Brazilian gastrointestinal tumour group.

    PubMed

    Riechelmann, Rachel P; Weschenfelder, Rui F; Costa, Frederico P; Andrade, Aline Chaves; Osvaldt, Alessandro Bersch; Quidute, Ana Rosa P; Dos Santos, Allan; Hoff, Ana Amélia O; Gumz, Brenda; Buchpiguel, Carlos; Vilhena Pereira, Bruno S; Lourenço Junior, Delmar Muniz; da Rocha Filho, Duilio Reis; Fonseca, Eduardo Antunes; Riello Mello, Eduardo Linhares; Makdissi, Fabio Ferrari; Waechter, Fabio Luiz; Carnevale, Francisco Cesar; Coura-Filho, George B; de Paulo, Gustavo Andrade; Girotto, Gustavo Colagiovanni; Neto, João Evangelista Bezerra; Glasberg, João; Casali-da-Rocha, Jose Claudio; Rego, Juliana Florinda M; de Meirelles, Luciana Rodrigues; Hajjar, Ludhmila; Menezes, Marcos; Bronstein, Marcello D; Sapienza, Marcelo Tatit; Fragoso, Maria Candida Barisson Villares; Pereira, Maria Adelaide Albergaria; Barros, Milton; Forones, Nora Manoukian; do Amaral, Paulo Cezar Galvão; de Medeiros, Raphael Salles Scortegagna; Araujo, Raphael L C; Bezerra, Regis Otaviano França; Peixoto, Renata D'Alpino; Aguiar, Samuel; Ribeiro, Ulysses; Pfiffer, Tulio; Hoff, Paulo M; Coutinho, Anelisa K

    2017-01-01

    Neuroendocrine tumours are a heterogeneous group of diseases with a significant variety of diagnostic tests and treatment modalities. Guidelines were developed by North American and European groups to recommend their best management. However, local particularities and relativisms found worldwide led us to create Brazilian guidelines. Our consensus considered the best feasible strategies in an environment involving more limited resources. We believe that our recommendations may be extended to other countries with similar economic standards.

  11. 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.

  12. Autoimmune pancreatitis mimicking Klatskin tumour on radiology.

    PubMed

    Hadi, Yousaf Bashir; Sohail, Abdul Malik Amir Humza; Haider, Zishan

    2015-04-09

    Autoimmune pancreatitis (AIP) is categorised into two distinct types, AIP type 1 and 2. Although there can be multisystem involvement, rarely, the cholangitis associated with AIP can present radiologically in a manner similar to that of Klatskin tumour. We present the case of a 65-year-old man who was almost misdiagnosed with a Klatskin tumour because of the similarity in radiological features of the two aforementioned clinical entities. The patient presented with a history of jaundice, pruritus and abdominal pain, and work up showed deranged liver function tests, elevated cancer antigen 19-9 levels and positive antinuclear antibodies. CT scan of the abdomen showed findings suggestive of Klatskin tumour but due to diffuse enlargement of the pancreas and surrounding low-attenuation halo found on a closer review, a diagnosis of AIP was performed. The patient was started on standard corticosteroid therapy and responded well, with complete resolution of the radiological findings.

  13. Pazopanib and depot octreotide in advanced, well-differentiated neuroendocrine tumours: a multicentre, single-group, phase 2 study

    PubMed Central

    Phan, Alexandria T; Halperin, Daniel M; Chan, Jennifer A; Fogelman, David R; Hess, Kenneth R; Malinowski, Paige; Regan, Eileen; Ng, Chaan S; Yao, James C; Kulke, Matthew H

    2015-01-01

    Summary Background Treatment options for advanced, well-differentiated neuroendocrine tumours (NETs) remain scarce. Pazopanib is an orally bioavailable, small molecule, multitargeted kinase inhibitor that inhibits VEGF receptors 1, 2, and 3. We did a study of the efficacy of pazopanib with depot octreotide in patients with advanced NETs. Methods We did a parallel cohort study of patients with metastatic or locally advanced grade 1–2 carcinoid tumours or pancreatic NETs, by use of a single-group, two-stage design. Patients received pazopanib 800 mg orally once per day and octreotide at their preprotocol dosage. The primary endpoint was the proportion of patients achieving an objective response, as assessed by investigators, by intention-to-treat analysis. This study is registered with ClinicalTrials.gov, identifier NCT00454363, and was completed in March, 2014. Findings Between April 12, 2007, and July 2, 2009, we enrolled 52 patients, including 32 individuals with pancreatic NETs and 20 individuals with carcinoid tumours. Seven (21.9%, 95% CI 11.0–38.8) of 32 patients with pancreatic NETs achieved an objective response. We detected no responses in the first stage of the cohort with carcinoid tumours, and we terminated accrual at 20 patients. Toxic effects included one patient with grade 4 hypertriglyceridaemia and one with grade 4 thrombosis, with the most common grade three events being aminotransferase increases and neutropenia, each of which happened in 3 patients. In all 52 patients, the most frequently observed toxic effects were fatigue (39 [75%]), nausea (33 [63%]), diarrhoea (33 [63%]), and hypertension (28 [54%]). Interpretation Treatment with pazopanib is associated with tumour response for patients with pancreatic NETs, but not for carcinoid tumours; a randomised controlled phase 3 study to assess pazopanib in advanced pancreatic NETs is warranted. Funding US National Cancer Institute of the National Institutes of Health. PMID:25956795

  14. [Surgical treatment and prognosis of pancreatic neuroendocrine carcinoma].

    PubMed

    Zhang, J W; Che, X; Lan, Z M; Chen, Y T; Huang, X H; Jiang, Q L; Wang, C F

    2016-12-23

    Objective: Pancreatic neuroendocrine carcinoma (pNEC) is a highly malignant tumor.This study aimed to evaluate the role of surgery and the prognosis for patients with pancreatic neuroendocrine carcinoma (pNEC). Methods: We collected and reviewed all clinical data of patients who underwent radical surgery for pNEC from Jan 2000 through Jan 2016 in our hospital. Cox-regression analysis wasused to evaluate the factors potentially influencing survival. Results: Twenty patients including 11 males and 9 females (median age, 62.5 years) were included in this study. All patients underwent radical surgery and 17 cases received postoperative platinum-based chemotherapy.The median follow-up time was 41 months (range, 1 to 127 months). The 1-, 3-, and 5-year survival rates of the patients were 66.7%, 51.5% and 28.1%, with a median survival time of 75.3 months.The multivariate analysis indicated that tumor size and Ki-67 index were of prognostic significance. Conclusions: Pancreatic neuroendocrine carcinomas are rare but increasing in incidence. Patients with localized nonmetastatic primary tumors seem to benefit from surgery. Early diagnosis and multimodality therapy are key points of an improved survival.

  15. Genetics and epigenetics in small intestinal neuroendocrine tumours.

    PubMed

    Stålberg, P; Westin, G; Thirlwell, C

    2016-12-01

    Neuroendocrine tumour of the small intestine (SI-NET), formerly known as midgut carcinoid tumour, is the most common small intestinal malignancy. The incidence is rising, with recent reports of 0.67 per 100 000 in the USA and 1.12 per 100 000 in Sweden. SI-NETs often present a challenge in terms of diagnosis and treatment, as patients often have widespread disease and are beyond cure by surgery. Somatostatin analogues provide the mainstay of medical treatment to control hormonal excess and increase the time to progression. Despite overall favourable prognosis (5-year overall survival of 65%), there is a need to find markers to identify both patients with worse outcome and new targets for therapy. Loss on chromosome 18 has been reported in 60-90% of SI-NETs, but mutated genes on this chromosome have failed detection. Recently, a putative tumour suppressor role has been suggested for TCEB3C occurring at 18q21 (encoding elongin A3), which may undergo epigenetic repression. CDKN1B has recently been revealed as the only recurrently mutated gene in SI-NETs but, with a frequency as low as 8%, its role as a driver in SI-NET development may be questioned. Integrated genomewide analysis including exome and whole-genome sequencing, gene expression, DNA methylation and copy number analysis has identified three novel molecular subtypes of SI-NET with differing clinical outcome. DNA methylation analysis has demonstrated that SI-NETs have significant epigenetic dysregulation in 70-80% of tumours. In this review, we focus on understanding of the genetic, epigenetic and molecular events that lead to development and progression of SI-NETs.

  16. Targeting pancreatic expressed PAX genes for the treatment of diabetes mellitus and pancreatic neuroendocrine tumors.

    PubMed

    Martin-Montalvo, Alejandro; Lorenzo, Petra I; López-Noriega, Livia; Gauthier, Benoit R

    2017-01-01

    Four members of the PAX family, PAX2, PAX4, PAX6 and PAX8 are known to be expressed in the pancreas. Accumulated evidences indicate that several pancreatic expressed PAX genes play a significant role in pancreatic development/functionality and alterations in these genes are involved in the pathogenesis of pancreatic diseases. Areas covered: In this review, we summarize the ongoing research related to pancreatic PAX genes in diabetes mellitus and pancreatic neuroendocrine tumors. We dissect the current knowledge at different levels; from mechanistic studies in cell lines performed to understand the molecular processes controlled by pancreatic PAX genes, to in vivo studies using rodent models that over-express or lack specific PAX genes. Finally, we describe human studies associating variants on pancreatic-expressed PAX genes with pancreatic diseases. Expert opinion: Based on the current literature, we propose that future interventions to treat pancreatic neuroendocrine tumors and diabetes mellitus could be developed via the modulation of PAX4 and/or PAX6 regulated pathways.

  17. Imaging of neuroendocrine tumours with gamma-emitting radiopharmaceuticals.

    PubMed

    Bombardieri, E; Coliva, A; Maccauro, M; Seregni, E; Orunesu, E; Chiti, A; Lucignani, G

    2010-02-01

    Nuclear medicine can image some tumors by means of receptor specific radiopharmaceuticals, and offers the possibility to characterize cancer through the detection of its receptor expression. This is the case of neuroendocrine tumours (NETs), that are visualized by different radiolabelled somatostatin analogues that bind 5 distinct somatostatin receptor types (named sstr1-5) that show different tissue distribution. The subtypes sstr2 and sstr5 are the most commonly expressed in NETs. Until now the most widely used radiolabelled somatostatin analogue for planar and single photon emission computed tomography (SPECT) has been [(111)In]pentetreotide, because of its commercial availability. Other analogues labelled with gamma emitting radionuclides are [(99m)Tc]EDDA/HYNIC-TOC, [(99m)Tc]P829, [(111)In]DOTA-lanreotide, [(111)In]DOTA-NOC-ATE, [(111)In]DOTA-BOC-ATE. However, these compounds have not been successful for the routine use. Moreover, NETs express various receptors that can be depicted by different radiopharmaceuticals, such as [(123)I]VIP and [(111)In]GLP-1. Besides this, some precursors of the catecholamines metabolism, as meta-iodo-benzyl-guanidine (MIBG), labelled with (123)I or (131)I, accumulates in neuroendocrine tissues, in particular those of sympathoadrenal lineage. MIBG scintigraphy is currently indicated for neuroblastoma, paraganglioma and phaeocromocitoma. An impressive technological progress has been achieved recently with PET and, in particular, with the development of hybrid instrumentations (PET/CT) combining nuclear imaging with radiological imaging providing both functional and morphologic information. Among positron emitting tracers, the [(18)F]FDG is the most diffuse in oncology, but other more effective tracers are available for NETs, such as the analogues labelled with 68Ga. The diagnostic sensitivity and accuracy of these technology is superior to that of gamma emitting radiopharmaceuticals, but the fact that they are not still registered

  18. Genetics of pancreatic neuroendocrine tumors: implications for the clinic

    PubMed Central

    Pea, Antonio; Hruban, Ralph H.; Wood, Laura D.

    2016-01-01

    Pancreatic neuroendocrine tumors (PanNETs) are a common and deadly neoplasm of the pancreas. Although the importance of genetic alterations in PanNETs has been known for many years, recent comprehensive sequencing studies have greatly expanded our knowledge of neuroendocrine tumorigenesis in the pancreas. These studies have identified specific cellular processes that are altered in PanNETs, highlighted alterations with prognostic implications, and pointed to pathways for targeted therapies. In this review, we will discuss the genetic alterations that play a key role in PanNET tumorigenesis, with a specific focus on those alterations with the potential to change the way patients with these neoplasms are diagnosed and treated. PMID:26413978

  19. Pancreatic neuroendocrine tumors in twelve baboons (Papio spp.).

    PubMed

    Owston, M A; LaRue, M K; Dick, E J; Ambrus, A; Porter, B F

    2016-04-01

    Pancreatic neuroendocrine tumors (PNETs) are rare in nonhuman primates and in humans. Twenty-one PNETs from twelve female baboons (Papio spp.) from the Southwest National Primate Research Center were evaluated using histopathology and immunohistochemistry. Histologically, all tumors were benign and had neuroendocrine packeting. Immunohistochemical staining for synaptophysin and chromogranin was positive in all tumors evaluated (17/17). Insulin was positive in 16 of 21 tumors. Somatostatin was positive in 9 of 20 tumors. Multifocal staining for glucagon and pancreatic polypeptide was evident in a minority of tumors (6/20 and 2/17, respectively). Gastrin and vasoactive intestinal peptide were negative in all tumors evaluated. Nine tumors expressed more than one hormone marker. This is the first detailed pathologic study of pancreatic endocrine tumors in the baboon. The findings suggest that these tumors are generally benign and have similar morphologic and immunohistochemical features as those described in people, including the ability to express multiple hormones. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Pancreatic Neuroendocrine Tumors in Twelve Baboons (Papio spp.)

    PubMed Central

    Owston, M.A.; LaRue, M.K.; Dick, E.J.; Ambrus, A.; Porter, B.F.

    2016-01-01

    Background Pancreatic neuroendocrine tumors (PNETs) are rare in nonhuman primates and in humans. Methods Twenty-one PNETs from twelve female baboons (Papio spp.) from the Southwest National Primate Research Center were evaluated using histopathology and immunohistochemistry. Results Histologically, all tumors were benign and had neuroendocrine packeting. Immunohistochemical staining for synaptophysin and chromogranin was positive in all tumors evaluated (17/17). Insulin was positive in 16/21 tumors. Somatostatin was positive in 9/20 tumors. Multifocal staining for glucagon and pancreatic polypeptide was evident in a minority of tumors (6/20 and 2/17, respectively). Gastrin and vasoactive intestinal peptide were negative in all tumors evaluated. Nine tumors expressed more than one hormone marker. Conclusions This is the first detailed pathologic study of pancreatic endocrine tumors in the baboon. The findings suggest that these tumors are generally benign and have similar morphologic and immunohistochemical features as those described in people, including the ability to express multiple hormones. PMID:26899153

  1. Prostate-Specific Membrane Antigen (PSMA) Avid Pancreatic Neuroendocrine Tumor.

    PubMed

    Vamadevan, Shankar; Shetty, Deepa; Le, Ken; Bui, Chuong; Mansberg, Robert; Loh, Han

    2016-10-01

    Ga-PSMA PET/CT is increasingly used to evaluate recurrent prostatic malignancy due to its high specificity. A 75-year-old man with a previous history of treated prostate cancer 3 years earlier presented with rising prostate-specific antigen (PSA) level and underwent Ga-PSMA PET/CT which demonstrated a PSMA-avid focus in the neck of the pancreas. Triple-phase abdominal CT demonstrated enhancement in the arterial phase and to a lesser extent the venous phase of a soft tissue mass in the neck of the pancreas. Cytological and histopathological examination of the soft tissue mass confirmed a low-grade pancreatic neuroendocrine tumor.

  2. A renaissance in therapeutic options for pancreatic neuroendocrine tumors.

    PubMed

    Kunz, Pamela L

    2012-01-01

    The field of pancreatic neuroendocrine tumors (NETs) has seen a remarkable renaissance in recent years with exponential increases in published research, clinical trials, and U.S. Food and Drug Administration (FDA)-approved treatments. Surgical resection remains the foundation for management of locoregional disease. However, for patients with advanced disease, novel therapeutic options have emerged. Two separate randomized placebo-controlled studies have shown prolonged progression-free survival (PFS) with everolimus or sunitinib. Future studies are designed to answer questions about the role of somatostatin analogs as antiproliferative agents, combinations of biologic therapies, and new cytotoxic chemotherapy backbones.

  3. 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

  4. Patient experiences of having a neuroendocrine tumour: a qualitative study.

    PubMed

    Feinberg, Y; Law, C; Singh, S; Wright, F C

    2013-10-01

    Limited qualitative studies exist regarding the patient experience of having a rare cancer. We sought to understand the patient experience of having a rare malignancy by interviewing patients diagnosed with neuroendocrine tumours (NET). Semi-structured qualitative interviews were used to examine the cancer journey experience of NET patients. Purposive sampling was utilized and 18 telephone interviews were completed by a single interviewer. Eight interviewees were female, median age was 63 (age range 45-77). Median interview time was 31 min (range 9 min - 2 h 8 min). Patient interviews were transcribed verbatim and analysed using qualitative research methodology. Grounded theory guided the generation of the interview guide and analysis. The dominant theme identified was that of 'no clear pathway' of care for the patient with NETs. Four subthemes that influenced this theory included: (1) difficulty with obtaining a diagnosis; (2) difficulty finding appropriate information about NETs from physicians; (3) difficulty finding treatment centres with knowledge of NETs and (4) difficulty finding disease specific support. Two global modifiers were also identified; satisfaction with a specialized clinic and long term physical and psychological side effects of treatment. These modifiers did not affect the overall theme but do potentially offer a solution for some of the difficulties the patients experienced. Patients with NETs had 'no clear pathway' of care in their cancer journey. A multidisciplinary specialized clinic for NETs is recommended as well as a strong role for nursing in providing support and building patient and family resilience. Copyright © 2013 Elsevier Ltd. All rights reserved.

  5. Gastric neuroendocrine cell hyperplasia and type 1 tumours occurring within gastric hyperplastic polyps.

    PubMed

    Chetty, Runjan; Gill, Pelvender; Mugon, Parassar; Shrimankar, Jyotsna; Hughes, Caroline

    2012-11-01

    We wish to highlight the unusual occurrence of gastric neuroendocrine cell hyperplasia and type I neuroendocrine tumours within three hyperplastic polyps. In all cases, the neuroendocrine component was present within and between the hyperplastic foveolar glands of the polyps and overall formed the minor part of the polyps. Two of the patients presented with epigastric pain and the other with fatigue from anaemia, and on endoscopy, all three were found to have superficially ulcerated gastric polyps in the body (cases 1 and 2) and fundus (case 3). Two of the cases had serologically proven autoimmune atrophic gastritis, while the third case had histological evidence of an atrophic gastritis, most likely also autoimmune in aetiology. Cases 1 and 3 had single hyperplastic polyps, while case 2 had three polyps. All polyps showed linear neuroendocrine cell hyperplasia within hyperplastic foveolar epithelium both at the surface and within deeper-situated glands. Neuroendocrine immunohistochemistry highlighted the neuroendocrine cell hyperplasia. The bulk of the neuroendocrine component was restricted to hyperplastic mucosa forming the polyps. Non-hyperplastic adjacent mucosa showed less prominent neuroendocrine cell hyperplasia. It is unclear whether the two pathologies occurred simultaneously or independently. The common feature and causal link is atrophic gastritis, which predisposed the gastric mucosa to the development of both neuroendocrine cell hyperplasia and tumours, and hyperplastic polyps.

  6. A Systematic Review of Proinsulin-Secreting Pancreatic Neuroendocrine Tumors.

    PubMed

    Murtha, Timothy D; Lupsa, Beatrice C; Majumdar, Sachin; Jain, Dhanpat; Salem, Ronald R

    2017-08-01

    Pancreatic neuroendocrine tumors (PNETs) are a heterogeneous group of islet cell-derived neoplasms with a propensity toward hormone production. Among PNETs, proinsulin-secreting tumors (proinsulinomas) are exceedingly rare. The objective of this study is to collect and summarize the existing literature to provide a comprehensive evaluation of this uncommon disease. A systematic review was performed to characterize the clinicopathologic features of proinsulinoma. Using the electronic biomedical databases PubMed, Ovid Medline, and Embase, 316 publications were screened for relevance of which 14 were selected. We also present two patients with proinsulinoma treated at Yale New Haven Hospital. Of the 16 patients included in the study, the mean age was 56.8 and there was a 2:1 female predominance. The majority of patients presented with symptomatic hypoglycemia with normal or low insulin levels. Median tumor diameter was 1.2 cm and 80% were located in the body and tail of the pancreas. Following resection, most patients had normalization of hormonal levels without recurrence (75%; 12/16). Proinsulinomas are rare pancreatic neuroendocrine tumors that have the potential to cause hypoglycemia. While insulinomas and proinsulin-secreting tumors have many physiologic parallels, these cases illustrate several key distinctions in their diagnosis and management.

  7. [Small cell neuroendocrine tumour of the bladder: with reference to a case and bibliographical revision].

    PubMed

    Lahoz Tornos, A; Marrón Penón, Maria C; Pardo López, Maria L; Nogueras Gimeno, M A; Pujol Obis, E; Del Villar Sordo, V

    2006-09-01

    The small cell neuroendocrine tumour is an infrecuent neoplasia, with inmunohistochemistry being the key to diagnosis. We present a new case making reference to treatment and its evolution there after. The clinic, diagnosis and treatment of this tumour is described. Bibliographical revision follours. The neuroendocrine tumour of small cell is an infrecuent neoplasia, in which the inmunohistochemistry study is key in the diagnosis. The differential diagnosis includes the high degree diferentiation transitionals cells carcinoma and primary and secondary linfoma. The standard treatment is based on chemotherapy plus surgery.

  8. Primary neuroendocrine tumour of the breast: a case report and review of the literature

    PubMed Central

    Tato-Varela, Sara; Albalat-Fernández, Rosa; Pabón-Fernández, Sara; Zarco, Enrique Rodríguez; Calle-Marcos, Manolo La

    2015-01-01

    Primary neuroendocrine tumour of the breast is a rare entity that first appeared in the 2003 World Health Organisation (WHO) classification of breast tumours. The data currently available on its prognosis are contradictory, although it seems clear that histological varieties such as small cell neuroendocrine carcinoma have a worse prognosis, due to their low degree of differentiation. The treatment of choice is surgery, and the indications for chemotherapy or radiotherapy do not differ greatly from those used for other breast tumours. It is crucial to underline the difficulty of establishing treatment protocols due to the low incidence of this histological type. PMID:26798407

  9. Ki-67 index and response to chemotherapy in patients with neuroendocrine tumours.

    PubMed

    Childs, Alexa; Kirkwood, Amy; Edeline, Julien; Luong, Tu Vinh; Watkins, Jennifer; Lamarca, Angela; Alrifai, Doraid; Nsiah-Sarbeng, Phyllis; Gillmore, Roopinder; Mayer, Astrid; Thirlwell, Christina; Sarker, Debashis; Valle, Juan W; Meyer, Tim

    2016-07-01

    Chemotherapy (CT) is widely used for neuroendocrine tumours (NETs), but there are no validated biomarkers to predict response. The Ki-67 proliferation index has been proposed as a means of selecting patients for CT, but robust data are lacking. The aim of this study was to investigate the relationship between response to chemotherapy and Ki-67 in NET. We reviewed data from 222 NET patients treated with CT. Tumours were graded according to Ki-67 index: G1 ≤2%, G2 3-20% and G3 >20%. Response was assessed according to RECIST and survival calculated from start of chemotherapy to death. To explore Ki-67 as a marker of response, we calculated the likelihood ratio and performed receiver operating characteristic analysis. Overall, 193 patients had a documented Ki-67 index, of which 173 were also evaluable for radiological response: 10% were G1, 46% G2 and 43% G3; 46% were pancreatic NET (PNET). Median overall survival was 22.1 months. Overall response rate was 30% (39% in PNET vs 22% in non-PNET) and 43% of patients had stable disease. Response rate increased with grade: 6% in G1 tumours, 24% in G2 and 43% in G3. However, maximum likelihood ratio was 2.3 at Ki-67=35%, and the area under the ROC curve was 0.60. As reported previously, a high Ki-67 was an adverse prognostic factor for overall survival. In conclusion, response to CT increases with Ki-67 index, but Ki-67 alone is an unreliable means to select patients for CT. Improved methods to stratify patients for systemic therapy are required. © 2016 Society for Endocrinology.

  10. Update on surgical treatment of pancreatic neuroendocrine neoplasms

    PubMed Central

    D’Haese, Jan G; Tosolini, Chiara; Ceyhan, Güralp O; Kong, Bo; Esposito, Irene; Michalski, Christoph W; Kleeff, Jörg

    2014-01-01

    Pancreatic neuroendocrine neoplasms (PNENs) are rare and account for only 2%-4% of all pancreatic neoplasms. All PNENs are potential (neurendocrine tumors PNETs) or overt (neuroendocrine carcinomas PNECs) malignant, but a subset of PNETs is low-risk. Even in case of low-risk PNETs surgical resection is frequently required to treat hormone-related symptoms and to obtain an appropriate pathological diagnosis. Low-risk PNETs in the body and the tail are ideal for minimally-invasive approaches which should be tailored to the individual patient. Generally, surgeons must aim for parenchyma sparing in these cases. In high-risk and malignant PNENs, indications for tumor resection are much wider than for pancreatic adenocarcinoma, in many cases due to the relatively benign tumor biology. Thus, patients with locally advanced and metastatic PNETs may benefit from extensive resection. In experienced hands, even multi-organ resections are accomplished with acceptable perioperative morbidity and mortality rates and are associated with excellent long term survival. However, poorly differentiated neoplasms with high proliferation rates are associated with a dismal prognosis and may frequently only be treated with chemotherapy. The evidence on surgical treatment of PNENs stems from reviews of mostly single-center series and some analyses of nation-wide tumor registries. No randomized trial has been performed to compare surgical and non-surgical therapies in potentially resectable PNEN. Though such a trial would principally be desirable, ethical considerations and the heterogeneity of PNENs preclude realization of such a study. In the current review, we summarize recent advances in the surgical treatment of PNENs. PMID:25320524

  11. Radionuclide therapy in neuroendocrine tumours: a systematic review.

    PubMed

    Gulenchyn, K Y; Yao, X; Asa, S L; Singh, S; Law, C

    2012-05-01

    The purpose of this systematic review was to investigate the effects of therapeutic radiopharmaceuticals in patients with different types of advanced neuroendocrine tumour (NETs). A literature search was carried out in MEDLINE and EMBASE from January 1998 to November 2010. The Cochrane Library (to Issue 10, 2010) and the Standards and Guidelines Evidence Inventory of Cancer Guidelines, including over 1100 English-language cancer guidelines from January 2003 to June 2010, were also checked. No existing systematic reviews or clinical practice guidelines based on a systematic review or randomised controlled trials focusing on this topic were found. Twenty-four fully published articles were abstracted and summarised: 16 articles focused on five peptide receptor radionuclide therapy ((111)In-DTPAOC, (90)Y-DOTALAN, (90)Y-DOTATOC, (90)Y-DOTATATE, and (177)Lu-DOTATATE) and eight focused on (131)I-MIBG treatment. Limited evidence from a historical comparison of studies in one centre supported that (177)Lu-DOTATATE might be associated with greater clinical outcomes compared with (90)Y-DOTATOC or (111)In-DTPAOC. The severe toxicities for (177)Lu-DOTATATE included hepatic insufficiency in 0.6%, myelodysplastic syndrome in 0.8% and renal insufficiency in 0.4% of patients in this study. Insufficient evidence suggested efficacy of (131)I-MIBG in adult NET patients, but the overall tumour response rate from (131)I-MIBG was 27-75% for malignant neuroblastoma, paraganglioma or pheochromocytoma. Haematological toxicities were the main severe side-effects after (131)I-MIBG and 4% of patients developed secondary malignancies in one study. To date, peptide receptor radionuclide therapy seems to be an acceptable option and is relatively safe in adult advanced NET patients with receptor uptake positive on scintigraphy, but patients' renal function must be monitored. (131)I-MIBG may be effective for malignant neuroblastoma, paraganglioma or pheochromocytoma, but its side-effects need to be

  12. Pancreatic neuroendocrine carcinoma with exocrine differentiation in a young cat.

    PubMed

    Michishita, Masaki; Takagi, Mariko; Kishimoto, Takuya E; Nakahira, Rei; Nogami, Takeshi; Yoshimura, Hisashi; Hatakeyama, Hitoshi; Azakami, Daigo; Ochiai, Kazuhiko; Takahashi, Kimimasa

    2017-05-01

    A 35-mo-old spayed female mixed-breed cat with continuous vomiting, emaciation, and abdominal distention for 2 wk was presented to a private veterinary clinic for evaluation. At 71 d after the initial visit, the cat died with anemia, jaundice, and hypoalbuminemia, and was subjected to autopsy. Grossly, numerous firm masses, 0.5-2.5 cm diameter, were randomly located in the left lobe of the pancreas. Histologic examination revealed that the pancreatic mass consisted of 2 tumor cell types: mostly small round cells with a minority of epithelial cells. The small cells were arranged in nests of various sizes, which were separated by thin fibrous stroma, and had small, round, hyperchromatic nuclei, scant cytoplasm containing argyrophilic granules, and often formed rosettes. The epithelial cells formed luminal structures. Metastases were observed in the liver, greater omentum, and pancreatic, gastric, pulmonary, and mediastinal lymph nodes. Immunohistochemical examination revealed that the small cells were positive for vimentin, neuron-specific enolase, chromogranin A, cytokeratin (CK) AE1/AE3, and trypsin, whereas the epithelial cells were positive for AE1/AE3, trypsin, CK19, and nestin. Ultrastructurally, the small cells contained abundant electron-dense granules, ~200 nm diameter, whereas the epithelial cells had apical microvilli and numerous zymogen granules, ~300 nm diameter. These findings indicated that the tumor was a pancreatic neuroendocrine carcinoma with exocrine differentiation and systemic metastases.

  13. Carcinoid Syndrome and Carcinoid Heart Disease as Manifestations of Non-Metastatic Ovarian Neuroendocrine Tumour.

    PubMed

    Simões-Pereira, Joana; Wang, Lai Mun; Kardos, Attila; Grossman, Ashley

    2017-05-31

    The carcinoid syndrome is rare but it is associated with carcinoid heart disease in more than a half of the cases. Carcinoid heart disease is typically characterised by morphological and functional modifications of right-sided valves. Its aetiology is probable multifactorial but serotonin appears to play a key role in the development of this valvular disease. Unlike gastrointestinal neuroendocrine tumours, ovarian neuroendocrine tumours can present with carcinoid syndrome and carcinoid heart disease in the absence of liver metastases; such ovarian neuroendocrine tumours are a unique clinical entity. The additional burden of cardiac impairment in these patients represents a significant reduction in survival. Early recognition and surgical valve replacement before advanced heart failure is established may improve the clinical outcome. We report the case of a woman with an ovarian neuroendocrine tumour and highly symptomatic carcinoid heart disease who was submitted to tumour resection followed by valvuloplasty. She demonstrated an outstanding clinical improvement and has remained free of tumour and symptomatology.

  14. Hypercalcitoninemia in a sporadic asymptomatic neuroendocrine tumor of the pancreatic tail.

    PubMed

    Machens, A; Haedecke, J; Hinze, R; Thomusch, O; Schneyer, U; Dralle, H

    2000-01-01

    Asymptomatic neuroendocrine tumors of the gastroenteropancreatic tract represent a significant challenge in terms of postoperative monitoring. A case report of a calcitonin-secreting asymptomatic neuroendocrine tumor of the pancreatic tail is presented. Hypercalcitoninemia was noted in the 76-year-old Caucasian man who had a recurrent neuroendocrine tumor of the pancreatic tail. Upon pentagastrin stimulation, basal calcitonin increased only moderately from 82.3 (<10) to 100.9 and 125 pg/ml after 2 and 5 min, respectively. Surgical removal of the neuroendocrine tumor resulted in postoperative normalization of both basal and stimulated serum calcitonin levels. On immunohistochemistry, the neuroendocrine tumor was positive for calcitonin. Routine measurements of serum calcitonin might be a highly sensitive adjunct capable of identifying a subset of neuroendocrine tumors in which calcitonin monitoring may aid in the early detection of postoperative recurrence. Copyright 2000 S. Karger AG, Basel.

  15. Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances

    PubMed Central

    Ito, Tetsuhide; Igarashi, Hisato; Jensen, Robert T.

    2013-01-01

    Pancreatic neuroendocrine tumors (pNETs) comprise with gastrointestinal carcinoids, the main groups of gastrointestinal neuroendocrine tumors (GI-NETs). Although these two groups of GI-NETs share many features including histological aspects; over-/ectopic expression of somatostatin receptors; the ability to ectopically secrete hormones/peptides/amines which can result in distinct functional syndromes; similar approaches used for tumor localization and some aspects of treatment, it is now generally agreed they should be considered separate. They differ in their pathogenesis, hormonal syndromes produced, many aspects of biological behavior and most important, in their response to certain anti-tumor treatment (chemotherapy, molecular targeted therapies). In this chapter the clinical features of the different types of pNETs will be considered as well as aspects of their diagnosis and medical treatment of the hormone-excess state. Emphasis will be on controversial areas or recent advances. The other aspects of the management of these tumors (surgery, treatment of advanced disease, tumor localization) are not dealt with here, because they are covered in other chapters in this volume. PMID:23582916

  16. Pancreatic Neuroendocrine Tumor in the Setting of Dorsal Agenesis of the Pancreas

    PubMed Central

    2016-01-01

    Dorsal agenesis of the pancreas (DAP) is an uncommon embryological abnormality where there is absence of the distal pancreas. DAP is mostly asymptomatic, but common presenting symptoms include diabetes mellitus, abdominal pain, pancreatitis, enlarged pancreatic head, and, in a few cases, polysplenia. MRCP and ERCP are the gold standard imaging techniques to demonstrate the absence of the dorsal pancreatic duct. The literature on the association of pancreatic neoplasia and DAP is limited. We present the case of a pancreatic neuroendocrine tumor in a patient with dorsal agenesis of the pancreas, with a review of the related literature. PMID:27738535

  17. 111In-labelled octreotide binding by the somatostatin receptor subtype 2 in neuroendocrine tumours.

    PubMed

    Hashemi, S H; Benjegård, S-A; Ahlman, H; Wängberg, B; Forssell-Aronsson, E; Billig, H; Nilsson, O

    2003-05-01

    The aim of this study was to investigate the importance of somatostatin receptor subtype 2 (SSTR2) expression for 111In-labelled diethylenetriamine-pentaacetic acid (DTPA)-D-Phe1-octreotide binding and uptake of 111In in neuroendocrine tumours. 111In activity concentrations in surgical biopsies from neuroendocrine tumours (midgut carcinoid and medullary thyroid carcinoma), breast carcinoma and blood were determined 1-8 days after intravenous injection of 111In-labelled DTPA-D-Phe1-octreotide (140-350 MBq). The ratio of 111In activity concentrations between tumour tissue and blood (T/B value) was calculated. The expression of SSTR2 messenger RNA (mRNA) in tumour biopsies was quantitated by ribonuclease protection assay and SSTR2 protein was localized by immunocytochemistry. T/B values were highest for tumour biopsies from midgut carcinoids (mean 160 (range 4-1200); n = 65) followed by medullary thyroid carcinoma (mean 38 (range 2-350); n = 88) and breast carcinoma (mean 18 (range 4-41); n = 4). The expression of SSTR2 mRNA (relative to the NCI-H69 cell line) was highest in tumour biopsies from midgut carcinoids (mean 2.5 (range 0.83-6.0); n = 40) followed by medullary thyroid carcinoma (mean 1.3 (range 0.20-6.0); n = 7) and breast carcinoma (mean 0.66 (range 0.29-1.0); n = 9). In tumour biopsies SSTR2 protein was localized exclusively to tumour cells. Midgut carcinoid tumours showed a much higher level of SSTR2 expression than medullary thyroid carcinoma in accordance with superior tumour imaging by octreotide scintigraphy. The high SSTR2 mRNA values and T/B values observed in midgut carcinoid tumours were positively correlated. Copyright 2003 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

  18. A new human chromogranin 'A' immunoradiometric assay for the diagnosis of neuroendocrine tumours

    PubMed Central

    Bernini, G P; Moretti, A; Ferdeghini, M; Ricci, S; Letizia, C; D'Erasmo, E; Argenio, G F; Salvetti, A

    2001-01-01

    We investigated whether plasma chromogranin A (CgA), measured by a new immunoradiometric assay, may be a sensitive and specific marker of phaeochromocytoma and of other neuroendocrine tumours. This study involved 121 patients of whom 20 with phaeochromocytoma, 28 with other neuroendocrine tumours (19 gastroenteropancreatic tumors, 3 medullary thyroid and 6 small cell lung carcinomas), 25 with solid nonfunctioning adrenocortical tumours and 48 with essential hypertension. In addition, 130 normal subjects were taken as controls. Plasma catecholamines were measured by using high-performance liquid chromatography, and CgA by a two-site sandwich immunoradiometric assay involving monoclonal antibodies raised against the unprocessed central domain (145–245) of human CgA. Plasma CgA in controls (49.0 ± 3.1 ng ml–1, mean ± SE) and in essential hypertensives (50.8 ± 3.5 ng ml–1) was lower (P< 0.0001) than in adrenocortical tumours (91.8 ± 13.2 ng ml–1), in phaeochromocytomas (254 ± 49 ng ml–1) and in patients with other neuroendocrine tumours (469 ± 84 ng ml–1). Plasma CgA and catecholamines identified 13 and 18 out of 20 phaeochromocytomas with sensitivity of 65% and 90%, respectively. Combined measurement of both markers improved sensitivity up to 100%. In the other neuroendocrine tumours, CgA was abnormal in 23/28 cases (sensitivity 82%) and in 6 it was the only circulating marker of disease. In gastroenteropancreatic tumours, CgA measurement identified all cases (sensitivity 100%). Specificity of CgA in patients with essential hypertension was 98%. In conclusion, CgA determination showed high sensitivity in identifying gastroenteropancreatic tumours and, in association with catecholamines, in detecting patients with phaeochromocytoma. CgA sometimes appeared to be the only circulating marker of disease. Since the specificity of CgA proved to be excellent, this assay may be useful for diagnosis both of functioning and non

  19. Molecular pathogenesis and targeted therapy of sporadic pancreatic neuroendocrine tumors.

    PubMed

    Capurso, Gabriele; Archibugi, Livia; Delle Fave, Gianfranco

    2015-08-01

    Over the past few years, knowledge regarding the molecular pathology of sporadic pancreatic neuroendocrine tumors (PNETs) has increased substantially, and a number of targeted agents have been tested in clinical trials in this tumor type. For some of these agents there is a strong biological rationale. Among them, the mammalian target of rapamycin inhibitor Everolimus and the antiangiogenic agent Sunitinib have both been approved for the treatment of PNETs. However, there is lack of knowledge regarding biomarkers able to predict their efficacy, and mechanisms of resistance. Other angiogenesis inhibitors, such as Pazopanib, inhibitors of Src, Hedgehog or of PI3K might all be useful in association or sequence with approved agents. On the other hand, the clinical significance, and potential for treatment of the most common mutations occurring in sporadic PNETs, in the MEN-1 gene and in ATRX and DAXX, remains uncertain. The present paper reviews the main molecular changes occurring in PNETs and how they might be linked with treatment options.

  20. Prognostic Value of Somatostatin Receptor Subtypes in Pancreatic Neuroendocrine Tumors.

    PubMed

    Song, Ki Byung; Kim, Song Cheol; Kim, Ji Hun; Seo, Dong-Wan; Hong, Seung-Mo; Park, Kwang-Min; Hwang, Dae Wook; Lee, Jae Hoon; Lee, Young-Joo

    2016-02-01

    Studies on the expression of somatostatin receptor (SSTR) subtypes in pancreatic neuroendocrine tumors (PNETs) are rare. The aim of this study was to determine the expression of the SSTR subtypes via immunohistochemistry analyses and assess the correlation between SSTR subtype expression and prognosis. We examined 199 patients with PNET who underwent surgical resection between January 1995 and December 2010 at the Asan Medical Center. For all cases, medical records, including demographic data, clinical symptoms, radiological findings, postoperative treatment outcomes, and expression of SSTR subtypes, were carefully reviewed. In total, 162 (81.4%) PNETs expressed more than 1 SSTR subtype. Functioning PNET expressed significantly more SSTR subtypes, compared to nonfunctioning PNET. The SSTR2(+) and SSTR5(+) groups had better prognosis than the SSTR2(-) (P = 0.009) and SSTR5(-) groups (P = 0.03), respectively. In the grade 2 PNET of 2010 World Health Organization classification, the SSTR(+) group had better prognosis than SSTR(-) group. The expression of SSTR 2 and 5 were related with good prognosis of PNET. In World Health Organization grade 2 PNET, the SSTR(+) group had better prognosis than SSTR(-) group. The SSTR expression(+) by immunohistochemistry might be related with good prognosis of the patients with surgically resected PNET.

  1. 24-Hydroxycholesterol participates in pancreatic neuroendocrine tumor development

    PubMed Central

    Soncini, Matias; Corna, Gianfranca; Moresco, Marta; Coltella, Nadia; Restuccia, Umberto; Maggioni, Daniela; Raccosta, Laura; Lin, Chin-Yo; Invernizzi, Francesca; Crocchiolo, Roberto; Doglioni, Claudio; Traversari, Catia; Bachi, Angela; Bernardi, Rosa; Bordignon, Claudio; Gustafsson, Jan-Åke; Russo, Vincenzo

    2016-01-01

    Cells in the tumor microenvironment may be reprogrammed by tumor-derived metabolites. Cholesterol-oxidized products, namely oxysterols, have been shown to favor tumor growth directly by promoting tumor cell growth and indirectly by dampening antitumor immune responses. However, the cellular and molecular mechanisms governing oxysterol generation within tumor microenvironments remain elusive. We recently showed that tumor-derived oxysterols recruit neutrophils endowed with protumoral activities, such as neoangiogenesis. Here, we show that hypoxia inducible factor-1a (HIF-1α) controls the overexpression of the enzyme Cyp46a1, which generates the oxysterol 24-hydroxycholesterol (24S-HC) in a pancreatic neuroendocrine tumor (pNET) model commonly used to study neoangiogenesis. The activation of the HIF-1α–24S-HC axis ultimately leads to the induction of the angiogenic switch through the positioning of proangiogenic neutrophils in proximity to Cyp46a1+ islets. Pharmacologic blockade or genetic inactivation of oxysterols controls pNET tumorigenesis by dampening the 24S-HC–neutrophil axis. Finally, we show that in some human pNET samples Cyp46a1 transcripts are overexpressed, which correlate with the HIF-1α target VEGF and with tumor diameter. This study reveals a layer in the angiogenic switch of pNETs and identifies a therapeutic target for pNET patients. PMID:27671648

  2. Extra pancreatic solid pseudopapillary tumour in a young male.

    PubMed

    Tariq, Naima; Qureshi, Asim; Dian, Asifa

    2016-10-01

    Solid pseudo-papillary tumour of pancreas is a rare neoplasm having a low malignant potential. It mostly affects young adolescent females. We report an unusual case of an 18 year old male with a mass in the mesocolon which was reported as solid pseudo-papillary tumour of pancreas. This case is unusual by virtue of extra pancreatic location and male gender of the patient.

  3. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion.

    PubMed

    Sousa, Cristovão M; Biancur, Douglas E; Wang, Xiaoxu; Halbrook, Christopher J; Sherman, Mara H; Zhang, Li; Kremer, Daniel; Hwang, Rosa F; Witkiewicz, Agnes K; Ying, Haoqiang; Asara, John M; Evans, Ronald M; Cantley, Lewis C; Lyssiotis, Costas A; Kimmelman, Alec C

    2016-08-25

    Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by an intense fibrotic stromal response and deregulated metabolism. The role of the stroma in PDAC biology is complex and it has been shown to play critical roles that differ depending on the biological context. The stromal reaction also impairs the vasculature, leading to a highly hypoxic, nutrient-poor environment. As such, these tumours must alter how they capture and use nutrients to support their metabolic needs. Here we show that stroma-associated pancreatic stellate cells (PSCs) are critical for PDAC metabolism through the secretion of non-essential amino acids (NEAA). Specifically, we uncover a previously undescribed role for alanine, which outcompetes glucose and glutamine-derived carbon in PDAC to fuel the tricarboxylic acid (TCA) cycle, and thus NEAA and lipid biosynthesis. This shift in fuel source decreases the tumour’s dependence on glucose and serum-derived nutrients, which are limited in the pancreatic tumour microenvironment. Moreover, we demonstrate that alanine secretion by PSCs is dependent on PSC autophagy, a process that is stimulated by cancer cells. Thus, our results demonstrate a novel metabolic interaction between PSCs and cancer cells, in which PSC-derived alanine acts as an alternative carbon source. This finding highlights a previously unappreciated metabolic network within pancreatic tumours in which diverse fuel sources are used to promote growth in an austere tumour microenvironment.

  4. Pancreatic neuroendocrine microadenomatosis: A case report of cytology and histology correlation.

    PubMed

    Vo, Nguyen; Cohen, David W; Dillhoff, Mary E; Jin, Ming

    2017-02-01

    Pancreatic neuroendocrine neoplasia is categorized by grade, size, and functional status. Neuroendocrine microadenoma (NEMA) is defined as a neuroendocrine tumor (NET) that measures less than 0.5 cm in diameter. Multiple NEMAs are termed neuroendocrine adenomatosis (NEMAtosis). The surgical pathology and clinical aspects of pancreatic NEMAtosis have been reported, but there has been no report regarding EUS-FNA cytology of NEMAtosis. We report a case of NEMAtosis with cytologic correlation and illustrate the diagnostic challenges and potential pitfalls. The pre-operative cytology can be problematic. The main differential diagnosis of the EUS-FNA specimen includes NET, normal pancreas, and islet cell hyperplasia/aggregation associated with chronic pancreatitis. The helpful cytopathologic feature of NEMAtosis is the presence of two intermingled populations of loosely-cohesive neuroendocrine cell clusters and tight acinar cell groups arranged in microacinar and/or grape-like structures. Although neuroendocrine cells and acinar cells possess different cytomorphology, the distinction is not always straightforward because both types of cells are small and cytologically bland. Cytologic assessment of both architecture and individual cell morphology is imperative to avoid interpretation error and further guide appropriate clinical management. Diagn. Cytopathol. 2017;45:143-147. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  5. MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors.

    PubMed

    Cros, J; Hentic, O; Rebours, V; Zappa, M; Gille, N; Theou-Anton, N; Vernerey, D; Maire, F; Lévy, P; Bedossa, P; Paradis, V; Hammel, P; Ruszniewski, P; Couvelard, A

    2016-08-01

    Temozolomide (TEM) showed encouraging results in well-differentiated pancreatic neuroendocrine tumors (WDPNETs). Low O(6)-methylguanine-DNA methyltransferase (MGMT) expression and MGMT promoter methylation within tumors correlate with a better outcome under TEM-based chemotherapy in glioblastoma. We aimed to assess whether MGMT expression and MGMT promoter methylation could help predict the efficacy of TEM-based chemotherapy in patients with WDPNET. Consecutive patients with progressive WDPNET and/or liver involvement over 50% who received TEM between 2006 and 2012 were retrospectively studied. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. Nuclear expression of MGMT was assessed by immunochemistry (H-score, 0-300) and MGMT promoter methylation by pyrosequencing. Forty-three patients (21 men, 58years (27-84)) with grade 1 WDPNET (n=6) or 2 (n=36) were analyzed. Objective response, stable disease, and progression rates were seen in 17 patients (39.5%), 18 patients (41.9%), and 8 patients (18.6%), respectively. Low MGMT expression (≤50) was associated with radiological objective response (P=0.04) and better progression-free survival (PFS) (HR=0.35 (0.15-0.81), P=0.01). Disease control rate at 18months of treatment remained satisfying with an MGMT score up to 100 (74%) but dropped with a higher expression. High MGMT promoter methylation was associated with a low MGMT expression and longer PFS (HR=0.37 (0.29-1.08), P=0.05). Low MGMT score (≤50) appears to predict an objective tumor response, whereas an intermediate MGMT score (50-100) seems to be associated with prolonged stable disease.

  6. A Step-by-Step Clinical Approach for the Management of Neuroendocrine Tumours.

    PubMed

    Yordanova, A; Ahmadzadehfar, H; Gonzalez-Carmona, M; Strassburg, C; Mayer, K; Feldmann, G; Schmidt-Wolf, I; Lingohr, P; Fischer, S; Kristiansen, G; Essler, M

    2017-02-01

    Neuroendocrine tumours (NET) are rare neoplasms, but the incidence is permanently increasing. Most of the NETs are slow proliferating and clinically silent, and for that reason, they are often diagnosed at a stage with advanced disease. The complexity and diversity of the NET-biology require the treatment of patients in specialised centres to guarantee a qualified, multidisciplinary treatment planning. At our institution, we developed an interdisciplinary model for the assessment and treatment of NET. The aim was to adapt the guidelines to the clinical practice, exchange of current knowledge, and a tailored approach to the individual patient. In our team are included medical professionals from pathology, radiology, oncology, gastroenterology, oncological surgery, and nuclear medicine. In this paper, we describe step-by-step a procedural algorithm for the management of patients with neuroendocrine tumours, focusing on midgut-NETs in terms of therapy.

  7. (177)Lu-DOTATATE treatment in neuroendocrine tumours. A preliminary study.

    PubMed

    Hervás, I; Bello, P; Falgas, M; Del Olmo, M I; Torres, I; Olivas, C; Vera, V; Oliván, P; Yepes, A M

    Therapy with radiolabelled somatostatin analogue peptides is a promising new therapy to treat neuroendocrine tumours. The aim of this preliminary study is to present our experience with (177)Lu-DOTATATE therapy, and evaluate tolerability and short-term efficacy in patients with tumours expressing somatostatin receptors. A total of 7 patients with metastatic neuroendocrine tumours were treated, each with 4 doses of (177)Lu-DOTATATE. The treatment response was evaluated in the form of biochemical response (tumour markers), imaging methods (somatostatin receptor scintigraphy, computed tomography, and magnetic resonance), and functional and quality of life responses using the Karnofsky performance status scale. Treatment toxicity was also evaluated. The results obtained were as follows: Biochemical response: 60% of patients showed tumour marker levels returning to normal, while they decreased significantly in the remaining 40%. Imaging response: 85.7% had a partial response, while 14.3% showed stable disease. All (100%) patients showed a significant improvement in quality of life, with increased Karnofsky scale scores. No patient had acute or chronic toxicity, and subacute transient haematological toxicity was observed in 42.8% of patients. Despite being a preliminary study, it was found that treatment with (177)Lu-DOTATATE is a safe treatment with few side effects, and an objective response was achieved in most patients. Copyright © 2016 Elsevier España, S.L.U. y SEMNIM. All rights reserved.

  8. 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

  9. Pancreatic neuroendocrine cancer with liver metastases and multiple peritoneal metastases: report of one case

    PubMed Central

    Wang, Yang

    2016-01-01

    Pancreatic neuroendocrine tumor (pNET) is a rare pancreatic tumor, with its incidence showing a rising trend in recent years. Most of its distant metastases are found in the liver. This article describes a 59-year-old male patient with pNET with liver metastasis and multiple abdominal metastases, focusing on the management of this tumor in its advanced stage. PMID:28138631

  10. Metformin with everolimus and octreotide in pancreatic neuroendocrine tumor patients with diabetes.

    PubMed

    Pusceddu, Sara; Buzzoni, Roberto; Vernieri, Claudio; Concas, Laura; Marceglia, Sara; Giacomelli, Luca; Milione, Massimo; Leuzzi, Livia; Femia, Daniela; Formisano, Barbara; Mazzaferro, Vincenzo; de Braud, Filippo

    2016-05-01

    A bidirectional relationship seems to exist between diabetes mellitus and development of pancreatic tumors. Metformin, the most widely used drug in the treatment of Type 2 diabetes mellitus, has recently emerged as a potentially active agent in cancer chemoprevention and treatment. In this article, we discuss the potential correlation between glycemic status, administration of antiglycemic treatments, such as metformin or insulin, and prognosis of pancreatic neuroendocrine tumors patients treated with everolimus and octreotide, on the basis of existing evidence and our experience.

  11. The Somatostatin Analogue Octreotide Inhibits Growth of Small Intestine Neuroendocrine Tumour Cells

    PubMed Central

    Li, Su-Chen; Martijn, Cécile; Cui, Tao; Essaghir, Ahmed; Luque, Raúl M.; Demoulin, Jean-Baptiste; Castaño, Justo P.; Öberg, Kjell; Giandomenico, Valeria

    2012-01-01

    Octreotide is a widely used synthetic somatostatin analogue that significantly improves the management of neuroendocrine tumours (NETs). Octreotide acts through somatostatin receptors (SSTRs). However, the molecular mechanisms leading to successful disease control or symptom management, especially when SSTRs levels are low, are largely unknown. We provide novel insights into how octreotide controls NET cells. CNDT2.5 cells were treated from 1 day up to 16 months with octreotide and then were profiled using Affymetrix microarray analysis. Quantitative real-time PCR and western blot analyses were used to validate microarray profiling in silico data. WST-1 cell proliferation assay was applied to evaluate cell growth of CNDT2.5 cells in the presence or absence of 1 µM octreotide at different time points. Moreover, laser capture microdissected tumour cells and paraffin embedded tissue slides from SI-NETs at different stages of disease were used to identify transcriptional and translational expression. Microarrays analyses did not reveal relevant changes in SSTR expression levels. Unexpectedly, six novel genes were found to be upregulated by octreotide: annexin A1 (ANXA1), rho GTPase-activating protein 18 (ARHGAP18), epithelial membrane protein 1 (EMP1), growth/differentiation factor 15 (GDF15), TGF-beta type II receptor (TGFBR2) and tumour necrosis factor (ligand) superfamily member 15 (TNFSF15). Furthermore, these novel genes were expressed in tumour tissues at transcript and protein levels. We suggest that octreotide may use a potential novel framework to exert its beneficial effect as a drug and to convey its action on neuroendocrine cells. Thus, six novel genes may regulate cell growth and differentiation in normal and tumour neuroendocrine cells and have a role in a novel octreotide mechanism system. PMID:23119007

  12. Nuclear medicine imaging and therapy of neuroendocrine tumours

    PubMed Central

    Gotthardt, Martin; Dijkgraaf, Ingrid; Boerman, Otto C; Oyen, Wim J G

    2006-01-01

    Radiolabelled peptides are used for specific targeting of receptors (over-)expressed by tumour cells. Dependent on the kind of labelling and the radionuclide used, these compounds may be utilised for imaging or for therapy. A concise overview is provided on basic principles of designing and developing radiopeptides for these applications. Furthermore, clinical application of these compounds for imaging and therapy is described. Advantages of the method compared to other techniques (such as the use of radiolabelled antibodies or antibody fragments) are discussed as well as pitfalls and limitations. PMID:17114073

  13. Correlation of Ki-67 indices from biopsy and resection specimens of neuroendocrine tumours.

    PubMed

    Barnes, J; Johnson, S J; French, J J

    2017-03-01

    INTRODUCTION Neuroendocrine tumours (NETs) are a heterogeneous group of tumours with a highly variable presentation and prognosis. Management decisions are complex. Ki-67 levels in tissue samples are a key indicator used to grade tumours and guide treatment. This study assessed whether the Ki-67 index and tumour grade generated from tissue samples correlated with that assessed in resection specimens. METHODS This was a retrospective cohort analysis of all patients who had both a tissue sample and a resection specimen analysed in our trust, a tertiary referral centre, during 2012 and 2013. RESULTS Data from 36 patients were reviewed. Ki-67 indices from tissue samples and resection specimens showed strong correlation (r=0.95, p<0.001). Tumour grading was the same in the tissue sample and resection specimens for 22 patients (61.1%). In four patients (11.1%), the tissue sample overestimated the grade while in ten (27.8%), the sample underestimated the grade. CONCLUSIONS In most cases, the Ki-67 index and tumour grade from the tissue sample matched that of the resection specimen. However, in nearly 40% of cases, the tissue sample grading did not match the resection tumour grading. In the majority of these, the tissue sample underestimated disease activity. A low Ki-67 index in a tissue sample should therefore be taken as provisional and should not, in isolation, persuade clinicians to choose a more conservative treatment approach if there is clinical, biochemical or radiological evidence suggestive of a more aggressive disease pathology.

  14. Prognostic significance of ATM and cyclin B1 in pancreatic neuroendocrine tumor.

    PubMed

    Shin, Jae Uk; Lee, Chang Hoon; Lee, Kyu Taek; Lee, Jong Kyun; Lee, Kwang Hyuck; Kim, Kwang Min; Kim, Kyoung-Mee; Park, Sang-Mo; Rhee, Jong Chul

    2012-10-01

    Ataxia telangiectasia mutated kinase (ATM) and cyclin B1 are involved in cell cycle control. The prognostic significance of both molecules has not yet been investigated in pancreatic neuroendocrine tumors. The aim of this study was to evaluate the clinical and prognostic significance of ATM and cyclin B1 in patients with pancreatic neuroendocrine tumors. A total of 107 pancreatic neuroendocrine tumor specimens that were surgically resected were immunohistochemically investigated using the tissue microarray technique. Clinicopathologic results and survival were evaluated retrospectively. High expression of ATM and cyclin B1 was related to well-differentiated endocrine tumors of the World Health Organization (WHO) classification, but not related to TNM stages. The high ATM expression group (ATM ≥ 4) had a significantly smaller tumor size, lower recurrence rate, more number of functioning tumor, and well differentiation of WHO classification. The high cyclin B1 expression group (cyclin B1 ≥ 5) was related to smaller tumor size, less vascular invasion, less recurrence rate, and less death rate. However, cyclin B1 was the only significant factor for survival following multivariate analysis (p = 0.008; OR, 0.54; 95 % CI, 0.35-0.85). The current results suggested that expression of ATM and cyclin B1 may be useful markers to identify patients with poor prognosis who may benefit from close follow-up and aggressive therapy in pancreatic neuroendocrine tumors.

  15. 68Ga-DOTA-TOC uptake in neuroendocrine tumour and healthy tissue: differentiation of physiological uptake and pathological processes in PET/CT.

    PubMed

    Kroiss, A; Putzer, D; Decristoforo, C; Uprimny, C; Warwitz, B; Nilica, B; Gabriel, M; Kendler, D; Waitz, D; Widmann, G; Virgolini, I J

    2013-04-01

    We wanted to establish the range of (68)Ga-DOTA-TOC uptake in liver and bone metastases of patients with neuroendocrine tumours (NET) and to establish the range of its uptake in pancreatic NET. This would allow differentiation between physiological uptake and tumour-related somatostatin receptor expression in the pancreas (including the uncinate process), liver and bone. Finally, we wanted to test for differences in patients with NET, either treated or not treated with peptide receptor radionuclide therapy (PRRT). In 249 patients, 390 (68)Ga-DOTA-TOC PET/CT studies were performed. The clinical indications for PET/CT were gastroenteropancreatic NET (194 studies), nongastroenteropancreatic NET (origin in the lung and rectum; 46 studies), NET of unknown primary (111 studies), phaeochromocytoma/glomus tumours (18 studies), and radioiodine-negative metastatic thyroid carcinoma (21 studies). SUVmax (mean ± standard deviation) values of (68)Ga-DOTA-TOC were 29.8 ± 16.5 in 162 liver metastases, 19.8 ± 18.8 in 89 bone metastases and 34.6 ± 17.1 in 43 pancreatic NET (33.6 ± 14.3 in 30 tumours of the uncinate process and 36.3 ± 21.5 in 13 tumours of the pancreatic tail). A significant difference in SUVmax (p < 0.02) was found in liver metastases of NET patients treated with PRRT. There were significant differences in SUVmax between nonmalignant and malignant tissue for both bone and liver metastases and for pancreatic NET including the uncinate process (p < 0.0001). At a cut-off value of 17.1 the specificity and sensitivity of SUVmax for differentiating tumours in the uncinate process were 93.6 % and 90.0 %, respectively (p < 0.0001). (68)Ga-DOTA-TOC is an excellent tracer for the imaging of tumours expressing somatostatin receptors on the tumour cell surface, facilitating the detection of even small tumour lesions. The noninvasive PET/CT approach by measurement of regional SUVmax can offer important clinical information to distinguish

  16. Neuroendocrine tumours of the head and neck: anatomical, functional and molecular imaging and contemporary management

    PubMed Central

    Subedi, Navaraj; Prestwich, Robin; Chowdhury, Fahmid; Patel, Chirag

    2013-01-01

    Abstract Neuroendocrine tumours (NETs) of the head and neck are rare neoplasms and can be of epithelial or non-epithelial differentiation. Although the natural history of NETs is variable, it is crucial to establish an early diagnosis of these tumours as they can be potentially curable. Conventional anatomical imaging and functional imaging using radionuclide scintigraphy and positron emission tomography/computed tomography can be complementary for the diagnosis, staging and monitoring of treatment response. This article describes and illustrates the imaging features of head and neck NETs, discusses the potential future role of novel positron-emitting tracers that are emerging into clinical practice and reviews contemporary management of these tumours. Familiarity with the choice of imaging techniques and the variety of imaging patterns and treatment options should help guide radiologists in the management of this rare but important subgroup of head and neck neoplasms. PMID:24240099

  17. Autocrine growth inhibition by transforming growth factor β-1 (TGFβ-1) in human neuroendocrine tumour cells

    PubMed Central

    Wimmel, A; Wiedenmann, B; Rosewicz, S

    2003-01-01

    Background and aim: The role of transforming growth factor β-1 (TGFβ-1) in neuroendocrine tumour biology is currently unknown. We therefore examined the expression and biological significance of TGFβ signalling components in neuroendocrine tumours (NETs) of the gastroenteropancreatic (GEP) tract. Methods: Expression of TGFβ-1 and its receptors, Smads and Smad regulated proteins, was examined in surgically resected NET specimens and human NET cell lines by immunohistochemistry, reverse transcriptase-polymerase chain reaction, immunoblotting, and ELISA. Activation of TGFβ-1 dependent promoters was tested by transactivation assays. Growth regulation was evaluated by cell numbers, soft agar assays, and cell cycle analysis using flow cytometry. The role of endogenous TGFβ was assessed by a TGFβ neutralising antibody and stable transfection of a dominant negative TGFβR II receptor construct. Results: Coexpression of TGFβ-1 and its receptors TGFβR I and TGFβR II was detected in 67% of human NETs and in all three NET cell lines examined. NET cell lines expressed the TGFβ signal transducers Smad 2, 3, and 4. In two of the three cell lines, TGFβ-1 treatment resulted in transactivation of a TGFβ responsive reporter construct as well as inhibition of c-myc and induction of p21(WAF1) expression. TGFβ-1 inhibited anchorage dependent and independent growth in a time and dose dependent manner in TGFβ-1 responsive cell lines. TGFβ-1 mediated growth inhibition was due to G1 arrest without evidence of induction of apoptosis. Functional inactivation of endogenous TGFβ revealed the existence of an autocrine antiproliferative loop in NET cells. Conclusions: Neuroendocrine tumour cells of the gastroenteropancreatic tract are subject to paracrine and autocrine growth inhibition by TGFβ-1, which may account in part for the low proliferative index of this tumour entity. PMID:12912863

  18. Malignant Neuroendocrine Tumour (Carcinoid) of the Spleen in an African Pygmy Hedgehog (Atelerix albiventris).

    PubMed

    Lowden, L R; Davies, J L

    2016-07-01

    A malignant neuroendocrine tumour (carcinoid) of the spleen was diagnosed on post-mortem examination of a 3-year-old, male African pygmy hedgehog (Atelerix albiventris). The animal presented with a history of inappetence, weight loss, lethargy, a wide-based gait and a palpable abdominal mass. The gross pathological, histopathological, histochemical and immunohistochemical findings are described. Primary splenic carcinoids are reported rarely in the human medical literature and this is believed to be the first report in a non-human animal. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. B-mode and contrast-enhancement characteristics of small nonincidental neuroendocrine pancreatic tumors

    PubMed Central

    Braden, Barbara; Jenssen, Christian; D’Onofrio, Mirko; Hocke, Michael; Will, Uwe; Möller, Kathleen; Ignee, Andre; Dong, Yi; Cui, Xin-Wu; Săftoiu, Adrian; Dietrich, Christoph F.

    2017-01-01

    Background and Objectives: Imaging of the pancreas for detection of neuroendocrine tumors is indicated as surveillance in multiple endocrine neoplasia type 1 (MEN1) or if typical clinical symptoms combined with hormone production raise the suspicion of a neuroendocrine tumor. Endoscopic ultrasound (EUS) is considered the best imaging modality to detect small pancreatic tumors. However, little is known about how small pancreatic neuroendocrine tumors (pNETs) present on EUS. Patients and Methods: In this multicenter study, we retrospectively analyzed the endosonographic characteristics of small pNETs which had been detected due to typical biochemistry and clinical symptoms or during surveillance of MEN 1. Only small pancreatic tumors ≤15 mm with histological confirmation as pNET were included. B-mode and contrast-enhanced ultrasound- and EUS patterns were analyzed. Results: Among 32 patients with histologically proven small pNETs, 7 patients had known MEN1. Among the pNETs, 20 were insulinoma, 2 gastrinoma, 3 glucagonoma, 6 nonfunctional in MEN1, and one PPoma. 94% of the pNET appeared hypoechogenic, only 1 isoechogenic and 1 hyperechogenic. After contrast injection, 90% of the pNETS showed hyperenhancement compared to the surrounding pancreatic parenchyma. Conclusion: The high spatial resolution of EUS allows detection and even cytological confirmation of pNET <7 mm diameter. Hypoechogenicity in B-mode and hyperenhancement after injection of contrast agents are endosonographic characteristics of small pNET and present in >90% of pNETs. PMID:28218201

  20. Bowel parasitosis and neuroendocrine tumours of the appendix. A report from the Italian TREP project.

    PubMed

    Virgone, C; Cecchetto, G; Besutti, V; Ferrari, A; Buffa, P; Alaggio, R; Alessandrini, L; Dall'Igna, P

    2015-05-01

    Five children with a neuroendocrine tumour (NET) of the appendix associated with a parasitic bowel infection are described, and the possibility of inflammation-triggered carcinogenesis is discussed. Schistosoma haematobium is linked primarily to bladder cancer but it has been reported in association with several other histotypes, including NETs of the gastrointestinal tract. Conversely, Enterobius vermicularis has not yet been claimed to participate in the onset of pre-cancerous conditions or tumours. The rare occurrence of contemporary appendiceal NETs and parasitic infection, raises the intriguing hypothesis of an inflammation-related carcinogenesis, although a cause-effect relationship cannot be established. Larger international series of childhood appendiceal NETs, which also include countries with higher prevalence of parasitic bowel infections, are needed to further clarify this possible cause-effect relationship.

  1. Resection of postoperative liver metastasis from pancreatic neuroendocrine tumors: report of one case

    PubMed Central

    Chen, Xiao; Ren, Hu; Chi, Yihebali; He, Shun; Huang, Zhen; Hu, Xuhui

    2016-01-01

    Pancreatic neuroendocrine tumor (pNET) is a rare type of pancreatic tumors. The incidence of pNET shows a gradually increasing trend in recent years. Except insulinoma, majority of pNET are metastatic when diagnosis. And liver is the most common organ of distant metastases. Liver metastases are the main determinant for long-term survival and quality of life of patients with pNET. A case of liver metastases of pNET of a 44-year-old female patient is presented in this study. Then we have a brief discussion of the diagnosis and multidisciplinary treatment of advanced pNET. PMID:28138614

  2. Everolimus and pancreatic neuroendocrine tumors (PNETs): Activity, resistance and how to overcome it.

    PubMed

    Capozzi, Monica; Caterina, Ieranò; De Divitiis, Chiara; von Arx, Claudia; Maiolino, Piera; Tatangelo, Fabiana; Cavalcanti, Ernesta; Di Girolamo, Elena; Iaffaioli, Rosario Vincenzo; Scala, Stefania; Tafuto, Salvatore

    2015-09-01

    Neuroendocrine tumors (NET) are rare malignancies, with the most common site of origin being from the gastrointestinal tract, particularly the pancreas, small bowel and appendix. Pancreatic neuroendocrine tumors (PNETs) can be functional, hormone secreting tumors, and can have distinctive symptoms leading to the diagnosis. In contrast nonfunctional tumors, the majority of PNETs, usually present later either incidentally or due to tumor bulk symptoms. Currently Everolimus, an inhibitor of mammalian target of rapamycin (mTOR), is the most promising drug for patients with unresectable, metastatic disease, in progressive well-differentiated PNETs and many studies are ongoing to demonstrate its effects on the other neuroendocrine histotipes. Food and Drug Administration (FDA) and European Medicines Agency (EMA) registered Everolimus in advanced/metastatic breast cancer, in advanced/metastatic renal cell carcinoma and in well/moderately differentiated pancreatic neuroendocrine tumors. Nevertheless only a subset of patients respond to the therapy due to the development of drug resistance. Thus the powerful Everolimus antitumor activity have prompted extensive efforts to overcome drug resistance and to maximize clinical benefit. In this review we aim to summarize current knowledge on mechanisms of Everolimus and other mTOR inhibitors molecules resistance with the intent to overcome it.

  3. Antiproliferative effects of lanreotide autogel in patients with progressive, well-differentiated neuroendocrine tumours: a Spanish, multicentre, open-label, single arm phase II study.

    PubMed

    Martín-Richard, Marta; Massutí, Bartomeu; Pineda, Eva; Alonso, Vicente; Marmol, Maribel; Castellano, Daniel; Fonseca, Emilio; Galán, Antonio; Llanos, Marta; Sala, Maria Angeles; Pericay, Carlos; Rivera, Fernando; Sastre, Javier; Segura, Angel; Quindós, Maria; Maisonobe, Pascal

    2013-09-20

    Somatostatin analogues (SSAs) are indicated to relieve carcinoid syndrome but seem to have antiproliferative effects on neuroendocrine tumours (NETs). This is the first prospective study investigating tumour stabilisation with the long-acting SSA lanreotide Autogel in patients with progressive NETs. This was a multicentre, open-label, phase II trial conducted in 17 Spanish specialist centres. Patients with well-differentiated NETs and radiologically confirmed progression within the previous 6 months received lanreotide Autogel, 120 mg every 28 days over ≤92 weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints were response rate, tumour biomarkers, symptom control, quality of life (QoL), and safety. Radiographic imaging was assessed by a blinded central radiologist. Of 30 patients included in the efficacy and safety analyses, 40% had midgut tumours and 27% pancreatic tumours; 63% of tumours were functioning. Median PFS time was 12.9 (95% CI: 7.9, 16.5) months, and most patients achieved disease stabilisation (89%) or partial response (4%). No deterioration in QoL was observed. Nineteen patients (63%) experienced treatment-related adverse events, most frequently diarrhoea and asthenia; only one treatment-related adverse event (aerophagia) was severe. Lanreotide Autogel provided effective tumour stabilisation and PFS >12 months in patients with progressive NETs ineligible for surgery or chemotherapy, with a safety profile consistent with the pharmacology of the class. ClinicalTrials.gov Identifier NCT00326469; EU Clinical Trial Register EudraCT no 2004-002871-18.

  4. 99mTc-HYNIC-TOC imaging in the evaluation of pancreatic masses which are potential neuroendocrine tumors.

    PubMed

    Qiao, Zhen; Zhang, Jingjing; Jin, Xiaona; Huo, Li; Zhu, Zhaohui; Xing, Haiqun; Li, Fang

    2015-05-01

    The aim of this investigation was to determine the accuracy of the findings and the diagnoses of Tc-hydrazinonicotinyl-Tyr3-octreotide scan (Tc-HYNIC-TOC imaging) in patients with pancreatic masses which were potential neuroendocrine tumors. Records of total 20 patients with pancreatic masses were retrospectively reviewed. All of the patients had been revealed by abdominal contrast CT and possibility of neuroendocrine tumors could not be excluded by CT imaging before Tc-HYNIC-TOC imaging. Tc-HYNIC-TOC imaging was performed at 1 and 4 hours post-tracer injection, and SPECT/CT images of the abdomen were also acquired. The image findings were compared to final diagnoses which were made from pathological examination. Among all 20 pancreatic masses evaluated, there were 16 malignant lesions which included 1 ductal adenocarcinoma and 15 neuroendocrine tumors. Tc-HYNIC-TOC imaging identified 14 of 15 pancreatic neuroendocrine tumors and excluded 4 of 5 lesions which were not neuroendocrine tumors. The overall sensitivity, specificity, and accuracy was therefore 93.3% (14 of 15), 80% (4 of 5), and 90.0% (18 of 20), respectively, in our patient population. Tc-HYNIC-TOC imaging provides reasonable accuracy in the evaluation pancreatic mass suspected to be neuroendocrine tumors.

  5. 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.

  6. Von Hippel Lindau disease with metastatic pancreatic neuroendocrine tumor causing ectopic Cushing's syndrome.

    PubMed

    Hatipoglu, Esra; Kepicoglu, Hasan; Rusen, Elif; Kabasakal, Levent; Gundogdu, Sadi; Kadioglu, Pinar

    2013-01-01

    We present a 39-year-old woman who was previously diagnosed with Von Hippel Lindau Disease (VHLD). She had surgery and radiotherapy for cranial hemangioblastoma (HA) 11 years ago and had unilateral adrenalectomy for pheochromocytoma in another hospital 6 month prior to her admission to our center. Moon face, buffalo hump, central obesity, progressive weight gain and menstrual irregularities persisted after adrenalectomy. Her laboratory results were consistent with ectopic Cushing's syndrome (ECS). A pancreatic solid mass with a nodule on the left lung were revealed upon computed tomography. In addition, Gallium-68 Somatostatin Receptor PET confirmed the pancreatic involvement and demonstrated additional lesions on the left lung and in the aortocaval lymphatic system on the right side, suggesting metastatic pancreatic neuroendocrine tumor (PNET). Peptide receptor radionuclide therapy (PRRT) with [177Lutetium-DOTA0,Tyr3] octreotate was performed on the patient, with no side effects observed. She was discharged from the hospital 10 days after the first cycle.

  7. Amenorrhea as a rare drug-related adverse event associated with everolimus for pancreatic neuroendocrine tumors.

    PubMed

    Kawaguchi, Yoshiaki; Maruno, Atsuko; Kawashima, Yohei; Ito, Hiroyuki; Ogawa, Masami; Mine, Tetsuya

    2014-11-14

    The patient was an asymptomatic 43-year-old woman. Abdominal ultrasonography and enhanced computed tomography showed a tumor lesion accompanied by multiple cystic changes in the liver and the pancreatic tail. Endoscopic ultrasound-fine needle aspiration was performed on the pancreatic tumor lesion and revealed pancreatic neuroendocrine tumor (PNET). As it was unresectable due to multiple liver metastases, the decision was made to initiate treatment with everolimus and transcatheter arterial chemoembolization. The patient ceased menstruating after the start of everolimus administration. When the administration was discontinued due to interstitial lung disease, menstruation resumed, but then again stopped with everolimus resumption. An association between everolimus and amenorrhea was highly suspected. Amenorrhea occurred as a rare adverse event of everolimus. As the younger women might be included in PNETs patients, we should put this adverse event into consideration.

  8. Neuroendocrine tumours of the digestive tract report of two cases and literature review.

    PubMed

    Nouira, Ramzi; Janabi, Iman; Ben Achour, Jamel; Guesmi, Fethi; Hani, Mohamed Aziz; Cherif, Ali; Daghfous, Mounir; Bouasker, Ibtissem; Zribi, Riadh; Ben Osman, Samia; Zoghlami, Ayoub; Najah, Nabil

    2003-07-01

    Neuroendocrine tumors (NET) of the digestive system are rare. They comprise only 1% of all the tumors of the gastrointestinal tract. The aim of this study is to report two cases of exceptional localization of non secretary neuroendocrine tumors. Their difficulty in diagnosis, treatment and controversy in chemotherapy merit their study in depth. These are two patients that were treated in the department of general surgery (Beau Séjour) in Charles Nicolle Hospital for non secretary (NET) of the pancreas and stomach. The first was presented as a painless epigastria mass with frequent diarrhea. The second was presented as a painful mass in the left hypochondriac area without any other symptoms. Biochemical evaluation confirmed their non secretary properties. Surgery remains the first line of treatment. It was possible for the gastric, but not for the pancreatic tumor. Both were very advanced and had metastasis. Histopathological evaluation and immunohistochemical study using the method of peroxydase antiperoxydase (PAP) complexes for some special monoclonal antibodies confirmed the diagnosis. Chemotherapy of both cases was mal tolerated and was discussed in details.

  9. Chemotherapy and metformin in pancreatic adenocarcinoma and neuroendocrine tumors.

    PubMed

    Burney, Saira; Khawaja, Khadija Irfan; Saif, Muhammad Wasif; Masud, Faisal

    2014-07-28

    Pancreatic cancer, despite being a relatively less commonly occurring cancer is among the deadliest ones, leading to a grave prognosis. Surgery stands as the mainstay of treatment of pancreatic cancer but is an option in less than 15% patients owing to the late presentation of the tumor. Chemotherapy offers an important part of treatment but can adversely affect the quality of life because of devastating side effects and has limited survival benefit. Unavailability of effective and less toxic treatment options for pancreatic cancer has prompted the search for new treatment strategies. One such drug being considered for its potential anti-neoplastic role is the time-tested and widely used oral hypoglycemic drug, metformin. Metformin is proposed to target metabolic pathways involved in tumorigenesis, specifically the AMPK-mTOR complex. Epidemiological evidence is mounting in favor of its role in various cancers both for treatment and prophylaxis. Herein, we aim to summarize the epidemiological data on metformin as a potential anti-cancer drug in various cancers followed by a look at some of the abstracts relating to this topic that were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2014.

  10. Ki-67 prognostic and therapeutic decision driven marker for pancreatic neuroendocrine neoplasms (PNENs): A systematic review.

    PubMed

    Pezzilli, Raffaele; Partelli, Stefano; Cannizzaro, Renato; Pagano, Nico; Crippa, Stefano; Pagnanelli, Michele; Falconi, Massimo

    2016-03-01

    We systematically evaluate the current evidence regarding Ki-67 as a prognostic factor in pancreatic neuroendocrine neoplasms to evaluate the differences of this marker in primary tumors and in distant metastases as well as the values of Ki-67 obtained by fine needle aspiration and by histology. The literature search was carried out using the MEDLINE/PubMed database, and only papers published in the last 10 years were selected. The pancreatic tissue suitable for Ki-67 evaluation was obtained from surgical specimens in the majority of the studies. There was a concordance of 83% between preoperative and postoperative Ki-67 evaluation. Pooling the data of the studies which compared the Ki-67 values obtained in both cytological and surgical specimens, we found that they were not related. The assessment of Ki-67 was manual in the majority of the papers considered for this review. In order to eliminate manual counting, several imaging methods have been developed but none of them are routinely used at present. Twenty-two studies also explored the role of Ki-67 utilized as a prognostic marker for pancreatic neuroendocrine neoplasms and the majority of them showed that Ki-67 is a good prognostic marker of disease progression. Three studies explored the Ki-67 value in metastatic sites and one study demonstrated that, in metachronous and synchronous liver metastases, there was no significant variation in the index of proliferation. Ki-67 is a reliable prognostic marker for pancreatic neuroendocrine neoplasms. Copyright © 2015 Medical University of Bialystok. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  11. Integrated clinicopathological features and gene microarray analysis of pancreatic neuroendocrine tumors.

    PubMed

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

    2017-08-20

    Pancreatic neuroendocrine tumors are relatively rare pancreatic neoplasms over the world. Investigations about molecular biology of PNETs are insufficient for nowadays. We aimed to explore the expression of messenger RNA and regulatory processes underlying pancreatic neuroendocrine tumors from different views. The expression profile of GSE73338 were downloaded, including samples with pancreatic neuroendocrine tumors. First, the Limma package was utilized to distinguish the differentially expressed messenger RNA. Gene Ontology classification and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed to explore the functions and pathways of target genes. In addition, we constructed a protein-protein interaction network. NEK2, UBE2C, TOP2A and PPP1R1A were revealed with continuous genomic alterations in higher tumor stage. 91 up-regulated and 36 down-regulated genes were identified to be differentially expressed in malignant PNETs. Locomotory behavior was significantly enriched for biological processes of metastasis PNETs. GCGR and GNAS were identified as the hub of proteins in the protein-protein interaction sub-network of malignant PNETs. We showed the gene expression differences in PNETs according to different clinicopathological aspects. NEK2, UBE2C, TOP2A are positively associated with high tumor grade, and PPP1R1A negatively. GCGR and GNAS are regarded as the hub of the PPI sub-network. CXCR4 may affect the progression of PNETs via the CXCR4-CXCL12-CXCR7 chemokine receptor axis. However, more studies are required. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Neuron-specific enolase and chromogranin A as markers of neuroendocrine tumours.

    PubMed Central

    Baudin, E.; Gigliotti, A.; Ducreux, M.; Ropers, J.; Comoy, E.; Sabourin, J. C.; Bidart, J. M.; Cailleux, A. F.; Bonacci, R.; Ruffié, P.; Schlumberger, M.

    1998-01-01

    Circulating neuron-specific enolase (NSE) and chromogranin A (CgA) were measured in 128 patients with neuroendocrine tumours (NET) to compare their sensitivity and specificity, to investigate factors associated with elevated serum levels and to determine the usefulness of these markers in the follow-up of NET patients. NSE (Cispack NSE, Cis Bio International, Gif-sur-Yvette, France; normal <12.5 microg l(-1)), and chromogranin A (CgA-Riact, Cis Bio International, normal <100 microg l(-1)) were measured in 128 patients without renal insufficiency. There were 99 patients with gastroenteropancreatic (GEP) NET, 19 with medullary thyroid carcinoma and ten with phaeochromocytoma. Fifty-three patients with non-NET were studied as controls. Serum NSE and CgA levels were elevated in 48 (38%) and 76 (59%) of the 128 NET patients respectively. In all groups of NET patients, CgA proved to be more sensitive than NSE. NSE and CgA had a specificity of 73% and 68% respectively. Immunostaining for NSE was positive in three out of eight controls with elevated CgA levels, whereas immunostaining for CgA and synaptophysin was negative in all cases. Elevated CgA levels were significantly associated with two independent parameters, namely the presence of other secretions (P = 0.0001) and a heavy tumour burden (P = 0.001). Elevated NSE levels were exclusively associated with poor tumour differentiation (P = 0.01). Among six patients with NET followed for 11-37 months, CgA appeared to be a better marker of tumour evolution than NSE. We suggest that CgA ought to be the only general marker screened in NET patients. PMID:9792158

  13. Ki67 Scoring in Pancreatic Neuroendocrine Tumors By a New Method.

    PubMed

    Öztürk Sari, Şule; Taşkin, Orhun Çiğ; Yegen, Gülçin; Özlük, Yasemin; Güllüoğlu, Mine

    2016-07-06

    Ki67 scoring is required for the grading of pancreatic neuroendocrine tumors. Ongoing debate exists about the best scoring method in terms of accuracy and practicality. Manual counting of cells in camera-captured/printed images is a widely used and accepted method and considered the most reliable one among the manual methods. It requires counting 500 to 2000 cells to determine the Ki67 score accurately and it is time and energy consuming. We investigated the possibility of achieving the same results by counting only a particular fraction of tumor cells in a printed image in a series of 45 (24 grade 1 and 21 grade 2) pancreatic neuroendocrine tumors. After counting Ki67-positive tumor cells in the whole image, the tumor cells were counted within one-tenth of the same image with the aid of a previously prepared grid on an acetate sheet. The cell number obtained was multiplied by 10 to estimate the total cell count and the Ki67 score was calculated. The agreement between the results of the acetate grid and conventional whole-image counting method was assessed. Near-perfect agreement was achieved regarding the total cell count and Ki67 score. The agreement on tumor grade between the two methods was perfect. The time spent on the process was significantly less than that spent on the conventional method. Although it needs to be validated in a larger series, the acetate grid method might be considered an alternative method for Ki67 scoring in neuroendocrine tumors.

  14. Pancreatic Neuroendocrine Neoplasms: Basic Biology, Current Treatment Strategies and Prospects for the Future.

    PubMed

    Ohmoto, Akihiro; Rokutan, Hirofumi; Yachida, Shinichi

    2017-01-13

    Pancreatic neuroendocrine neoplasms (pNENs) are rare tumors accounting for only 1%-2% of all pancreatic tumors. pNENs are pathologically heterogeneous and are categorized into three groups (neuroendocrine tumor: NET G1, NET G2; and neuroendocrine carcinoma: NEC) on the basis of the Ki-67 proliferation index and the mitotic count according to the 2010 World Health Organization (WHO) classification of gastroenteropancreatic NENs. NEC in this classification includes both histologically well-differentiated and poorly differentiated subtypes, and modification of the WHO 2010 classification is under discussion based on genetic and clinical data. Genomic analysis has revealed NETs G1/G2 have genetic alterations in chromatin remodeling genes such as MEN1, DAXX and ATRX, whereas NECs have an inactivation of TP53 and RB1, and these data suggest that different treatment approaches would be required for NET G1/G2 and NEC. While there are promising molecular targeted drugs, such as everolimus or sunitinib, for advanced NET G1/G2, treatment stratification based on appropriate predictive and prognostic biomarkers is becoming an important issue. The clinical outcome of NEC is still dismal, and a more detailed understanding of the genetic background together with preclinical studies to develop new agents, including those already under investigation for small cell lung cancer (SCLC), will be needed to improve the prognosis.

  15. Pancreatic Neuroendocrine Neoplasms: Basic Biology, Current Treatment Strategies and Prospects for the Future

    PubMed Central

    Ohmoto, Akihiro; Rokutan, Hirofumi; Yachida, Shinichi

    2017-01-01

    Pancreatic neuroendocrine neoplasms (pNENs) are rare tumors accounting for only 1%–2% of all pancreatic tumors. pNENs are pathologically heterogeneous and are categorized into three groups (neuroendocrine tumor: NET G1, NET G2; and neuroendocrine carcinoma: NEC) on the basis of the Ki-67 proliferation index and the mitotic count according to the 2010 World Health Organization (WHO) classification of gastroenteropancreatic NENs. NEC in this classification includes both histologically well-differentiated and poorly differentiated subtypes, and modification of the WHO 2010 classification is under discussion based on genetic and clinical data. Genomic analysis has revealed NETs G1/G2 have genetic alterations in chromatin remodeling genes such as MEN1, DAXX and ATRX, whereas NECs have an inactivation of TP53 and RB1, and these data suggest that different treatment approaches would be required for NET G1/G2 and NEC. While there are promising molecular targeted drugs, such as everolimus or sunitinib, for advanced NET G1/G2, treatment stratification based on appropriate predictive and prognostic biomarkers is becoming an important issue. The clinical outcome of NEC is still dismal, and a more detailed understanding of the genetic background together with preclinical studies to develop new agents, including those already under investigation for small cell lung cancer (SCLC), will be needed to improve the prognosis. PMID:28098761

  16. Methods to assess the biodistribution of radiolabelled somatostatin analogues and treatment response of neuroendocrine tumours

    NASA Astrophysics Data System (ADS)

    Gnanasegaran, Gopinath

    Introduction: During the past decade, proof of the principle that somatostatin receptors can be successfully used for in vivo targeting of neuroendocrine tumours (NETs) has been provided. These tumours are imaged with 111Indium-pentetreotide and treated with 90Yttrium labeled somatostatin analogues. The aim of this study was to assess (a) the biodistribution and residency of 90Y labelled agents using the brehmsstrahlung imaging technique (b) the tumour response to various treatment modalities using a simplified scintigraphic method [Functional SPECT tumour volume (STV)]. Material and methods: 1) 19 patients with NETs were imaged with 111In-pentetreotide and 14 of them underwent treatment with 90Y-lanreotide. The rest underwent treatment with 90Y-SMT. All the patients were imaged 24 hours post-therapy. Brehmsstrahlung images obtained post therapies were used to assess the 90Y-lanreotide biodistribution in 14 patients and the 5 patients treated with 90Y-SMT, comparing them with 111In-pentetreotide. 2) In 42 patients with NETs a retrospective analysis was performed of the 111In-pentetreotide imaging and CT scan in patients treated with different therapies. A simplified scintigraphic method using 111In-pentetreotide SPECT liver imaging was used to monitor changes in tumour response and to determine how this correlates with CT scan and clinical response. Results: 1) 90Y-lanreotide and 90Y-SMT (with amino acids) have much lower uptake in the kidney (p 0.000 and 0.041 respectively) than 111In-pentetreotide. G Gnanasegaran MD 2 2) 22/42 patients had a good clinical response. A mean fall in total functional STV of 37% was seen in patients with symptomatic relief and a mean increase of 72 % was seen in patients with no symptomatic relief STV predicted the clinical outcome in 34 patients (81%) and CT predicted the outcome in 21 (50%) patients. Conclusion: There was a difference in biodistribution between 111In-pentetreotide and 90Y-lanreotide/ 90Y-SMT, especially in the

  17. Gene Amplifications in Well-Differentiated Pancreatic Neuroendocrine Tumors Inactivate the p53 Pathway

    PubMed Central

    Hu, Wenwei; Feng, Zhaohui; Modica, Ippolito; Klimstra, David S.; Song, Lin; Allen, Peter J.; Brennan, Murray F.; Levine, Arnold J.; Tang, Laura H.

    2010-01-01

    Neuroendocrine tumors (NETs) comprise a group of rare tumors derived from the diffuse neuroendocrine system or islet endocrine cells of the pancreas. The molecular mechanisms underlying NETs are largely unknown. The tumor suppressor p53 plays a critical role in maintaining genomic stability and tumor prevention. The p53 pathway is tightly regulated by a number of proteins, among which MDM2, MDM4, and WIP1 are key negative regulators of p53 protein levels or activity. Aberrant activation of these negative regulators can attenuate the p53 function that serves as an important mechanism of tumorigenesis. In this study, several genetic alterations in pancreatic NETs were studied. These tumors exhibit various chromosomal aberrations throughout the whole genome as examined by array-based comparative genomic hybridization. Although p53 mutations are rare in NETs (<3%), this study presents evidence that the p53 pathway is altered in pancreatic NETs through aberrant activation of its negative regulators. A high percentage of pancreatic NETs contain extra gene copies of MDM2 (22%), MDM4 (30%), and WIP1 (51%), which are correlated with expression of corresponding mRNAs and proteins. In addition, there is a higher frequency (23% v. 15% in the control population) of the G/G genotype of MDM2 SNP309, a functional single-nucleotide polymorphism in the MDM2 gene that attenuates the function of the p53 protein. Overall, approximately 70% of pancreatic NETs have one or more of these genetic changes. These findings suggest that the negative regulation of p53 function could be an important mechanism for the initiation and/or progression of pancreatic NETs, and reactivation of p53 could be a potential therapeutic strategy for patients with this disease. PMID:20871795

  18. Calcitonin-secreting pancreatic neuroendocrine tumors: a case report and review of the literature.

    PubMed

    Kováčová, Martina; Filková, Marta; Potočárová, Mária; Kiňová, Soňa; Pajvani, Utpal B

    2014-08-01

    We report the presentation and novel therapy of a calcitonin-secreting pancreatic neuroendocrine tumor (PNET) and review the literature on this unusual neoplasm. We cite the history of a 38-year-old male who presented with fatigue, weight loss, and diarrhea and was found to have a pancreatic head mass on cross-sectional imaging, as well as liver metastases. The patient's laboratory evaluation was notable for a >100-fold elevation of the peptide hormone calcitonin in serum. As calcitonin is typically secreted by thyroid C-cells, hypercalcitoninemia is considered a marker for medullary thyroid cancer (MTC) or C-cell hyperplasia, but it may be present in several physiologic or pathologic conditions or may be ectopically secreted in rare PNETs. An octreotide scan confirmed the presence of somatostatin (SST) receptors on the pancreatic mass and liver metastases, leading to the diagnosis of a calcitonin-secreting PNET. We initiated treatment with long-acting SST analogs and peptide receptor radionuclide therapy (90Yttrium-DOTATOC) and achieved disease regression while maintaining a high quality of life. Functional PNETs that secrete calcitonin are exceedingly rare, but they are important to consider in the differential diagnosis of nonthyroid-mediated hypercalcitonemia or pancreatic tumors that present with diarrhea, as the management differs markedly from both MTC and other pancreatic malignancies.

  19. New Genetics and Genomic Data on Pancreatic Neuroendocrine Tumors: Implications for Diagnosis, Treatment, and Targeted Therapies.

    PubMed

    Schmitt, Anja M; Marinoni, Ilaria; Blank, Annika; Perren, Aurel

    2016-09-01

    The recent findings on the roles of death-associated protein 6/α-thalassemia/mental retardation X-linked (DAXX/ATRX) in the development of pancreatic neuroendocrine tumors (PanNETs) have led to major advances in the molecular understanding of these rare tumors and open up completely new therapeutic windows. This overview aims at giving a simplified view on these findings and their possible therapeutic implications. The importance of epigenetic changes in PanNET is also underlined by recent findings of a cross-species study on microRNA (miRNA) and messenger RNA (mRNA) profiles in PanNETs.

  20. Extrathyroidal Calcitonin Secreting Tumors: Pancreatic Neuroendocrine Tumors in Patients With Multinodular Goiter: Two Case Reports.

    PubMed

    Giannetta, Elisa; Gianfrilli, Daniele; Pozza, Carlotta; Lauretta, Rosa; Graziadio, Chiara; Sbardella, Emilia; Baroli, Alberto; Caronna, Roberto; Chirletti, Piero; Lenzi, Andrea; Isidori, Andrea M

    2016-01-01

    Calcitonin is the hallmark of medullary thyroid carcinoma. However, extrathyroidal neuroendocrine tumors can also release calcitonin.We report 2 cases of calcitonin-secreting pancreatic tumors found in asymptomatic patients with thyroid nodules referred to our center within 11 months.Case 1: A man initially referred for thyroid nodule characterization was found to have hypercalcitoninemia (>200 pg/mL) during non-neoplastic fine-needle aspiration.Case 2: A woman evaluated for liver metastasis was found to have hypercalcitoninemia and multinodular goiter.Our research emphasizes that marked hypercalcitoninemia in the presence of thyroid nodules is not necessarily due to medullary thyroid carcinoma; awareness of this could avoid unnecessary thyroidectomy. The lack of specific symptoms related to hypercalcitoninemia may be the reason that the prevalence of calcitonin-secreting pancreatic tumors is underestimated.

  1. Extrathyroidal Calcitonin Secreting Tumors: Pancreatic Neuroendocrine Tumors in Patients With Multinodular Goiter

    PubMed Central

    Giannetta, Elisa; Gianfrilli, Daniele; Pozza, Carlotta; Lauretta, Rosa; Graziadio, Chiara; Sbardella, Emilia; Baroli, Alberto; Caronna, Roberto; Chirletti, Piero; Lenzi, Andrea; Isidori, Andrea M.

    2016-01-01

    Abstract Calcitonin is the hallmark of medullary thyroid carcinoma. However, extrathyroidal neuroendocrine tumors can also release calcitonin. We report 2 cases of calcitonin-secreting pancreatic tumors found in asymptomatic patients with thyroid nodules referred to our center within 11 months. Case 1: A man initially referred for thyroid nodule characterization was found to have hypercalcitoninemia (>200 pg/mL) during non-neoplastic fine-needle aspiration. Case 2: A woman evaluated for liver metastasis was found to have hypercalcitoninemia and multinodular goiter. Our research emphasizes that marked hypercalcitoninemia in the presence of thyroid nodules is not necessarily due to medullary thyroid carcinoma; awareness of this could avoid unnecessary thyroidectomy. The lack of specific symptoms related to hypercalcitoninemia may be the reason that the prevalence of calcitonin-secreting pancreatic tumors is underestimated. PMID:26817871

  2. Molar pregnancy after tubal ligation in a patient with neuroendocrine tumour: when a rare condition coincides with an unexpected diagnosis.

    PubMed

    Semenya, Afi Mansa; Roberts, Caroline; Mounsey, Anne

    2014-04-30

    A 40-year-old woman with a history of bilateral tubal ligation and a recent diagnosis of metastatic neuroendocrine tumour in the liver presented with severe nausea, vomiting, diarrhoea and dehydration. She had an inconclusive urine pregnancy test in the emergency department that was followed by an extremely high serum β-human chorionic gonadotropin. Transvaginal ultrasound, MRI and subsequent pathology from a dilation and curettage (D&C) revealed that the patient had a complete molar pregnancy. This is a case of an unusual patient who reminds us that one person can have a rare diagnosis and an unexpected obstetrical outcome. We could find no evidence in the medical literature of a causal link between these two diagnoses but present this case report of a reproductive age woman with neuroendocrine tumour and complete molar pregnancy. This case also serves as an example of the phenomenon of the 'hook effect.'

  3. Are contrast media required for (68)Ga-DOTATOC PET/CT in patients with neuroendocrine tumours of the abdomen?

    PubMed

    Mayerhoefer, Marius E; Schuetz, Matthias; Magnaldi, Silvia; Weber, Michael; Trattnig, Siegfried; Karanikas, Georgios

    2012-04-01

    To determine the value of intravenous contrast medium in (68)Ga-DOTA-Phe(1)-Tyr(3)-octreotide - (68)Ga-DOTATOC - PET/CT for the detection of abdominal neuroendocrine tumours (NET). In fifty-five patients with known or suspected NETs of the abdomen PET/CT was performed on a 64-row multi-detector hybrid system. For PET, 150 MBq of (68)Ga-DOTATOC were injected intravenously. Full-dose unenhanced, and arterial- and venous-phase contrast-enhanced CT images were obtained. Unenhanced and contrast-enhanced PET/CT images were evaluated separately for the presence of NETs on a per-region basis, by two separate teams with different experience levels. On unenhanced PET/CT, sensitivity and specificity ranged from 89.3% (junior team) to 92% (senior team), and 99.1% (junior team) to 99.2% (senior team), respectively. On contrast-enhanced PET/CT, sensitivity and specificity ranged from 92.3% (junior team) to 98.5% (senior team), and 99.4% (junior team) to 99.5% (senior team), respectively. These increases in sensitivity and specificity, due to the use of contrast-enhanced images, were statistically significant (P < 0.05). Intravenous contrast medium only moderately, aleit significantly, improves the sensitivity of (68)Ga-DOTATOC PET/CT for the detection of abdominal NETs, and hardly affects specificity. Thus, while contrast enhancement is justified to achieve maximum sensitivity, unenhanced images may be sufficient for routine PET/CT in NET patients. Contrast media moderately improve the sensitivity of (68)Ga-DOTATOC PET/CT for neuroendocrine tumours. Contrast media hardly affect the specificity of (68)Ga-DOTATOC PET/CT for neuroendocrine tumours. Unenhanced PET/CT is sufficient for routine imaging of patients with neuroendocrine tumours.

  4. Stage IV Gastro-Entero-Pancreatic Neuroendocrine Neoplasms: A Risk Score to Predict Clinical Outcome.

    PubMed

    Panzuto, Francesco; Merola, Elettra; Pavel, Marianne Ellen; Rinke, Anja; Kump, Patrizia; Partelli, Stefano; Rinzivillo, Maria; Rodriguez-Laval, Victor; Pape, Ulrich Frank; Lipp, Rainer; Gress, Thomas; Wiedenmann, Bertram; Falconi, Massimo; Delle Fave, Gianfranco

    2017-04-01

    Several risk factors predict clinical outcome in gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs); however, the impact of their combination has not been investigated so far. A retrospective analysis of stage IV GEP-NENs was performed. Multivariate analysis for progression of disease (PD) was performed by Cox proportional hazards method to obtain a risk score. Area under the curve obtained by receiver operating characteristic analysis was used to assess the score performance. Progression-free survival analysis was performed by Kaplan-Meier method. Two hundred eighty-three stage IV GEP-NENs were evaluated, including 93 grade 1 neuroendocrine tumors (32.9%), 153 grade 2 neuroendocrine tumors (54%), and 37 grade 3 neuroendocrine carcinomas (13.1%). Independent risk factors for PD were Ki67, proportion of metastatic liver involvement, and presence of extra-abdominal metastases. The risk score was calculated as follows: (0.025 × Ki67) + [(0 if no liver metastases or liver involvement <25%) OR (0.405 if liver involvement 25%-50%) OR (0.462 if liver involvement >50%)] + [(0 if no extra-abdominal metastases) OR (0.528 if extra-abdominal metastases present)]. The risk score accuracy to predict PD was superior compared with the G grading system (area under the curve: 0.705 and 0.622, respectively). Three subgroups of patients with low, intermediate, and high risk of PD according to risk score were identified, median progression-free survival being 26 months, 19 months, and 12 months, respectively. In stage IV GEP-NENs, a risk score able to predict PD was obtained by combining Ki67, proportion of metastatic liver involvement, and presence of extra-abdominal metastases. The score may help to discriminate patients with different progression risk level to plan tailored therapeutic approaches and follow-up programs. The Oncologist 2017;22:409-415Implications for Practice: Clinical outcome of patients with advanced gastro-entero-pancreatic neuroendocrine

  5. Tumour-educated macrophages display a mixed polarisation and enhance pancreatic cancer cell invasion.

    PubMed

    Karnevi, Emelie; Andersson, Roland; Rosendahl, Ann H

    2014-07-01

    At the time of diagnosis, almost 80% of pancreatic cancer patients present with new-onset type 2 diabetes (T2D) or impaired glucose tolerance. T2D and pancreatic cancer are both associated with low-grade inflammation. Tumour-associated macrophages (TAMs) have a key role in cancer-related inflammation, immune escape, matrix remodelling and metastasis. In this study, the interplay between tumour cells and immune cells under the influence of different glucose levels was investigated. Human peripheral blood mononuclear cells were exposed in vitro to conditioned medium from BxPC-3 human pancreatic cancer cells, in normal (5 mM) or high (25 mM) glucose levels. Flow cytometry analyses demonstrated that tumour-derived factors stimulated differentiation of macrophages, with a mixed classical (M1-like) and alternatively activated (M2-like) phenotype polarisation (CD11c(+)CD206(+)). High-glucose conditions further enhanced the tumour-driven macrophage enrichment and associated interleukin (IL)-6 and IL-8 cytokine levels. In addition, hyperglycaemia enhanced the responsiveness of tumour-educated macrophages to lipopolysaccharide, with elevated cytokine secretion compared with normal glucose levels. Tumour-educated macrophages were found to promote pancreatic cancer cell invasion in vitro, which was significantly enhanced at high glucose. The anti-diabetic drug metformin shifted the macrophage phenotype polarisation and reduced the tumour cell invasion at normal, but not high, glucose levels. In conclusion, this study demonstrates that pancreatic cancer cells stimulate differentiation of macrophages with pro-tumour properties that are further enhanced by hyperglycaemia. These findings highlight important crosstalk between tumour cells and TAMs in the local tumour microenvironment that may contribute to disease progression in pancreatic cancer patients with hyperglycaemia and T2D.

  6. [Patients' Priorities in the Treatment of Neuroendocrine Tumours: An Analytical Hierarchy Process].

    PubMed

    Mühlbacher, A C; Juhnke, C; Kaczynski, A

    2016-10-01

    Background: Neuroendocrine tumours (NET) are relatively rare, usually slow-growing malignant tumours. So far there are no data on the patient preferences/priorities regarding the therapy for NET. This empirical study aimed at the elicitation of patient priorities in the drug treatment of NET. Method: Qualitative patient interviews (N=9) were conducted. To elicit the patient's perspective regarding various treatment aspects of NET a self-administered questionnaire using the Analytical Hierarchy Process (AHP) was developed. The data collection was carried out using paper questionnaires supported by an item response system in a group discussion. To evaluate the patient-relevant outcomes, the eigenvector method was applied. Results: N=24 patients, experts and relatives participated in the AHP survey. In the AHP all respondents had clear priorities for all considered attributes. The attribute "overall survival" was the most significant feature of a drug therapy for all respondents. As in the qualitative interviews, "efficacy attributes" dominated the side effects in the AHP as well. The evaluation of all participants thus showed the attributes "overall survival" (Wglobal:0.418), "progression-free survival" (Wglobal:0.172) and "response to treatment" (Wglobal:0.161) to be most relevant. "Occurrence of abdominal pain" (Wglobal:0.051) was ranked sixth, with "tiredness/fatigue" and "risk of a hypoglycaemia" (Wglobal:0.034) in a shared seventh place. Conclusion: The results thus provide evidence about how much influence a treatment capacity has on therapeutic decisions. Using the AHP major aspects of drug therapy from the perspective of those affected were captured, and positive and negative therapeutic properties could be related against each other. Based on the assessment of the patient's perspective further investigation must elicit patient preferences for NET drug therapy. In the context of a discrete choice experiment or another choice-based method of preference

  7. 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

    2017-10-05

    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

  8. PET-Guided Surgery - High Correlation between Positron Emission Tomography with 11C-5-Hydroxytryptophane (5-HTP) and Surgical Findings in Abdominal Neuroendocrine Tumours.

    PubMed

    Orlefors, Håkan; Sundin, Anders; Eriksson, Barbro; Skogseid, Britt; Oberg, Kjell; Akerström, Göran; Hellman, Per

    2012-02-08

    Positron emission tomography (PET) with 11C-labeled 5-hydroxytryptophane (5-HTP) is a sensitive technique to visualize neuroendocrine tumours (NETs), due to high intracellular uptake of amine-precursors like L-dihydroxyphenylalanine (L-DOPA) and 5-HTP. NETs are often small and difficult to localize in spite of overt clinical symptoms due to hormonal excess. In our study, 38 consecutive NET patients underwent 11C-5-HTP-PET and morphological imaging by CT within 12 weeks prior to surgery. Surgical, histopathological and 5-HTP PET findings were correlated. 11C-5-HTP-PET corresponded to the surgical findings in 31 cases, was false negative in six, and true negative in one case resulting in 83.8% sensitivity and 100% specificity. Positive predicted value was 100%. In 11 patients 11C-5-HTP-PET was the only imaging method applied to localize the tumour. Thus, we could demonstrate that functional imaging by 11C-5-HTP-PET in many cases adds vital preoperative diagnostic information and in more than every fourth patient was the only imaging method that will guide the surgeon in finding the NET-lesion. Although the present results demonstrates that 11C-5-HTP may be used as an universal NET tracer, the sensitivity to visualize benign insulinomas and non functioning pancreatic NETs was lower.

  9. PET-Guided Surgery — High Correlation between Positron Emission Tomography with 11C-5-Hydroxytryptophane (5-HTP) and Surgical Findings in Abdominal Neuroendocrine Tumours

    PubMed Central

    Örlefors, Håkan; Sundin, Anders; Eriksson, Barbro; Skogseid, Britt; Öberg, Kjell; Åkerström, Göran; Hellman, Per

    2012-01-01

    Positron emission tomography (PET) with 11C-labeled 5-hydroxytryptophane (5-HTP) is a sensitive technique to visualize neuroendocrine tumours (NETs), due to high intracellular uptake of amine-precursors like L-dihydroxyphenylalanine (L-DOPA) and 5-HTP. NETs are often small and difficult to localize in spite of overt clinical symptoms due to hormonal excess. In our study, 38 consecutive NET patients underwent 11C-5-HTP-PET and morphological imaging by CT within 12 weeks prior to surgery. Surgical, histopathological and 5-HTP PET findings were correlated. 11C-5-HTP-PET corresponded to the surgical findings in 31 cases, was false negative in six, and true negative in one case resulting in 83.8% sensitivity and 100% specificity. Positive predicted value was 100%. In 11 patients 11C-5-HTP-PET was the only imaging method applied to localize the tumour. Thus, we could demonstrate that functional imaging by 11C-5-HTP-PET in many cases adds vital preoperative diagnostic information and in more than every fourth patient was the only imaging method that will guide the surgeon in finding the NET-lesion. Although the present results demonstrates that 11C-5-HTP may be used as an universal NET tracer, the sensitivity to visualize benign insulinomas and non functioning pancreatic NETs was lower. PMID:24213229

  10. 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).

  11. Pazopanib Hydrochloride in Treating Patients With Advanced Neuroendocrine Cancer

    ClinicalTrials.gov

    2015-10-15

    Gastrin-Producing Neuroendocrine Tumor; Lung Carcinoid Tumor; Metastatic Digestive System Neuroendocrine Tumor G1; Multiple Endocrine Neoplasia Type 1; Pancreatic Glucagonoma; Pancreatic Insulinoma; Pancreatic Polypeptide Tumor; Recurrent Digestive System Neuroendocrine Tumor G1; Recurrent Pancreatic Neuroendocrine Carcinoma; Regional Digestive System Neuroendocrine Tumor G1; Somatostatin-Producing Neuroendocrine Tumor

  12. Primary neuroendocrine tumour of the right ventricle presenting with heart failure and cyanosis.

    PubMed

    Naqvi, Syed Yaseen; Henry, David; Furukawa, Satoshi; Haber, Howard

    2016-03-11

    A 68-year-old woman presented to the emergency department owing to exertional dyspnoea and bilateral leg oedema for 3 weeks. Her vital signs included the following: heart rate of 95 bpm, respiratory rate of 24 breaths/min, oxygen saturation of 73% on room air and a blood pressure of 184/108 mm Hg. Physical examination revealed tachypnoea with clear lungs to auscultation, elevated jugular veins, cyanosis and bilateral pitting oedema. A chest X-ray demonstrated cardiomegaly without obvious pulmonary oedema. A CT of the chest was negative for pulmonary embolus; however, the scan did reveal a large right ventricular (RV) mass. An echocardiogram with bubble study confirmed a patent foramen ovale with significant right-to-left shunting and a large RV mass that significantly obstructed the pulmonary outflow tract. A cardiac biopsy revealed a low-grade neuroendocrine tumour. The patient underwent successful debridement and adjuvant chemotherapy. She improved greatly and was asymptomatic at a 9-month follow-up visit. 2016 BMJ Publishing Group Ltd.

  13. Malignant neuroendocrine tumour of the gallbladder with elevated carcinoembryonic antigen: case report and literature review

    PubMed Central

    Furrukh, Muhammad; Qureshi, Asim; Saparamadu, Anna; Kumar, Shiyam

    2013-01-01

    A 58-year-old woman presented to a tertiary care centre with signs and symptoms of acute cholecystitis, cholelithiasis and diagnoses of a high-grade neuroendocrine tumour of the gallbladder primarily with peritoneal and liver metastases. She had a liver abscess secondary to Salmonella and Enterococcus fecalis that was drained and treated with appropriate antibiotics. Interestingly, the serum chromogranin A levels were within normal limits, but carcinoembryonic antigen was elevated, which helped evaluate responses and pick progression. She was treated with 10 cycles of palliative chemotherapy when malignancy associated complications started to recur, that is, cholangitis, worsening pain, cachexia, intestinal obstruction, etc leading to chemotherapy delays. Her disease progressed during these times with rapid deterioration of performance status. She died of septic complications postlaparotomy for intestinal obstruction. Her progression-free survival remained for 8 months with subjective and objective improvements, and her overall survival remained at 13 months. We describe the course of her illness and give a brief review of the literature. PMID:23661652

  14. 18F-fluorodihydroxyphenylalanine vs other radiopharmaceuticals for imaging neuroendocrine tumours according to their type.

    PubMed

    Balogova, Sona; Talbot, Jean-Noël; Nataf, Valérie; Michaud, Laure; Huchet, Virginie; Kerrou, Khaldoun; Montravers, Françoise

    2013-06-01

    6-Fluoro-((18)F)-L-3,4-dihydroxyphenylalanine (FDOPA) is an amino acid analogue for positron emission tomography (PET) imaging which has been registered since 2006 in several European Union (EU) countries and by several pharmaceutical firms. Neuroendocrine tumour (NET) imaging is part of its registered indications. NET functional imaging is a very competitive niche, competitors of FDOPA being two well-established radiopharmaceuticals for scintigraphy, (123)I-metaiodobenzylguanidine (MIBG) and (111)In-pentetreotide, and even more radiopharmaceuticals for PET, including fluorodeoxyglucose (FDG) and somatostatin analogues. Nevertheless, there is no universal single photon emission computed tomography (SPECT) or PET tracer for NET imaging, at least for the moment. FDOPA, as the other PET tracers, is superior in diagnostic performance in a limited number of precise NET types which are currently medullary thyroid cancer, catecholamine-producing tumours with a low aggressiveness and well-differentiated carcinoid tumours of the midgut, and in cases of congenital hyperinsulinism. This article reports on diagnostic performance and impact on management of FDOPA according to the NET type, emphasising the results of comparative studies with other radiopharmaceuticals. By pooling the results of the published studies with a defined standard of truth, patient-based sensitivity to detect recurrent medullary thyroid cancer was 70 % [95 % confidence interval (CI) 62.1-77.6] for FDOPA vs 44 % (95 % CI 35-53.4) for FDG; patient-based sensitivity to detect phaeochromocytoma/paraganglioma was 94 % (95 % CI 91.4-97.1) for FDOPA vs 69 % (95 % CI 60.2-77.1) for (123)I-MIBG; and patient-based sensitivity to detect midgut NET was 89 % (95 % CI 80.3-95.3) for FDOPA vs 80 % (95 % CI 69.2-88.4) for somatostatin receptor scintigraphy with a larger gap in lesion-based sensitivity (97 vs 49 %). Previously unpublished FDOPA results from our team are reported in some rare NET, such as small cell

  15. Single-cell mRNA profiling reveals transcriptional heterogeneity among pancreatic circulating tumour cells.

    PubMed

    Lapin, Morten; Tjensvoll, Kjersti; Oltedal, Satu; Javle, Milind; Smaaland, Rune; Gilje, Bjørnar; Nordgård, Oddmund

    2017-05-31

    Single-cell mRNA profiling of circulating tumour cells may contribute to a better understanding of the biology of these cells and their role in the metastatic process. In addition, such analyses may reveal new knowledge about the mechanisms underlying chemotherapy resistance and tumour progression in patients with cancer. Single circulating tumour cells were isolated from patients with locally advanced or metastatic pancreatic cancer with immuno-magnetic depletion and immuno-fluorescence microscopy. mRNA expression was analysed with single-cell multiplex RT-qPCR. Hierarchical clustering and principal component analysis were performed to identify expression patterns. Circulating tumour cells were detected in 33 of 56 (59%) examined blood samples. Single-cell mRNA profiling of intact isolated circulating tumour cells revealed both epithelial-like and mesenchymal-like subpopulations, which were distinct from leucocytes. The profiled circulating tumour cells also expressed elevated levels of stem cell markers, and the extracellular matrix protein, SPARC. The expression of SPARC might correspond to an epithelial-mesenchymal transition in pancreatic circulating tumour cells. The analysis of single pancreatic circulating tumour cells identified distinct subpopulations and revealed elevated expression of transcripts relevant to the dissemination of circulating tumour cells to distant organ sites.

  16. Exocrine pancreatic cancer: symptoms at presentation and their relation to tumour site and stage.

    PubMed

    Porta, Miquel; Fabregat, Xavier; Malats, Núria; Guarner, Luisa; Carrato, Alfredo; de Miguel, Ana; Ruiz, Laura; Jariod, Manuel; Costafreda, Sergi; Coll, Susana; Alguacil, Juan; Corominas, Josep M; Solà, Ricard; Salas, Antonio; Real, Francisco X

    2005-06-01

    The need to detect pancreatic cancer at earlier stages is undisputed. We recorded the signs and symptoms of patients presenting with exocrine pancreatic cancer and evaluated their association with clinical characteristics such as tumour site and disease stage. All patients (n = 185) with exocrine pancreatic cancer newly diagnosed at five general hospitals in Eastern Spain were prospectively recruited over 5 years. Symptoms were elicited through personal interviews and signs were recorded by the attending physician on admission. At diagnosis, one third of tumours of the pancreas head were in stage I and another third in stage IV. None of the tumours of the body and tail were in stage I, and over 80% were in stage IV (p < 0.001) . At presentation, the most frequent symptoms were asthenia (86%), anorexia (85%), weight-loss (85%), abdominal pain (79%), and choluria (59%). Cholestatic symptoms were more common in tumours affecting only the pancreatic head (p < 0.001) . There was a clear trend toward more localized tumours with increasing numbers of cholestatic signs (p < 0.001) . Asthenia, anorexia and weight-loss were unrelated to stage. An increased symptom-to-diagnosis interval was associated with more advanced stage (p = 0.048). Proper attention to signs and symptoms, especially cholestasis, may help identify patients with pancreatic cancer at an earlier stage. Results also provide a current picture of the semiology of pancreatic cancer which could be of use in studies on the potential of proteomic tests in the early detection of this neoplasm.

  17. Capsaicin induces cytotoxicity in pancreatic neuroendocrine tumor cells via mitochondrial action.

    PubMed

    Skrzypski, M; Sassek, M; Abdelmessih, S; Mergler, S; Grötzinger, C; Metzke, D; Wojciechowicz, T; Nowak, K W; Strowski, M Z

    2014-01-01

    Capsaicin (CAP), the pungent ingredient of chili peppers, inhibits growth of various solid cancers via TRPV1 as well as TRPV1-independent mechanisms. Recently, we showed that TRPV1 regulates intracellular calcium level and chromogranin A secretion in pancreatic neuroendocrine tumor (NET) cells. In the present study, we characterize the role of the TRPV1 agonist - CAP - in controlling proliferation and apoptosis of pancreatic BON and QGP-1 NET cells. We demonstrate that CAP reduces viability and proliferation, and stimulates apoptotic death of NET cells. CAP causes mitochondrial membrane potential loss, inhibits ATP synthesis and reduces mitochondrial Bcl-2 protein production. In addition, CAP increases cytochrome c and cleaved caspase 3 levels in cytoplasm. CAP reduces reactive oxygen species (ROS) generation. The antioxidant N-acetyl-l-cysteine (NAC) acts synergistically with CAP to reduce ROS generation, without affecting CAP-induced toxicity. TRPV1 protein reduction by 75% reduction fails to attenuate CAP-induced cytotoxicity. In summary, these results suggest that CAP induces cytotoxicity by disturbing mitochondrial potential, and inhibits ATP synthesis in NET cells. Stimulation of ROS generation by CAP appears to be a secondary effect, not related to CAP-induced cytotoxicity. These results justify further evaluation of CAP in modulating pancreatic NETs in vivo.

  18. Resected Pancreatic Neuroendocrine Tumors: Patterns of Failure and Disease-Related Outcomes With or Without Radiotherapy

    SciTech Connect

    Zagar, Timothy M.; White, Rebekah R.; Willett, Christopher G.; Tyler, Douglas S.; Papavassiliou, Paulie; Papalezova, Katia T.; Guy, Cynthia D.; Broadwater, Gloria; Clough, Robert W.; Czito, Brian G.

    2012-07-15

    Purpose: Pancreatic neuroendocrine tumors (NET) are rare and have better disease-related outcomes compared with pancreatic adenocarcinoma. Surgical resection remains the standard of care, although many patients present with locally advanced or metastatic disease. Little is known regarding the use of radiotherapy in the prevention of local recurrence after resection. To better define the role of radiotherapy, we performed an analysis of resected patients at our institution. Methods: Between 1994 and 2009, 33 patients with NET of the pancreatic head and neck underwent treatment with curative intent at Duke University Medical Center. Sixteen patients were treated with surgical resection alone while an additional 17 underwent resection with adjuvant or neoadjuvant radiation therapy, usually with concurrent fluoropyrimidine-based chemotherapy (CMT). Median radiation dose was 50.4 Gy and median follow-up 28 months. Results: Thirteen patients (39%) experienced treatment failure. Eleven of the initial failures were distant, one was local only and one was local and distant. Two-year overall survival was 77% for all patients. Two-year local control for all patients was 87%: 85% for the CMT group and 90% for the surgery alone group (p = 0.38). Two-year distant metastasis-free survival was 56% for all patients: 46% and 69% for the CMT and surgery patients, respectively (p = 0.10). Conclusions: The primary mode of failure is distant which often results in mortality, with local failure occurring much less commonly. The role of radiotherapy in the adjuvant management of NET remains unclear.

  19. Neuroendocrine tumour metastatic brain disease during immunosuppressive treatment for paraneoplastic GABAB receptor antibodies encephalitis: Is immunosuppression always beneficial?

    PubMed

    André, Ana; Félix, Ana; Shamasna, Motasem; Nzwalo, Hipólito; Basílio, Carlos

    2017-09-15

    Limbic autoimmune encephalitis (LE) should be considered in any patient with acute or subacute neuropsychiatric manifestations, without other common causes of encephalitis. Y-Aminobutyric-acid-B-receptor (anti-GABABR) antibodies are rarely encountered in association with LE. A 74-year-old patient presented with a progressive cognitive degradation and generalized tonic-clonic seizures, with positive anti-GABABR. He declined under immunosuppression treatment. Control magnetic resonance revealed brain lesions, which became positive for pulmonary neuroendocrine tumour metastatic disease. The occurrence of diversified neurological manifestations of an underling tumour is difficult to manage. We speculate if in some cases, immunosuppression can itself facilitate tumour progression. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Immunohistochemical study of the neural development transcription factors (TTF1, ASCL1 and BRN2) in neuroendocrine prostate tumours.

    PubMed

    Rodríguez-Zarco, E; Vallejo-Benítez, A; Umbría-Jiménez, S; Pereira-Gallardo, S; Pabón-Carrasco, S; Azueta, A; González-Cámpora, R; Espinal, P S; García-Escudero, A

    2017-10-01

    Prostatic small-cell neuroendocrine carcinoma is an uncommon malignancy that constitutes 0.5-1% of all prostate malignancies. The median cancer-specific survival of patients with prostatic small-cell neuroendocrine carcinoma is 19 months, and 60.5% of the patients have metastatic disease. Neural development transcription factors are molecules involved in the organogenesis of the central nervous system and of neuroendocrine precursors of various tissues, including the suprarenal gland, thyroid glands, lungs and prostate. We present 3 cases of this uncommon condition, applying the new World Health Organisation criteria. We conducted studies through haematoxylin and eosin staining and analysed the expression of the neural development transcription factors achaete-scute homolog like 1, thyroid transcription factor 1 and the class III/IV POU transcription factors, as a new research line in the carcinogenesis of prostatic neuroendocrine tumours. In case 1, there was no TTF1 immunoexpression. Cases 2 and 3 had positive immunostaining for ASCL1, and Case 1 had negative immunostaining. BRN2 immunostaining was negative in case 1 and positive in cases 2 and 3. The World Health Organisation does not recognise any molecular or genetic marker with prognostic value. ASCL-1 is related to the NOTCH and WNT signalling pathways. ASCL-1, TTF1 and BRN2 could be used for early diagnosis and as prognostic factors and therapeutic targets. Copyright © 2017 AEU. All rights reserved.

  1. Sequential treatment in disseminated well- and intermediate-differentiated pancreatic neuroendocrine tumors: Common sense or low rationale?

    PubMed

    Grande, Enrique

    2016-04-10

    Fortunately, the landscape of the systemic treatment for grade 1 and 2 pancreatic neuroendocrine tumors has changed in the last decade with at least four different alternatives approved in the field. Chemotherapy, somatostatin analogues, sunitinib and everolimus remind valid options according to the most referenced international guidelines. However, and although this is something done in the routine practice, there is a lack of evidence for the use of any of these strategies after failure to the others. Moreover, further sequential alternatives in third or fourth line have never been tested prospectively. The need for a better understanding of the rationale to sequence different systemic options is even greater in non-pancreatic neuroendocrine tumors since available therapies are scarce. Sequential strategies in other solid tumors have led to a clear improvement in overall survival. This is also believed to occur in neuroendocrine tumors but no clear data on it has been delivered yet. We postulate that the different mode of action of the systemic options available for the treatment of neuroendocrine tumors may avoid the complete resistance of one option after the other and that sequential use of these agents will be translated into a longer overall survival of patients. Prospective and randomized trials that seek for the activity of drugs after failure to another systemic alternatives are highly needed in this field of neuroendocrine tumors.

  2. Capecitabine, Temozolomide and Bevacizumab for Metastatic or Unresectable Pancreatic Neuroendocrine Tumors

    ClinicalTrials.gov

    2016-09-21

    Gastrinoma; Glucagonoma; Insulinoma; Pancreatic Polypeptide Tumor; Recurrent Islet Cell Carcinoma; Recurrent Pancreatic Cancer; Somatostatinoma; Stage III Pancreatic Cancer; Stage IV Pancreatic Cancer

  3. Future Directions in the Treatment of Gastrointestinal and Pancreatic Neuroendocrine Tumors.

    PubMed

    Asmis, Timothy

    2016-07-01

    Recently, the landscape of the diagnosis and treatment of patients with well-differentiated gastrointestinal/pancreatic neuroendocrine tumors (previously referred to as carcinoid tumors) has changed dramatically. We will need to work with all of the stakeholders including clinicians, patients, regulatory agencies, and industry to best navigate future treatment and research. Future protocols will require us to define clinically relevant end points. In designing future clinical trials, we will need to determine which patients will be included in these studies. Future research will need to address the best way to image and follow patient's disease both in the clinic and on research studies. Timely access to new therapies will be the utmost importance to both current and future patients. We must work together to establish relevant clinical questions and to pursue collaborative research that promotes the health of our patients.

  4. Use of cinacalcet and sunitinib to treat hypercalcaemia due to a pancreatic neuroendocrine tumor.

    PubMed

    Valdes-Socin, Hernan; Almanza, Matilde Rubio; Fernández-Ladreda, Mariana Tomé; Daele, Daniel Van; Polus, Marc; Chavez, Marcela; Beckers, Albert

    2017-09-18

    Neuroendocrine tumors (NETs) can secrete hormones, including ectopic secretions, but they have been rarely associated with malignant hypercalcemia. A 52-year-old man with a history of diabetes mellitus was diagnosed with a pancreatic tumor. A pancreatic biopsy confirmed a well-differentiated pancreatic NET (pNET). The patient subsequently developed liver metastasis and hypercalcemia with high 1,25 OH vitamin D and suppressed parathyroid hormone (PTH) levels. Hypercalcemia was refractory to chemotherapy, intravenous saline fluids, diuretics, calcitonin and zoledronate. Cinacalcet administration (120 mg/day) resulted in a significant calcium reduction. Hypocalcemia was observed when sunitinib was added three months later and cinacalcet was stopped. Subsequently, the calcium and PTH levels normalized. After six months, we observed 20% shrinkage of the pancreatic tumor and necrosis of a liver metastasis. Cinacalcet is an allosteric activator of the calcium receptor agonist, and it is used for severe hypercalcemia in patients with primary (benign and malignant) hyperparathyroidism. In this patient, cinacalcet demonstrated a calcium lowering effect, normalized hypophosphatemia, and improved the clinical condition of the patient. The mechanism through which cinacalcet improved PTH-rp mediated hypercalcemia is still unclear, but studies have suggested that a potential mechanism is the activation of calcitonin secretion. Sunitinib is an oral multi-targeted tyrosine kinase inhibitor used to treat advanced pNETs. The hypocalcemic effects of sunitinib have not been previously described in a patient with pNET. Here, we report for the first time the successful combination of cinacalcet and sunitinib in the treatment of a pNET patient presenting with malignant hypercalcemia.

  5. Risk Factors for Sporadic Pancreatic Neuroendocrine Tumors: A Case-Control Study

    PubMed Central

    Ben, Qiwen; Zhong, Jie; Fei, Jian; Chen, Haitao; Yv, Lifen; Tan, Jihong; Yuan, Yaozong

    2016-01-01

    The current study examined risk factors for sporadic pancreatic neuroendocrine tumors (PNETs), including smoking, alcohol use, first-degree family history of any cancer (FHC), and diabetes in the Han Chinese ethnic group. In this clinic-based case-control analysis on 385 patients with sporadic PNETs and 614 age- and sex-matched controls, we interviewed subjects using a specific questionnaire on demographics and potential risk factors. An unconditional multivariable logistic regression analysis was used to estimate adjusted odds ratios (AORs). No significant differences were found between patients and controls in terms of demographic variables. Most of the patients with PNETs had well-differentiated PNETs (G1, 62.9%) and non-advanced European Neuroendocrine Tumor Society (ENETS) stage (stage I or II, 83.9%). Ever/heavy smoking, a history of diabetes and a first-degree FHC were independent risk factors for non-functional PNETs. Only heavy drinking was found to be an independent risk factor for functional PNETs (AOR = 1.87; 95% confidence interval [CI], 1.01–3.51). Ever/heavy smoking was also associated with advanced ENETS staging (stage III or IV) at the time of diagnosis. This study identified first-degree FHC, ever/heavy smoking, and diabetes as risk factors for non-functional PNETs, while heavy drinking as a risk factor for functional PNETs. PMID:27782199

  6. Case Report of Cirrhosis following Yttrium-90 Radioembolization for Pancreatic Neuroendocrine Liver Metastases.

    PubMed

    Loree, Jonathan M; Hiruki, Tadaaki; Kennecke, Hagen F

    2016-01-01

    Management options for pancreatic neuroendocrine tumors (pNETs) metastatic to the liver include surgical, ablative, cytotoxic, and radioisotope approaches. One potential local treatment option includes selective internal radiotherapy utilizing yttrium-90 ((90)Y) microspheres. (90)Y has also been used in the treatment of hepatocellular carcinoma and tumors metastatic to the liver. It appears to be well tolerated; however, there is no randomized controlled trial reporting long-term toxicities. Previous retrospective reports have described biliary damage as a potential complication of therapy with (90)Y and chemoembolization; however, the long-term sequelae of (90)Y treatment are poorly understood. We present the case of a 65-year-old Caucasian woman who suffered biliary damage following (90)Y administration for metastatic pNETs and subsequently developed cirrhosis. Given the timeline of her various treatments and the lack of any other identifiable etiology for her cirrhosis, we believe this to be a potential long-term complication of (90)Y therapy. This case provides pathologic confirmation of cirrhosis as a potential long-term sequela of (90)Y treatment. This long-term risk needs to be considered when sequencing therapy for patients with neuroendocrine tumors who have a good prognosis. There are now several other systemic and ablative treatment options available to these patients, and long-term complications must be considered during treatment.

  7. Case Report of Cirrhosis following Yttrium-90 Radioembolization for Pancreatic Neuroendocrine Liver Metastases

    PubMed Central

    Loree, Jonathan M.; Hiruki, Tadaaki; Kennecke, Hagen F.

    2016-01-01

    Background Management options for pancreatic neuroendocrine tumors (pNETs) metastatic to the liver include surgical, ablative, cytotoxic, and radioisotope approaches. One potential local treatment option includes selective internal radiotherapy utilizing yttrium-90 (90Y) microspheres. 90Y has also been used in the treatment of hepatocellular carcinoma and tumors metastatic to the liver. It appears to be well tolerated; however, there is no randomized controlled trial reporting long-term toxicities. Previous retrospective reports have described biliary damage as a potential complication of therapy with 90Y and chemoembolization; however, the long-term sequelae of 90Y treatment are poorly understood. Case Presentation We present the case of a 65-year-old Caucasian woman who suffered biliary damage following 90Y administration for metastatic pNETs and subsequently developed cirrhosis. Given the timeline of her various treatments and the lack of any other identifiable etiology for her cirrhosis, we believe this to be a potential long-term complication of 90Y therapy. Conclusion This case provides pathologic confirmation of cirrhosis as a potential long-term sequela of 90Y treatment. This long-term risk needs to be considered when sequencing therapy for patients with neuroendocrine tumors who have a good prognosis. There are now several other systemic and ablative treatment options available to these patients, and long-term complications must be considered during treatment. PMID:26933423

  8. RSUME is implicated in tumorigenesis and metastasis of pancreatic neuroendocrine tumors

    PubMed Central

    Wu, Yonghe; Tedesco, Lucas; Lucia, Kristin; Schlitter, Anna M.; Garcia, Jose Monteserin; Esposito, Irene; Auernhammer, Christoph J.; Theodoropoulou, Marily; Arzt, Eduardo; Renner, Ulrich; Stalla, Günter K.

    2016-01-01

    The factors triggering pancreatic neuroendocrine tumor (PanNET) progression are largely unknown. Here we investigated the role and mechanisms of the sumoylation enhancing protein RSUME in PanNET tumorigenesis. Immunohistochemical studies showed that RSUME is strongly expressed in normal human pancreas, in particular in β-cells. RSUME expression is reduced in insulinomas and is nearly absent in other types of PanNETs suggesting a role in PanNET tumorigenesis. In human pancreatic neuroendocrine BON1 cells, RSUME stimulates hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor-A (VEGF-A), which are key components of tumor neovascularisation. In contrast, RSUME suppresses nuclear factor-κB (NF-κB) and its target interleukin-8 (IL-8). Correspondingly, PanNET cells with RSUME knockdown showed decreased HIF-1α activity and increased NF-κB and IL-8 production leading to a moderate reduction of VEGF-A release as reduced HIF-1α/VEGF-A production is partly compensated by NF-κB/IL-8-induced VEGF-A. Notably, RSUME stabilizes the tumor suppressor PTEN, which is frequently lost in PanNETs and whose absence is associated with metastasis formation. In vivo orthotopic transplantation of PanNET cells with or without RSUME expression into nude mice showed that PanNETs without RSUME have reduced PTEN expression, grow faster and form multiple liver metastases. In sum, RSUME differentially regulates key components of PanNET formation suggesting that the observed loss of RSUME in advanced PanNETs is critically involved in PanNET tumorigenesis, particularly in metastasis formation. PMID:27506944

  9. Association between ABO blood types and sporadic pancreatic neuroendocrine tumors in the Chinese Han population.

    PubMed

    Ben, Qiwen; Liu, Jun; Wang, Weiyi; Guo, Fang; Yao, Weiyan; Zhong, Jie; Yuan, Yaozong

    2017-08-15

    Although the relationship between non-O blood types and the risk of exocrine pancreatic cancer has been demonstrated, the association between ABO blood types and sporadic pancreatic neuroendocrine tumor (PNET) has not been reported thus far. This hospital-based, case-control study included 387 patients with PNET and 542 age- and sex-matched controls. Unconditional multivariable logistic regression analysis was performed to estimate the adjusted odds ratios (AORs) and 95% confidence intervals (CIs). The relationship between ABO blood types and clinicopathologic features was also analyzed. After adjusting for age, sex, smoking status, alcohol drinking, and first-degree family history of any cancer, the AORs (95% CI) of functional PNET were 0.87 (0.59-1.28) for blood type A, 0.86 (0.58-1.28) for blood type B, and 0.71 (0.39-1.26) for blood type AB compared with subjects with blood type O. A similar ABO blood-type distribution was observed among cases with non-functional PNETs compared with controls. On comparing blood type B with non-B blood type, cases with non-functional PNETs had marginally higher rates of lymph node invasion (P = 0.047), distant metastasis (P = 0.044), and advanced European Neuroendocrine Tumor Society Stage (P = 0.040). There is no association between the ABO blood group and the development of functional and non-functional PNETs. The ABO blood types are not associated with the clinicopathologic features in patients with functional and non-functional PNETs.

  10. 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

  11. Expression of receptors for gut peptides in human pancreatic adenocarcinoma and tumour-free pancreas.

    PubMed Central

    Tang, C.; Biemond, I.; Offerhaus, G. J.; Verspaget, W.; Lamers, C. B.

    1997-01-01

    Gut hormones that modulate the growth of normal pancreas may also modulate the growth of cancers originating from pancreas. This study visualized and compared the receptors for cholecystokinin (CCK), bombesin (BBS), secretin and vasoactive intestinal peptide (VIP) in tumour-free tissue sections of human pancreas (n = 10) and pancreatic ductal adenocarcinomas (n = 12) with storage phosphor autoradiography using radioligands. CCK-B receptors, present in control pancreata, were not detected in any of the pancreatic cancers. BBS receptors were visualized in control pancreata, but they were absent in 10 of 12 pancreatic cancers. In 5 of 12 pancreatic cancers, receptors for secretin were visualized, while binding for secretin was present in all tumour-free pancreata. Conversely, no specific binding of VIP was detected in control pancreata but was identified in 3 of 12 pancreatic cancer specimens. It is concluded that the expression of gut peptide receptors in pancreatic cancer differs from that in tumour-free pancreas. Receptors for these peptides are present in only a minority of pancreatic cancer specimens. Images Figure 1 PMID:9166939

  12. Comprehensive treatment of a functional pancreatic neuroendocrine tumor with multifocal liver metastases

    PubMed Central

    Wang, Wei; Seeruttun, Sharvesh Raj; Fang, Cheng

    2014-01-01

    A 64-year-old man was admitted to the Sun Yat-Sen University Cancer Center with chief complaints of recurrent abdominal pain and diarrhea for about 3 years and with a history of surgical repair for intestinal perforation owing to stress ulcer. Positron emission tomography (PET)/computed tomography (CT) demonstrated a primary tumor on the pancreatic tail with multifocal liver metastases. Pathological and immunohistochemistry staining revealed the lesion to be a pancreatic neuroendocrine tumor (pNET). According to the latest World Health Organization (WHO, 2013) classification, the tumor was classified as stage IV functional G1 pNET. After referral to the multidisciplinary treatment board (MDT), the patient was started on periodic dose of omeprazole, somatostatin analogues and Interferon α (IFNα) and had scanning follow-ups. Based upon the imaging results, CT-guided radioactive iodine-125 (125I) seeds implantation therapy, radiofrequency ablation therapy (RFA) or microwave ablation technique were chosen for the treatment of the primary tumor. Transarterial chemoembolization (TACE), RFA and microwave ablation techniques were decided upon for liver metastases. The patient showed beneficial response to the treatment with clinically manageable low-grade side effects and attained partial remission (RECIST criteria) with a good quality of life. PMID:25232226

  13. Comprehensive treatment of a functional pancreatic neuroendocrine tumor with multifocal liver metastases.

    PubMed

    Wang, Wei; Seeruttun, Sharvesh Raj; Fang, Cheng; Zhou, Zhiwei

    2014-08-01

    A 64-year-old man was admitted to the Sun Yat-Sen University Cancer Center with chief complaints of recurrent abdominal pain and diarrhea for about 3 years and with a history of surgical repair for intestinal perforation owing to stress ulcer. Positron emission tomography (PET)/computed tomography (CT) demonstrated a primary tumor on the pancreatic tail with multifocal liver metastases. Pathological and immunohistochemistry staining revealed the lesion to be a pancreatic neuroendocrine tumor (pNET). According to the latest World Health Organization (WHO, 2013) classification, the tumor was classified as stage IV functional G1 pNET. After referral to the multidisciplinary treatment board (MDT), the patient was started on periodic dose of omeprazole, somatostatin analogues and Interferon α (IFNα) and had scanning follow-ups. Based upon the imaging results, CT-guided radioactive iodine-125 ((125)I) seeds implantation therapy, radiofrequency ablation therapy (RFA) or microwave ablation technique were chosen for the treatment of the primary tumor. Transarterial chemoembolization (TACE), RFA and microwave ablation techniques were decided upon for liver metastases. The patient showed beneficial response to the treatment with clinically manageable low-grade side effects and attained partial remission (RECIST criteria) with a good quality of life.

  14. An intestinal neuroendocrine tumour associated with paroxysmal ventricular tachycardia and melaena in a 10-year-old boxer.

    PubMed

    Tappin, S; Brown, P; Ferasin, L

    2008-01-01

    A 10-year-old female neutered boxer was presented with a five-week history of episodic collapse and melaena. Twenty-four-hour electrocardiograph (Holter) analysis revealed the collapsing episodes to coincide with episodes of paroxysmal ventricular tachycardia. Investigation of the dog's melaena revealed a gastric ulcer which was treated medically and an ileocaecal mass which was surgically excised. Histopathological examination of the mass was consistent with a neuroendocrine (carcinoid) tumour. The patient's recovery after surgery was unremarkable. At six-week follow-up, there had been no further episodes of melaena or collapse and repeat Holter analysis did not show any significant abnormalities. In this dog the gastric ulceration and paroxysmal ventricular tachycardia could be attributed to a paraneoplastic syndrome as a result of circulating vasoactive substances released by the tumour; this is supported by the evidence that all clinical signs resolved after surgical excision of the mass and the dog was clinically well 18 months after surgery.

  15. High-dose lanreotide in the treatment of poorly differentiated pancreatic neuroendocrine carcinoma: a case report.

    PubMed

    Van Fraeyenhove, Frank; Meireson, Nathalie; Terriere, Luc; Willemsen, Paul; Kunnen, Jan; Mattelaer, Caroline; Van Acker, Frank; Schrijvers, Dirk

    2014-01-01

    Pancreatic neuroendocrine tumors (NETs), including poorly differentiated carcinomas (NECs), are rarely encountered. The majority of these tumors do not secrete excess hormones, but functioning NETs produce large amounts of vasoactive peptides and may cause carcinoid syndrome. Synthetic somatostatin analogs (SSAs) have been widely used in NETs for control of hormonal syndromes. Here, we present a case of poorly differentiated, grade 3 pancreatic NEC associated with carcinoid syndrome, for which adequate symptom control was achieved for 2 years and 4 months using the long-acting SSA lanreotide Autogel(®). In February 2009, a 55-year-old woman presented with episodes of flushing, diarrhea and epigastric pain. Imaging techniques revealed the presence of a metabolically active mass expressing somatostatin receptors in the hilar area of the liver. Histopathological examination confirmed the malignant nature of the mass, which was identified as a poorly differentiated grade 3 pancreatic NEC (TNM staging: T4NxM0). Therapeutic options were limited for the patient because of the extent of the primary mass involving the celiac axis, severe gastrointestinal toxicity experienced as a side effect of chemotherapy with cisplatin-etoposide and, later in the course of the disease, extensive liver metastases and carcinoid heart syndrome. Along with a palliative debulking surgery and right portal vein embolization, biotherapy with a high dose of lanreotide Autogel (120 mg/14 days) contributed to alleviation of symptoms caused by hormone overproduction, even after the development of liver metastases. These results suggest that patients with poorly differentiated NECs who exhibit signs of carcinoid syndrome can benefit from treatment with somatostatin analogs.

  16. High-Dose Lanreotide in the Treatment of Poorly Differentiated Pancreatic Neuroendocrine Carcinoma: A Case Report

    PubMed Central

    Van Fraeyenhove, Frank; Meireson, Nathalie; Terriere, Luc; Willemsen, Paul; Kunnen, Jan; Mattelaer, Caroline; Van Acker, Frank; Schrijvers, Dirk

    2014-01-01

    Pancreatic neuroendocrine tumors (NETs), including poorly differentiated carcinomas (NECs), are rarely encountered. The majority of these tumors do not secrete excess hormones, but functioning NETs produce large amounts of vasoactive peptides and may cause carcinoid syndrome. Synthetic somatostatin analogs (SSAs) have been widely used in NETs for control of hormonal syndromes. Here, we present a case of poorly differentiated, grade 3 pancreatic NEC associated with carcinoid syndrome, for which adequate symptom control was achieved for 2 years and 4 months using the long-acting SSA lanreotide Autogel®. In February 2009, a 55-year-old woman presented with episodes of flushing, diarrhea and epigastric pain. Imaging techniques revealed the presence of a metabolically active mass expressing somatostatin receptors in the hilar area of the liver. Histopathological examination confirmed the malignant nature of the mass, which was identified as a poorly differentiated grade 3 pancreatic NEC (TNM staging: T4NxM0). Therapeutic options were limited for the patient because of the extent of the primary mass involving the celiac axis, severe gastrointestinal toxicity experienced as a side effect of chemotherapy with cisplatin-etoposide and, later in the course of the disease, extensive liver metastases and carcinoid heart syndrome. Along with a palliative debulking surgery and right portal vein embolization, biotherapy with a high dose of lanreotide Autogel (120 mg/14 days) contributed to alleviation of symptoms caused by hormone overproduction, even after the development of liver metastases. These results suggest that patients with poorly differentiated NECs who exhibit signs of carcinoid syndrome can benefit from treatment with somatostatin analogs. PMID:24707264

  17. 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.

  18. Predicting survival of pancreatic cancer patients treated with gemcitabine using longitudinal tumour size data.

    PubMed

    Wendling, Thierry; Mistry, Hitesh; Ogungbenro, Kayode; Aarons, Leon

    2016-05-01

    Measures derived from longitudinal tumour size data have been increasingly utilised to predict survival of patients with solid tumours. The aim of this study was to examine the prognostic value of such measures for patients with metastatic pancreatic cancer undergoing gemcitabine therapy. The control data from two Phase III studies were retrospectively used to develop (271 patients) and validate (398 patients) survival models. Firstly, 31 baseline variables were screened from the training set using penalised Cox regression. Secondly, tumour shrinkage metrics were interpolated for each patient by hierarchical modelling of the tumour size time-series. Subsequently, survival models were built by applying two approaches: the first aimed at incorporating model-derived tumour size metrics in a parametric model, and the second simply aimed at identifying empirical factors using Cox regression. Finally, the performance of the models in predicting patient survival was evaluated on the validation set. Depending on the modelling approach applied, albumin, body surface area, neutrophil, baseline tumour size and tumour shrinkage measures were identified as potential prognostic factors. The distributional assumption on survival times appeared to affect the identification of risk factors but not the ability to describe the training data. The two survival modelling approaches performed similarly in predicting the validation data. A parametric model that incorporates model-derived tumour shrinkage metrics in addition to other baseline variables could predict reasonably well survival of patients with metastatic pancreatic cancer. However, the predictive performance was not significantly better than a simple Cox model that incorporates only baseline characteristics.

  19. Combination therapy of gemcitabine or oral S-1 with the anti-VEGF monoclonal antibody bevacizumab for pancreatic neuroendocrine carcinoma.

    PubMed

    Kasuya, Kazuhiko; Nagakawa, Yuichi; Suzuki, Minako; Suzuki, Yoshiaki; Kyo, Bunso; Suzuki, Satoru; Matsudo, Takaaki; Itoi, Takao; Tsuchida, Akihiko; Aoki, Tatsuya

    2012-04-01

    We previously reported that the administration of bevacizumab for pancreatic neuroendocrine tumors inhibited angiogenesis in the host, resulting in tumor growth inhibition. In light of these results, we compared the effect of bevacizumab/gemcitabine/S-1 combination therapy vs. bevacizumab monotherapy. The QGP-1 pancreatic neuroendocrine carcinoma cell line and the BxPC-3 ductal cell carcinoma cell line were transplanted into the subcutaneous tissue of mice, and the mice were treated for 3 weeks with bevacizumab [50 mg/kg intraperitoneally (i.p.) twice weekly], gemcitabine (240 mg/kg i.p. once weekly) and S-1 (10 mg/kg orally five times weekly). The antitumor effect and side effects were evaluated by measuring the tumor volume and weight and by changes in body weight, respectively. The tumor volume became smaller (from the maximum volume) in the group treated with bevacizumab, gemcitabine and S-1 (BGS) and the group treated with bevacizumab and gemcitabine (BG). A significant difference was noted in the tumor weight between the BG group and the group treated with bevacizumab alone. A relatively significant decrease in the body weight was observed in the BGS and BG groups. We conclude that gemcitabine is appropriate as a drug used in combination with bevacizumab for pancreatic neuroendocrine tumors.

  20. Combination therapy of gemcitabine or oral S-1 with the anti-VEGF monoclonal antibody bevacizumab for pancreatic neuroendocrine carcinoma

    PubMed Central

    KASUYA, KAZUHIKO; NAGAKAWA, YUICHI; SUZUKI, MINAKO; SUZUKI, YOSHIAKI; KYO, BUNSO; SUZUKI, SATORU; MATSUDO, TAKAAKI; ITOI, TAKAO; TSUCHIDA, AKIHIKO; AOKI, TATSUYA

    2012-01-01

    We previously reported that the administration of bevacizumab for pancreatic neuroendocrine tumors inhibited angiogenesis in the host, resulting in tumor growth inhibition. In light of these results, we compared the effect of bevacizumab/gemcitabine/S-1 combination therapy vs. bevacizumab monotherapy. The QGP-1 pancreatic neuroendocrine carcinoma cell line and the BxPC-3 ductal cell carcinoma cell line were transplanted into the subcutaneous tissue of mice, and the mice were treated for 3 weeks with bevacizumab [50 mg/kg intraperitoneally (i.p.) twice weekly], gemcitabine (240 mg/kg i.p. once weekly) and S-1 (10 mg/kg orally five times weekly). The antitumor effect and side effects were evaluated by measuring the tumor volume and weight and by changes in body weight, respectively. The tumor volume became smaller (from the maximum volume) in the group treated with bevacizumab, gemcitabine and S-1 (BGS) and the group treated with bevacizumab and gemcitabine (BG). A significant difference was noted in the tumor weight between the BG group and the group treated with bevacizumab alone. A relatively significant decrease in the body weight was observed in the BGS and BG groups. We conclude that gemcitabine is appropriate as a drug used in combination with bevacizumab for pancreatic neuroendocrine tumors. PMID:22969935

  1. A rare case of metastasized non-functional pancreatic neuroendocrine tumor with a good long-term survival

    PubMed Central

    Mirică, A; Bădărău, IA; Mirică, R; Păun, S; Păun, DL

    2016-01-01

    Background: Non-functional neuroendocrine tumors of the pancreas (NF-pNETs) are a varied group of extremely rare malignancies. The majority of patients already have liver metastases at the diagnosis moment, thus, treatment options are restricted, and the survival rate is reserved. Case report: We presented the case of 59-year-old patient, diagnosed with non-functional well-differentiated pancreatic neuroendocrine tumor grade II (NET G2) with the presence of chromogranin A, synaptophysin and somatostatin receptor 2, together with liver and bone metastases. Patient underwent a surgical excision of the pancreatic tumor, started long-acting somatostatin analogues (octreotide), interferon therapy for liver metastases and local radiotherapy for bone metastases. After one year, the patient developed diabetes, needing insulin therapy. At approximately three years after the diagnosis, the patient was still living, had a good quality of life, and was free of local recurrence of the tumor or other metastases. Conclusion: Our case report presented a rare case of metastatic non-functional well-differentiated pancreatic neuroendocrine tumor, involving a multidisciplinary therapeutic approach in order to obtain a good long-term survival. PMID:27928440

  2. A rare case of metastasized non-functional pancreatic neuroendocrine tumor with a good long-term survival.

    PubMed

    A, Mirică; Ia, Bădărău; R, Mirică; S, Păun; Dl, Păun

    2016-01-01

    Background: Non-functional neuroendocrine tumors of the pancreas (NF-pNETs) are a varied group of extremely rare malignancies. The majority of patients already have liver metastases at the diagnosis moment, thus, treatment options are restricted, and the survival rate is reserved. Case report: We presented the case of 59-year-old patient, diagnosed with non-functional well-differentiated pancreatic neuroendocrine tumor grade II (NET G2) with the presence of chromogranin A, synaptophysin and somatostatin receptor 2, together with liver and bone metastases. Patient underwent a surgical excision of the pancreatic tumor, started long-acting somatostatin analogues (octreotide), interferon therapy for liver metastases and local radiotherapy for bone metastases. After one year, the patient developed diabetes, needing insulin therapy. At approximately three years after the diagnosis, the patient was still living, had a good quality of life, and was free of local recurrence of the tumor or other metastases. Conclusion: Our case report presented a rare case of metastatic non-functional well-differentiated pancreatic neuroendocrine tumor, involving a multidisciplinary therapeutic approach in order to obtain a good long-term survival.

  3. Efficacy of endoscopic ultrasonography-guided fine needle aspiration for pancreatic neuroendocrine tumor grading

    PubMed Central

    Sugimoto, Mitsuru; Takagi, Tadayuki; Hikichi, Takuto; Suzuki, Rei; Watanabe, Ko; Nakamura, Jun; Kikuchi, Hitomi; Konno, Naoki; Waragai, Yuichi; Asama, Hiroyuki; Takasumi, Mika; Watanabe, Hiroshi; Obara, Katsutoshi; Ohira, Hiromasa

    2015-01-01

    AIM: To evaluate the efficacy of endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) for grading pancreatic neuroendocrine tumors (PNETs). METHODS: A total of 22 patients were diagnosed with PNET by EUS-FNA between October 2001 and December 2013 at Fukushima Medical University Hospital. Among these cases, we targeted 10 PNET patients who were evaluated according to the World Health Organization (WHO) 2010 classification. Surgery was performed in eight patients, and chemotherapy was performed in two patients due to multiple liver metastases.Specimens obtained by EUS-FNA were first stained with hematoxylin and eosin and then stained with chromogranin, synaptophysin, CD56, and Ki-67. The specimens were graded by the Ki-67 index according to the WHO 2010 classification. Specimens obtained by surgery were graded by the Ki-67 index and mitotic count (WHO 2010 classification). For the eight specimens obtained by EUS-FNA, the Ki-67 index results were compared with those obtained by surgery. In the two cases treated with chemotherapy, the effects and prognoses were evaluated. RESULTS: The sampling rate for histological diagnosis by EUS-FNA was 100%. No adverse effects were observed. The concordance rate between specimens obtained by EUS-FNA and surgery was 87.5% (7/8). For the two cases treated with chemotherapy, case 1 received somatostatin analog therapy and transcatheter arterial infusion (TAI) targeting multiple liver metastases. Subsequent treatment consisted of everolimus. During chemotherapy, the primary tumor remained unconfirmed, although the multiple liver metastases diminished dramatically. Case 2 was classified as neuroendocrine carcinoma (NEC) according to the Ki-67 index of a specimen obtained by EUS-FNA; therefore, cisplatin and irinotecan therapy was started. However, severe adverse effects, including renal failure and diarrhea, were observed, and the therapy regimen was changed to cisplatin and etoposide. TAI targeting multiple liver

  4. Tumour-derived exosomes as a signature of pancreatic cancer - liquid biopsies as indicators of tumour progression.

    PubMed

    Nuzhat, Zarin; Kinhal, Vyjayanthi; Sharma, Shayna; Rice, Gregory E; Joshi, Virendra; Salomon, Carlos

    2017-03-07

    Pancreatic cancer is the fourth most common cause of death due to cancer in the world. It is known to have a poor prognosis, mostly because early stages of the disease are generally asymptomatic. Progress in pancreatic cancer research has been slow, leaving several fundamental questions pertaining to diagnosis and treatment unanswered. Recent studies highlight the putative utility of tissue-specific vesicles (i.e. extracellular vesicles) in the diagnosis of disease onset and treatment monitoring in pancreatic cancer. Extracellular vesicles are membrane-limited structures derived from the cell membrane. They contain specific molecules including proteins, mRNA, microRNAs and non-coding RNAs that are secreted in the extracellular space. Extracellular vesicles can be classified according to their size and/or origin into microvesicles (~150-1000 nm) and exosomes (~40-120 nm). Microvesicles are released by budding from the plasmatic membrane, whereas exosomes are released via the endocytic pathway by fusion of multivesicular bodies with the plasmatic membrane. This endosomal origin means that exosomes contain an abundance of cell-specific biomolecules which may act as a 'fingerprint' of the cell of origin. In this review, we discuss our current knowledge in the diagnosis and treatment of pancreatic cancer, particularly the potential role of EVs in these facets of disease management. In particular, we suggest that as exosomes contain cellular protein and RNA molecules in a cell type-specific manner, they may provide extensive information about the signature of the tumour and pancreatic cancer progression.

  5. Neuroendocrine neoplasms of the small intestine and appendix - management guidelines (recommended by the Polish Network of Neuroendocrine Tumours).

    PubMed

    Bednarczuk, Tomasz; Bolanowski, Marek; Zemczak, Anna; Bałdys-Waligórska, Agata; Blicharz-Dorniak, Jolanta; Boratyn-Nowicka, Agnieszka; Borowska, Małgorzata; Cichocki, Andrzej; Ćwikła, Jarosław B; 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; Londzin-Olesik, Magdalena; Marek, Bogdan; Nasierowska-Guttmejer, Anna; Nowakowska-Duława, Ewa; Pałucki, Jakub; Pilch-Kowalczyk, Joanna; 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; Zgliczyński, Wojciech; Kos-Kudła, Beata

    2017-01-01

    This study presents the revised Polish guidelines regarding the management of patients suffering from neuroendocrine neoplasms (NENs) of the small intestine and appendix. The small intestine, especially the ileum, is the most common location for these neoplasms. Most are well differentiated and slow growing. Their symptoms may be atypical, which can result in delayed or accidental diagnosis. Appendicitis is usually the first manifestation of NEN in this location. Typical symptoms of carcinoid syndrome occur in approximately 20-30% of patients suffering from small intestinal NENs with distant metastases. The main cause of death in patients with carcinoid syndrome is carcinoid heart disease. The most useful laboratory test is the determination of chromogranin A, while concentration of 5-hydroxyindoleacetic acid is helpful in the diagnostics of carcinoid syndrome. For visualisation, ultrasound, computed tomography, magnetic resonance imaging, colonoscopy, video capsule endoscopy, double-balloon enteroscopy, and somatostatin receptor scintigraphy may be used. A detailed his-tological report is crucial for the proper diagnostics and therapy of NENs of the small intestine and appendix. The treatment of choice is surgical management, either radical or palliative. The pharmacological treatment of the hormonally active and non-active small intestinal NENs as well as NENs of the appendix is based on long-acting somatostatin analogues. In patients with generalised NENs of the small intestine in progress during the SSA treatment, with good expression of somatostatin receptors, the first-line treatment should be radio-isotope therapy, while targeted therapies, such as everolimus, should be considered afterwards. When the above therapies are exhausted, in certain cases chemotherapy may be considered.

  6. Expression of gremlin 1 correlates with increased angiogenesis and progression-free survival in patients with pancreatic neuroendocrine tumors.

    PubMed

    Chen, Ming-Huang; Yeh, Yi-Chen; Shyr, Yi-Ming; Jan, Yi-Hua; Chao, Yee; Li, Chung-Pin; Wang, Shin-E; Tzeng, Cheng-Hwai; Chang, Peter Mu-Hsin; Liu, Chun-Yu; Chen, Ming-Han; Hsiao, Michael; Huang, Chi-Ying F

    2013-01-01

    Gremlin 1 (GREM1) is a bone morphogenetic protein antagonist and a novel proangiogenic factor. Our aim was to evaluate the prognostic value of GREM1 expression and GREM1-related factors in tumor-associated angiogenesis in pancreatic neuroendocrine tumors (NETs). The immunohistochemical expression of GREM1 and microvessel density (MVD) were examined in 35 patients with pancreatic NETs and then compared with other clinicopathologic characteristics, including the World Health Organization classification. The presence of expression of GREM1 (p = 0.016) and high MVD (p = 0.020) were significant and favorable prognostic factors. Moreover, GREM1 expression was significantly associated with high MVD (p = 0.011). MVD was significantly higher in well-differentiated NETs than in well-differentiated or poorly differentiated neuroendocrine carcinomas (p < 0.001). GREM1 expression was correlated with tumor-associated angiogenesis and was found to be a novel prognostic marker in pancreatic NETS. Our data support a tumor suppressor role of GREM1 in pancreatic NETs.

  7. 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.

  8. Targeting Focal Adhesion Kinase and Resistance to mTOR Inhibition in Pancreatic Neuroendocrine Tumors

    PubMed Central

    François, Rony A.; Maeng, Kyungah; Nawab, Akbar; Kaye, Frederic J.; Hochwald, Steven N.; Zajac-Kaye, Maria

    2015-01-01

    Background: Focal adhesion kinase (FAK) mediates survival of normal pancreatic islets through activation of AKT. Upon malignant transformation of islet cells into pancreatic neuroendocrine tumors (PanNETs), AKT is frequently overexpressed and mutations in the AKT/mTOR pathway are detected. Because mTOR inhibitors rarely induce PanNET tumor regression, partly because of feedback activation of AKT, novel combination strategies are needed to target FAK/AKT/mTOR signaling. Methods: We characterized the activation of FAK in PanNETs using immunohistochemistry and Western blot analysis and tested the FAK inhibitor PF-04554878 in human PanNET cells in vitro and in vivo (at least three mice per group). In addition, we evaluated the effect of combined FAK and mTOR inhibition on PanNET viability and apoptosis. All statistical tests were two-sided. Results: We found that FAK is overexpressed and hyperphosphorylated in human PanNETs and that PF-04554878 strongly inhibited FAK (Tyr397) autophosphorylation in a dose-dependent manner. We found that PF-04554878 inhibited cell proliferation and clonogenicity and induced apoptosis in PanNET cells. Moreover, oral administration of PF-04554878 statistically significantly reduced tumor growth in a patient-derived xenograft model of PanNET (P = .02) and in a human PanNET xenograft model of peritoneal carcinomatosis (P = .03). Importantly, PF-04554878 synergized with the mTOR inhibitor everolimus by preventing feedback AKT activation. Conclusions: We demonstrate for the first time that FAK is overexpressed in PanNETs and that inhibition of FAK activity induces apoptosis and inhibits PanNET proliferation. We found that the novel FAK inhibitor PF-04554878 synergizes with everolimus, a US Food and Drug Administration–approved agent for PanNETs. Our findings warrant the clinical investigation of combined FAK and mTOR inhibition in PanNETs. PMID:25971297

  9. 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

    2017-06-29

    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.

  10. Epidrug-induced upregulation of functional somatostatin type 2 receptors in human pancreatic neuroendocrine tumor cells.

    PubMed

    Veenstra, Marije J; van Koetsveld, Peter M; Dogan, Fadime; Farrell, William E; Feelders, Richard A; Lamberts, Steven W J; de Herder, Wouter W; Vitale, Giovanni; Hofland, Leo J

    2016-05-19

    Somatostatin receptors are a pivotal target for treatment of pancreatic neuroendocrine tumors (pNET), either with somatostatin analogues (SSA) or radiolabeled SSA. The highest affinity target for the most commonly used SSA is the somatostatin receptor type 2 (sst2). An important factor that may complicate treatment efficacy, is the variable number of receptors expressed on pNETs. Gene expression is subject to complex regulation, in which epigenetics has a central role. In this study we explored the possible role of epigenetic modifications in the variations in sst2 expression levels in two human pNET cell lines, BON-1 and QGP-1. We found upregulation of sst2 mRNA after treatment with the epidrugs 5-aza-2'-deoxycytidine (5-aza-dC) and valproic acid (VPA), an increased uptake of radiolabeled octreotide, as well as increased sensitivity to the SSA octreotide in functional cAMP inhibition. At epigenetic level we observed low methylation levels of the sst2 gene promoter region irrespective of expression. Activating histone mark H3K9Ac can be regulated with epidrug treatment, with an angle of effect corresponding to the effect on mRNA expression. Repressive histone mark H3K27me3 is not regulated by either 5-aza-dC or VPA. We conclude that epidrug treatment, in particular with combined 5-aza-dC and VPA treatment, might hold promise for improving and adding to current SSA treatment strategies of patients with pNETs.

  11. Targeted Therapies Provide Treatment Options for Poorly Differentiated Pancreatic Neuroendocrine Carcinomas.

    PubMed

    Gilabert, Marine; Rho, Young Soo; Kavan, Petr

    2017-01-01

    Poorly differentiated pancreatic neuroendocrine carcinoma (PD pNECs) is a rare disease that has a poor prognosis and is treated with systemic chemotherapy as the standard of care. We present 6 cases of chemo-naïve patients diagnosed with PD pNECs who refused systemic chemotherapy and received targeted therapies with sunitinib (37.5 mg/day, 5 patients) or the mammalian target of rapamycin (mTOR) inhibitor everolimus (10 mg/day, 1 patient) as the first-line treatment. We evaluated the drugs' toxicities and survival. The median age of the patients was 55 years (4 males, 2 females, functioning tumor in 1 of 6 patients). The median of the Ki67 index was 45% (range 20-80). Targeted therapies were combined with somatostatin analogues in 4 of 6 patients (30 mg Sandostatine LAR monthly). Toxicities (acute and late) were manageable and no toxicities necessitated cessation of treatment. All patients had progression-free survival during the 15-month treatment and an overall survival of more than 2 years after diagnosis. Even though this is a small cohort of selected patients, we conclude that sunitinib or everolimus are both feasible and safe and have encouraging results of efficacy as first-line therapies for PD pNEC.

  12. 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.

  13. Digital Subtraction of Magnetic Resonance Images Improves Detection and Characterization of Pancreatic Neuroendocrine Neoplasms.

    PubMed

    De Robertis, Riccardo; Tinazzi Martini, Paolo; Cingarlini, Sara; Ortolani, Silvia; Butturini, Giovanni; Regi, Paolo; Landoni, Luca; Tortora, Giampaolo; Pederzoli, Paolo; D'Onofrio, Mirko

    The aim of this study was to evaluate the usefulness of digital image subtraction of contrast-enhanced magnetic resonance (MR) images for detection and characterization of pancreatic neuroendocrine neoplasms (PanNENs). Magnetic resonance examinations of 50 histologically verified PanNENs were retrospectively evaluated by 2 radiologists; 50 ductal adenocarcinomas were included as a control group. Late arterial phase images and correspondent subtracted images were analyzed. Tumor detectability on a subjective 3-point scale and contrast-to-noise ratios were compared across sequences using paired Student t tests. Tumor signal intensity was compared between sequences using χ or Fisher exact tests. Subjective conspicuity and contrast-to-noise ratios of PanNENs were significantly higher on subtracted images compared with correspondent late arterial phase images (P < 0.001 and P = 0.002). The rate of clearly hyperenhancing PanNENs was higher on subtracted images compared with arterial phase images (76% vs 36%). Digital image subtraction improves tumor conspicuity and allows better characterization of PanNENs compared with late arterial phase images.

  14. Perfusion CT Changes in Liver Metastases from Pancreatic Neuroendocrine Tumors During Everolimus Treatment.

    PubMed

    D'Onofrio, Mirko; Cingarlini, Sara; Ortolani, Silvia; Crosara, Stefano; DE Robertis, Riccardo; Vallerio, Paola; Grego, Elisabetta; Ciaravino, Valentina; Ruzzenente, Andrea; Landoni, Luca; Scarpa, Aldo; Bassi, Claudio; Tortora, Giampaolo

    2017-03-01

    To evaluate modifications of perfusional parameters assessed by perfusion computed tomography (P-CT) of liver metastases (LM) from pancreatic neuroendocrine tumors (PanNETs) during everolimus treatment. All patients with LMs from G1-2 PanNETs undergoing everolimus treatment between January 2013 and January 2015 were prospectively evaluated with P-CT at baseline, and after 2 and 4 months of therapy. Size, perfusion, blood volume (BV), peak enhancement intensity (PEI) and time to peak for each lesion were calculated. A total of 33 LMs in nine patients with G1-2 PanNETs were prospectively evaluated: 23/33 (69.7%) were responders, 10/33 (30.3%) were non-responders. Among perfusional parameters, only numerical peak enhancement intensity values significantly differed between the two groups at baseline (p=0.043). BV increase was the most significant perfusional modification identifying responding lesions, even at an early stage of treatment, with a high positive predictive value (89.47%). P-CT seems to be useful for prediction of response to everolimus of LMs from PanNETs. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  15. Pancreatic Neuroendocrine Tumors: Computed Tomography Enhancement, But Not Histological Grade, Correlates With Tumor Aggression.

    PubMed

    Yano, Motoyo; Misra, Sunil; Carpenter, Danielle H; Salter, Amber; Hildebolt, Charles F

    2017-09-19

    The aims of this study were to assess computed tomography enhancement of pancreatic neuroendocrine tumors (NETs), determine correlation with histological vascularity and fibrosis, and identify a biomarker for tumor aggression. The arterial and venous enhancement of NET was calculated on computed tomography for 56 patients. Tumor size and vascularity/fibrosis were assessed. Tumor aggression was grouped by World Health Organization and Hochwald grade and the presence of metastases. Variables were assessed for correlation. Groups were compared using t test/Wilcoxon rank sum test. Arterial enhancement and dynamic washout (r = 0.35, P = 0.02; r = 0.34, P = 0.02, respectively) correlate with vascularity. There is inverse correlation between vascularity and fibrosis (r = -0.62, P < 0.001), but no correlation between enhancement and fibrosis. Metastatic NET had less arterial (mean, -2 [standard deviationi {SD}, 27.1] Hounsfield unit [HU]; 35.7 [SD, 57.5] HU; P = 0.01) and venous (12.6 [SD, 14.4] HU; 29.2 [SD, 38.3] HU; P = 0.04) enhancement and less washout (8.5 [SD, 18.5] HU; 26.8 [SD, 30] HU, P = 0.02) compared with nonmetastatic NET. These differences were not present when comparing by tumor grade. Arterial hypoenhancement was the only significant predictor of metastases. Aggressive tumors, as determined by metastases, but not histological grade, enhance less than nonmetastatic tumors.

  16. Pancreatic neuroendocrine tumor and solid-pseudopapillary neoplasm: Key immunohistochemical profiles for differential diagnosis

    PubMed Central

    Ohara, Yusuke; Oda, Tatsuya; Hashimoto, Shinji; Akashi, Yoshimasa; Miyamoto, Ryoichi; Enomoto, Tsuyoshi; Satomi, Kaishi; Morishita, Yukio; Ohkohchi, Nobuhiro

    2016-01-01

    AIM To reveal better diagnostic markers for differentiating neuroendocrine tumor (NET) from solid-pseudopapillary neoplasm (SPN), focusing primarily on immunohistochemical analysis. METHODS We reviewed 30 pancreatic surgical specimens of NET (24 cases) and SPN (6 cases). We carried out comprehensive immunohistochemical profiling using 9 markers: Synaptophysin, chromogranin A, pan-cytokeratin, E-cadherin, progesterone receptor, vimentin, α-1-antitrypsin, CD10, and β-catenin. RESULTS E-cadherin staining in NETs, and nuclear labeling of β-catenin in SPNs were the most sensitive and specific markers. Dot-like staining of chromogranin A might indicate the possibility of SPNs rather than NETs. The other six markers were not useful because their expression overlapped widely between NETs and SPNs. Moreover, two cases that had been initially diagnosed as NETs on the basis of their morphological features, demonstrated SPN-like immunohistochemical profiles. Careful diagnosis is crucial as we actually found two confusing cases showing disagreement between the tumor morphology and immunohistochemical profiles. CONCLUSION E-cadherin, chromogranin A, and β-catenin were the most useful markers which should be employed for differentiating between NET and SPN. PMID:27784972

  17. 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.

  18. Identification and Characterization of Poorly Differentiated Invasive Carcinomas in a Mouse Model of Pancreatic Neuroendocrine Tumorigenesis

    PubMed Central

    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. PMID:23691228

  19. A case of pancreatic neuroendocrine tumor in a patient with neurofibromatosis-1

    PubMed Central

    2012-01-01

    Patients with neurofibromatosis-1 (NF-1) sometime develop neuroendocrine tumors (NET). Although these NETs usually occur in the duodenum or peri-ampullary region, they occasionally grow in the pancreas (PNET). A 62-year-old man with NF-1 had mild liver dysfunction and was admitted to our hospital for further examination. An abdominal contrast-enhanced computed tomography scan demonstrated a 30-mm tumor in the head of the pancreas. The scan showed an invasion of the tumor into the duodenum, and biopsy under an endoscopic ultrasonography indicated that the tumor was a NET. A subtotal stomach-preserving pancreaticoduodenectomy was performed. Macroscopically, the pancreatic tumor was white and elastic hard. Microscopically, tumor cells were composed of ribbons, cords, and solid nests with an acinus-like structure. The tumor was diagnosed as NET G2 according to the WHO classification (2010). The product of theNF-1 gene, i.e., neurofibromin, was weakly positive in the tumor cells, suggesting that the tumor was induced by a mutation in the NF-1 gene. This is the seventh case of PNET arising in NF-1 patients worldwide. PMID:22824559

  20. Cixutumumab, Everolimus, and Octreotide Acetate in Treating Patients With Advanced Low to Intermediate Grade Neuroendocrine Carcinoma

    ClinicalTrials.gov

    2016-07-14

    Gastrin-Producing Neuroendocrine Tumor; Lung Carcinoid Tumor; Metastatic Digestive System Neuroendocrine Tumor G1; Pancreatic Glucagonoma; Pancreatic Insulinoma; Pancreatic Polypeptide Tumor; Paraganglioma; Recurrent Digestive System Neuroendocrine Tumor G1; Recurrent Merkel Cell Carcinoma; Recurrent Pancreatic Neuroendocrine Carcinoma; Regional Digestive System Neuroendocrine Tumor G1; Somatostatin-Producing Neuroendocrine Tumor; Stage III Merkel Cell Carcinoma; Stage IV Merkel Cell Carcinoma; Thyroid Gland Medullary Carcinoma

  1. The prognostic influence of the proliferative discordance in metastatic pancreatic neuroendocrine carcinoma revealed by peptide receptor radionuclide therapy

    PubMed Central

    Montanier, Nathanaëlle; Joubert-Zakeyh, Juliette; Pétorin, Caroline; Montoriol, Pierre François; Maqdasy, Salwan; Kelly, Antony

    2017-01-01

    Abstract Rationale: Pancreatic neuroendocrine tumors (pNET) are rare slowly growing tumors with a high metastatic potential. Peptide receptor radionuclide therapy (PRRT) with radiolabeled analogues has been developed as a new tool for the management of metastatic well-differentiated (grade 1 and 2) neuroendocrine tumors expressing somatostatin receptor (SSTR2). Chemotherapy is the mainstay in the management of grade 3 (G3) unresectable pancreatic neuroendocrine carcinoma (pNEC). To date, no study has evaluated the efficacy of PRRT in such tumors. Diagnoses and interventions: We describe a case of a progressive G3 pNEC with huge liver metastases successfully treated with PRRT (177Lu DOTATATE). Outcomes: Complete remission was obtained for 3 years. Indeed, the mitotic index was low (as G2 tumors) but with a very high Ki-67 index (45%–70%). Such discordance between the proliferative markers should consider the use of PRRT before chemotherapy in unresectable metastatic G3 tumors expressing SSTR2. Lessons: This case supports the hypotheses highlighting the heterogeneity of G3 pNEC. The latter should be subdivided into 2 distinct categories: proliferation-discordant (well differentiated) and concordant (poorly differentiated) NEC. PRRT could be suggested for the former group before the conventional chemotherapy. PMID:28178157

  2. p53 status determines the role of autophagy in pancreatic tumour development

    NASA Astrophysics Data System (ADS)

    Rosenfeldt, Mathias T.; O'Prey, Jim; Morton, Jennifer P.; Nixon, Colin; Mackay, Gillian; Mrowinska, Agata; Au, Amy; Rai, Taranjit Singh; Zheng, Liang; Ridgway, Rachel; Adams, Peter D.; Anderson, Kurt I.; Gottlieb, Eyal; Sansom, Owen J.; Ryan, Kevin M.

    2013-12-01

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

  3. Pancreatic neuroendocrine neoplasms at magnetic resonance imaging: comparison between grade 3 and grade 1/2 tumors

    PubMed Central

    Guo, Chuangen; Chen, Xiao; Xiao, Wenbo; Wang, Qidong; Sun, Ke; Wang, Zhongqiu

    2017-01-01

    Background The grading of pancreatic neuroendocrine neoplasms (PanNENs) is associated with the choice of treatment strategy. The aim of this study is to identify the magnetic resonance imaging (MRI) features in differentiating pancreatic neuroendocrine tumors (PanNETs) grade 1/2 (G1/G2) and pancreatic neuroendocrine carcinoma grade 3 (PanNEC G3). Patients and methods A total of 59 patients with histologically proven PanNENs and who underwent pretreatment MRI were retrospectively analyzed. Tumor location, size, boundary, cystic or solid appearance, enhancement degree, pancreatic duct dilatation, metastases and MRI signal were evaluated. Apparent diffusion coefficients (ADCs) were measured on ADC maps. Receiver operating characteristic curve was used to determine the cut off values and the sensitivity and specificity of prediction. Spearman correlation and logistic regression analysis were adopted to identify the association between MRI features and pathological parameters. Results A total of 47 lesions were PanNETs G1/G2 and 12 lesions were PanNEC G3. G1/G2 tumors were more common with well-circumscribed border compared with PanNEC G3. Ill- defined boundary, big size, necrosis, low-moderate enhancement, pancreatic duct dilatation, metastases and high diffusion-weighted imaging (DWI) intensity were more common in PanNEC G3 than in PanNETs G1/G2. The ADC values of PanNEC G3 were also significantly lower compared with the PanNETs G1/G2 and normal pancreatic parenchyma. The cut off value of ADC was 0.95×10−3 mm2/s for differentiating PanNEC G3 from PanNETs G1/G2 with 72.3% sensitivity and 91.6% specificity, respectively. Ki-67 index and mitosis count positively correlated with tumor size, pancreatic duct dilatation and metastases (P<0.05) and negatively correlated with ADC values (P<0.01), respectively. Regression analysis further showed that metastases and ADC value were associated with PanNENs grade. Conclusion Metastases and ADC value may have potential for

  4. Evaluation of the efficacy and safety of lanreotide in combination with targeted therapies in patients with neuroendocrine tumours in clinical practice: a retrospective cross-sectional analysis.

    PubMed

    Capdevila, Jaume; Sevilla, Isabel; Alonso, Vicente; Antón Aparicio, Luís; Jiménez Fonseca, Paula; Grande, Enrique; Reina, Juan José; Manzano, José Luís; Alonso Lájara, Juan Domingo; Barriuso, Jorge; Castellano, Daniel; Medina, Javier; López, Carlos; Segura, Ángel; Carrera, Sergio; Crespo, Guillermo; Fuster, José; Munarriz, Javier; García Alfonso, Pilar

    2015-07-04

    Based on the mechanism of action, combining somatostatin analogues (SSAs) with mTOR inhibitors or antiangiogenic agents may provide synergistic effects for the treatment of patients with neuroendocrine tumours (NETs). Herein, we investigate the use of these treatment combinations in clinical practice. This retrospective cross-sectional analysis of patients with NETs treated with the SSA lanreotide and targeted therapies at 35 Spanish hospitals evaluated the efficacy and safety of lanreotide treatment combinations in clinical practice. The data of 159 treatment combinations with lanreotide in 133 patients was retrospectively collected. Of the 133 patients, with a median age of 59.4 (16-83) years, 70 (52.6%) patients were male, 64 (48.1%) had pancreatic NET, 23 (17.3%) had ECOG PS ≥ 2, 41 (30.8%) had functioning tumours, 63 (47.7%) underwent surgery of the primary tumour, 45 (33.8%) had received prior chemotherapy, and 115 (86.5%) had received prior SSAs. 115 patients received 1 lanreotide treatment combination and 18 patients received between 2 and 5 combinations. Lanreotide was mainly administered in combination with everolimus (73 combinations) or sunitinib (61 combinations). The probability of being progression-free was 78.5% (6 months), 68.6% (12 months) and 57.0% (18 months) for patients who only received everolimus plus lanreotide (n = 57) and 89.3% (6 months), 73.0% (12 months), and 67.4% (18 months) for patients who only received sunitinib and lanreotide (n = 50). In patients who only received everolimus plus lanreotide the median time-to-progression from the initiation of lanreotide combination treatment was 25.8 months (95% CI, 11.3, 40.3) and it had not yet been reached among the subgroup of patients only receiving sunitinib plus lanreotide. The safety profile of the combination treatment was comparable to that of the targeted agent alone. The combination of lanreotide and targeted therapies, mainly everolimus and sunitinib, is widely used in clinical

  5. Molecular strategies and 111in-labelled somatostatin analogues in defining the management of neuroendocrine tumour disease: a new paradigm for surgical management.

    PubMed

    Modlin, I M; Kidd, M; Hinoue, T; Lye, K D; Murren, J; Argiris, A

    2003-06-01

    This manuscript provides a gene-chip examination of gastric ECL cell proliferation in an animal model of neuroendocrine tumour disease. Data that were used to identify molecular targets were then utilised to develop novel therapeutic strategies as appropriate adjuncts to surgery in human disease. Alterations in growth-mediated cell signaling (the AP-1 pathway) and in the cell cycle were identified in ECL cell tumours in the animal model and confirmed in human tumour tissue. The growth-inhibitory somatostatin receptor subtype 2 was identified as a potential clinical target. An investigation of patients with neuroendocrine tumours treated using SSTR2 targeted radiotherapy [111In]pentetreotide producing encouraging preliminary results. Fifty-six per cent of patients with evaluable hormone markers demonstrated stable levels or a significant decrease in one or more measured markers. This data demonstrate that gene pathways recognised to be altered in an animal model of a human disease can be used to identify therapeutic agents. This approach was successfully used to discover novel strategies that can be both effective and appropriate adjuncts to surgery for patients with neuroendocrine tumour disease.

  6. Role of nitric oxide in pancreatic tumour growth: in vivo and in vitro studies.

    PubMed Central

    Hajri, A.; Metzger, E.; Vallat, F.; Coffy, S.; Flatter, E.; Evrard, S.; Marescaux, J.; Aprahamian, M.

    1998-01-01

    Nitric oxide (NO), an endogenous free radical, has been implicated in a wide range of biological functions. NO is generated enzymatically from the terminal guanidinonitrogen of L-arginine by nitric oxide synthase (NOS). Despite intensive investigations, the role of NO--either as the primary product of the L-arginine/NOS pathway or provided from the NO donor sodium nitroprusside (SNP)--in carcinogenesis and tumour cell growth remains unclear and controversial. The objective of this study was to examine the growth effects of NO on a ductal pancreatic adenocarcinoma in the rat and on a human pancreatic tumour cell line (HA-hpc2). In vivo, both SNP and endogenous induction of NO by endotoxins [lipopolysaccharide (LPS)] plus L-arginine significantly reduced the tumour growth. To investigate the mechanisms of NO anti-tumour growth action, the effects of either the SNP or L-arginine/NOS pathway were analysed on the HA-hpc2 cell line. Nitrite/nitrate production, NOS activity and iNOS expression [assessed by reverse transcription-polymerase chain reaction (RT-PCR)] were tested and related to growth (assessed by [3H]thymidine incorporation assay) and apoptosis (assessed by internucleosomal DNA cleavage). SNP exerted a dual effect on tumour cells: stimulation of the proliferation up to 1 mM and inhibition at higher concentrations. These effects were related to NO production. Both proliferative and cytostatic responses were inhibited by NO scavenger 2-phenyl-4,4,5,5-tetramethyl-hemidazoline-1-oxyl3-oxide (carboxy-PTIO). The marked apoptotic DNA fragmentation induced by SNP was also abolished by PTIO association. Unlike macrophages, the human pancreatic tumour cells did not seem to express intrinsically the L-arginine/NOS pathway. Macrophages were activated by HA-hpc2 cells as well as by LPS plus cytokines [interleukin (IL)-1beta plus tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma]. In HA-hpc2/macrophage co-cultures, NOS activity and inducible NOS (i

  7. A case of primary pancreatic non-Hodgkin B-cell lymphoma mimicking autoimmune pancreatitis.

    PubMed

    Anderloni, Andrea; Genco, Chiara; Ballarè, Marco; Carmagnola, Stefania; Battista, Serena; Repici, Alessandro

    2015-06-01

    Non Hodgkin lymphoma frequently involves the gastrointestinal tract, in particular the stomach and the small bowel. Rarely, it can also be a cause of pancreatic masses. Clinical presentation is often non-specific and may overlap with other pancreatic conditions such as carcinoma, neuroendocrine tumours and autoimmune pancreatitis. We report a case of primary pancreatic lymphoma in a young woman with jaundice, fever and abdominal pain mimicking autoimmune pancreatitis. Clinical evaluation included the abdominal Computed Tomography scan, Magnetic Resonance Imaging and an upper gastrointestinal endoscopy that revealed a large duodenal mass. Endoscopic biopsies were performed and eventually histological examination was coherent with a diagnosis of primary pancreatic lymphoma.

  8. Cousins not twins: intra and inter-tumoral heterogeneity in syndromic neuroendocrine tumours.

    PubMed

    Flynn, Aidan; Dwight, Trisha; Benn, Diana; Deb, Siddhartha; Colebatch, Andrew J; Fox, Stephen; Harris, Jessica; Duncan, Emma L; Robinson, Bruce; Hogg, Annette; Ellul, Jason; To, Henry; Duong, Cuong; Miller, Julie A; Yates, Christopher; James, Paul; Trainer, Alison; Gill, Anthony J; Clifton-Bligh, Roderick; Hicks, Rodney J; Tothill, Richard W

    2017-03-31

    Hereditary endocrine neoplasias, including phaeochromocytoma/paraganglioma and medullary thyroid cancer, are caused by autosomal dominant mutations in several familial cancer genes. A common feature of these diseases is the presentation of multiple primary tumours, or multifocal disease representing independent tumour clones that have arisen from the same initiating genetic lesion, but have undergone independent clonal evolution. Such tumours provide an opportunity to discover common co-operative changes required for tumorigenesis, while controlling for the genetic background of the individual. We performed genomic analysis of synchronous and metachronous tumours from five patients bearing germline mutations in the genes SDHB, RET and MAX. Using whole exome sequencing and high-density SNP arrays, we analyzed two to four primary tumours from each patient. We also applied multi-regional sampling, to assess intra-tumoral heterogeneity and clonal evolution, in two cases involving phaeochromocytoma/paraganglioma and medullary thyroid cancer, respectively. Heterogeneous patterns of genomic change existed between synchronous or metachronous tumours, with evidence of branching evolution. We observed striking examples of evolutionary convergence involving the same rare somatic copy-number events in synchronous primary phaeochromocytoma/paraganglioma. Convergent events also occurred during clonal evolution of metastatic medullary thyroid cancer. These observations suggest that genetic or epigenetic changes acquired early within precursor cells, or pre-existing within the genetic background of the individual, create contingencies that determine the evolutionary trajectory of the tumour.

  9. Pancreatic extra-gastrointestinal stromal tumour masquerading as a bleeding duodenal mass

    PubMed Central

    Wegge, Jacqueline; Bartholomew, David M; Burke, Leandra H; Miller, Lisa A

    2012-01-01

    We describe a 55-year-old man presenting to our institution with a gastrointestinal bleed. He was found to have a 5 cm pancreatic extra-gastrointestinal stromal tumours (EGISTs) eroding into the duodenum and ampulla of Vater. Pancreaticoduodenectomy was performed and the tumour was noted to be positive for CD117 and CD34 with six mitotic figures per 50/high-powered field. At 5 months postoperatively he is receiving treatment with imatinib and doing well. To the best of our knowledge, our patient is only the 18th case reported in the literature to date. PMID:23087281

  10. Whole-exome characterization of pancreatic neuroendocrine tumor cell lines BON-1 and QGP-1.

    PubMed

    Vandamme, Timon; Peeters, Marc; Dogan, Fadime; Pauwels, Patrick; Van Assche, Elvire; Beyens, Matthias; Mortier, Geert; Vandeweyer, Geert; de Herder, Wouter; Van Camp, Guy; Hofland, Leo J; Op de Beeck, Ken

    2015-04-01

    The human BON-1 and QGP-1 cell lines are two frequently used models in pancreatic neuroendocrine tumor (PNET) research. Data on the whole-exome genetic constitution of these cell lines is largely lacking. This study presents, to our knowledge, the first whole-exome profile of the BON-1 and QGP-1 cell lines. Cell line identity was confirmed by short tandem repeat profiling. Using GTG-banding and a CytoSNP-12v2 Beadchip array, cell line ploidy and chromosomal alterations were determined in BON-1 and QGP-1. The exomes of both cell lines were sequenced on Ilumina's HiSeq next-generation sequencing (NGS) platform. Single-nucleotide variants (SNVs) and insertions and deletions (indels) were detected using the Genome Analysis ToolKit. SNVs were validated by Sanger sequencing. Ploidy of BON-1 and QGP-1 was 3 and 4 respectively, with long stretches of loss of heterozygosity across multiple chromosomes, which is associated with aggressive tumor behavior. In BON-1, 57 frameshift indels and 1725 possible protein-altering SNVs were identified in the NGS data. In the QGP-1 cell line, 56 frameshift indels and 1095 SNVs were identified. ATRX, a PNET-associated gene, was mutated in both cell lines, while mutation of TSC2 was detected in BON-1. A mutation in NRAS was detected in BON-1, while KRAS was mutated in QGP-1, implicating aberrations in the RAS pathway in both cell lines. Homozygous mutations in TP53 with possible loss of function were identified in both cell lines. Various MUC genes, implicated in cell signaling, lubrication and chemical barriers, which are frequently expressed in PNET tissue samples, showed homozygous protein-altering SNVs in the BON-1 and QGP-1 cell lines.

  11. Everolimus in the treatment of patients with advanced pancreatic neuroendocrine tumors: latest findings and interpretations

    PubMed Central

    Liu, Eric; Marincola, Paula

    2013-01-01

    Pancreatic neuroendocrine tumors (pNETs) are a heterogeneous group of neoplasms with various clinical presentations. More than half of patients present with so-called nonfunctioning tumors with no hormone-related symptoms, whereas other tumors produce symptoms like gastric problems, ulcers, hypoglycemia, skin rash and diarrhea related to hormone production. The traditional treatment for pNETs over the last three decades has been cytotoxic agents, mainly streptozotocin plus 5-fluorouracil or doxorubicin. Most recently two new compounds have been registered worldwide for the treatment of pNETs, the mammalian target of rapamycin (mTOR) inhibitor everolimus and the tyrosine kinase inhibitor sunitinib. This paper concentrates on the use of mTOR inhibitors and the mechanisms of action. The mTOR pathway is altered in a number of pNETs. Everolimus (RAD001) is an orally active rapamycin analog and mTOR inhibitor. It blocks activity of the mTOR pathway by binding with high affinity to the cytoplasmic protein FKBP-12. The efficacy of everolimus in pNETs has been demonstrated in two multicenter studies (RADIANT 1 and 3). The RADIANT 3 study was a randomized controlled study in pNETs of everolimus 10 mg/day versus placebo, showing an increased progression-free survival (11.7 months versus 4.6 months) and hazard ratio of 0.35 (p < 0.001). Current studies indicate that there is strong evidence to support the antitumor effect of rapalogs in pNETs. However, significant tumor reduction is very rarely obtained, usually in less than 10% of treated patients. Therefore, these drugs may be more effective in combination with other anticancer agents, including chemotherapy, targeted therapies as well as peptide receptor radiotherapy. PMID:24003341

  12. Nonfunctioning, small, incidental pancreatic neuroendocrine tumors: Results of a nonoperative approach cohort.

    PubMed

    Uribe Galeano, Catalina; Fabregat Prous, Joan; Busquets Barenys, Juli; Pelaez Serra, Nuria; Secanella Medayo, Lluís; Ramos Rubio, Emilio; Ruiz Osuna, Sandra; Villabona Artero, Carlos

    2017-02-01

    The availability of new imaging techniques has conditioned an increase in the incidental diagnosis of small nonfunctioning pancreatic neuroendocrine tumors (PNET-NF). The best treatment is controversial, some authors advise a conservative approach in selected cases. Our aim is to analyze the evolution of incidental, small size PNET-NF, treated with clinical follow-up without surgery. We performed a retrospective analysis of a prospective database of patients diagnosed incidentally with PNET-NF since November 2007 to September 2015. We include those with PNET-NF ≤2cm and asymptomatic. The diagnosis was performed using imaging tests indicating endoscopic ultrasound-guided fine-needle aspiration in case of doubts in the diagnosis. The follow-up was performed at our center, registering clinical and/or radiological changes. We included 24 patients with a median age of 70 years, and a similar distribution in terms of sex. The diagnosis was made through computed tomography multidetector or magnetic resonance imaging and octreotide scan. The tumors were located mainly in the head and neck (46%), with a mean size of 11,5±3,55mm at diagnosis (5-19mm). In 2 cases endoscopic ultrasound fine needle aspiration was used (8%), confirming the diagnosis of low-grade PNET with Ki67<5%. The median follow-up was 39 months (7-100). In 19 patients (79%) they remained the same size, 21% (5) increased its size with a mean of 2,6±2mm (1-6). No cases had progression of disease. In selected patients, non-surgical management of PNET-NF is an option to consider, when they are asymptomatic and ≤2cm. Larger studies with more patients and more time of follow-up are needed to validate this non-operative approach. Copyright © 2016 AEC. Publicado por Elsevier España, S.L.U. All rights reserved.

  13. 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.

  14. 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

  15. Prediction of survival and tumor recurrence in patients undergoing surgery for pancreatic neuroendocrine neoplasms.

    PubMed

    Kaltenborn, Alexander; Matzke, Svenja; Kleine, Moritz; Krech, Till; Ramackers, Wolf; Vondran, Florian W R; Klempnauer, Jürgen; Bektas, Hüseyin; Schrem, Harald

    2016-02-01

    This study strives to define prognostic models for outcome after surgery for malignant pancreatic neuroendocrine tumors. Forty-one patients were included. Prognostic models for mortality and disease recurrence were developed with multivariate binary logistic regression. The proposed prognostic model for tumor recurrence risk after surgery in percentage (AUROC = 0.774, 95%CI = 0.611-0.937) is: Risk in % = Exp(Y)/(1 + Exp(Y)), with Y = -4.360 + (0.015 × tumor diameter in cm) + (0.010 × preoperative platelet count in thousand/μl) + (1.077 × distant metastases, if yes = 1; if no = 0) + (-0.026 × Ki-67-positive cells in %) + (-1.086 × upper abdominal pain, if yes = 1; if no = 0). The proposed prognostic model for observed 3-year survival probability after surgery in % (AUROC = 0.932, 95%CI = 0.857-0.999) is: Survival probability in % = Exp(Y)/(1 + Exp(Y)), with Y = -12.492 + (0.054 × preoperative platelet count in thousand/μl) + (0.112 × minimal distance of the resection margin from the tumor in mm) + (-1.574 × number of positive lymph nodes) + (2.292 × histological tumor infiltration, if yes = 1; if no = 0) CONCLUSIONS: The platelet count was identified as a relevant risk factor. Proposed prognostic models with good model-fit display properties that indicate potential clinical usefulness. © 2015 Wiley Periodicals, Inc.

  16. Microscopic venous invasion in patients with pancreatic neuroendocrine tumor as a potential predictor of postoperative recurrence.

    PubMed

    Nanno, Yoshihide; Toyama, Hirochika; Otani, Kyoko; Asari, Sadaki; Goto, Tadahiro; Terai, Sachio; Ajiki, Tetsuo; Zen, Yoh; Fukumoto, Takumi; Ku, Yonson

    2016-01-01

    Microscopic venous and lymphatic invasion is a known prognostic factor for various cancers, but its prognostic relevance for pancreatic neuroendocrine tumors (PNETs) is unclear. Thirty-two consecutive patients with PNET who had complete resection were included in this study. Venous and lymphatic invasion was identified on elastic tissue or immunohistochemical staining, and correlated with other clinicopathological factors, including recurrence-free survival. Venous and lymphatic invasion was identified in nine (28%) and three (9%) patients, respectively. Tumors with venous invasion were of significantly larger size, higher Ki-67 index, and higher mitotic counts. Patients with venous invasion showed significantly worse prognosis than those without venous invasion (P = 0.001). Five of nine patients (56%) with venous invasion had tumor recurrence, while a relapse was found in one case in patients without venous invasion (n = 23). Lymphatic invasion was not correlated with any other clinicopathological parameters including lymph node metastasis and recurrence-free survival. Predictive factors for recurrence in univariate analysis included microscopic venous invasion, tumor size ≥ 20 mm, non-functionality, and WHO grades. In multivariate analysis where WHO grades and microscopic venous invasion were applied, venous invasion remained a significant predictor of poor recurrence-free survival (P = 0.021). Microscopic venous invasion may serve as a predictive factor for tumor recurrence in patients with resectable PNET. The combination of WHO grades and microscopic venous invasion may assist in the stratification of the patients for risk of tumor recurrence. Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.

  17. Metastatic Pancreatic Neuroendocrine Tumor that Progressed to Ectopic Adrenocorticotropic Hormone (ACTH) Syndrome with Growth Hormone-releasing Hormone (GHRH) Production

    PubMed Central

    Tadokoro, Rie; Sato, Shotaro; Otsuka, Fumiko; Ueno, Makoto; Ohkawa, Shinichi; Katakami, Hideki; Taniyama, Matsuo; Nagasaka, Shoichiro

    2016-01-01

    The patient was a 61-year-old woman who had a well-differentiated pancreatic neuroendocrine tumor (PNET) with lymph node metastasis. After 15 months of octreotide treatment, glucose control deteriorated and pigmentation of the tongue and moon face developed, leading to the diagnosis of ectopic adrenocorticotropic hormone (ACTH) syndrome. An abnormal secretion of growth hormone (GH) was identified, and the plasma growth hormone-releasing hormone (GHRH) level was elevated. A tumor biopsy specimen positively immunostained for ACTH and GHRH. Ectopic hormone secretion seems to have evolved along with the progression of the PNET. PMID:27746436

  18. Metastatic Pancreatic Neuroendocrine Tumor that Progressed to Ectopic Adrenocorticotropic Hormone (ACTH) Syndrome with Growth Hormone-releasing Hormone (GHRH) Production.

    PubMed

    Tadokoro, Rie; Sato, Shotaro; Otsuka, Fumiko; Ueno, Makoto; Ohkawa, Shinichi; Katakami, Hideki; Taniyama, Matsuo; Nagasaka, Shoichiro

    The patient was a 61-year-old woman who had a well-differentiated pancreatic neuroendocrine tumor (PNET) with lymph node metastasis. After 15 months of octreotide treatment, glucose control deteriorated and pigmentation of the tongue and moon face developed, leading to the diagnosis of ectopic adrenocorticotropic hormone (ACTH) syndrome. An abnormal secretion of growth hormone (GH) was identified, and the plasma growth hormone-releasing hormone (GHRH) level was elevated. A tumor biopsy specimen positively immunostained for ACTH and GHRH. Ectopic hormone secretion seems to have evolved along with the progression of the PNET.

  19. Development of single vial kits for preparation of (68)Ga-labelled peptides for PET imaging of neuroendocrine tumours.

    PubMed

    Mukherjee, Archana; Pandey, Usha; Chakravarty, Rubel; Sarma, Haladhar Dev; Dash, Ashutosh

    2014-08-01

    The present work was aimed at the formulation and evaluation of freeze-dried kits of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-peptides for the preparation of (68)Ga-labelled peptides for PET imaging of neuroendocrine tumours. The (68)GaCl3 was obtained from the locally produced nanoceria-PAN, composite-sorbent-based (68)Ge/(68)Ga generator. Single vial kits of somatostatin analogues DOTA-[Tyr(3)]-octreotide (DOTA-TOC), DOTA-[NaI(3)]-octreotide (DOTA-NOC) and DOTA-Tyr(3)-Thre(8)-octreotide (DOTA-TATE) were formulated. Optimization of radiolabelling with (68)Ga from the in-house generator, characterization, long term evaluation of stability of kits and bioevaluation studies in animals was carried out. DOTA-TOC, DOTA-NOC and DOTA-TATE kits could be successfully formulated. Consistently high radiochemical yields (>95 %) were obtained on radiolabelling with (68)Ga. The radiolabelled peptides exhibited excellent in vitro stability. Biodistribution studies in normal non-tumour bearing Swiss mice revealed fast clearance of activity via renal route as reported for the respective peptides. Availability of ready to use DOTA-peptide kits in conjunction with (68)Ge/(68)Ga generators would pave way for the establishment of (68)Ga radiopharmacy, a long-felt need of the nuclear medicine community.

  20. Periampullary mass--a rare presentation of poorly differentiated neuroendocrine cancer of duodenum in a young adult: a case report and review of literature.

    PubMed

    Singh, Neha; Nayak, Hemanta K; Bagchi, Avishek; Kar, Premashis

    2012-10-09

    Poorly differentiated neuroendocrine tumour in the periampullary region of the duodenum is a rare entity. This entity usually present in old men. Here we report a periampullary poorly differentiated neuroendocrine cancer (PDEC) of duodenum presenting in a young man with subacute history of jaundice, abdominal pain, pancreatitis and constitutional symptoms. MRI localised the tumour and endoscopy-guided biopsy of the lesion proved the diagnosis. Although palliative surgery and chemotherapy were planned, the patient opted to leave against medical advice.

  1. Clinical features of gastroenteropancreatic tumours

    PubMed Central

    Czarnywojtek, Agata; Bączyk, Maciej; Ziemnicka, Katarzyna; Fischbach, Jakub; Wrotkowska, Elżbieta; Ruchała, Marek

    2015-01-01

    Gastroenteropancreatic (GEP) endocrine tumours (carcinoids and pancreatic islet cell tumours) are composed of multipotent neuroendocrine cells that exhibit a unique ability to produce, store, and secrete biologically active substances and cause distinct clinical syndromes. The classification of GEP tumours as functioning or non-functioning is based on the presence of symptoms that accompany these syndromes secondary to the secretion of hormones, neuropeptides and/or neurotransmitters (functioning tumours). Non-functioning tumours are considered to be neoplasms of neuroendocrine differentiation that are not associated with obvious symptoms attributed to the hypersecretion of metabolically active substances. However, a number of these tumours are either capable of producing low levels of such substances, which can be detected by immunohistochemistry but are insufficient to cause symptoms related to a clinical syndrome, or alternatively, they may secrete substances that are either metabolically inactive or inappropriately processed. In some cases, GEP tumours are not associated with the production of any hormone or neurotransmitter. Both functioning and non-functioning tumours can also produce symptoms due to mass effects compressing vital surrounding structures. Gastroenteropancreatic tumours are usually classified further according to the anatomic site of origin: foregut (including respiratory tract, thymus, stomach, duodenum, and pancreas), midgut (including small intestine, appendix, and right colon), and hindgut (including transverse colon, sigmoid, and rectum). Within these subgroups the biological and clinical characteristics of the tumours vary considerably, but this classification is still in use because a significant number of previous studies, mainly observational, have used it extensively. PMID:26516377

  2. Solid pseudopapillary epithelial neoplasm--a rare but curable pancreatic tumour in young women.

    PubMed

    Frost, M; Krige, J E J; Bornman, P C; Panieri, E; Beningfield, S J; Wainwright, H

    2011-04-01

    Solid pseudopapillary epithelial neoplasms (SPENs) of the pancreas are rare but curable tumours that have a low-grade malignant potential and occur almost exclusively in young women, with an excellent prognosis after complete resection. This study examines the clinicopathological characteristics of these tumours and evaluates the role of surgery in relation to their size and location. We reviewed the pre-, intra- and postoperative data on 21 patients with SPENs who underwent resection during a 30-year period. Data including demographic information, presenting symptoms and signs, extent of operation, histology, tumour markers and postoperative complications were evaluated to establish the optimal surgical management. All 21 tumours occurred in women (mean age 24.6 years, range 13-51 years). Sixteen patients presented with nonspecific abdominal complaints and a palpable abdominal mass, in 1 patient the tumour was found during emergency laparotomy for a complicated ovarian cyst, 1 patient presented with severe abdominal pain and shock due to a ruptured tumour, and in 3 patients the tumour was detected incidentally during imaging. The correct pre-operative diagnosis of SPEN was made in 10 patients. Incorrect preoperative diagnoses included hydatid cyst (3 patients), mesenteric cyst (2), pancreatic cystadenoma (2), ovarian cysts (1), islet cell tumour of the pancreas (1), and cavernous haemangioma of the liver (1). The mean diameter of the tumours was 12.5 cm (range 8 - 20 cm), and they occurred in the head (8), neck (5), body (2), and tail (6) of the pancreas. All SPENs were resected. Five patients had a pylorus-preserving pancreaticoduodenectomy, 4 a central pancreatectomy with distal pancreaticogastrostomy, 8 a distal pancreatectomy, 3 a local resection and one a total pancreatectomy and portal vein graft. In 1 patient, 2 liver metastases were resected in addition to the pancreatic primary tumour. The patient who presented in shock with tumour rupture and bleeding

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

    PubMed Central

    Khoja, L; Backen, A; Sloane, R; Menasce, L; Ryder, D; Krebs, M; Board, R; Clack, G; Hughes, A; Blackhall, F; Valle, J W; Dive, C

    2012-01-01

    Background: Obtaining tissue for pancreatic carcinoma diagnosis and biomarker assessment to aid drug development is challenging. Circulating tumour cells (CTCs) may represent a potential biomarker to address these unmet needs. We compared prospectively the utility of two platforms for CTC enumeration and characterisation in pancreatic cancer patients in a pilot exploratory study. Patients and methods: Blood samples were obtained prospectively from 54 consenting patients and analysed by CellSearch and isolation by size of epithelial tumour cells (ISET). CellSearch exploits immunomagnetic capture of CTCs-expressing epithelial markers, whereas ISET is a marker independent, blood filtration device. Circulating tumour cell expression of epithelial and mesenchymal markers was assessed to explore any discrepancy in CTC number between the two platforms. Results: ISET detected CTCs in more patients than CellSearch (93% vs 40%) and in higher numbers (median CTCs/7.5 ml, 9 (range 0–240) vs 0 (range 0–144)). Heterogeneity observed for epithelial cell adhesion molecule, pan-cytokeratin (CK), E-Cadherin, Vimentin and CK 7 expression in CTCs may account for discrepancy in CTC number between platforms. Conclusion: ISET detects more CTCs than CellSearch and offers flexible CTC characterisation with potential to investigate CTC biology and develop biomarkers for pancreatic cancer patient management. PMID:22187035

  4. Tumour budding is a strong and independent prognostic factor in pancreatic cancer.

    PubMed

    Karamitopoulou, E; Zlobec, I; Born, D; Kondi-Pafiti, A; Lykoudis, P; Mellou, A; Gennatas, K; Gloor, B; Lugli, A

    2013-03-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer that escapes detection and resists treatment. Tumour budding, defined as the presence of de-differentiated single tumour cells or small cell clusters at the invasive front of gastrointestinal carcinomas like colorectal, oesophageal, gastric and ampullary, is linked to adverse prognosis. Tumour budding has not yet been reported in PDAC. To assess the frequency and prognostic impact of tumour budding in PDAC. Whole-tissue sections of 117 PDACs with full clinico-pathological and follow-up information, including postoperative therapy, were stained using a pancytokeratin marker. Tumour budding was assessed in 10 high-power fields (HPFs) by two pathologists. High-grade budding was defined as an average of >10buds across 10HPFs. Measurements were correlated to patient and tumour characteristics. The study was performed according to the REMARK guidelines. Inter-observer agreement was considered strong (ICC=0.72). Low-grade budding was observed in 29.7% and high-grade budding in 70.3% cases. High-grade budding was linked to advanced pT classification (p=0.0463), lymphatic invasion (p=0.0192) and decreased disease-free (p=0.0005) and overall survival (p<0.0001). There was no association with pN, pM, R-status or blood vessel invasion. In multivariate analysis, the prognostic effect of tumour budding was independent of lymph node metastasis, lymphatic invasion and R-status (p<0.0001; HR (95% CI): 3.65 (2.1-6.4)). Our results show that high-grade tumour budding occurs frequently in PDAC and is a strong, independent and reproducible, highly unfavourable prognostic factor that could be used to guide future individualised therapeutic approaches. Copyright © 2012 Elsevier Ltd. All rights reserved.

  5. Pancreatic neuroendocrine neoplasms: Magnetic resonance imaging features according to grade and stage

    PubMed Central

    De Robertis, Riccardo; Cingarlini, Sara; Tinazzi Martini, Paolo; Ortolani, Silvia; Butturini, Giovanni; Landoni, Luca; Regi, Paolo; Girelli, Roberto; Capelli, Paola; Gobbo, Stefano; Tortora, Giampaolo; Scarpa, Aldo; Pederzoli, Paolo; D’Onofrio, Mirko

    2017-01-01

    AIM To describe magnetic resonance (MR) imaging features of pancreatic neuroendocrine neoplasms (PanNENs) according to their grade and tumor-nodes-metastases stage by comparing them to histopathology and to determine the accuracy of MR imaging features in predicting their biological behavior. METHODS This study was approved by our institutional review board; requirement for informed patient consent was waived due to the retrospective nature of the study. Preoperative MR examinations of 55 PanNEN patients (29 men, 26 women; mean age of 57.6 years, range 21-83 years) performed between June 2013 and December 2015 were reviewed. Qualitative and quantitative features were compared between tumor grades and stages determined by histopathological analysis. RESULTS Ill defined margins were more common in G2-3 and stage III-IV PanNENs than in G1 and low-stage tumors (P < 0.001); this feature had high specificity in the identification of G2-3 and stage III-IV tumors (90.3% and 96%, 95%CI: 73.1-97.5 and 77.7-99.8). The mean apparent diffusion coefficient value was significantly lower in G2-3 and stage III-IV lesions compared to well differentiated and low-stage tumors (1.09 × 10-3 mm2/s vs 1.45 × 10-3 mm2/s and 1.10 × 10-3 mm2/s vs 1.53 × 10-3 mm2/s, P = 0.003 and 0.001). Receiving operator characteristic analysis determined optimal cut-offs of 1.21 and 1.28 × 10-3 mm2/s for the identification of G2-3 and stage III-IV tumors, with sensitivity and specificity values of 70.8/80.7% and 64.5/64% (95%CI: 48.7-86.6/60-92.7 and 45.4-80.2/42.6-81.3). CONCLUSION MR features of PanNENs vary according to their grade of differentiation and their stage at diagnosis and could predict the biological behavior of these tumors. PMID:28127201

  6. Pancreatic neuroendocrine tumors: correlation between histogram analysis of apparent diffusion coefficient maps and tumor grade.

    PubMed

    Pereira, Jose Antonio Sousa; Rosado, Elsa; Bali, Maria; Metens, Thierry; Chao, Shih-Li

    2015-10-01

    To explore the role of histogram analysis of apparent diffusion coefficient (ADC) MRI maps based on entire tumor volume data in determining pancreatic neuroendocrine tumor (PNT) grade. Retrospective evaluation of 22 patients with PNTs included low-grade (G1; n = 15), intermediate-grade (G2; n = 4), and high-grade (G3; n = 3) tumors. Regions of interest containing the lesion were drawn on every section of the ADC map containing the tumor and summated to obtain histograms for entire tumor volume. Calculated histographic parameters included mean ADC (mADC), 5th percentile ADC, 10th percentile ADC, 25th percentile ADC, 50th percentile ADC, 75th percentile ADC (ADC75), 90th percentile ADC (ADC90) and 95th percentile ADC (ADC95), skewness and kurtosis. Histogram parameters were correlated with tumor grade by repeated measures analysis of variance with Tukey-Kramer post hoc comparisons. The mADC, ADC75, ADC90, and ADC95 were significantly higher in G1 tumors (1283 ± 267; 1404 ± 300; 1495 ± 318; 1562 ± 347 × 10(-6) mm(2)/s) compared to G2 (892 ± 390; 952 ± 381; 1036 ± 384; 1072 ± 374 × 10(-6) mm(2)/s) and to G3 tumors (733 ± 225; 864 ± 284; 1008 ± 288; 1152 ± 192 × 10(-6) mm(2)/s) (p value <0.05). Skewness and kurtosis were significantly different between G1 (0.041 ± 0.466; 2.802 ± 0.679) and G3 (1.01 ± 1.140; 5.963 ± 4.008) tumors (p value <0.05). Tumor volume (mL) was significantly higher on G3 (55 ± 15.7) compared to G1 (1.9 ± 2.7) and G2 (4.5 ± 3.6) tumors (p value <0.05). In this small sample size, we did not detect statistically significant parameters between G2 (n = 4) and G3 (n = 3) tumors. Histographic analysis of ADC maps on the basis of the entire tumor volume can be useful in differentiating histologic grades of PNTs.

  7. Pancreatic Neuroendocrine Tumors With Involved Surgical Margins: Prognostic Factors and the Role of Adjuvant Radiotherapy

    SciTech Connect

    Arvold, Nils D.; Willett, Christopher G.; Fernandez-del Castillo, Carlos; Ryan, David P.; Ferrone, Cristina R.; Clark, Jeffrey W.; Blaszkowsky, Lawrence S.; Deshpande, Vikram; Niemierko, Andrzej; Allen, Jill N.; Kwak, Eunice L.; Wadlow, Raymond C.; Zhu, Andrew X.; Warshaw, Andrew L.; Hong, Theodore S.

    2012-07-01

    Purpose: Pancreatic neuroendocrine tumors (pNET) are rare neoplasms associated with poor outcomes without resection, and involved surgical margins are associated with a worse prognosis. The role of adjuvant radiotherapy (RT) in these patients has not been characterized. Methods and Materials: We retrospectively evaluated 46 consecutive patients with positive or close (<1 mm) margins after pNET resection, treated from 1983 to 2010, 16 of whom received adjuvant RT. Median RT dose was 50.4 Gy in 1.8-Gy fractions; half the patients received concurrent chemotherapy with 5-fluorouracil or capecitabine. No patients received adjuvant chemotherapy. Cox multivariate analysis (MVA) was used to analyze factors associated with overall survival (OS). Results: Median age at diagnosis was 56 years, and 52% of patients were female. Median tumor size was 38 mm, 57% of patients were node-positive, and 11% had a resected solitary liver metastasis. Patients who received RT were more likely to have larger tumors (median, 54 mm vs. 30 mm, respectively, p = 0.002) and node positivity (81% vs. 33%, respectively, p = 0.002) than those not receiving RT. Median follow-up was 39 months. Actuarial 5-year OS was 62% (95% confidence interval [CI], 41%-77%). In the group that did not receive RT, 3 patients (10%) experienced local recurrence (LR) and 5 patients (18%) developed new distant metastases, while in the RT group, 1 patient (6%) experienced LR and 5 patients (38%) developed distant metastases. Of all recurrences, 29% were LR. On MVA, male gender (adjusted hazard ratio [AHR] = 3.81; 95% CI, 1.21-11.92; p = 0.02) and increasing tumor size (AHR = 1.02; 95% CI, 1.01-1.04; p = 0.007) were associated with decreased OS. Conclusions: Long-term survival is common among patients with involved-margin pNET. Despite significantly worse pathologic features among patients receiving adjuvant RT, rates of LR between groups were similar, suggesting that RT might aid local control, and merits further

  8. Long-term outcomes and prognostic factors in 78 Japanese patients with advanced pancreatic neuroendocrine neoplasms: a single-center retrospective study

    PubMed Central

    Lee, Lingaku; Igarashi, Hisato; Fujimori, Nao; Hijioka, Masayuki; Kawabe, Ken; Oda, Yoshinao; Jensen, Robert T.; Ito, Tetsuhide

    2015-01-01

    Objective Despite an increase in the number of Japanese patients with pancreatic neuroendocrine neoplasms, long-term outcomes and prognostic factors, especially for those with advanced disease, remain unclear. Methods We retrospectively reviewed the medical records of 78 patients with unresectable pancreatic neuroendocrine neoplasms treated at our hospital from January 1987 to March 2015. Survival analyses were performed using Kaplan–Meier methods. Prognostic significance of several clinicopathological factors were analyzed by univariate and multivariate analyses using a Cox regression model. Results Median overall survivals of pancreatic neuroendocrine tumor (n = 64) and pancreatic neuroendocrine carcinoma (n = 14) were 83.7 and 9.1 months, respectively (hazard ratio: 0.02, 95% confidence interval: 0.01–0.08, P < 0.001). Although no significant differences were observed using a Ki-67 cut-off value of 2% (hazard ratio: 0.46, 95% confidence interval: 0.16–1.13, P = 0.0989), a Ki-67 cut-off of 10% was a significant predictor in patients with pancreatic neuroendocrine tumor (hazard ratio: 9.95, 95% confidence interval, 3.01–32.97, P < 0.001). Treatment after the advent of targeted therapy (hazard ratio: 0.07, 95% confidence interval: 0.03–0.19, P < 0.001) and the presence of bone metastases (hazard ratio: 4.38, 95% confidence interval: 1.42–11.29, P = 0.013) were significant prognostic factors in patients with pancreatic neuroendocrine tumor evaluated by univariate analysis. Multivariate analysis also revealed that a Ki-67 index ≥10% (hazard ratio: 38.8, 95% confidence interval: 8.42–226.62, P < 0.001), approval of targeted therapy (hazard ratio: 0.02, 95% confidence interval: 0.00–0.11, P < 0.001) and bone metastases (hazard ratio: 5.56, 95% confidence interval: 1.10–24.00, P = 0.039) were independent prognostic factors. Conclusions We elucidated the long-term outcomes and prognostic factors in Japanese patients with advanced pancreatic

  9. Somatostatin-based radiopeptide therapy with [177Lu-DOTA]-TOC versus [90Y-DOTA]-TOC in neuroendocrine tumours.

    PubMed

    Romer, A; Seiler, D; Marincek, N; Brunner, P; Koller, M T; Ng, Q K T; Maecke, H R; Müller-Brand, J; Rochlitz, C; Briel, M; Schindler, C; Walter, M A

    2014-02-01

    Somatostatin-based radiopeptide treatment is generally performed using the β-emitting radionuclides (90)Y or (177)Lu. The present study aimed at comparing benefits and harms of both therapeutic approaches. In a comparative cohort study, patients with advanced neuroendocrine tumours underwent repeated cycles of [(90)Y-DOTA]-TOC or [(177)Lu-DOTA]-TOC until progression of disease or permanent adverse events. Multivariable Cox regression and competing risks regression were employed to examine predictors of survival and adverse events for both treatment groups. Overall, 910 patients underwent 1,804 cycles of [(90)Y-DOTA]-TOC and 141 patients underwent 259 cycles of [(177)Lu-DOTA]-TOC. The median survival after [(177)Lu-DOTA]-TOC and after [(90)Y-DOTA]-TOC was comparable (45.5 months versus 35.9 months, hazard ratio 0.91, 95% confidence interval 0.63-1.30, p = 0.49). Subgroup analyses revealed a significantly longer survival for [(177)Lu-DOTA]-TOC over [(90)Y-DOTA]-TOC in patients with low tumour uptake, solitary lesions and extra-hepatic lesions. The rate of severe transient haematotoxicities was lower after [(177)Lu-DOTA]-TOC treatment (1.4 vs 10.1%, p = 0.001), while the rate of severe permanent renal toxicities was similar in both treatment groups (9.2 vs 7.8%, p = 0.32). The present results revealed no difference in median overall survival after [(177)Lu-DOTA]-TOC and [(90)Y-DOTA]-TOC. Furthermore, [(177)Lu-DOTA]-TOC was less haematotoxic than [(90)Y-DOTA]-TOC.

  10. Genetic polymorphisms of inflammatory response gene TNF-α and its influence on sporadic pancreatic neuroendocrine tumors predisposition risk.

    PubMed

    Karakaxas, Dimitrios; Gazouli, Maria; Coker, Ahmet; Agalianos, Christos; Papanikolaou, Ioannis S; Patapis, Pavlos; Liakakos, Theodoros; Dervenis, Christos

    2014-10-01

    The diagnosed incidence of pancreatic neuroendocrine tumors (pNETs) is increasing; however, their etiology remains poorly understood. PNETs are a rare, heterogeneous group of tumors arising from the endocrine cells of the pancreas, and genetic risk factors for sporadic pNETs are inadequately understood. It is known that pNETs secrete biogenic amines, hormones and growth factors, tumor necrosis factor-a (TNF-α) being one of them. Furthermore, cytokines and other proinflammatory mediators have been implicated in inflammatory pancreatic diseases including pancreatitis and cancer. The aim of our study was to analyze TNF-α promoter gene polymorphisms as risk factors for pNETs using germline DNA collected in a population-based case-control study of pancreatic cancer [42 pNET cases, 78 pancreatic ductal adenocarcinoma (PDAC) cases, 17 intraductal papillary mucinous neoplasm (IPMN) and 98 healthy controls] conducted in the Athens, Greece and Izmir, Turkey areas. For subsequent analysis, we excluded cases and controls with known genetic syndromes. The CC genotype at the -1031 position was more frequent in pNET and IPMN patients (p=0.0002 and p=0.009, respectively), suggesting its possible role in pNET development. Furthermore, the AA genotype at the -308 position was overrepresented in IPMN cases (p=0.03), and AA genotype at the -238 position was more frequent in PDAC cases (p=0.03) compared to healthy individuals. With regard to tumor characteristics, no statistically significant association was detected. Our findings suggest the putative role of TNF-α -1031 polymorphism in the development of pNET and IPMN, whereas the -308 polymorphism seems to be overrepresented among IPMN cases and -238 polymorphism among PDAC cases.

  11. Cisplatin and Etoposide or Temozolomide and Capecitabine in Treating Patients With Neuroendocrine Carcinoma of the Gastrointestinal Tract or Pancreas That Is Metastatic or Cannot Be Removed by Surgery

    ClinicalTrials.gov

    2016-01-05

    Colorectal Large Cell Neuroendocrine Carcinoma; Esophageal Large Cell Neuroendocrine Carcinoma; Gallbladder Large Cell Neuroendocrine Carcinoma; Gastric Large Cell Neuroendocrine Carcinoma; Pancreatic Large Cell Neuroendocrine Carcinoma; Small Intestinal Large Cell Neuroendocrine Carcinoma

  12. [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

  13. Multiple endocrine neoplasia type 1 knockout mice develop parathyroid, pancreatic, pituitary and adrenal tumours with hypercalcaemia, hypophosphataemia and hypercorticosteronaemia

    PubMed Central

    Harding, Brian; Lemos, Manuel C; Reed, Anita A C; Walls, Gerard V; Jeyabalan, Jeshmi; Bowl, Michael R; Tateossian, Hilda; Sullivan, Nicky; Hough, Tertius; Fraser, William D; Ansorge, Olaf; Cheeseman, Michael T; Thakker, Rajesh V

    2009-01-01

    Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized in man by parathyroid, pancreatic, pituitary and adrenal tumours. The MEN1 gene encodes a 610-amino acid protein (menin) which is a tumour suppressor. To investigate the in vivo role of menin, we developed a mouse model, by deleting Men1 exons 1 and 2 and investigated this for MEN1-associated tumours and serum abnormalities. Men1+/− mice were viable and fertile, and 220 Men1+/− and 94 Men1+/+ mice were studied between the ages of 3 and 21 months. Survival in Men1+/− mice was significantly lower than in Men1+/+ mice (<68% vs >85%, P<0.01). Men1+/− mice developed, by 9 months of age, parathyroid hyperplasia, pancreatic tumours which were mostly insulinomas, by 12 months of age, pituitary tumours which were mostly prolactinomas, and by 15 months parathyroid adenomas and adrenal cortical tumours. Loss of heterozygosity and menin expression was demonstrated in the tumours, consistent with a tumour suppressor role for the Men1 gene. Men1+/− mice with parathyroid neoplasms were hypercalcaemic and hypophosphataemic, with inappropriately normal serum parathyroid hormone concentrations. Pancreatic and pituitary tumours expressed chromogranin A (CgA), somatostatin receptor type 2 and vascular endothelial growth factor-A. Serum CgA concentrations in Men1+/− mice were not elevated. Adrenocortical tumours, which immunostained for 3-β-hydroxysteroid dehydrogenase, developed in seven Men1+/− mice, but resulted in hypercorticosteronaemia in one out of the four mice that were investigated. Thus, these Men1+/− mice are representative of MEN1 in man, and will help in investigating molecular mechanisms and treatments for endocrine tumours. PMID:19620250

  14. Combining conventional and stroma-derived tumour markers in pancreatic ductal adenocarcinoma.

    PubMed

    Franklin, Oskar; Öhlund, Daniel; Lundin, Christina; Öman, Mikael; Naredi, Peter; Wang, Wanzhong; Sund, Malin

    2015-01-01

    A lack of disease-specific symptoms and good tumour markers makes early detection and diagnosis of pancreatic ductal adenocarcinoma (PDAC) challenging. To analyse the tissue expression and circulating levels of four stroma-derived substances (type IV collagen, endostatin/type XVIII collagen, osteopontin and tenascin C) and four conventional tumour markers (CA 19-9, TPS, CEA and Ca 125) in a PDAC cohort. Tissue expression of markers in normal pancreas and PDAC tissue was analysed with immunofluorescence. Plasma concentrations of markers were measured before and after surgery. Patients with non-malignant disorders served as controls. The conventional and stromal substances were expressed in the cancer cell compartment and the stroma, respectively. Although most patients had increased levels of many markers before surgery, 2/12 (17%) of patients had normal levels of Ca 19-9 at this stage. High preoperative endostatin/type XVIII collagen, and postoperative type IV collagen was associated with short survival. Neither the pre- nor postoperative levels of TPS, Ca 125 or CA 19-9 were associated to survival. PDAC is characterized by an abundant stroma. These initial observations indicate that the stroma can be a source of PDAC tumour markers that are found in different compartments of the cancer, thus reflecting different aspects of tumour biology.

  15. Genetic deletion of the desmosomal component desmoplakin promotes tumor microinvasion in a mouse model of pancreatic neuroendocrine carcinogenesis.

    PubMed

    Chun, Matthew G H; Hanahan, Douglas

    2010-09-16

    We used the RIP1-Tag2 (RT2) mouse model of islet cell carcinogenesis to profile the transcriptome of pancreatic neuroendocrine tumors (PNET) that were either non-invasive or highly invasive, seeking to identify pro- and anti-invasive molecules. Expression of multiple components of desmosomes, structures that help maintain cellular adhesion, was significantly reduced in invasive carcinomas. Genetic deletion of one of these desmosomal components, desmoplakin, resulted in increased local tumor invasion without affecting tumor growth parameters in RT2 PNETs. Expression of cadherin 1, a component of the adherens junction adhesion complex, was maintained in these tumors despite the genetic deletion of desmoplakin. Our results demonstrate that loss of desmoplakin expression and resultant disruption of desmosomal adhesion can promote increased local tumor invasion independent of adherens junction status.

  16. Gene expression profiling of liver metastases and tumour invasion in pancreatic cancer using an orthotopic SCID mouse model.

    PubMed

    Niedergethmann, M; Alves, F; Neff, J K; Heidrich, B; Aramin, N; Li, L; Pilarsky, C; Grützmann, R; Allgayer, H; Post, S; Gretz, N

    2007-11-19

    The prognosis of pancreatic adenocarcinoma is affected by early metastases and local tumour invasion beyond surgical margins. Gene expression profiling in pancreatic cancer tissue is complicated due to the high amount of RNAses being present in human tissue and that of suitable models. In order to demonstrate early metastases, the models should take into account the anatomical environment of the tumour. Using the orthotopic transplantation of pancreatic tumour cells in SCID (severe combined immunodeficiency) mice, these interactions are taken into consideration. In order to identify genes associated with local tumour invasion and metastases in ductal pancreatic cancer, we investigated a human pancreatic tumour cell line derived from an orthopic pancreatic tumour model in SCID mice. Differential gene expression was performed on the basis of microarray technique. The human MiaPaca-2 cell line was implanted orthotopically in SCID mice. Transcriptional profiling was performed on fresh frozen tissue derived from the primary tumour, the tumour invasion front and the liver metastases. Differentially expressed genes were identified using statistical analyses, and were validated with external databases and with immunohistochemistry. A total of 1066 of 14 500 genes were significantly differentially expressed. Comparing the primary tumour with the tumour invasion front, there were 614 statistically significant up- and 348 downregulated genes. Twenty-five statistically significant up- and 181 downregulated genes were identified comparing the liver metastases with the primary tumour. Eight genes (PAI-1, BNIP3l, VEGF, NSE, RGS4, HSP27, GADD45A, PTPN14) were chosen and validated in a semi-quantitative immunohistochemical analysis, which revealed a positive correlation to the array data. Overrepresentation analyses revealed a total of 66 significantly regulated pathways associated with cell proliferation, cell stress, cell communication metabolic and cytokine function. In

  17. Effectiveness of radiolabelled somatostatin analogues ((90)Y-DOTATOC and (177)Lu-DOTATATE) in patients with metastatic neuroendocrine tumours: a single centre experience in Mexico.

    PubMed

    Medina-Ornelas, S S; García-Pérez, F O

    To determine the effectiveness of therapy with the radiolabelled somatostatin analogues, (90)Y-DOTATOC and (177)Lu-DOTATATE, in the treatment of metastatic neuroendocrine tumours with progression to first-line treatment. A study was conducted on 30 patients diagnosed with neuroendocrine tumours (gastroenteropancreatic, bronchopulmonary, MEN2A, MEN2B, phaeochromocytoma, and paraganglioma) with metastatic disease diagnosed by the pathology department, with progression to first-line treatment, and recruited from December 2014 to February 2016. Efficacy was analysed using computed tomography (CT) according RECIST 1.1 criteria, and the molecular changes using the SUVmax of PET/CT with (68)Ga-DOTATOC. Safety was carried out with a renal scan with (99m)Tc-MAG3. The 30 patients received a total of 49 cycles (90)Y-DOTATOC (21 doses) and (177) Lu-DOTATATE (28 doses), with a mean of 1.5 cycles per patient. Of these, 17 (56.7%) showed a partial morphological response, 22 (73.3%) molecular and biochemical response, and 23 (76.6%) clinical response. One patient died during the median follow-up of 13 months. The median overall survival from diagnosis was 54 months (95% CI; 31.18-76.81), and median progression-free survival was 32 months (95% CI; 15.00-48.99). Therapy with (90)Y-DOTATOC and (177)Lu-DOTATATE is a promising therapy for patients with well and moderately differentiated neuroendocrine tumours. The efficacy is better the larger the number of cycles administered, inversely proportional to the number of metastases (<10), and is associated with the level of uptake according to the SUVmax by the metastases, regardless of metabolically active tumour volume. Copyright © 2016 Elsevier España, S.L.U. y SEMNIM. All rights reserved.

  18. Long-term disease control of a pancreatic neuroendocrine tumor with lanreotide autogel(®): a case report.

    PubMed

    Lybaert, Willem; Van Hul, Erik; Woestenborghs, Heidi

    2014-09-01

    The CLARINET study (ClinicalTrials.gov: NCT00353496) showed that somatostatin analogs are able to stabilize tumor growth in patients with intestinal and pancreatic neuroendocrine tumors (NETs). Here, we present a case of NET originating from the pancreatic tail that was treated with lanreotide Autogel(®). A 60-year-old patient underwent resection of a pancreatic NET with splenectomy and distal pancreatectomy. Four months after surgery, there was an increase in chromogranin A levels, along with a hypercaptating lesion of approximately 3.5 cm at the residual part of the pancreatic corpus. Treatment with 30 mg monthly-administered octreotide long-acting release (LAR) was initiated. After 3 months of treatment, a control CT scan revealed diffuse metastases in the liver, although the patient presented no symptoms and liver tests were normal. Due to difficulties with the administration of octreotide LAR, treatment was switched to lanreotide Autogel(®) 120 mg, administered as monthly deep-subcutaneous injections. Progression-free survival, as shown by 3-monthly CT scans, was obtained for 2 years without the need to increase the lanreotide Autogel(®) dose, and the patient reported no side effects. After these 2 years, deterioration of the patient's clinical status and weight loss were observed, along with increased size of the liver lesions and appearance of peritoneal metastases. Chemotherapy treatment with cisplatinum-etoposide was initiated, while the lanreotide Autogel(®) injections were continued. After three chemotherapy cycles, a rapid decline in the patient's quality of life was noted, and she requested discontinuation of the chemotherapy and lanreotide injections. One month later, the patient died due to clinical progressive disease.

  19. Differential diagnosis between pancreatic neuroendocrine and solid pseudopapillary neoplasms on endoscopic ultrasound-guided fine-needle aspiration

    PubMed Central

    Raddaoui, Emad M.; Almadi, Majid A.; Aljebreen, Abdulrahman M.; Alsaif, Faisal A.; AlShedoukhy, Ahlam A.; Al-Lehibi, Abed H.; Almohameed, Khalid A.; Tsolakis, Apostolos V.; AlAbbadi, Mousa A.; Almutrafi, Amna R.

    2016-01-01

    Objectives: To evaluate the role of applying a limited panel of immunohistochemical stains on the cellblock preparation from samples obtained by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in the aim of differentiating solid pseudopapillary neoplasms (SPNs) from neuroendocrine tumors (NETs). Methods: We retrospectively retrieved all the EUS-FNAs of the pancreas that have a diagnosis of NET or SPN that were performed at 2 tertiary care hospitals in Riyadh, Kingdom of Saudi Arabia from May 2004 to December 2014. Diff-Quik, Papanicolaou, and Immunohistochemistry stains on cellblock preparations were performed. Results: Twenty cases were available (16 pancreatic neuroendocrine tumors (pNETs) and 4 SPNs). The pNETs were immunoreactive for synaptophysin, chromogranin A and CD56 while E-cadherin was diffusely to focally cytoplasmic positive. β-catenin was negative or showed focal cytoplasmic immunoreactivity. In comparison, SPNs were positive for vimentin, CD10, CD-56, focally positive for progesterone receptors and synaptophysin, and revealed nuclear immunostaining for β-catenin. They were negative for chromogranin A and E-cadherin. Conclusion: Based on EUS-FNA samples, nuclear immunoreactivity for β-catenin with loss of membranous immunostaining for E-Cadherin can potentially facilitate differentiating SPNs from pNETs. PMID:27381533

  20. Calculation of the Ki67 index in pancreatic neuroendocrine tumors: a comparative analysis of four counting methodologies.

    PubMed

    Reid, Michelle D; Bagci, Pelin; Ohike, Nobuyuki; Saka, Burcu; Erbarut Seven, Ipek; Dursun, Nevra; Balci, Serdar; Gucer, Hasan; Jang, Kee-Taek; Tajiri, Takuma; Basturk, Olca; Kong, So Yeon; Goodman, Michael; Akkas, Gizem; Adsay, Volkan

    2015-05-01

    Ki67 index is now an essential part of classification of pancreatic neuroendocrine tumors. However, its adaptation into daily practice has been fraught with challenges related to counting methodology. In this study, three reviewers used four counting methodologies to calculate Ki67 index in 68 well-differentiated pancreatic neuroendocrine tumors: (1) 'eye-ball' estimation, which has been advocated as reliable and is widely used; (2) automated counting by image analyzer; (3) manual eye-counting (eye under a microscope without a grid); and (4) manual count of camera-captured/printed image. Pearson's correlation (R) was used to measure pair-wise correlation among three reviewers using all four methodologies. Average level of agreement was calculated using mean of R values. The results showed that: (1) 'eye-balling' was least expensive and fastest (average time <1 min) but had poor reliability and reproducibility. (2) Automated count was the most expensive and least practical with major impact on turnaround time (limited by machine and personnel accessibility), and, more importantly, had inaccuracies in overcounting unwanted material. (3) Manual eye count had no additional cost, averaged 6 min, but proved impractical and poorly reproducible. (4) Camera-captured/printed image was most reliable, had highest reproducibility, but took longer than 'eye-balling'. In conclusion, based on its comparatively low cost/benefit ratio and reproducibility, camera-captured/printed image appears to be the most practical for calculating Ki67 index. Although automated counting is generally advertised as the gold standard for index calculation, in this study it was not as accurate or cost-effective as camera-captured/printed image and was highly operator-dependent. 'Eye-balling' produces highly inaccurate and unreliable results, and is not recommended for routine use.

  1. Risk factors for aggressive nonfunctional pancreatic neuroendocrine tumors and the role of endoscopic ultrasound guided fine-needle aspiration

    PubMed Central

    Ende, Alexander R.; Sedarat, Alireza; Shah, Pari; Jhala, Nirag; Fraker, Douglas L.; Drebin, Jeffrey A.; Metz, David C.; Kochman, Michael L.

    2016-01-01

    Background: Nonfunctional pancreatic neuroendocrine tumors (NF-pNETs) are increasingly being diagnosed but management, especially of small tumors, remains a clinical dilemma. Endoscopic ultrasound guided fine-needle aspiration (EUS-FNA) is now routinely used for diagnosis of pancreatic neuroendocrine tumors (pNETs) but has not been well studied as a tool for identifying aggressive disease. Materials and Methods: A systematic search of the cytology database identified all patients at our center who underwent EUS-FNA from 1999 through 2011 and were diagnosed with NF-pNET. Results: A total of 50 patients were identified. Though patients with metastatic disease had a mean tumor size of 40 mm compared to 25 mm in patients without metastatic disease (P = 0.04), we also identified several patients with tumors <20 mm who presented with metastatic disease. Furthermore, we found no statistically significant difference in metastatic disease between tumors <20 mm and >20 mm (P = 0.13). Using receiver operating characteristic (ROC) analysis, we found that using a cutoff point of 20 mm only led to a sensitivity of 85% in screening for metastases, while lowering the cutoff point to 18 mm allowed for a sensitivity of 95%. Conclusion: Currently, guidelines suggest that only patients with tumors greater than 20 mm undergo surgical resection, as tumors less than this size are thought to have low risk of metastases. Our analysis suggests that these recommendations could lead to undertreating patients with small tumors. Tumor size alone may be inadequate as a marker for aggressive NF-pNETs. Given this, other risk factors for aggressive pNETs should be studied to help identify the patients most likely to benefit from surgery. PMID:26879167

  2. In vivo imaging of pancreatic tumours and liver metastases using 7 Tesla MRI in a murine orthotopic pancreatic cancer model and a liver metastases model

    PubMed Central

    2011-01-01

    Background Pancreatic cancer is the fourth leading cause of tumour death in the western world. However, appropriate tumour models are scarce. Here we present a syngeneic murine pancreatic cancer model using 7 Tesla MRI and evaluate its clinical relevance and applicability. Methods 6606PDA murine pancreatic cancer cells were orthotopically injected into the pancreatic head. Liver metastases were induced through splenic injection. Animals were analyzed by MRI three and five weeks following injection. Tumours were detected using T2-weighted high resolution sequences. Tumour volumes were determined by callipers and MRI. Liver metastases were analyzed using gadolinium-EOB-DTPA and T1-weighted 3D-Flash sequences. Tumour blood flow was measured using low molecular gadobutrol and high molecular gadolinium-DTPA. Results MRI handling and applicability was similar to human systems, resolution as low as 0.1 mm. After 5 weeks tumour volumes differed significantly (p < 0.01) when comparing calliper measurments (n = 5, mean 1065 mm3+/-243 mm3) with MRI (mean 918 mm3+/-193 mm3) with MRI being more precise. Histology (n = 5) confirmed MRI tumour measurements (mean size MRI 38.5 mm2+/-22.8 mm2 versus 32.6 mm2+/-22.6 mm2 (histology), p < 0,0004) with differences due to fixation and processing of specimens. After splenic injection all mice developed liver metastases with a mean of 8 metastases and a mean volume of 173.8 mm3+/-56.7 mm3 after 5 weeks. Lymphnodes were also easily identified. Tumour accumulation of gadobutrol was significantly (p < 0.05) higher than gadolinium-DTPA. All imaging experiments could be done repeatedly to comply with the 3R-principle thus reducing the number of experimental animals. Conclusions This model permits monitoring of tumour growth and metastasis formation in longitudinal non-invasive high-resolution MR studies including using contrast agents comparable to human pancreatic cancer. This multidisciplinary environment enables radiologists, surgeons and

  3. Anti-vascular endothelial growth factor antibody single therapy for pancreatic neuroendocrine carcinoma exhibits a marked tumor growth-inhibitory effect.

    PubMed

    Kasuya, Kazuhiko; Nagakawa, Yuichi; Suzuki, Minako; Tanaka, Hiroaki; Ohta, Hiroshi; Itoi, Takao; Tsuchida, Akihiko

    2011-11-01

    At present, no effective chemotherapy for pancreatic neuroendocrine carcinoma (PNEC) exists. However, anti-angiogenic therapy is expected to be effective for PNEC, a hypervascular tumor. We treated PNEC and hypovascular pancreatic ductal cell carcinoma (DCC) cell lines with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab, and compared the antitumor effect between the two different types of cell lines. The PNEC cell line QGP-1 and the DCC cell lines BxPC-3 and AsPC-1 were used. We evaluated the ability of the cell lines to proliferate and secrete VEGF in vitro, the antitumor effect of bevacizumab administration in vivo and the side effects of bevacizumab on the pancreas in a caerulein-induced pancreatitis model. Comparison of the QGP-1 and DCC cell lines showed that QGP-1 secreted a higher level of VEGF under a hypoxic environment than the DCC cell line, and bevacizumab exerted the most marked growth-inhibitory effect on QGP-1; the number of intratumoral blood vessels decreased and the percentage of proliferating cells was approximately the same. In the pancreatitis model, bevacizumab administration did not adversely affect the pancreatitis or the associated hypoxic environment. Bevacizumab does not affect the pancreas itself; therefore, its potent inhibitory effect on the growth of pancreatic neuroendocrine tumors alone can be expected.

  4. Anti-vascular endothelial growth factor antibody single therapy for pancreatic neuroendocrine carcinoma exhibits a marked tumor growth-inhibitory effect

    PubMed Central

    KASUYA, KAZUHIKO; NAGAKAWA, YUICHI; SUZUKI, MINAKO; TANAKA, HIROAKI; OHTA, HIROSHI; ITOI, TAKAO; TSUCHIDA, AKIHIKO

    2011-01-01

    At present, no effective chemotherapy for pancreatic neuroendocrine carcinoma (PNEC) exists. However, anti-angiogenic therapy is expected to be effective for PNEC, a hypervascular tumor. We treated PNEC and hypovascular pancreatic ductal cell carcinoma (DCC) cell lines with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab, and compared the antitumor effect between the two different types of cell lines. The PNEC cell line QGP-1 and the DCC cell lines BxPC-3 and AsPC-1 were used. We evaluated the ability of the cell lines to proliferate and secrete VEGF in vitro, the antitumor effect of bevacizumab administration in vivo and the side effects of bevacizumab on the pancreas in a caerulein-induced pancreatitis model. Comparison of the QGP-1 and DCC cell lines showed that QGP-1 secreted a higher level of VEGF under a hypoxic environment than the DCC cell line, and bevacizumab exerted the most marked growth-inhibitory effect on QGP-1; the number of intratumoral blood vessels decreased and the percentage of proliferating cells was approximately the same. In the pancreatitis model, bevacizumab administration did not adversely affect the pancreatitis or the associated hypoxic environment. Bevacizumab does not affect the pancreas itself; therefore, its potent inhibitory effect on the growth of pancreatic neuroendocrine tumors alone can be expected. PMID:22977618

  5. Dose response of pancreatic neuroendocrine tumors treated with peptide receptor radionuclide therapy using 177Lu-DOTATATE.

    PubMed

    Ilan, Ezgi; Sandström, Mattias; Wassberg, Cecilia; Sundin, Anders; Garske-Román, Ulrike; Eriksson, Barbro; Granberg, Dan; Lubberink, Mark

    2015-02-01

    Peptide receptor radionuclide therapy (PRRT) is a promising treatment for patients with neuroendocrine tumors, giving rise to improved survival. Dosimetric calculations in relation to PRRT have been concentrated to normal organ dosimetry in order to limit side effects. However, the relation between the absorbed dose to the tumor and treatment response has so far not been established. Better knowledge in this respect may improve the understanding of treatment effects, allow for improved selection of those patients who are expected to benefit from PRRT, and avoid unnecessary treatments. The aim of the present work was to evaluate the dose-response relationship for pancreatic neuroendocrine tumors treated with PRRT using (177)Lu-DOTATATE. Tumor-absorbed dose calculations were performed for 24 lesions in 24 patients with metastasized pancreatic neuroendocrine tumors treated with repeated cycles of (177)Lu-DOTATATE at 8-wk intervals. The absorbed dose calculations relied on sequential SPECT/CT imaging at 24, 96, and 168 h after infusion of (177)Lu-DOTATATE. The unit density sphere model from OLINDA was used for absorbed dose calculations. The absorbed doses were corrected for partial-volume effect based on phantom measurements. On the basis of these results, only tumors larger than 2.2 cm in diameter at any time during the treatment were included for analysis. To further decrease the effect of partial-volume effect, a subgroup of tumors (>4.0 cm) was analyzed separately. Tumor response was evaluated by CT using Response Evaluation Criteria In Solid Tumors. Tumor-absorbed doses until best response ranged approximately from 10 to 340 Gy. A 2-parameter sigmoid fit was fitted to the data, and a significant correlation between the absorbed dose and tumor reduction was found, with a Pearson correlation coefficient (R(2)) of 0.64 for tumors larger than 2.2 cm and 0.91 for the subgroup of tumors larger than 4.0 cm. The largest tumor reduction was 57% after a total absorbed dose

  6. 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

  7. Intraductal Tubulopapillary Neoplasm of the Pancreas Masquerading as Pancreatic Neuroendocrine Carcinoma: Review of the Literature with a Case Report.

    PubMed

    Savant, Deepika; Lee, Lili; Das, Kasturi

    2016-01-01

    Intraductal tubulopapillary neoplasm of the pancreas (ITPN) is a rare tumor which was first described in 2009. We report a case with cytologic and histologic findings and discuss the pitfalls in diagnosing this entity on cytology. An 82-year-old female presented with a pancreatic body mass measuring 3.3 cm. Endoscopic ultrasound-guided fine-needle aspiration showed cells in cohesive clusters with high-grade nuclear atypia. Immunohistochemistry (IHC) showed the neoplastic cells to be positive for CK19, CD56 and chromogranin (focal). Ki-67 was high at 50-60%, and chymotrypsin was negative. On the basis of this pattern of staining, the cytologic diagnosis rendered was 'favors high-grade neuroendocrine carcinoma'. Distal pancreatic resection revealed a cystic 4-cm mass. Histologically, the tumor was seen arising from the duct with a solid growth pattern, tubule formation and papillary structures. IHC showed the tumor to be negative for chromogranin, synaptophysin, CD56, trypsin and chymotrypsin. The Ki-67 index was 70%. The final diagnosis was noninvasive ITPN. We review the literature and discuss the cytomorphologic features and IHC patterns characteristic of this new entity on cytology material in addition to the pitfalls of the cytologic diagnosis. © 2016 S. Karger AG, Basel.

  8. Safety and efficacy of doxorubicin-eluting superabsorbent polymer microspheres for the treatment of liver metastases from neuroendocrine tumours: preliminary results

    PubMed Central

    Verslype, Chris; Laenen, Annouschka; Cornelissen, Sandra; Deroose, Christophe M.; Prenen, Hans; Vandecaveye, Vincent; Van Cutsem, Eric; Maleux, Geert

    2017-01-01

    Abstract Background The aim of the study was to retrospectively evaluate the symptom control, tumour response, and complication rate in patients with liver-predominant metastatic neuroendocrine tumours treated with transarterial chemoembolization using doxorubicin-eluting superabsorbent polymer (SAP) microspheres. Patients and methods Patients with neuroendocrine liver metastases who underwent hepatic transarterial chemoembolization using doxorubicin-eluting SAP-microspheres (50–100 μm Hepasphere/Quadrasphere Microsphere® particles, Merit Medical, South Jordan, Utah, USA) were included in this study. Pre-and post-procedure imaging studies were evaluated to assess short and intermediate-term tumour response using modified RECIST criteria. Symptom relief and procedure-related complications were evaluated. Results A total of 27 embolization procedures were performed on 17 patients. Twelve of 17 patients (70%) were symptomatic, including carcinoid syndrome (n = 8) and severe, uncontrollable hypoglycemia (n = 4). Eight of 12 patients (67%) had complete symptom relief, and the remaining 4 (33%) had partial relief. One patient developed ischemic cholecystitis (6%). No other hepatobiliary complications occurred. Short-term and intermediate-term imaging follow-up was available for 15/17 patients (88%) and 12/14 patients (86%) respectively. At short-term follow-up (< 3 months), 14 patients (93%) showed partial response and the remaining patient had progressive disease (7%). At intermediate-term imaging follow-up (> 3 months), partial response, stable disease and progressive disease were found respectively in 7 (58%), 3 (25%) and 2 (17%) patients. Conclusions Chemoembolization with doxorubicin-eluting SAP-microspheres is a safe and effective treatment option for neuroendocrine liver metastases and is associated with a low complication rate. In particular, no clinically evident liver necrosis or bile duct complications were encountered. PMID:28265235

  9. Proteolysis of microtubule associated protein 2 and sensitivity of pancreatic tumours to docetaxel

    PubMed Central

    Veitia, R; David, S; Barbier, P; Vantard, M; Gounon, P; Bissery, M C; Fellous, A

    2000-01-01

    We have studied the state of microtubule associated protein 2 (MAP2) in the pancreatic ductal adenocarcinomas P03 and P02 (sensitive and refractory to docetaxel respectively) since they express the corresponding mRNA and MAP2-related peptides. Immunohistochemical localization showed that in tumour P03 the MAP2-related peptides are highly expressed and confined to the epithelial malignant cells while in P02 the intensity of the immunostaining is lower. However, anti α-tubulin staining followed a similar pattern suggesting that the net amount of macromolecular structures in the sensitive tumour is higher than in the refractory one. This may explain its higher sensitivity to docetaxel, because tubulin assembled into microtubules is the target of the drug. We found that protein extracts from both tumours differed in their proteolytic activity on rat brain MAP2. Since the proteolysis pattern obtained was similar to the one produced by Cathepsin D, we studied the effect of MAP2 proteolysed by this enzyme on microtubule formation in vitro. Proteolysis was found to increase the tendency of tubulin to assemble into macromolecular structures (microtubules and aggregates) in the presence of docetaxel. This suggests that in vivo proteolysis of MAP2 might increase microtubule alterations and potentiate the antitumour effect of docetaxel. © 2000 Cancer Research Campaign PMID:10945505

  10. 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.

  11. Anti-metastatic action of FAK inhibitor OXA-11 in combination with VEGFR-2 signaling blockade in pancreatic neuroendocrine tumors

    PubMed Central

    Moen, Ingrid; Gebre, Matthew; Alonso-Camino, Vanesa; Chen, Debbie; Epstein, David

    2015-01-01

    The present study sought to determine the anti-tumor effects of OXA-11, a potent, novel small-molecule amino pyrimidine inhibitor (1.2 pM biochemical IC50) of focal adhesion kinase (FAK). In studies of cancer cell lines, OXA-11 inhibited FAK phosphorylation at phospho-tyrosine 397 with a mechanistic IC50 of 1 nM in TOV21G tumor cells, which translated into functional suppression of proliferation in 3-dimensional culture with an EC50 of 9 nM. Studies of OXA-11 activity in TOV21G tumor-cell xenografts in mice revealed a pharmacodynamic EC50 of 1.8 nM, indicative of mechanistic inhibition of pFAK [Y397] in these tumors. OXA-11 inhibited TOV21G tumor growth in a dose-dependent manner and also potentiated effects of cisplatin on tumor cell proliferation and apoptosis in vitro and on tumor growth in mice. Studies of pancreatic neuroendocrine tumors in RIP-Tag2 transgenic mice revealed OXA-11 suppression of pFAK [Y397] and pFAK [Y861] in tumors and liver. OXA-11 given daily from age 14 to 17 weeks reduced tumor vascularity, invasion, and when given together with the anti-VEGFR-2 antibody DC101 reduced the incidence, abundance, and size of liver metastases. Liver micrometastases were found in 100 % of mice treated with vehicle, 84 % of mice treated with OXA-11, and 79 % of mice treated with DC101 (19–24 mice per group). In contrast, liver micrometastases were found in only 52 % of 21 mice treated with OXA-11 plus DC101, and those present were significantly smaller and less numerous. Together, these findings indicate that OXA-11 is a potent and selective inhibitor of FAK phosphorylation in vitro and in vivo. OXA-11 slows tumor growth, potentiates the anti-tumor actions of cisplatin and—when combined with VEGFR-2 blockade—reduces metastasis of pancreatic neuroendocrine tumors in RIP-Tag2 mice. PMID:26445848

  12. 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

  13. MYB is a novel regulator of pancreatic tumour growth and metastasis.

    PubMed

    Srivastava, Sanjeev K; Bhardwaj, Arun; Arora, Sumit; Singh, Seema; Azim, Shafquat; Tyagi, Nikhil; Carter, James E; Wang, Bin; Singh, Ajay P

    2015-12-22

    MYB encodes for a transcription factor regulating the expression of a wide array of genes involved in cellular functions. It is reported to be amplified in a sub-set of pancreatic cancer (PC) cases; however, its pathobiological association has remained unclear thus far. Expression of MYB and other cellular proteins was analysed by immunoblot or qRT-PCR analyses. MYB was stably overexpressed in non-expressing (BxPC3) and silenced in highly expressing (MiaPaCa and Panc1) PC cells. Effect on growth was analysed by automated cell counting at 24-h interval. Cell-cycle progression and apoptotic indices of PC cells with altered MYB expression were measured through flow cytometry upon staining with respective biomarkers. Cell motility/invasion was examined in a Boyden's chamber assay using non-coated or Matrigel-coated membranes. Effect on tumorigenicity and metastatic potential was examined by non-invasive imaging and through end-point measurements of luciferase-tagged MYB-altered PC implanted in the pancreas of nude mice. MYB was aberrantly expressed in all malignant cases of pancreas, whereas remained undetectable in normal pancreas. All the tested established PC cell lines except BxPC3 also exhibited MYB expression. Forced expression of MYB in BxPC3 cells promoted their growth, cell-cycle progression, survival and malignant behaviour, whereas its silencing in MiaPaCa and Panc1 cells produced converse effects. More importantly, ectopic MYB expression was sufficient to confer tumorigenic and metastatic capabilities to non-tumorigenic BxPC3 cells, while its silencing resulted in significant loss of the same in MYB-overexpressing cells as demonstrated in orthotopic mouse model. We also identified several MYB-regulated genes in PC cells that might potentially mediate its effect on tumour growth and metastasis. MYB is aberrantly overexpressed in PC cells and acts as a key determinant of pancreatic tumour growth and metastasis.

  14. Fine-needle aspiration biopsy of pancreatic neuroendocrine tumors: Correlation between Ki-67 index in cytological samples and clinical behavior.

    PubMed

    Díaz Del Arco, Cristina; Esteban López-Jamar, J Miguel; Ortega Medina, Luis; Díaz Pérez, J Ángel; Fernández Aceñero, Ma Jesús

    2017-01-01

    Mitotic count in hematoxylin-eosin stained slides and Ki-67 index allow stratification of patients for prognosis and therapeutic decision making in pancreatic neuroendocrine tumors (PNETs). However, the utility of Ki-67 determination in cytological material and its association to PNET prognosis are under discussion. We have retrospectively reviewed all cases of EUS-FNA cytology of pancreatic lesions performed in the Hospital Clínico San Carlos (Madrid) between 2006 and 2016. We have analyzed the potential association between the Ki-67 estimation in PNET cytological material and patient outcomes. We identified 24 PNET cases. Mean age was 56.8 years and most patients were males (54%). PNETs were mainly located in the head and tail of the pancreas and the mean tumor size was 36 mm. Cell block from cytology was available in 12 cases (50%), and there were 19 G1, 2 G2, and 3 G3 tumors. All cases graded as G2 (2 patients) or G3 (three patients) on cytology were stage IV, and the 19 cases graded as G1 ranged from stages IA to IV. All patients with G2 tumors on cytology died due to PNET. Of the three patients with G3 lesions, two died of disease and the other died 2 months after diagnosis from causes other than PNET. 78% of the patients with G1 tumors are stable and currently being followed-up. Higher Ki-67 index in cytology specimens portends a worse outcome, although some G1 tumors may progress or cause death. Diagn. Cytopathol. 2017;45:29-35. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  15. Systemic Inflammatory Response and Elevated Tumour Markers Predict Worse Survival in Resectable Pancreatic Ductal Adenocarcinoma

    PubMed Central

    Salmiheimo, Aino; Mustonen, Harri; Stenman, Ulf-Håkan; Puolakkainen, Pauli; Kemppainen, Esko; Seppänen, Hanna; Haglund, Caj

    2016-01-01

    Background Estimation of the prognosis of resectable pancreatic ductal adenocarcinoma (PDAC) currently relies on tumour-related factors such as resection margins and on lymph-node ratio (LNR) both inconveniently available only postoperatively. Our aim was to assess the accuracy of preoperative laboratory data in predicting PDAC prognosis. Methods Collection of laboratory and clinical data was retrospective from 265 consecutive patients undergoing surgery for PDAC at Helsinki University Hospital. Cancer-specific survival assessment utilized Kaplan-Meier analysis, and independent associations between factors were by the Cox regression model. Results During follow-up, 76% of the patients died of PDAC, with a median survival time of 19.6 months. In univariate analysis, CRP, albumin, CEA, and CA19-9 were significantly associated with postoperative cancer-specific survival. In multivariate analysis, taking into account age, gender, LNR, resection margins, tumour status, and adjuvant chemotherapy, the preoperative biomarkers independently associated with adverse prognosis were hypoalbuminemia (< 36 g/L, hazard ratio (HR) 1.56, 95% confidence interval (CI) 1.10–2.19, p = 0.011), elevated CRP (> 5 mg/L, HR 1.44, 95% CI 1.03–2.02, p = 0.036), CEA (> 5 μg/L, HR 1.60, 95% CI 1.07–2.53, p = 0.047), and CA19-9 (≥555 kU/L, HR 1.91, 95% CI 1.18–3.08, p = 0.008). Conclusion For patients with resectable PDAC, preoperative CRP, along with albumin and tumour markers, is useful for predicting prognosis. PMID:27632196

  16. Systemic Inflammatory Response and Elevated Tumour Markers Predict Worse Survival in Resectable Pancreatic Ductal Adenocarcinoma.

    PubMed

    Salmiheimo, Aino; Mustonen, Harri; Stenman, Ulf-Håkan; Puolakkainen, Pauli; Kemppainen, Esko; Seppänen, Hanna; Haglund, Caj

    2016-01-01

    Estimation of the prognosis of resectable pancreatic ductal adenocarcinoma (PDAC) currently relies on tumour-related factors such as resection margins and on lymph-node ratio (LNR) both inconveniently available only postoperatively. Our aim was to assess the accuracy of preoperative laboratory data in predicting PDAC prognosis. Collection of laboratory and clinical data was retrospective from 265 consecutive patients undergoing surgery for PDAC at Helsinki University Hospital. Cancer-specific survival assessment utilized Kaplan-Meier analysis, and independent associations between factors were by the Cox regression model. During follow-up, 76% of the patients died of PDAC, with a median survival time of 19.6 months. In univariate analysis, CRP, albumin, CEA, and CA19-9 were significantly associated with postoperative cancer-specific survival. In multivariate analysis, taking into account age, gender, LNR, resection margins, tumour status, and adjuvant chemotherapy, the preoperative biomarkers independently associated with adverse prognosis were hypoalbuminemia (< 36 g/L, hazard ratio (HR) 1.56, 95% confidence interval (CI) 1.10-2.19, p = 0.011), elevated CRP (> 5 mg/L, HR 1.44, 95% CI 1.03-2.02, p = 0.036), CEA (> 5 μg/L, HR 1.60, 95% CI 1.07-2.53, p = 0.047), and CA19-9 (≥555 kU/L, HR 1.91, 95% CI 1.18-3.08, p = 0.008). For patients with resectable PDAC, preoperative CRP, along with albumin and tumour markers, is useful for predicting prognosis.

  17. 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

    2016-07-12

    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.

  18. Antiproliferative effect of somatostatin analogs in advanced gastro-entero-pancreatic neuroendocrine tumors: a systematic review and meta-analysis

    PubMed Central

    Merola, Elettra; Panzuto, Francesco; Fave, Gianfranco Delle

    2017-01-01

    A meta-analysis has systematically investigated the antineoplastic efficacy and safety of somatostatin analogs (SSAs) in advanced gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). Randomized controlled trials (RCTs) reporting the hazard ratio (HR) for disease progression (DP) were evaluated. Response rate and risk ratio (RR) for adverse events were also analyzed. A total of 289 patients (143 receiving SSAs vs. 146 placebo) were evaluated from two RCTs. A significant benefit from SSAs in terms of disease control was observed (HR 0.41, 95% CI: 0.29 to 0.58, P < 0.01; I20%), response rate being 58.0% vs. 32.2%, respectively. The occurrence of adverse events significantly differed from the placebo arm only in terms of biliary stones (RR 3.79, 95% CI: 1.28 to 11.17, P = 0.02; I20%). In conclusion, SSAs showed an antiproliferative effect in advanced GEP-NETs, with a good safety profile. PMID:28402955

  19. 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

  20. Dual Inhibition of PI3K and mTOR Signaling Pathways Decreases Human Pancreatic Neuroendocrine Tumor (PNET) Metastatic Progression

    PubMed Central

    Djukom, Clarisse; Porro, Laura J.; Mrazek, Amy; Townsend, Courtney M.; Hellmich, Mark R.; Chao, Celia

    2013-01-01

    Objectives Patients with advanced pancreatic neuroendocrine tumors (PNET) have limited therapeutic options. RAD001, an inhibitor of the mammalian target of rapamycin (mTOR) pathway, has been shown to increase progression-free survival, but not overall survival, indicating a need to identify additional therapeutic targets. Inhibition of mTORC1 by RAD001 may induce upstream AKT upregulation. We hypothesized that dual inhibition of AKT along with mTOR will overcome the limited activity of RAD001 alone. Methods The BON cell line has been used as a model to study PNET cell biology. Western blots and cell growth assays were performed with mTOR inhibitor RAD001 (50 nM), MEK inhibitor PD0325901 (50 nM), PI3K inhibitor LY294002 (25 μM) or vehicle control. Nude mice were treated daily for 6 weeks with RAD001 (oral gavage), LY29400 (SQ) one week after intrasplenic injection of BON cells. Results Cellular proliferation was most attenuated with the combination therapy LY29400 and RAD001. Similarly, the volume of liver metastasis was lowest in the group treated with both LY29400 (100 mg/kg/week, SQ) and RAD001 (2.5 mg/kg/d) compared to vehicle (p=0.04). Conclusion The combination LY29400 and RAD001 decreased the cell growth in vitro and progression of liver metastasis in vivo compared vehicle or to single drug. PMID:24263107

  1. Inhibition of Six1 affects tumour invasion and the expression of cancer stem cell markers in pancreatic cancer.

    PubMed

    Lerbs, Tristan; Bisht, Savita; Schölch, Sebastian; Pecqueux, Mathieu; Kristiansen, Glen; Schneider, Martin; Hofmann, Bianca T; Welsch, Thilo; Reissfelder, Christoph; Rahbari, Nuh N; Fritzmann, Johannes; Brossart, Peter; Weitz, Jürgen; Feldmann, Georg; Kahlert, Christoph

    2017-04-07

    Epithelial-to-mesenchymal transition (EMT) and cancer stem cells (CSC) contribute to tumour progression and metastasis. Assessment of transcription factors involved in these two mechanisms can help to identify new targets for an oncological therapy. In this study, we focused on the evaluation of the transcription factor Six1 (Sine oculis 1). This protein is involved in embryologic development and its contribution to carcinogenesis has been described in several studies. Immunohistochemistry against Six1 was performed on a tissue microarray containing specimens of primary pancreatic ductal adenocarcinomas (PDAC) of 139 patients. Nuclear and cytoplasmic expression was evaluated and correlated to histopathological parameters. Expression of Six1 was inhibited transiently by siRNA in Panc1 and BxPc3 cells and stably by shRNA in Panc1 cells. Expression analysis of CDH1 and Vimentin mRNA was performed and cell motility was tested in a migration assay. Panc1 cells transfected with Six1 shRNA or scrambled shRNA were injected subcutaneously into nude mice. Tumour growth was observed for four weeks. Afterwards, tumours were stained against Six1, CD24 and CD44. Six1 was overexpressed in the cytoplasm and cellular nuclei in malignant tissues (p < 0.0001). No correlation to histopathological parameters could be detected. Six1 down-regulation decreased pancreatic cancer cell motility in vitro. CDH1 and vimentin expression was decreased after inhibition of the expression of Six1. Pancreatic tumours with impaired expression of Six1 showed significantly delayed growth and displayed loss of the CD24(+)/CD44(+) phenotype. We show that Six1 is overexpressed in human PDAC and that its inhibition results in a decreased tumour progression in vitro and in vivo. Therefore, targeting Six1 might be a novel therapeutic approach in patients with pancreatic cancer.

  2. The prognostic influence of the proliferative discordance in metastatic pancreatic neuroendocrine carcinoma revealed by peptide receptor radionuclide therapy: Case report and review of literature.

    PubMed

    Montanier, Nathanaëlle; Joubert-Zakeyh, Juliette; Pétorin, Caroline; Montoriol, Pierre François; Maqdasy, Salwan; Kelly, Antony

    2017-02-01

    Pancreatic neuroendocrine tumors (pNET) are rare slowly growing tumors with a high metastatic potential. Peptide receptor radionuclide therapy (PRRT) with radiolabeled analogues has been developed as a new tool for the management of metastatic well-differentiated (grade 1 and 2) neuroendocrine tumors expressing somatostatin receptor (SSTR2). Chemotherapy is the mainstay in the management of grade 3 (G3) unresectable pancreatic neuroendocrine carcinoma (pNEC). To date, no study has evaluated the efficacy of PRRT in such tumors. We describe a case of a progressive G3 pNEC with huge liver metastases successfully treated with PRRT (Lu DOTATATE). Complete remission was obtained for 3 years. Indeed, the mitotic index was low (as G2 tumors) but with a very high Ki-67 index (45%-70%). Such discordance between the proliferative markers should consider the use of PRRT before chemotherapy in unresectable metastatic G3 tumors expressing SSTR2. This case supports the hypotheses highlighting the heterogeneity of G3 pNEC. The latter should be subdivided into 2 distinct categories: proliferation-discordant (well differentiated) and concordant (poorly differentiated) NEC. PRRT could be suggested for the former group before the conventional chemotherapy.

  3. Nuclear medicine imaging of gastro-entero-pancreatic neuroendocrine tumors. The key role of cellular differentiation and tumor grade: from theory to clinical practice

    PubMed Central

    Rust, Edmond; Hubele, Fabrice; Marzano, Ettore; Goichot, Bernard; Pessaux, Patrick; Kurtz, Jean-Emmanuel

    2012-01-01

    Abstract Nuclear medicine imaging is a powerful diagnostic tool for the management of patients with gastro-entero-pancreatic neuroendocrine tumors, mainly developed considering some cellular characteristics that are specific to the neuroendocrine phenotype. Hence, overexpression of specific trans membrane receptors as well as the cellular ability to take up, accumulate, and decarboxylate amine precursors have been considered for diagnostic radiotracer development. Moreover, the glycolytic metabolism, which is not a specific energetic pathway of neuroendocrine tumors, has been proposed for radionuclide imaging of neuroendocrine tumors. The results of scintigraphic examinations reflect the pathologic features and tumor metabolic properties, allowing the in vivo characterization of the disease. In this article, the influence of both cellular differentiation and tumor grade in the scintigraphic pattern is reviewed according to the literature data. The relationship between nuclear imaging results and prognosis is also discussed. Despite the existence of a relationship between the results of scintigraphic imaging and cellular differentiation, tumor grade and patient outcome, the mechanism explaining the variability of the results needs further investigation. PMID:22743056

  4. Neurokinin A monitoring of response to interferon alpha in a patient with an advanced small bowel neuroendocrine tumour uncontrolled by somatostatin analogue therapy.

    PubMed

    Ardill, Joy Es; Johnston, Brian T; McCance, David R; Eatock, Martin

    2017-03-01

    A 52-year-old lady presented with a history of occasional, severe abdominal cramps, postprandial diarrhoea and weight loss. After routine gastrointestinal investigations, she was diagnosed with irritable bowel syndrome. Over six months, she developed occasional facial flushing prompting assessment of neuroendocrine tumour markers. Urinary 5HIAA, 5HT, chromogranin A and neurokinin A were significantly elevated. Scans showed extensive hepatic metastases but did not show the location of a primary tumour. Somatostatin analogue therapy was commenced but despite increasing doses, symptoms increased and biomarkers rose dramatically. Interferon alpha was introduced concomitant with somatostatin analogue therapy. Biomarkers were monitored regularly. Within six months, symptoms abated and biomarkers reduced, continuing to fall over the next year, close to reference range. To manage side-effects of interferon alpha, dose was reduced from time to time. During these short periods, neurokinin A showed significant transient increases (75-150 ng/L) and carcinoid symptoms returned. For more than seven years, and with the co-operation of the patient, a balance was achieved between interferon alpha side-effects and disease control. Scans showed tumour load to be stable. The patient survived for 10 years post diagnosis. She chose to discontinue interferon alpha and received peptide receptor radiation therapy in her final year. Throughout, neurokinin A remained the most sensitive monitor of her disease progression.

  5. Outcomes of patients treated with capecitabine and temozolamide for advanced pancreatic neuroendocrine tumors (PNETs) and non-PNETs

    PubMed Central

    Noonan, Krista L.; Pavlovich, Peter; Kennecke, Hagen F.; Lim, Howard J.

    2014-01-01

    Background Retrospective studies have demonstrated high response rates among patients with advanced pancreatic neuroendocrine tumors (PNETs) treated with capecitabine and temozolamide (CapTem), while responses are infrequently seen among non-PNETs. The objective of the study was to describe progression free survival (PFS) among neuroendocrine tumor (NET) patients treated with CapTem, and to identify factors associated with better activity. Methods Patients who were referred to one of five provincial cancer treatment centers between 2009 and 2013 for advanced NETs and initiated CapTem were included. Patients received Cap 1,500 mg/m2 on days 1-14 and TMZ 200 mg/m2 on days 10-14 every 28 days. Their characteristics and outcomes were retrospectively analyzed. Results In our cohort, 29 patients (16 males) with a median age of 59 (range 26-76) received palliative CapTem, 15 of them as first-line chemotherapy. Primary tumors included pancreas (48.3%), small bowel (20.7%), lung (10.3%), unknown (10.3%), rectum (6.9%) and appendix (3.4%). Median number of cycles was three. Fifteen patients (51.7%) received CapTem as first-line chemotherapy and 14 (48.3%) as subsequent lines. Median PFS for the entire cohort was 4.7 months. PNETs had a median PFS of 4.9 months compared to 2.8 months for non-PNETs (P=0.178). Patients with PNETs who received CapTem in the first-line setting had a median PFS of 15.9 months as compared to only 3.1 months for the remainder [P=0.047, hazard ratios (HR) 0.342]. Patients with Ki67 above 5% and ≤5% had median PFS of 4.0 and 4.7 months, respectively (P=0.260). Conclusions CapTem showed good activity among PNETs, but its broader role in the treatment of carcinoid tumors remains unclear. PMID:25083296

  6. Growth hormone-releasing hormone-producing pancreatic neuroendocrine tumor in a multiple endocrine neoplasia type 1 family with an uncommon phenotype.

    PubMed

    Sala, Elisa; Ferrante, Emanuele; Verrua, Elisa; Malchiodi, Elena; Mantovani, Giovanna; Filopanti, Marcello; Ferrero, Stefano; Pietrabissa, Andrea; Vanoli, Alessandro; La Rosa, Stefano; Zatelli, Maria C; Beck-Peccoz, Paolo; Verga, Uberta

    2013-07-01

    The objective of this study was to describe a multiple endocrine neoplasia type 1 (MEN1) family characterized by primary hyperparathyroidism, in association with acromegaly because of ectopic growth hormone-releasing hormone (GHRH) secretion by a pancreatic neuroendocrine tumor in a young man and with a bronchial carcinoid in his mother. We investigate the clinical, radiological imaging, histopathologic findings, and therapy. An 18-year-old man successfully underwent subtotal parathyroidectomy for primary hyperparathyroidism. A subsequent genetic analysis showed a MEN1 gene mutation. Three years later, acromegaly because of ectopic GHRH secretion was diagnosed (pituitary MRI negative and elevated GHRH levels). A search for an ectopic tumor was unsuccessful and somatostatin analog therapy was started. Successively, scintigraphy with somatostatin analogs (68-Ga-DOTATOC-PET) showed three focal areas in the pancreatic tail. Distal pancreatectomy showed multiple pancreatic neuroendocrine tumors and hormonal status was normalized. Afterwards, the evaluation of the patient's mother, carrying the same mutation, indicated a primary hyperparathyroidism and a 4 cm lung mass. The patient underwent subtotal pneumonectomy and the histological analysis was consistent with the diagnosis of a typical bronchial carcinoid. In conclusion, an atypical phenotype may be recorded in MEN1 families, thus emphasizing the importance of the new imaging and surgical techniques in the diagnosis and treatment of such a rare disease.

  7. Gastro-entero-pancreatic neuroendocrine tumors: Is now time for a new approach?

    PubMed

    Berardi, Rossana; Torniai, Mariangela; Savini, Agnese; Rinaldi, Silvia; Cascinu, Stefano

    2016-04-10

    Gastro-entero-pancreatic tumors (GEP-NETs) are rare neoplasms often characterized by an overexpression of somatostatin receptors. Thus, radiolabeled somatostatin analogues have showed an increasing relevance both in diagnosis and treatment, especially in low- and intermediate-differentiated GEP-NETs. These evidences have led to a growing development of new functional imaging techniques as 68Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) proved useful in the management of these neoplasms. However these tumors have a heterogeneous behavior also modifying their aggressiveness through time. Therefore sometimes 18F-fluorodeoxyglucose PET/CT appears to be more appropriate to obtain a better assessment of the disease. According to these considerations, the combination of different functional imaging techniques should be considered in the management of GEP-NETs patients allowing clinicians to choose the tailored therapeutic approach among available options.

  8. Best sensitivity of (18)F-FDOPA PET/CT to detect metastasis in one case of neuroendocrine tumour of the ileum.

    PubMed

    Testart Dardel, N; Montravers, F; Triviño-Ibañez, E; Gauthé, M; Houry, S; Talbot, J N

    Neuroendocrine tumours (NET) are heterogeneous and frequently spread over the body, making their imaging difficult. With this aim, nuclear medicine imaging, using PET or SPECT with different tracers, has been proposed for decades, but there is currently no consensus on the most appropriate technique, even when only considering gastrointestinal NET. The case is presented of a 67year old woman with a well differentiated NET of the ileum with suspected recurrence, which was not detected by any imaging technique except (18)F-FDOPA PET/CT. Subsequent follow up showed disease progression, which confirmed the true positivity of (18)F-FDOPA. Using this case, we discuss and compare different radiotracers for the diagnosis of gastrointestinal NET, focusing on those embryologically originating from the mid-gut. Copyright © 2016 Elsevier España, S.L.U. y SEMNIM. All rights reserved.

  9. Role of hepatic intra-arterial therapies in metastatic neuroendocrine tumours (NET): guidelines from the NET-Liver-Metastases Consensus Conference

    PubMed Central

    Kennedy, Andrew; Bester, Lourens; Salem, Riad; Sharma, Ricky A; Parks, Rowan W; Ruszniewski, Philippe

    2015-01-01

    Objectives Liver metastasis from a neuroendocrine tumour (NET) represents a significant clinical entity. A multidisciplinary group of experts was convened to develop state-of-the-art recommendations for its management. Methods Peer-reviewed published reports on intra-arterial therapies for NET hepatic metastases were reviewed and the findings presented to a jury of peers. The therapies reviewed included transarterial embolization (TAE), transarterial chemoembolization (TACE) and radioembolization (RE). Two systems were used to evaluate the level of evidence in each publication: (i) the US National Cancer Institute (NCI) system, and (ii) the GRADE system. Results Eighteen publications were reviewed. These comprised 11 reports on TAE or TACE and seven on RE. Four questions posed to the panel were answered and recommendations offered. Conclusions Studies of moderate quality support the use of TAE, TACE and RE in hepatic metastases of NETs. The quality and strength of the reports available do not allow any modality to be determined as superior in terms of imaging response, symptomatic response or impact on survival. Radioembolization may have advantages over TAE and TACE because it causes fewer side-effects and requires fewer treatments. Based on current European Neuroendocrine Tumor Society (ENETS) Consensus Guidelines, RE can be substituted for TAE or TACE in patients with either liver-only disease or those with limited extrahepatic metastases. PMID:25186181

  10. Molecular imaging of late somatostatin receptor-positive metastases of renal cell carcinoma in the pancreas by 68Ga DOTATOC PET/CT: a rare differential diagnosis to multiple primary pancreatic neuroendocrine tumors.

    PubMed

    Peter, Luisa; Sänger, Jörg; Hommann, Merten; Baum, Richard Paul; Kaemmerer, Daniel

    2014-08-01

    Ga somatostatin receptor PET/CT, currently the most sensitive imaging modality for well-differentiated neuroendocrine tumors, is based on the molecular imaging of somatostatin receptors (SSTRs) that are expressed in different tumor entities such as neuroendocrine neoplasms, lymphomas, meningiomas, or renal cell cancer (RCC). Most neuroendocrine neoplasms show a high expression of SSTR subtypes 2A and 5, whereas the overexpression of SSTR2A in RCC is mainly seen in peritumoral vessels. Here we report a case with strongly SSTR-positive pancreatic lesions detected by Ga DOTATOC PET/CT, which histologically turned out to be ultralate metastases of a RCC.

  11. Immunoregulatory Forkhead Box Protein p3-Positive Lymphocytes Are Associated with Overall Survival in Patients with Pancreatic Neuroendocrine Tumors.

    PubMed

    de Reuver, Philip R; Mehta, Shreya; Gill, Preetjote; Andrici, Juliana; D'Urso, Lisa; Clarkson, Adele; Mittal, Anubhav; Hugh, Thomas J; Samra, Jaswinder S; Gill, Anthony J

    2016-03-01

    Forkhead box protein p3-positive (FoxP3(+)) regulatory T cells (Tregs) suppress host T-cell-mediated immune responses, limit surveillance against cancers, and have been associated with a poor prognosis. This study aims to identify the prognostic significance of FoxP3(+) Tregs in pancreatic neuroendocrine tumors (PNETs). Patients diagnosed with PNETs between 1992 and 2014 (n = 101) were included in this retrospective analysis. Clinical data, histopathology, and expression of FoxP3(+) Tregs and Ki-67 by immunohistochemistry were assessed. The association of these factors with survival was tested by log-rank test and in additional multivariable analysis. A total of 101 patients were included in this study. Mean age was 58.0 years (range 18 to 87 years) and median tumor size was 25 mm (range 8 to 160 mm). The degree of infiltration of tumor by FoxP3(+) Tregs was graded as 0 (n = 75), 1 (n = 15), or 2 (n = 11). Median follow-up was 50 months (interquartile range 123 months; Q1 = 20 months and Q3 = 123 months). In univariate analyses, patient age older than 57 years, TNM stage III or IV, tumor size >25 mm, Ki-67 labeling index >20, and a high number of FoxP3(+) tumor-infiltrating lymphocytes were significantly associated with poorer overall survival. In multivariable analyses, FoxP3(+) expression score of 2 (hazard ratio = 6.9; 95% CI 1.4-34.4) was the only statistically significant predictor for overall mortality. FoxP3(+) Treg expression is an independent prognostic factor in patients with PNETs, associated with statistically significant shorter overall survival. There is a role for additional research into the immune-mediated role of FoxP3(+) Tregs in PNETs. Copyright © 2016 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

  12. Altered PTEN, ATRX, CHGA, CHGB & TP53 Expression are Associated with Aggressive VHL-Associated Pancreatic Neuroendocrine Tumors

    PubMed Central

    Weisbrod, Allison B.; Zhang, Lisa; Jain, Meenu; Barak, Stephanie; Quezado, Martha M.; Kebebew, Electron

    2013-01-01

    Von Hippel-Lindau (VHL) syndrome is an inherited cancer syndrome in which 8-17% of germline mutation carriers develop pancreatic neuroendocrine tumors (PNETs). There is limited data on prognostic markers for PNETs other than Ki-67, which is included in the World Health Organization classification system. Recently, specific genes and pathways have been identified by whole exome sequencing which may be involved in the tumorigenesis of PNETs and may be markers of disease aggressiveness. The objective of this study was to identify molecular markers of aggressive disease in VHL-associated PNETs. The protein expression of 8 genes (PTEN, CHGA, CHGB, ATRX, DAXX, CC-3, VEGF, TP53) was analyzed in PNETs by immunohistochemistry and compared to clinical data, VHL genotype, functional imaging results, and pathologic findings. Subcellular distribution of PTEN, CHGA and ATRX were significantly different by WHO classifications (p<0.05). There was decreased PTEN nuclear to cytoplasmic ratio (p<0.01) and decreased CHGA nuclear expression (p=0.03) in malignant samples as compared to benign. Lower cytoplasmic CHGB expression (p=0.03) was associated with malignant tumors and metastasis. Higher nuclear expression of PTEN was associated with VHL mutations in exon 3 (p=0.04). Higher PTEN and CHGB expression was associated with higher FDG-PET avidity (p<0.05). Cytoplasmic expression of CC-3 was associated with higher serum Chromogranin A levels (σ=0.72, p= 0.02). Lastly, greater cytoplasmic expression of p53 was associated with metastasis. Our findings suggest that altered PTEN, ATRX, CHGA and CHGB expression are associated with aggressive PNET phenotype in VHL and may serve as useful adjunct prognostic markers to Ki-67 in PNETs. PMID:23361940

  13. Genes involved in angiogenesis and mTOR pathways are frequently mutated in Asian patients with pancreatic neuroendocrine tumors

    PubMed Central

    Chou, Wen-Chi; Lin, Po-Han; Yeh, Yi-Chen; Shyr, Yi-Ming; Fang, Wen-Liang; Wang, Shin-E; Liu, Chun-Yu; Chang, Peter Mu-Hsin; Chen, Ming-Han; Hung, Yi-Ping; Li, Chung-Pin; Chao, Yee; Chen, Ming-Huang

    2016-01-01

    Introduction: To address the issue of limited data on and inconsistent findings for genetic alterations in pancreatic neuroendocrine tumors (pNETs), we analyzed sequences of known pNET-associated genes for their impact on clinical outcomes in a Taiwanese cohort. Methods: Tissue samples from 40 patients with sporadic pNETs were sequenced using a customized sequencing panel that analyzed 43 genes with either an established or potential association with pNETs. Genetic mutations and clinical outcomes were analyzed for potential associations. Results: Thirty-three patients (82.5%) survived for a median 5.9 years (range, 0.3-18.4) of follow up. The median number of mutations per patient was 3 (range, 0-16). The most frequent mutations were in ATRX (28%), MEN1 (28%), ASCL1 (28%), TP53 (20%), mTOR (20%), ARID1A (20%), and VHL (20%). The mutation frequencies in the MEN1 (including MEN1/PSIP1/ARID1A), mTOR (including mTOR/PIK3CA/AKT1/PTEN /TS1/TSC2/ATM), DAXX/ATRX, and angiogenesis (including VHL/ANGPT1/ANGPT2 /HIF1A) pathways were 48%, 48%, 38%, and 45%, respectively. Mutations in ATRX were associated with WHO grade I pNET (vs. grade II or III, p = 0.043), and so were those in genes involved in angiogenesis (p = 0.002). Patients with mutated MEN1 and DAXX/ATRX pathways showed a trend toward better survival, compared to patients with the wild-type genes (p = 0.08 and 0.12, respectively). Conclusion: Genetic profiles of Asian patients with pNETs were distinct from Caucasian patient profiles. Asian patients with pNETs were more frequently mutated for the mTOR and angiogenesis pathways. This could partially explain the better outcome observed for targeted therapy in Asian patients with pNETs. PMID:27994516

  14. C-Reactive Protein as a New Prognostic Factor for Survival in Patients With Pancreatic Neuroendocrine Neoplasia.

    PubMed

    Wiese, Dominik; Kampe, Katharina; Waldmann, Jens; Heverhagen, Anna E; Bartsch, Detlef K; Fendrich, Volker

    2016-03-01

    Patients with pancreatic neuroendocrine neoplasia (pNEN) show great variability in prognosis and treatment response. Additional prognostic markers might help in individual therapeutic decision making. The objective of the study was to investigate the association between preoperative plasma levels of C-reactive protein (CRP) and overall survival (OS) in pNEN. This was a single-center, retrospective analysis of long-term prospective patient-database. The study was conducted at a tertiary referral center. All 149 patients with sporadic pNENs were eligible for retrospective analysis. Cumulative overall survival, compared between patients with elevated and normal CRP levels, was measured. Median OS for patients with elevated CRP levels was 1093 days (SE 1261, 95% confidence interval [CI] 0-3565), compared with 6859 days (SE 1252, 95% CI 4405-9313) for patients with normal CRP levels. Log rank test showed a significant correlation between CRP and OS (P < .001). In univariate Cox regression, patients with elevated CRP levels had a significantly higher hazard ratio for death (3.27; 95%-CI 1.74-6.16; P < .001). This finding persisted after multivariable adjustment. Furthermore, OS was associated with the presence of liver metastases (hazard ratio 3.17; 95% CI 1.88-5.35; P < .001), incomplete resection (R1/R2 status; hazard ratio 3.99; 95% CI 2.16-7.35; P < .001) and Ki-67 percentage (hazard ratio 5.05; 95% CI 2.17-11.76; P < .001). CRP is an independent prognostic marker in patients with pNEN. Pretreatment CRP measurements should be considered for incorporation into prospective studies of outcome in patients with pNENs and clinical trials of systemic therapies for these tumors.

  15. FDA Approval Summary: Sunitinib for the Treatment of Progressive Well-Differentiated Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors

    PubMed Central

    Cortazar, Patricia; Zhang, Jenny J.; Tang, Shenghui; Sridhara, Rajeshwari; Murgo, Anthony; Justice, Robert; Pazdur, Richard

    2012-01-01

    On May 20, 2011, the U.S. Food and Drug Administration (FDA) approved sunitinib malate capsules (Sutent®; Pfizer, Inc., New York) for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNETs) in patients with unresectable locally advanced or metastatic disease. In a phase III randomized trial, 171 patients received either sunitinib (37.5 mg) or placebo once daily. The progression-free survival (PFS) interval was the primary efficacy endpoint. Secondary endpoints included the overall survival (OS) time, objective response rate (ORR), patient-reported outcomes, and safety. Based on early results favoring sunitinib, the independent data monitoring committee recommended trial termination prior to the prespecified interim analysis. This premature analysis may have led to an overestimate of the treatment effect. In the FDA analysis of investigator-assessed PFS times, the median values for the sunitinib and placebo arms were 10.2 months and 5.4 months, respectively. The ORRs were 9.3% and 0% in the sunitinib and placebo arms, respectively. The OS data were not mature at the time of approval and were confounded by 69% crossover. Common adverse reactions in patients receiving sunitinib included diarrhea, nausea, asthenia, fatigue, neutropenia, hypertension, and palmar–plantar erythrodysesthesia syndrome. Two patients on sunitinib died as a result of cardiac failure. The Oncologic Drugs Advisory Committee voted eight to two that, despite residual uncertainty about the magnitude of the PFS effect because of early trial termination, sunitinib demonstrated a favorable benefit–risk profile in pNET patients. The FDA concurred with the committee's assessment and granted sunitinib regular approval for this rare malignancy with few available therapies. PMID:22836448

  16. FDA approval summary: sunitinib for the treatment of progressive well-differentiated locally advanced or metastatic pancreatic neuroendocrine tumors.

    PubMed

    Blumenthal, Gideon M; Cortazar, Patricia; Zhang, Jenny J; Tang, Shenghui; Sridhara, Rajeshwari; Murgo, Anthony; Justice, Robert; Pazdur, Richard

    2012-01-01

    On May 20, 2011, the U.S. Food and Drug Administration (FDA) approved sunitinib malate capsules (Sutent®; Pfizer, Inc., New York) for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNETs) in patients with unresectable locally advanced or metastatic disease. In a phase III randomized trial, 171 patients received either sunitinib (37.5 mg) or placebo once daily. The progression-free survival (PFS) interval was the primary efficacy endpoint. Secondary endpoints included the overall survival (OS) time, objective response rate (ORR), patient-reported outcomes, and safety. Based on early results favoring sunitinib, the independent data monitoring committee recommended trial termination prior to the prespecified interim analysis. This premature analysis may have led to an overestimate of the treatment effect. In the FDA analysis of investigator-assessed PFS times, the median values for the sunitinib and placebo arms were 10.2 months and 5.4 months, respectively. The ORRs were 9.3% and 0% in the sunitinib and placebo arms, respectively. The OS data were not mature at the time of approval and were confounded by 69% crossover. Common adverse reactions in patients receiving sunitinib included diarrhea, nausea, asthenia, fatigue, neutropenia, hypertension, and palmar-plantar erythrodysesthesia syndrome. Two patients on sunitinib died as a result of cardiac failure. The Oncologic Drugs Advisory Committee voted eight to two that, despite residual uncertainty about the magnitude of the PFS effect because of early trial termination, sunitinib demonstrated a favorable benefit-risk profile in pNET patients. The FDA concurred with the committee's assessment and granted sunitinib regular approval for this rare malignancy with few available therapies.

  17. Reduced Expression of the Polymeric Immunoglobulin Receptor in Pancreatic and Periampullary Adenocarcinoma Signifies Tumour Progression and Poor Prognosis

    PubMed Central

    Fristedt, Richard; Elebro, Jacob; Gaber, Alexander; Jonsson, Liv; Heby, Margareta; Yudina, Yulyana; Nodin, Björn; Uhlén, Mathias; Eberhard, Jakob; Jirström, Karin

    2014-01-01

    The polymeric immunoglobulin receptor (pIgR) is a key component of the mucosal immune system that mediates epithelial transcytosis of immunoglobulins. High pIgR expression has been reported to correlate with a less aggressive tumour phenotype and an improved prognosis in several human cancer types. Here, we examined the expression and prognostic significance of pIgR in pancreatic and periampullary adenocarcinoma. The study cohort encompasses a consecutive series of 175 patients surgically treated with pancreaticoduodenectomy for pancreatic and periampullary adenocarcinoma in Malmö and Lund University Hospitals, Sweden, between 2001–2011. Tissue microarrays were constructed from primary tumours (n = 175) and paired lymph node metastases (n = 105). A multiplied score was calculated from the fraction and intensity of pIgR staining. Classification and regression tree analysis was used to select the prognostic cut-off. Unadjusted and adjusted hazard ratios (HR) for death and recurrence within 5 years were calculated. pIgR expression could be evaluated in 172/175 (98.3%) primary tumours and in 96/105 (91.4%) lymph node metastases. pIgR expression was significantly down-regulated in lymph node metastases as compared with primary tumours (p = 0.018). Low pIgR expression was significantly associated with poor differentiation grade (p<0.001), perineural growth (p = 0.027), lymphatic invasion (p = 0.016), vascular invasion (p = 0.033) and infiltration of the peripancreatic fat (p = 0.039). In the entire cohort, low pIgR expression was significantly associated with an impaired 5-year survival (HR = 2.99, 95% confidence interval (CI) 1.71–5.25) and early recurrence (HR = 2.89, 95% CI 1.67–4.98). This association remained significant for survival after adjustment for conventional clinicopathological factors, tumour origin and adjuvant treatment (HR = 1.98, 95% CI 1.10–3.57). These results demonstrate, for the first time, that high

  18. Biokinetics and dosimetry with 177Lu-DOTA-TATE in athymic mice with induced pancreatic malignant tumours

    NASA Astrophysics Data System (ADS)

    Rodríguez-Cortés, J.; de Murphy, C. Arteaga; Ferro-Flores, Ge; Pedraza-López, M.; Murphy-Stack, E.

    Malignant pancreatic tumours induced in athymic mice are a good model for peptide receptor targeted radiotherapy. The objective of this research was to determine biokinetic parameters in mice, in order to estimate the induced pancreatic tumour absorbed doses and to evaluate an `in house' 177Lu-DOTA-TATE radiopharmaceutical as part of preclinical studies for targeted therapy in humans. AR42J murine pancreas cancer cells expressing somatostatin receptors, were implanted in athymic mice (nD22) to obtain biokinetic and dosimetric data of 177Lu-DOTA-TATE. The mean tumour uptake 2 h post injection was 14.76±1.9% I.A./g; kidney and pancreas uptake, at the same time, were 7.27±1.1% I.A./g (1.71±0.90%/organ) and 4.20±0.98% I.A./g (0.42±0.03%/organ), respectively. The mean absorbed dose to tumour, kidney and pancreas was 0.58±0.02 Gy/MBq; 0.23±0.01 Gy/MBq and 0.14±0.01 Gy/MBq, respectively. These studies justify further dosimetric estimations to ensure that 177Lu-DOTA-TATE will act as expected in humans.

  19. Relevant infrastructural alterations in a pancreatic neuroendocrine tumor: an insulinoma case.

    PubMed

    Mirancea, Gabriel-Valeriu; Moroşanu, Ana-Maria; Carniciu, Simona; Dima, Simona; Bacalbaşa, Nicolae; Popescu, Irinel; Ionescu-Tîrgovişte, Constantin; Mirancea, Nicolae

    2014-01-01

    In this study, we focus our interest on some peculiar infrastructural abnormalities detected in an insulinoma case. Tumor pancreatic endocrine cells proliferated detrimental to exocrine counterpart, so that extensive areas of prevalent β-tumor cells can be seen. Two phenotypes of β-tumor cells can be identified: (1) β-tumor cells with full euchromatic and nucleolated nuclei and (2) β-tumor cells with heterochromatic and shrink nuclei. Because of stroma alteration, including basement membrane, cell-extracellular matrix junctions are also compromised. The mostly striking and important finding in this report for a case of insulinoma is the high fragility of plasma membrane of both two phenotypes of β-tumor cells. Cell-cell junctions, especially desmosomal junctions are severely altered, almost missing, plasma membranes showed shedding membrane vesicles and extensive dissolutions leading to pseudo-syncytia formation. Extravasated blood cells, including inflammatory cells contribute to the dramatic and extensive destructive areas of epithelial cells as well as stroma counterpart. Moreover, also the inner cell cytomembranes exhibit abnormalities: many β-tumor cells have excessive dilatations of nuclear envelope and endoplasmic reticulum. All above severe infrastructural abnormalities, especially down regulation of cell-cell and cell-extracellular matrix adhesions and plasma membranes fragility might result in aberrant cell behavior and, consequently, much care should be taken for the postoperatory patient evolution.

  20. Sunitinib treatment for multifocal renal cell carcinoma (RCC) and pancreatic neuroendocrine tumor (NET) in patient with Von Hippel-Lindau disease. Case Report.

    PubMed

    Babinska, Anna; Studniarek, Michał; Świątkowska-Stodulska, Renata; Sworczak, Krzysztof

    2015-12-01

    Von Hippel-Lindau disease (VHL) is an autosomal, dominant, hereditary disease occurring in approximately one in 36,000 births. VHL disease produces a variety of tumors and cysts in the central nervous system and visceral organs. Surgical management, when possible, improves prognosis and extends patient's life. When surgery is impossible, treatment with tyrosine kinase inhibitors demonstrates encouraging response rates. We present a 60-year old patient with coexistence of multifocal renal cell carcinomas (RCC) and pancreatic neuroendocrine tumor (NET) in VHL disease, who received Sunitinib as the best option of treatment. Progression - free survival time is over 4 years. Regarding her acceptable tolerance for tyrosine kinase inhibitors, medical treatment is continued. RCC and pancreatic NET associated with VHL are responsive to Sunitinib for prolonged periods of time. Tyrosine kinase inhibitors treatment for patients with multiple neoplasms associated with VHL disease may too be considered. Sunitinib showed acceptable toxicity.

  1. In vivo molecular imaging of somatostatin receptors in pancreatic islet cells and neuroendocrine tumors by miniaturized confocal laser-scanning fluorescence microscopy.

    PubMed

    Fottner, C; Mettler, E; Goetz, M; Schirrmacher, E; Anlauf, M; Strand, D; Schirrmacher, R; Klöppel, G; Delaney, P; Schreckenberger, M; Galle, P R; Neurath, M F; Kiesslich, R; Weber, M M

    2010-05-01

    The aim of the study was to evaluate real time in vivo molecular imaging of somatostatin receptors (sstrs) using a handheld miniaturized confocal laser scan microscope (CLM) in conjunction with fluorescein-labeled octreotate (OcF) in healthy mice and murine models of neuroendocrine tumors. For CLM a small rigid probe (diameter 7 mm) with an integrated single line laser (488 nm) was used (optical slice thickness 7 mum; lateral resolution 0.7 mum). OcF was synthesized via Fmoc solid-phase peptide synthesis and purified by HPLC showing high-affinity binding to the sstr2 (IC(50) 6.2 nmol). For in vitro evaluation, rat and human pancreatic cancer cells were used and characterized with respect to its sstr subtype expression and functional properties. For in vivo confocal imaging, healthy mouse pancreatic islet and renal tubular cells as well as immunoincompetent nude mice harboring sstr-expressing tumors were evaluated. Incubation of sstr-positive cells with OcF showed a specific time- and dose-dependent staining of sstr-positive cells. CLM showed rapid internalization and homogenous cytoplasmatic distribution. After systemic application to mice (n = 8), specific time-dependent internalization and cytoplasmatic distribution into pancreatic islet cells and tubular cells of the renal cortex was recorded. After injection in tumor-harboring nude mice (n = 8), sstr-positive cells selectively displayed a cell surface and cytoplasmatic staining. CLM-targeted biopsies detected sstr-positive tumor cells with a sensitivity of 87.5% and a specificity of 100% as correlated with ex vivo immunohistochemistry. CLM with OcF permits real-time molecular, functional, and morphological imaging of sstr-expressing cell structures, allowing the specific visualization of pancreatic islet cells and neuroendocrine tumors in vivo.

  2. 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.

  3. Lipid-rich variant of pancreatic endocrine tumour with inhibin positivity and microscopic foci of microcystic adenoma-like areas: emphasis on histopathology.

    PubMed

    Rao, Anuradha Calicut Kini; Monappa, Vidya; Shetty, Prashanth

    2013-02-01

    Pancreatic endocrine tumours (PETs) are uncommon tumours with typical morphology characterised by relatively uniform cuboidal cells arranged in nests and festoons, with distinctive nuclear salt-and-pepper chromatin. A lipid-rich variant poses diagnostic difficulties in the midst of other pancreatic tumours and metastatic goblet cell carcinoid. A 22-year-old man presented with symptoms of abdominal pain and jaundice. His liver function test and blood glucose level were normal, but computed tomography of the abdomen suggested the presence of a tumour in the head of the pancreas. Specimen obtained by pancreaticoduodenectomy revealed an infiltrating yellow-tan tumour composed of nests and a cribriform arrangement of polygonal vacuolated cells with pyknotic nuclei, along with focal classical areas of PET. Two foci of early serous microcystic adenoma were seen. Immunohistochemistry contributed to the arrival of a conclusive diagnosis. Von Hippel-Lindau disease was excluded in our patient, as other supportive classical features of the syndrome were absent.

  4. Metastases of pancreatic neuroendocrine tumor to the liver as extremely rare indication for liver transplantation in children. Case report and review of the literature.

    PubMed

    Ismail, Hor; Broniszczak, Dorota; Markiewicz-Kijewska, Małgorzata; Ciopiński, Mateusz; Teisseyre, Joanna; Kluge, Przemysław; Dembowska-Bagińska, Bożenna; Kościesza, Andrzej; Socha, Piotr; Kaliciński, Piotr

    2016-09-01

    Neuroendocrine tumors (NET) are extremely rare in children (0.75 cases per 100,000 children and adolescents a year) and the majority of these tumors are benign or present low grade of malignancy. According to the American registry Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute, less than 2% of all neuroendocrine tumors in children occur in the pancreas, making it a rare site for these tumors. The majority of them are found in children over 10years of age, especially those with malignant potential. Treatment of NET consists of different methods: surgery, somatostatin analogues and chemotherapy. Radical surgical resection remains the standard of treatment; however, it is not always feasible because of distant metastases. The authors present a case report of pancreatic NET with multiple metastases to the liver. The patient was treated with pancreatic resection and liver transplantation for liver metastases. Prior to liver transplantation, the patient was treated with somatostatin analogues, sunitinib and chemotherapy. Management of liver metastases with liver transplantation is discussed.

  5. Combination of tumour markers CEA and CA19-9 improves the prognostic prediction in patients with pancreatic cancer.

    PubMed

    Reitz, Daniel; Gerger, Armin; Seidel, Julia; Kornprat, Peter; Samonigg, Hellmut; Stotz, Michael; Szkandera, Joanna; Pichler, Martin

    2015-06-01

    Tumour markers including carcinoembryonic antigen (CEA) or carbohydrate antigen 19-9 (CA19-9) are frequently determined at the time of diagnosis in patients with pancreatic cancer. Several studies indicate a prognostic relevance of these markers in pancreatic cancer, but space for improvement with regard to the predictive accuracy and ability is given. In this work, the main focus is on mathematical combinations of these two tumour markers in order to validate an improvement of prognostic test results in terms of sensitivity and specificity. This retrospective study includes 393 patients with pancreatic cancer, who were treated between the years 2005 and 2012 at the Division of Oncology, Medical University of Graz, Austria. The goal of this study was to explore whether an appropriate combination of two tumour markers leads to a statistically significant improvement of the prognostic prediction. Receiver operating characteristic curves comparison analyses with the classification variable cancer-specific survival showed that the mathematical product of two tumour markers (TM(product)= (CEA×CA19-9); area under the curve (AUC)=0.727; 95% CI 0.680 to 0.770) is significantly better than CEA alone (AUC=0.644; 95% CI 0.594 to 0.691; p=0.003) but not significant compared with CA19-9 (AUC=0.710; 95% CI 0.662 to 0.754; p=0.1215). A linear combination of CEA and CA19-9 (TM(linear)=(85×CEA+CA19-9); AUC=0.748; 95% CI 0.702 to 0.790) is significantly better than CEA (p<0.0001) as well as CA19-9 alone (p=0.0304). Mathematical combinations of pretherapeutic tumour markers CEA and CA19-9 are feasible and can significantly improve the prognostic prediction in patients with pancreatic cancer. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  6. Sonoporation with Acoustic Cluster Therapy (ACT®) induces transient tumour volume reduction in a subcutaneous xenograft model of pancreatic ductal adenocarcinoma.

    PubMed

    Kotopoulis, Spiros; Stigen, Endre; Popa, Mihaela; Safont, Mireia Mayoral; Healey, Andrew; Kvåle, Svein; Sontum, Per; Gjertsen, Bjørn Tore; Gilja, Odd Helge; McCormack, Emmet

    2017-01-10

    Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers with survival averaging only 3months if untreated following diagnosis. A major limitation in effectively treating PDAC using conventional and targeted chemotherapeutic agents, is inadequate drug delivery to the target location, predominantly due to a poorly vascularised, desmoplastic tumour microenvironment. Ultrasound in combination with ultrasound contrast agents, i.e., microbubbles, that flow through the vasculature and capillaries can be used to disrupt such mechanical barriers, potentially allowing for a greater therapeutic efficacy. This phenomenon is commonly referred to as sonoporation. In an attempt to improve the efficacy of sonoporation, novel microbubble formulations are being developed to address the limitation of commercially produced clinical diagnostic ultrasound contrast agents. In our work here we evaluate the ability of a novel formulation; namely Acoustic Cluster Therapy (ACT®) to improve the therapeutic efficacy of the chemotherapeutic agent paclitaxel, longitudinally in a xenograft model of PDAC. Results indicated that ACT® bubbles alone demonstrated no observable toxic effects, whilst ACT® in combination with paclitaxel can transiently reduce tumour volumes significantly, three days posttreatment (p=0.0347-0.0458). Quantitative 3D ultrasound validated the calliper measurements. Power Doppler ultrasound imaging indicated that ACT® in combination with paclitaxel was able to transiently sustain peak vasculature percentages as observed in the initial stages of tumour development. Nevertheless, there was no significant difference in tumour vasculature percentage at the end of treatment. The high vascular percentage correlated to the transient decrease and overall inhibition of the tumour volumes. In conclusion, ACT® improves the therapeutic efficacy of paclitaxel in a PDAC xenograft model allowing for transient tumour volume reduction and sustained tumour vasculature

  7. Alternative Lengthening of Telomeres in Primary Pancreatic Neuroendocrine Tumors Is Associated with Aggressive Clinical Behavior and Poor Survival.

    PubMed

    Kim, Joo Young; Brosnan-Cashman, Jacqueline A; An, Soyeon; Kim, Sung Joo; Song, Ki-Byung; Kim, Min-Sun; Kim, Mi-Ju; Hwang, Dae Wook; Meeker, Alan K; Yu, Eunsil; Kim, Song Cheol; Hruban, Ralph H; Heaphy, Christopher M; Hong, Seung-Mo

    2017-03-15

    Purpose: Alternative lengthening of telomeres (ALT), a telomerase-independent telomere maintenance mechanism, is strongly associated with ATRX and DAXX alterations and occurs frequently in pancreatic neuroendocrine tumors (PanNET).Experimental Design: In a Korean cohort of 269 surgically resected primary PanNETs and 19 sporadic microadenomas, ALT status and nuclear ATRX and DAXX protein expression were assessed and compared with clinicopathologic factors.Results: In PanNETs, ALT or loss of ATRX/DAXX nuclear expression was observed in 20.8% and 19.3%, respectively, whereas microadenomas were not altered. ALT-positive PanNETs displayed a significantly higher grade, size, and pT classification (all, P < 0.001). ALT also strongly correlated with lymphovascular (P < 0.001) and perineural invasion (P = 0.001) and the presence of lymph node (P < 0.001) and distant metastases (P = 0.002). Furthermore, patients with ALT-positive primary PanNETs had a shorter recurrence-free survival [HR = 3.38; 95% confidence interval (CI), 1.83-6.27; P < 0.001]. Interestingly, when limiting to patients with distant metastases, those with ALT-positive primary tumors had significantly better overall survival (HR = 0.23; 95% CI, 0.08-0.68; P = 0.008). Similarly, tumors with loss of ATRX/DAXX expression were significantly associated with ALT (P < 0.001), aggressive clinical behavior, and reduced recurrence-free survival (P < 0.001). However, similar to ALT, when limiting to patients with distant metastases, loss of ATRX/DAXX expression was associated with better overall survival (P = 0.003).Conclusions: Both primary ALT-positive and ATRX/DAXX-negative PanNETs are independently associated with aggressive clinicopathologic behavior and displayed reduced recurrence-free survival. In contrast, ALT activation and loss of ATRX/DAXX are both associated with better overall survival in patients with metastases. Therefore, these biomarkers may be used as prognostic markers depending on the context of

  8. Src family kinase activity regulates adhesion, spreading and migration of pancreatic endocrine tumour cells.

    PubMed

    Di Florio, Alessia; Capurso, Gabriele; Milione, Massimo; Panzuto, Francesco; Geremia, Raffaele; Delle Fave, Gianfranco; Sette, Claudio

    2007-03-01

    Pancreatic endocrine tumours (PETs) are rare and 'indolent' neoplasms that usually develop metastatic lesions and exhibit poor response to standard medical treatments. Few studies have investigated pathways responsible for PET cell growth and invasion and no alternative therapeutic strategies have been proposed. In a recent microarray analysis for genes up-regulated in PETs, we have described the up-regulation of soluble Src family tyrosine kinases in this neoplasia, which may represent potentially promising candidates for therapy. Herein, we have investigated the expression and function of Src family kinases in PETS and PET cell lines. Western blot analysis indicated that Src is highly abundant in the PET cell lines CM and QGP-1. Immunohistochemistry and Western blot analyses showed that Src is up-regulated also in human PET lesions. Pharmacological inhibition of Src family kinases by the specific inhibitor PP2 strongly interfered with adhesion, spreading and migration of PET cell lines. Accordingly, the actin cytoskeleton was profoundly altered after inhibition of Src kinases, whereas even prolonged incubation with PP2 exerted no effect on cell cycle progression and/or apoptosis of PET cells. A transient increase in tyrosine phosphorylation of a subset of proteins was observed in QGP-1 cells adhering to the plate, with a peak at 75 min after seeding, when approximately 80% of cells were attached. Inhibition of Src kinases caused a dramatic reduction in the phosphorylation of proteins with different molecular weight that were isolated from the cell extracts by anti-phosphotyrosine immunoprecipitation or pull-down with the SH2 domain of Src. Among them, the docking protein p130Cas interacted with Src and is a major substrate of the Src kinases in QGP-1 cells undergoing adhesion. Our results suggest that Src kinases play a specific role during adhesion, spreading and migration of PET cells and may indicate therapeutical approaches directed to limiting the metastatic

  9. 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.

  10. Induction of matrix metalloprotease-1 gene expression by retinoic acid in the human pancreatic tumour cell line Dan-G

    PubMed Central

    Marschall, Z von; Riecken, E-O; Rosewicz, S

    1999-01-01

    We have investigated the effects of retinoic acid (RA) on matrix metalloprotease-1 (MMP-1) gene expression in the human pancreatic tumour cell line Dan-G. 13-cis RA results in a time- and dose-dependent increase of MMP-1 protein concentration. These stimulatory effects were paralleled by a time- and dose-dependent increase of MMP-1 mRNA steady-state concentrations. Nuclear run-on analysis revealed that the increase of MMP-1 mRNA was partially due to an increase of MMP-1 gene transcription. In addition, 13-cis RA treatment results in an increase of MMP-1 mRNA stability. These data demonstrate that RA stimulates MMP-1 gene expression in human pancreatic carcinoma cells by transcriptional and post-transcriptional mechanisms. © 1999 Cancer Research Campaign PMID:10362099

  11. GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer

    PubMed Central

    Martinelli, Paola; Carrillo-de Santa Pau, Enrique; Cox, Trevor; Sainz, Bruno; Dusetti, Nelson; Greenhalf, William; Rinaldi, Lorenzo; Costello, Eithne; Ghaneh, Paula; Malats, Núria; Büchler, Markus; Pajic, Marina; Biankin, Andrew V; Iovanna, Juan; Neoptolemos, John; Real, Francisco X

    2016-01-01

    Background and aims The role of GATA factors in cancer has gained increasing attention recently, but the function of GATA6 in pancreatic ductal adenocarcinoma (PDAC) is controversial. GATA6 is amplified in a subset of tumours and was proposed to be oncogenic, but high GATA6 levels are found in well-differentiated tumours and are associated with better patient outcome. By contrast, a tumour-suppressive function of GATA6 was demonstrated using genetic mouse models. We aimed at clarifying GATA6 function in PDAC. Design We combined GATA6 silencing and overexpression in PDAC cell lines with GATA6 ChIP-Seq and RNA-Seq data, in order to understand the mechanism of GATA6 functions. We then confirmed some of our observations in primary patient samples, some of which were included in the ESPAC-3 randomised clinical trial for adjuvant therapy. Results GATA6 inhibits the epithelial–mesenchymal transition (EMT) in vitro and cell dissemination in vivo. GATA6 has a unique proepithelial and antimesenchymal function, and its transcriptional regulation is direct and implies, indirectly, the regulation of other transcription factors involved in EMT. GATA6 is lost in tumours, in association with altered differentiation and the acquisition of a basal-like molecular phenotype, consistent with an epithelial-to-epithelial (ET2) transition. Patients with basal-like GATA6low tumours have a shorter survival and have a distinctly poor response to adjuvant 5-fluorouracil (5-FU)/leucovorin. However, modulation of GATA6 expression in cultured cells does not directly regulate response to 5-FU. Conclusions We provide mechanistic insight into GATA6 tumour-suppressive function, its role as a regulator of canonical epithelial differentiation, and propose that loss of GATA6 expression is both prognostic and predictive of response to adjuvant therapy. PMID:27325420

  12. Somatostatin receptor PET in neuroendocrine tumours: 68Ga-DOTA0,Tyr3-octreotide versus 68Ga-DOTA0-lanreotide.

    PubMed

    Putzer, Daniel; Kroiss, Alexander; Waitz, Dietmar; Gabriel, Michael; Traub-Weidinger, Tatjana; Uprimny, Christian; von Guggenberg, Elisabeth; Decristoforo, Clemens; Warwitz, Boris; Widmann, Gerlig; Virgolini, Irene Johanna

    2013-02-01

    The aim of this study was to evaluate the impact of (68)Ga-labelled DOTA(0)-lanreotide ((68)Ga-DOTA-LAN) on the diagnostic assessment of neuroendocrine tumour (NET) patients with low to moderate uptake on planar somatostatin receptor (SSTR) scintigraphy or (68)Ga-labelled DOTA(0),Tyr(3)-octreotide ((68)Ga-DOTA-TOC) positron emission tomography (PET). Fifty-three patients with histologically confirmed NET and clinical signs of progressive disease, who had not qualified for peptide receptor radionuclide therapy (PRRT) on planar SSTR scintigraphy or (68)Ga-DOTA-TOC PET (n = 38) due to lack of tracer uptake, underwent (68)Ga-DOTA-LAN PET to evaluate a treatment option with (90)Y-labelled lanreotide according to the MAURITIUS trial. The included patients received 150 ± 30 MBq of each radiopharmaceutical intravenously. PET scans were acquired 60-90 min after intravenous bolus injection. Image results from both PET scans were compared head to head, focusing on the intensity of tracer uptake in terms of treatment decision. CT was used for morphologic correlation of tumour lesions. To further evaluate the binding affinities of each tracer, quantitative and qualitative values were calculated for target lesions. (68)Ga-DOTA-LAN and (68)Ga-DOTA-TOC both showed equivalent findings in 24/38 patients when fused PET/CT images were interpreted. The sensitivity, specificity and accuracy of (68)Ga-DOTA-LAN in comparison to CT were 0.63, 0.5 and 0.62 (n = 53; p < 0.0001) and for (68)Ga-DOTA-TOC in comparison to CT 0.78, 0.5 and 0.76 (n = 38; p < 0.013), respectively. (68)Ga-DOTA-TOC showed a significantly higher maximum standardized uptake value (SUV(max)) regarding the primary tumour in 25 patients (p < 0.003) and regarding the liver in 30 patients (p < 0.009) compared to (68)Ga-DOTA-LAN. Corresponding values of both PET scans for tumour and liver did not show any significant correlation. (68)Ga-DOTA-TOC revealed more tumour sites than (68)Ga

  13. Current status of PET imaging of neuroendocrine tumours ([18F]FDOPA, [68Ga]tracers, [11C]/[18F]-HTP).

    PubMed

    Ambrosini, V; Morigi, J J; Nanni, C; Castellucci, P; Fanti, S

    2015-03-01

    Neuroendocrine neoplasms (NEN) functional imaging is an evolving field that witnessed major advances in the past two decades. The routine use of PET/CT with an array of new radiotracers to specifically study NEN resulted in an increase in lesions detection. Currently, PET radiopharmaceuticals for NEN imaging include both metabolic ([18F]DOPA, [18F]FDG, [11C]/[18F]-HTP) and receptor-mediated compounds ([68Ga]DOTA-peptides). Discussion is still on-going regarding the clinical setting that may benefit the most from the use of one tracer over the other. [68Ga]DOTA-peptides are accurate for the detection of well differentiated NEN and are increasingly employed. Moreover, providing data on somatostatin receptors expression on NEN cells, they represent a fundamental procedure to be performed before starting therapy, as well as to guide treatment, with either hot or cold somatostatin analogues. The easy and economic synthesis process also favours their clinical employment even in centres without an on-site cyclotron. [18F]DOPA is accurate for studying well differentiated tumours however the difficult and expensive synthesis have limited its clinical employment. It currently can be successfully used for imaging tumours with variable to low expression of SSR (medullary thyroid carcinoma, neuroblastoma, pheocromocytoma), that cannot be accurately studied with [68Ga]DOTA-peptides. [11C]/[18F]-HTP has also been proposed to image well differentiated NEN, on the basis of serotonin pathway activity, for which [11C]/[18F]-HTP can be used as precursor. However, although preliminary data are encouraging, the feasibility of its widespread clinical use is still under discussion, mainly limited by a complex synthesis process and more proven advantages over other currently employed compounds. This review aims to provide an overview of the current status and clinical application of PET tracers to image well differentiated NEN and to focus on the still open-issues of debate.

  14. The somatostatin receptor-targeted radiotherapeutic [90Y-DOTA-DPhe1, Tyr3]octreotide (90Y-SMT 487) eradicates experimental rat pancreatic CA 20948 tumours.

    PubMed

    Stolz, B; Weckbecker, G; Smith-Jones, P M; Albert, R; Raulf, F; Bruns, C

    1998-07-01

    Somatostatin receptor-expressing tumours are potential targets for therapy with radiolabelled somatostatin analogues. We have synthesized a number of such analogues in the past and identified [DOTA-dPhe1, Tyr3]octreotide (SMT 487) as the most promising candidate molecule because of its advantageous properties in cellular and in vivo tumour models. In the current paper we describe the radiotherapeutic effect of yttrium-90 labelled SMT 487 in Lewis rats bearing the somatostatin receptor-positive rat pancreatic tumour CA 20948. SMT 487 binds with nanomolar affinity to both the human and the rat somatostatin receptor subtype 2 (sst2) (human sst2 IC50=0.9 nM, rat sst2 IC50=0.5 nM). In vivo, 90Y-SMT 487 distributed rapidly to the sst2 expressing CA 20948 rat pancreatic tumour, with a tumour-to-blood ratio of 49.15 at 24 h post injection. A single intravenous administration of 10 mCi/kg 90Y-SMT 487 resulted in a complete remission of the tumours in five out of seven CA 20948 tumour-bearing Lewis rats. No regrowth of the tumours occurred 8 months post injection. Control animals that were treated with 30 microg/kg of unlabelled SMT 487 had to be sacrificed 10 days post injection due to excessive growth or necrotic areas on the tumour surface. Upon re-inoculation of tumour cells into those rats that had shown complete remission, the tumours disappeared after 3-4 weeks of moderate growth without any further treatment. The present study shows for the first time the curative potential of 90Y-SMT 487-based radiotherapy for somatostatin receptor-expressing tumours. Clinical phase I studies with yttrium-labelled SMT 487 have started in September 1997.

  15. Survival Analyses for Patients With Surgically Resected Pancreatic Neuroendocrine Tumors by World Health Organization 2010 Grading Classifications and American Joint Committee on Cancer 2010 Staging Systems.

    PubMed

    Yang, Min; Ke, Neng-wen; Zeng, Lin; Zhang, Yi; Tan, Chun-lu; Zhang, Hao; Mai, Gang; Tian, Bo-le; Liu, Xu-bao

    2015-12-01

    In 2010, World Health Organization (WHO) reclassified pancreatic neuroendocrine tumors (p-NETs) into 4 main groups: neuroendocrine tumor G1 (NET G1), neuroendocrine tumor G2 (NET G2), neuroendocrine carcinoma G3 (NEC G3), mixed adeno and neuroendocrine carcinoma (MANEC). Clinical value of these newly updated WHO grading criteria has not been rigorously validated. The authors aimed to evaluate the clinical consistency of the new 2010 grading classifications by WHO and the 2010 tumor-node metastasis staging systems by American Joint Committee on Cancer (AJCC) on survivals for patients with surgically resected p-NETs. Moreover, the authors would validate the prognostic value of both criteria for p-NETs.The authors retrospectively collected the clinicopathologic data of 120 eligible patients who were all surgically treated and histopathologically diagnosed as p-NETs from January 2004 to February 2014 in our single institution. The new WHO criteria were assigned to 4 stratified groups with a respective distribution of 62, 35, 17, and 6 patients. Patients with NET G1 or NET G2 obtained a statistically better survival compared with those with NEC G3 or MANEC (P < 0.001). Survivals of NET G1 was also better than those of NET G2 (P = 0.023), whereas difference of survivals between NEC G3 and MANEC present no obvious significance (P = 0.071). The AJCC 2010 staging systems were respectively defined in 61, 36, 12, and 11 patients for each stage. Differences of survivals of stage I with stage III and IV were significant (P < 0.001), as well as those of stage II with III and IV (P < 0.001); whereas comparisons of stage I with stage II and stage III with IV were not statistically significant (P = 0.129, P = 0.286; respectively). Together with radical resection, these 2 systems were both significant in univariate and multivariate analysis (P < 0.05).The newly updated WHO 2010 grading classifications and the AJCC 2010 staging systems could consistently reflect the clinical outcome

  16. Value of image fusion using single photon emission computed tomography with integrated low dose computed tomography in comparison with a retrospective voxel-based method in neuroendocrine tumours.

    PubMed

    Amthauer, H; Denecke, T; Rohlfing, T; Ruf, J; Böhmig, M; Gutberlet, M; Plöckinger, U; Felix, R; Lemke, A J

    2005-07-01

    The objective was the evaluation of single photon emission computed tomography (SPECT) with integrated low dose computed tomography (CT) in comparison with a retrospective fusion of SPECT and high-resolution CT and a side-by-side analysis for lesion localisation in patients with neuroendocrine tumours. Twenty-seven patients were examined by multidetector CT. Additionally, as part of somatostatin receptor scintigraphy (SRS), an integrated SPECT-CT was performed. SPECT and CT data were fused using software with a registration algorithm based on normalised mutual information. The reliability of the topographic assignment of lesions in SPECT-CT, retrospective fusion and side-by-side analysis was evaluated by two blinded readers. Two patients were not enrolled in the final analysis because of misregistrations in the retrospective fusion. Eighty-seven foci were included in the analysis. For the anatomical assignment of foci, SPECT-CT and retrospective fusion revealed overall accuracies of 91 and 94% (side-by-side analysis 86%). The correct identification of foci as lymph node manifestations (n=25) was more accurate by retrospective fusion (88%) than from SPECT-CT images (76%) or by side-by-side analysis (60%). Both modalities of image fusion appear to be well suited for the localisation of SRS foci and are superior to side-by-side analysis of non-fused images especially concerning lymph node manifestations.

  17. TERT promoter mutations in pancreatic endocrine tumours are rare and mainly found in tumours from patients with hereditary syndromes

    PubMed Central

    Vinagre, João; Nabais, Joana; Pinheiro, Jorge; Batista, Rui; Oliveira, Rui Caetano; Gonçalves, António Pedro; Pestana, Ana; Reis, Marta; Mesquita, Bárbara; Pinto, Vasco; Lyra, Joana; Cipriano, Maria Augusta; Ferreira, Miguel Godinho; Lopes, José Manuel; Sobrinho-Simões, Manuel; Soares, Paula

    2016-01-01

    One of the hallmarks of cancer is its unlimited replicative potential that needs a compensatory mechanism for the consequential telomere erosion. Telomerase promoter (TERTp) mutations were recently reported as a novel mechanism for telomerase re-activation/expression in order to maintain telomere length. Pancreatic endocrine tumors (PETs) were so far recognized to rely mainly on the alternative lengthening of telomeres (ALT) mechanism. It was our objective to study if TERTp mutations were present in pancreatic endocrine tumors (PET) and could represent an alternative mechanism to ALT. TERTp mutations were detected in 7% of the cases studied and were mainly associated to patients harbouring hereditary syndromes. In vitro, using PET-derived cell lines and by luciferase reporter assay, these mutations confer a 2 to 4-fold increase in telomerase transcription activity. These novel alterations are able to recruit ETS transcription factor members, in particular GABP-α and ETV1, to the newly generated binding sites. We report for the first time TERTp mutations in PETs and PET-derived cell lines. Additionally, our data indicate that these mutations serve as an alternative mechanism and in an exclusive manner to ALT, in particular in patients with hereditary syndromes. PMID:27411289

  18. TERT promoter mutations in pancreatic endocrine tumours are rare and mainly found in tumours from patients with hereditary syndromes.

    PubMed

    Vinagre, João; Nabais, Joana; Pinheiro, Jorge; Batista, Rui; Oliveira, Rui Caetano; Gonçalves, António Pedro; Pestana, Ana; Reis, Marta; Mesquita, Bárbara; Pinto, Vasco; Lyra, Joana; Cipriano, Maria Augusta; Ferreira, Miguel Godinho; Lopes, José Manuel; Sobrinho-Simões, Manuel; Soares, Paula

    2016-07-14

    One of the hallmarks of cancer is its unlimited replicative potential that needs a compensatory mechanism for the consequential telomere erosion. Telomerase promoter (TERTp) mutations were recently reported as a novel mechanism for telomerase re-activation/expression in order to maintain telomere length. Pancreatic endocrine tumors (PETs) were so far recognized to rely mainly on the alternative lengthening of telomeres (ALT) mechanism. It was our objective to study if TERTp mutations were present in pancreatic endocrine tumors (PET) and could represent an alternative mechanism to ALT. TERTp mutations were detected in 7% of the cases studied and were mainly associated to patients harbouring hereditary syndromes. In vitro, using PET-derived cell lines and by luciferase reporter assay, these mutations confer a 2 to 4-fold increase in telomerase transcription activity. These novel alterations are able to recruit ETS transcription factor members, in particular GABP-α and ETV1, to the newly generated binding sites. We report for the first time TERTp mutations in PETs and PET-derived cell lines. Additionally, our data indicate that these mutations serve as an alternative mechanism and in an exclusive manner to ALT, in particular in patients with hereditary syndromes.

  19. [A Newly Diagnosed Case of Multiple Myeloma in Which Lenalidomide Was Continued after Surgery for a Pancreatic Neuroendocrine Tumor That Developed during Lenalidomide Maintenance Therapy].

    PubMed

    Kuroda, Hiroyuki; Yoshida, Masahiro; Usami, Makoto; Shimoyama, Saori; Sakamoto, Hiroki; Yamada, Michiko; Fujii, Shigeyuki; Maeda, Masahiro; Fujita, Miri; Kanari, Yusuke; Sato, Tsutomu; Kato, Junji

    2015-08-01

    A 75-year-old woman was diagnosed with symptomatic IgG-l multiple myeloma (good-prognosis group) in December 2010. A stringent complete response (sCR) was achieved by using induction therapy with bortezomib (BOR, Velcade®)+ dexamethasone (DEX)(VD) and consolidation therapy with BOR+lenalidomide (LEN, Revlimid®)+DEX(VRD). Although maintenance therapy with Revlimid®+DEX(Rd) was initiated, a pancreatic neuroendocrine tumor was detected in April 2013. Therefore, LEN was discontinued and distal pancreatectomy was performed in September 2013. Because discontinuation of LEN was followed by exacerbation of myeloma, LEN was resumed with the consent of the patient; however, she became resistant to the treatment. The course of this case suggests that some patients must continue to receive LEN even if a sCR is achieved.

  20. Cost comparison of 111In-DTPA-octreotide scintigraphy and 68Ga-DOTATOC PET/CT for staging enteropancreatic neuroendocrine tumours.

    PubMed

    Schreiter, Nils F; Brenner, Winfried; Nogami, Munenobu; Buchert, Ralph; Huppertz, Alexander; Pape, Ulrich-Frank; Prasad, Vikas; Hamm, Bernd; Maurer, Martin H

    2012-01-01

    Although somatostatin receptor positron emission tomography (PET)/CT is gaining increasing popularity and has shown its diagnostic superiority in several studies, (111)In-diethylenetriaminepentaacetic acid (DTPA)-octreotide is still the current standard for diagnosis of neuroendocrine tumours (NET). The aim of this study was to compare the costs for the two diagnostic tests and the respective consequential costs. From January 2009 to July 2009, 51 consecutive patients with enteropancreatic NET who underwent contrast-enhanced (68)Ga-DOTATOC PET/CT (n = 29) or (111)In-DTPA-octreotide (mean 3 whole-body scans plus 1.6 low-dose single photon emission computed tomography/CT; n = 22) were included. For cost analysis, direct costs (equipment) and variable costs (material, labour) per examination were calculated. Additionally required CT and/or MRI examinations within the staging process were assessed as consequential costs. An additional deterministic sensitivity analysis was performed. A (68)Ga-DOTATOC PET/CT examination yielded total costs (equipment, personnel and material costs) of 548 euro. On the other hand, an (111)In-DTPA-octreotide examination resulted in 827 euro total costs. Costs for equipment and material had a share of 460 euro/720 euro for (68)Ga-DOTATOC/(111)In-DTPA-octreotide and labour costs of 89 euro/106 euro. With (68)Ga-DOTATOC additional MRI had to be performed in 7% of the patients resulting in a mean of 20 euro for supplementary imaging per patient; 82% of patients with (111)In-DTPA-octreotide needed additional MRI and/or CT resulting in mean additional costs of 161 euro per patient. (68)Ga-DOTATOC PET/CT was considerably cheaper than (111)In-DTPA-octreotide with respect to both material and personnel costs. Furthermore, by using (68)Ga-DOTATOC PET/CT considerably fewer additional examinations were needed reducing the consequential costs significantly.

  1. Incremental value of (99m)Tc-HYNIC-TOC SPECT/CT over whole-body planar scintigraphy and SPECT in patients with neuroendocrine tumours.

    PubMed

    Trogrlic, Mate; Težak, Stanko

    2017-06-12

    The aim of this study was to evaluate the additional value of (99m)Tc-HYNIC-TOC SPECT/CT over planar whole-body (WB) scintigraphy and SPECT alone in the detection and accurate localisation of neuroendocrine tumour (NET) lesions. This study included 65 patients with a definitive histological diagnosis of NET prior to scintigraphy. Planar WB scintigraphy, SPECT, and SPECT/CT images were acquired at 4 h post-administration of 670 MBq (99m)Tc-HYNIC-TOC. Additional SPECT images at 10 min after tracer administration were also acquired. Clinical and imaging follow-up findings were considered as the reference standards (minimum follow-up period, 15 months). Patient and lesion-based analyses of the efficacies of the imaging modalities were performed. While 38 patients exhibited metastasis of NETs, 27 presented no evidence of metastasis. Upon patient-based analysis, the sensitivity and specificity of SPECT/CT were found to be 88.9 and 79.3 %, respectively. The diagnostic accuracies of WB scintigraphy, 4h-SPECT, and SPECT/CT were 72.3, 73.8, and 84.6 %, respectively. The area under curve (AUC) value for SPECT/CT (0.84) was the highest, followed by those for 4h-SPECT (0.75) and WB scintigraphy (0.74). The accuracy and AUC values of SPECT/CT were significantly better compared to those of WB scintigraphy (p < 0.001), 10 min-SPECT (p < 0.001), and 4 h-SPECT (p = 0.001). The findings of SPECT/CT led to the change in treatment plan of 11 patients (16.9 %). The sensitivity and diagnostic accuracy of SPECT/CT in the evaluation of NET lesions outperforms planar WB imaging or SPECT alone.

  2. Expression of E-cadherin repressors SNAIL, ZEB1 and ZEB2 by tumour and stromal cells influences tumour-budding phenotype and suggests heterogeneity of stromal cells in pancreatic cancer.

    PubMed

    Galván, J A; Zlobec, I; Wartenberg, M; Lugli, A; Gloor, B; Perren, A; Karamitopoulou, E

    2015-06-09

    There is evidence that tumour-stroma interactions have a major role in the neoplastic progression of pancreatic ductal adenocarcinoma (PDAC). Tumour budding is thought to reflect the process of epithelial-mesenchymal transition (EMT); however, the relationship between tumour buds and EMT remains unclear. Here we characterize the tumour-budding- and stromal cells in PDAC at protein and mRNA levels concerning factors involved in EMT. mRNA in situ hybridisation and immunostaining for E-cadherin, β-catenin, SNAIL1, ZEB1, ZEB2, N-cadherin and TWIST1 were assessed in the main tumour, tumour buds and tumour stroma on multipunch tissue microarrays from 120 well-characterised PDACs and associated with the clinicopathological features, including peritumoural (PTB) and intratumoural (ITB) budding. Tumour-budding cells showed increased levels of ZEB1 (P<0.0001) and ZEB2 (P=0.0119) and reduced E-cadherin and β-catenin (P<0.0001, each) compared with the main tumour. Loss of membranous β-catenin in the main tumour (P=0.0009) and tumour buds (P=0.0053), without nuclear translocation, as well as increased SNAIL1 in tumour and stromal cells (P=0.0002, each) correlated with high PTB. ZEB1 overexpression in the main tumour-budding and stromal cells was associated with high ITB (P=0.0084; 0.0250 and 0.0029, respectively) and high PTB (P=0.0005; 0.0392 and 0.0007, respectively). ZEB2 overexpression in stromal cells correlated with higher pT stage (P=0.03), lymphatic invasion (P=0.0172) and lymph node metastasis (P=0.0152). In the tumour microenvironment of phenotypically aggressive PDAC, tumour-budding cells express EMT hallmarks at protein and mRNA levels underlining their EMT-type character and are surrounded by stromal cells expressing high levels of the E-cadherin repressors ZEB1, ZEB2 and SNAIL1, this being strongly associated with the tumour-budding phenotype. Moreover, our findings suggest the existence of subtypes of stromal cells in PDAC with phenotypical and functional

  3. Cushing's syndrome due to a pancreatic neuroendocrine tumor metastatic to the ovaries: a clinicopathological description of a case.

    PubMed

    La Rosa, Stefano; Marando, Alessandro; Ghezzi, Fabio; Colombo, Paolo; Finzi, Giovanna; Capella, Carlo

    2011-06-01

    We report the case of a 36-year-old woman with Cushing's syndrome caused by a malignant unresectable neuroendocrine carcinoma of the pancreas that developed bilateral ovarian metastases 7 years after diagnosis. In November 2001, because of abdominal pain and jaundice, the patient underwent radiological investigations and exploratory laparotomy that demonstrated the presence of a 3-cm mass of the head of the pancreas, infiltrating the superior mesenteric vein, associated with enlargement of multiple abdominal lymph nodes and with a liver nodule. Histological examination of one lymph node and of the liver nodule demonstrated the presence of metastases from a well-differentiated neuroendocrine carcinoma showing corticotropin immunoreactivity. A few months later, the patient started to show the clinical symptoms of Cushing's syndrome and underwent steroid-blocking ketoconazole therapy. The clinical endocrine picture was controlled until the end of 2008, when the endocrine symptoms of the Cushing's syndrome worsened and bilateral ovarian tumors appeared. Hysteroannexectomy was performed and ovarian tumors were found to be metastases from a well-differentiated neuroendocrine carcinoma with morphological and immunohistochemical features overlapping those observed in 2002. The clinical situation worsened and the patient died in November 2009. The clinical aspects and the problems in the differential diagnosis are discussed.

  4. Oral bacteria in pancreatic cancer: mutagenesis of the p53 tumour suppressor gene.

    PubMed

    Öğrendik, Mesut

    2015-01-01

    Carcinoma of exocrine pancreas is the fourth leading cause of cancer deaths, worldwide. The prevalence of this disease is very high in patients with chronic pancreatitis. Orodigestive cancers are frequently seen in patients with periodontitis. These findings suggest that this type of cancer may have some bacterial origins. This study hypothesizes that the peptidyl arginine deaminase (PAD) enzymes found in oral bacteria may be responsible for the p53 point mutations that occur in patients with pancreatic cancer. Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythia, and Treponema denticola possess the PAD enzyme, and p53 arginine mutations have been detected in patients with pancreatic cancer. Moreover, the Pro allele p53Arg72-Pro is a risk factor for the development of this cancer. Anti-P. gingivalis antibody titers have been found to be higher in patients with pancreatic cancer as compared to healthy controls. The hypothesis in question can be tested if the DNA of P. gingivalis or the antibodies against P. gingivalis can be detected in patients with the p53 arginine mutation.If this hypothesis is true, it could reveal the real cause of pancreatic cancer, which is a fatal disease. Further studies are necessary in order to confirm this hypothesis.

  5. Sorafenib Tosylate in Treating Patients With Progressive Metastatic Neuroendocrine Tumors

    ClinicalTrials.gov

    2014-11-14

    Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Neuroendocrine Tumor; Pancreatic Polypeptide Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Somatostatinoma; WDHA Syndrome

  6. 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.

  7. [Accurate grading of pancreatic neuroendocrine tumors with Ki-67 index in fine-needle aspiration specimens: a comparative cytologic and histologic study].

    PubMed

    He, S R; Cui, D; Gong, H; Zhu, Y P; Chen, L; Hu, S T; Liu, D G

    2017-06-08

    Objective: To study the cytomorphologic features and determine whether pancreatic neuroendocrine tumors (PanNET) sampled by fine-needle aspiration (FNA) can be accurately graded based on the Ki-67 index when compared to surgical samples. Methods: Corresponding intraoperative (19 cases) or endoscopic ultrasound-guided (3 cases) FNA cytology and surgical tissue specimens were obtained from 22 tumors, which were reviewed and stained for Ki-67 proliferation marker. The cytological samples included more than 200 tumor cells. Samples were graded by scoring the Ki-67 positive index in accordance with the 2010 WHO criteria. The grading scores assigned to the FNA cytology samples were compared with the scores assigned to the corresponding histological samples. Concordance was achieved by using 5% (instead of 2%) as a cut-off value for defining G2 tumors. One cytological sample included less than 500 tumor cells was excluded in the concordance calculation. Results: The cytological smears consisted of uniform, monotonous and isolated cells, loose cellular aggregates and rosette-like formations. Some tumor cells clustered around segments of capillaries. The cells demonstrated distinct cytoplasmic and nuclear features. Mitoses and necrosis were rarely seen. When traditional 2% Ki-67 index cut-off value were used to classify G2 tumors, the majority (86.4%, κ=0.812, P<0.01) of FNA cytology samples and corresponding surgical tissue specimens demonstrated concordance. When a 5% cut-off value was adopted, the concordance rate was 95.5% (21/22, κ=1.000, P<0.01). Similar concordance rates between the cytological and histological grades were achieved with threshold value of cytological assessment material set at more than 500 or 200 cells. Conclusions: The cytological Ki-67 index in adequate material (>200 tumor cells) is useful in grading pancreatic neuroendocrine tumors, and a cut-off value of 5% showed better predictive value compared with that of 2%. Accurate grading of PanNET is

  8. Evaluation of (68)Ga-DOTATOC PET/MRI for whole-body staging of neuroendocrine tumours in comparison with (68)Ga-DOTATOC PET/CT.

    PubMed

    Sawicki, Lino M; Deuschl, Cornelius; Beiderwellen, Karsten; Ruhlmann, Verena; Poeppel, Thorsten D; Heusch, Philipp; Lahner, Harald; Führer, Dagmar; Bockisch, Andreas; Herrmann, Ken; Forsting, Michael; Antoch, Gerald; Umutlu, Lale

    2017-04-24

    To compare the diagnostic performance of (68)Ga-DOTATOC PET/MRI and (68)Ga-DOTATOC PET/CT in the whole-body staging of patients with neuroendocrine tumours (NET). Thirty patients with histopathologically confirmed NET underwent PET/CT and PET/MRI in a single-injection protocol. PET/CT and PET/MRI scans were prospectively evaluated with regard to lesion count, localization, nature (NET/non-NET), and conspicuity (four-point scale). Histopathology and follow-up imaging served as the reference standards. The proportions of NET and non-NET lesions rated correctly were compared using McNemar's chi-squared test. The Wilcoxon test was used to assess differences in SUVmax and lesion conspicuity. The correlation between the SUVmax for the same lesions from each modality was analysed using Pearson's correlation coefficient (r). According to the reference standard, there were 197 lesions (142 NET, 55 non-NET). Lesion-based analysis showed a higher proportion of correctly rated NET lesions on PET/MRI than on PET/CT (90.8% vs. 86.7%, p = 0.031), whereas on PET/CT there was a higher proportion of correctly rated non-NET lesions (94.5% vs. 83.6%, p = 0.031). SUVmax was strongly correlated (r = 0.86; p < 0.001) and did not differ significantly (p = 0.35) between the modalities. Overall conspicuity and NET lesion conspicuity were higher on PET/MRI (both p < 0.01). Ga-DOTATOC PET/MRI yielded a higher proportion of correctly rated NET lesions and should be regarded as a valuable alternative to (68)Ga-DOTATOC PET/CT in whole-body staging of NET patients. • (68) Ga-DOTATOC PET/MRI correctly identified more NET lesions than (68) Ga-DOTATOC PET/CT. • (68) Ga-DOTATOC PET/MRI provides better NET lesion conspicuity than (68) Ga-DOTATOC PET/CT. • SUVmax values from the two modalities are strongly correlated and do not differ significantly.

  9. Masitinib Combined with Standard Gemcitabine Chemotherapy: In Vitro and In Vivo Studies in Human Pancreatic Tumour Cell Lines and Ectopic Mouse Model

    PubMed Central

    Humbert, Martine; Castéran, Nathalie; Letard, Sébastien; Hanssens, Katia; Iovanna, Juan; Finetti, Pascal; Bertucci, François; Bader, Thomas; Mansfield, Colin D.; Moussy, Alain; Hermine, Olivier; Dubreuil, Patrice

    2010-01-01

    Background Tyrosine kinases are attractive targets for pancreatic cancer therapy because several are over-expressed, including PDGFRα/β, FAK, Src and Lyn. A critical role of mast cells in the development of pancreatic cancer has also been reported. Masitinib is a tyrosine kinase inhibitor that selectively targets c-Kit, PDGFRα/β, Lyn, and to a lesser extent the FAK pathway, without inhibiting kinases of known toxicities. Masitinib is particularly efficient in controlling the proliferation, differentiation and degranulation of mast cells. This study evaluates the therapeutic potential of masitinib in pancreatic cancer, as a single agent and in combination with gemcitabine. Methodology/Findings Proof-of-concept studies were performed in vitro on human pancreatic tumour cell lines and then in vivo using a mouse model of human pancreatic cancer. Molecular mechanisms were investigated via gene expression profiling. Masitinib as a single agent had no significant antiproliferative activity while the masitinib/gemcitabine combination showed synergy in vitro on proliferation of gemcitabine-refractory cell lines Mia Paca2 and Panc1, and to a lesser extent in vivo on Mia Paca2 cell tumour growth. Specifically, masitinib at 10 µM strongly sensitised Mia Paca2 cells to gemcitabine (>400-fold reduction in IC50); and moderately sensitised Panc1 cells (10-fold reduction). Transcriptional analysis identified the Wnt/β-catenin signalling pathway as down-regulated in the cell lines resensitised by the masitinib/gemcitabine combination. Conclusions These data establish proof-of-concept that masitinib can sensitise gemcitabine-refractory pancreatic cancer cell lines and warrant further in vivo investigation. Indeed, such an effect has been recently observed in a phase 2 clinical study of patients with pancreatic cancer who received a masitinib/gemcitabine combination. PMID:20209107

  10. Comparison of the pharmacokinetics of 68Ga-DOTATOC and [18F]FDG in patients with metastatic neuroendocrine tumours scheduled for 90Y-DOTATOC therapy.

    PubMed

    Koukouraki, Sophia; Strauss, Ludwig G; Georgoulias, Vassilios; Eisenhut, Michael; Haberkorn, Uwe; Dimitrakopoulou-Strauss, Antonia

    2006-10-01

    The purpose of this study was to evaluate and compare, by means of dynamic PET, the pharmacokinetics of 68Ga-DOTATOC, a tracer which reflects the expression of somatostatin receptors (SSTRs), and of [18F]FDG, a marker of tumour viability, in patients with metastatic neuroendocrine tumours (NETs) in whom 90Y-DOTATOC therapy was planned. Fifteen patients (63 lesions) with confirmed metastatic NETs were enrolled in this study. Dynamic [18F]FDG and 68Ga-DOTATOC PET scans were performed on two different days in the same week. The data analysis was based on qualitative and quantitative analysis using a two-tissue compartment model with a blood compartment and a non-compartment model based on the fractal dimension (FD). Multivariate analysis was used for evaluation of the kinetic data. Enhanced [18F]FDG uptake was observed in 43/63 lesions. 68Ga-DOTATOC showed pathologically enhanced uptake in all evaluated patients and in 57/63 lesions. Discordant scintigraphic results for [18F]FDG and 68Ga-DOTATOC were observed in 6/15 patients. Global SUV was defined as the SUV measured in the last frame (55-60 min p.i.) of the dynamic series, for each tracer. The median global SUV uptake was 7.9 for 68Ga-DOTATOC and 4.6 for [18F]FDG. The selection of patients for 90Y-DOTATOC therapy was based on the uptake of 68Ga-DOTATOC. Multiple linear regression analysis was applied to determine the effect of each kinetic parameter (K1-k4, VB) on the global SUV of both tracers. The highest positive t-ratio was found for K1 (receptor binding), followed by k3 (cellular internalisation) and VB (fractional blood volume), when using the global 68Ga-DOTATOC uptake (SUV) as a target variable. Analysis of the [18F]FDG data revealed the highest positive t-ratio for VB, followed by k3 (phosphorylation) and K1 (influx). The comparison of global SUV, K1-k4 and the FD for [18F]FDG and 68Ga-DOTATOC did not show any statistically significant correlation. The only parameter that demonstrated a significant linear

  11. High-grade fetal adenocarcinoma of the lung is a tumour with a fetal phenotype that shows diverse differentiation, including high-grade neuroendocrine carcinoma: a clinicopathological, immunohistochemical and mutational study of 20 cases.

    PubMed

    Suzuki, Masaki; Yazawa, Takuya; Ota, Satoshi; Morimoto, Junichi; Yoshino, Ichiro; Yamanaka, Shoji; Inayama, Yoshiaki; Kawabata, Yoshinori; Shimizu, Yoshihiko; Komatsu, Masayo; Notohara, Kenji; Koda, Kenji; Nakatani, Yukio

    2015-12-01

    High-grade fetal adenocarcinoma (H-FLAC) is a rare variant of pulmonary adenocarcinoma; this study aims to elucidate its clinicopathological features and genetic abnormalities. Clinicopathological, immunohistochemical and mutational analyses were performed on 20 surgically resected lung cancers that showed H-FLAC histology in various proportions. These tumours predominantly occurred in elderly males and in 10 patients who were heavy smokers. Four cases were pure H-FLAC, and 16 cases were mixed H-FLAC, which were found to be combined with conventional-type adenocarcinoma (15 cases), large-cell neuroendocrine carcinoma (three cases), small-cell carcinoma (one case), enteric adenocarcinoma (two cases), choriocarcinoma (two cases), and a solid-clear cell pattern (seven cases). The fetal phenotype and diverse differentiation were supported by the immunoexpression of α-fetoprotein (95%), thyroid transcription factor-1 (TTF-1) (50%), neuroendocrine markers (30-45%), proneural markers (50-69%), and CDX2 (40%). Except for TTF-1 expression (pure H-FLACs, 0%; mixed H-FLACs, 63%), there were no significant differences in histological or immunohistochemical findings between pure and mixed H-FLACs. EGFR, KRAS, BRAF and PIK3CA mutations were identified in 20%, 0%, 0% and 7% of the tumours, respectively. Lung adenocarcinomas with H-FLAC features possess the potential for multidirectional differentiation, and are not strongly associated with known major driver gene mutations. © 2015 John Wiley & Sons Ltd.

  12. RABL6A promotes G1-S phase progression and pancreatic neuroendocrine tumor cell proliferation in an Rb1-dependent manner

    PubMed Central

    Hagen, Jussara; Muniz, Viviane P.; Falls, Kelly; Reed, Sara M.; Taghiyev, Agshin F.; Quelle, Frederick W.; Gourronc, Francoise; Klingelhutz, Aloysius J.; Major, Heather J.; Askeland, Ryan; Sherman, Scott K.; O'Dorisio, Thomas M.; Bellizzi, Andrew M.; Howe, James R.; Darbro, Benjamin W.; Quelle, Dawn E.

    2014-01-01

    Mechanisms of neuroendocrine tumor (NET) proliferation are poorly understood and therapies that effectively control NET progression and metastatic disease are limited. We found amplification of a putative oncogene, RABL6A, in primary human pancreatic NETs(PNETs) that correlated with high level RABL6A protein expression. Consistent with those results, stable silencing of RABL6A in cultured BON-1 PNET cells revealed that it is essential for their proliferation and survival. Cells lacking RABL6A predominantly arrested in G1 phase with a moderate mitotic block. Pathway analysis of microarray data suggested activation of the p53 and retinoblastoma (Rb1) tumor suppressor pathways in the arrested cells. Loss of p53 had no effect on the RABL6A knockdown phenotype, indicating RABL6A functions independent of p53 in this setting. By comparison, Rb1 inactivation partially restored G1 to S phase progression in RABL6A knockdown cells although it was insufficient to override the mitotic arrest and cell death caused by RABL6A loss. Thus, RABL6A promotes G1 progression in PNET cells by inactivating Rb1, an established suppressor of PNET proliferation and development. This work identifies RABL6A as a novel negative regulator of Rb1 that is essential for PNET proliferation and survival. We suggest RABL6A is a new potential biomarker and target for anticancer therapy in PNET patients. PMID:25273089

  13. RABL6A promotes G1-S phase progression and pancreatic neuroendocrine tumor cell proliferation in an Rb1-dependent manner.

    PubMed

    Hagen, Jussara; Muniz, Viviane P; Falls, Kelly C; Reed, Sara M; Taghiyev, Agshin F; Quelle, Frederick W; Gourronc, Francoise A; Klingelhutz, Aloysius J; Major, Heather J; Askeland, Ryan W; Sherman, Scott K; O'Dorisio, Thomas M; Bellizzi, Andrew M; Howe, James R; Darbro, Benjamin W; Quelle, Dawn E

    2014-11-15

    Mechanisms of neuroendocrine tumor (NET) proliferation are poorly understood, and therapies that effectively control NET progression and metastatic disease are limited. We found amplification of a putative oncogene, RABL6A, in primary human pancreatic NETs (PNET) that correlated with high-level RABL6A protein expression. Consistent with those results, stable silencing of RABL6A in cultured BON-1 PNET cells revealed that it is essential for their proliferation and survival. Cells lacking RABL6A predominantly arrested in G1 phase with a moderate mitotic block. Pathway analysis of microarray data suggested activation of the p53 and retinoblastoma (Rb1) tumor-suppressor pathways in the arrested cells. Loss of p53 had no effect on the RABL6A knockdown phenotype, indicating that RABL6A functions independent of p53 in this setting. By comparison, Rb1 inactivation partially restored G1 to S phase progression in RABL6A-knockdown cells, although it was insufficient to override the mitotic arrest and cell death caused by RABL6A loss. Thus, RABL6A promotes G1 progression in PNET cells by inactivating Rb1, an established suppressor of PNET proliferation and development. This work identifies RABL6A as a novel negative regulator of Rb1 that is essential for PNET proliferation and survival. We suggest RABL6A is a new potential biomarker and target for anticancer therapy in PNET patients.

  14. Pancreatic neuroendocrine tumors: role of novel agents. Highlights from the "2011 ASCO Gastrointestinal Cancers Symposium". San Francisco, CA, USA. January 20-22, 2011.

    PubMed

    Strimpakos, Alexios S; Syrigos, Konstantinos N; Saif, Muhammad Wasif

    2011-03-09

    Neuroendocrine tumors of pancreas (PNET) are very rare, consisting of heterogeneous histological subtypes with a variable natural history and different clinical manifestations. Although the vast majority of these neoplasms are sporadic, it is possible to be part of a genetic syndrome such as multiple endocrine neoplasia 1 (MEN-1) or tuberous sclerosis (TSC). When systemic treatment is required the options are limited and management strategy is generally based on experts' consensus or clinical experience. The prognosis is usually better than in pancreatic adenocarcinoma, though poorly differentiated PNET behave aggressively and survival is shortened. Since last year, there has been a significant advance in the management of PNET, after reported data confirmed the efficacy of everolimus, an mTOR inhibitor, in patients with advanced disease. At the 2011 American Society of Clinical Oncology (ASCO) Gastrointestinal Symposium, updated results of the phase III trial (RADIANT-3) regarding the efficacy of everolimus in PNET (Abstract #158) were reported, along with the results of a subgroup analysis of the Japanese patients enrolled in this study (Abstract #289). Another agent with promising activity in PNET which will be discussed in this review is sunitinib, a biological agent with multikinase inhibitor properties (Abstract #244).

  15. Successful treatment of a case with pancreatic neuroendocrine carcinoma with focal hepatoid differentiation: a case report and literature review

    PubMed Central

    Xin, Bao-Bao; Li, Jian-Ang; Han, Xu; Zhao, Jing; Ji, Yuan; Lou, Wen-Hui; Xu, Xue-Feng

    2014-01-01

    A 33-year-old Chinese woman was admitted to our hospital because of an elevated serum alpha-fetoprotein (AFP) level (300 ng/mL) found in a regular medical checkup. Computed tomography imaging of the abdomen revealed a 1.6 × 2.2 cm low-attenuation mass in the head of the pancreas, with no enlarged lymph nodes and no metastatic liver nodules, and a pancreaticoduodenectomy was performed and the tumor was completely removed. The tumor was solid, unencapsulated and poorly demarcated, measuring 2 × 1.4 × 1.8 cm, and the cut surface was grey-yellowish. Histologically, most of the areas of the tumor were composed of small monotonous and round shaped neuroendocrine cells, and approximately 20% of the areas were cells with indistinct cytoplasmic borders, large oval nuclei, prominent nucleoli and abundant eosinophilic cytoplasm, resembling the appearance of HCC. Immunohistochemical stains revealed that the neuroendocrine areas were diffusely positive for chromogranin, and the hepatoid areas showed diffuse and strong positive reaction to AFP. After surgery the AFP level reduced to normal. She received six cycles of postoperative chemotherapy and three years after the surgery was found to have an elevated serum AFP level again which gave rise to the suspicion of tumor recurrence, and a positron emission tomography-computed tomography confirmed the speculation by showing a hypermetabolic lymph node behind the body of the pancreas. She then underwent radiotherapy and the AFP level reduced to normal. Up till now she has survived 46 months since the initial diagnosis. This case and previous cases suggest that the serum AFP could be a useful marker for early detection of the disease, but careful differential diagnosis should be performed, and AFP could also be a marker for evaluation of therapeutic response and recurrence of the AFP-producing hepatoid carcinomas of pancreas. PMID:25419403

  16. Comparison of World Health Organization 2000/2004 and World Health Organization 2010 classifications for gastrointestinal and pancreatic neuroendocrine tumors.

    PubMed

    Pasaoglu, Esra; Dursun, Nevra; Ozyalvacli, Gulzade; Hacihasanoglu, Ezgi; Behzatoglu, Kemal; Calay, Ozden

    2015-04-01

    Gastroenteropancreatic neuroendocrine tumors (GEPNETs) were divided into 4 groups based on tumor diameter and stage in World Health Organization (WHO) 2000/2004 classification as well-differentiated endocrine tumor benign (WDETB), well-differentiated endocrine tumor with uncertain behavior (WDETUB), well-differentiated endocrine carcinoma (WDEC), and poorly differentiated endocrine carcinoma (PDEC). World Health Organization 2000/2004 was not widely accepted because of stage-related classification and the category of "uncertain behavior." The European NET Society proposed a grading classification and site-specific staging system in 2010. Gastroenteropancreatic NETs were divided into 3 groups as NET grade 1 (G1), NET grade 2 (G2), and neuroendocrine carcinoma (NEC) grade 3 (G3) based on mitoses and the Ki-67 index. We evaluated 63 GEPNET cases according to both classifications. We compared two classifications and the tumor groups in terms of prognostic parameters (diameter, mitosis, Ki-67 index, angioinvasion, perineural invasion, necrosis, and metastasis) and pathologic stage. All 14 cases diagnosed as PDEC were included in the NEC G3 according to WHO 2010. Seventeen cases were diagnosed as WDETB, 9 as WDETUB, and 23 as WDEC. There was statistically significant difference between these groups in terms of all prognostic parameters except for necrosis, mitosis, Ki-67 index, and grade. All WDETB cases, 89% of WDETUBs, and 87% of WDECs were included in the NET G1. There were 45 cases evaluated as NET G1 and 4 cases as NET G2 according to WHO 2010. Metastasis and perineural invasion were more common in NET G2, no significant differences in other parameters. In conclusion, WHO 2010 is easier to use, whereas WHO 2000/2004 shows higher correlation with prognosis. However, it includes benign and uncertain behavior categories, although small tumors with low proliferative activity can also cause metastases. All GEPNETs should be considered potentially malignant. Copyright

  17. Is there a role for near-infrared technology in laparoscopic resection of pancreatic neuroendocrine tumors? Results of the COLPAN "colour-and-resect the pancreas" study.

    PubMed

    Paiella, Salvatore; De Pastena, Matteo; Landoni, Luca; Esposito, Alessandro; Casetti, Luca; Miotto, Marco; Ramera, Marco; Salvia, Roberto; Secchettin, Erica; Bonamini, Deborah; Manzini, Gessica; D'Onofrio, Mirko; Marchegiani, Giovanni; Bassi, Claudio

    2017-04-03

    The intraoperative identification of pancreatic neuroendocrine tumors (PanNETs) is of utmost importance to drive their laparoscopic resection. Near-infrared (NIR) surgery has emerged as a new technique for localizing tumors or neoplastic tissue. This study aimed to explore the results of the application of NIR in the laparoscopic resection of PanNETs. Per protocol we enrolled ten subjects undergoing laparoscopic pancreatic surgery for PanNET from March 2016 to October 2016. During surgery, the patients were injected with indocyanine green dye (ICG, 25 mg given in 5 boli of 5 mg each). The switch-activation of NIR was performed to identify PanNETs. An ex-post analysis of the images was realized using ImageJ Software® to calculate the fluorescence signal. NIR imaging identified all ten PanNETs. Nine (90%) laparoscopic distal pancreatectomy with splenectomy and one (10%) laparoscopic enucleation were performed. The mean maximum tumor dimension was 2.4 cm (range 1-4 cm). Eight non-functioning PanNETs (80%) and two insulinomas (20%) were found at the final pathology. Nine out of ten (90%) PanNETs were detected after the second ICG bolus. The mean latency time was 80 s and the mean visibility time was 220 s. The peak of tumor visualization was reached 20 min after the last bolus. This finding was confirmed by the ex-post analysis of the fluorescence signal (mean signal-to-background ratio of 7.7, p = 0.001). NIR identified two additional lesions, which turned out to be normal lymph nodes at final pathology. A fluorescent signal was identified at the bed of the enucleation, and thus, a further exeresis was performed and final pathology revealed that is was residual neoplastic tissue. This explorative study shows that NIR with ICG can have a role in laparoscopic pancreatic resection of PanNETs. Further studies are needed to assess the proper setting and role of this new and promising technology.

  18. 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.

  19. The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms.

    PubMed

    Basturk, Olca; Yang, Zhaohai; Tang, Laura H; Hruban, Ralph H; Adsay, Volkan; McCall, Chad M; Krasinskas, Alyssa M; Jang, Kee-Taek; Frankel, Wendy L; Balci, Serdar; Sigel, Carlie; Klimstra, David S

    2015-05-01

    The 2010 World Health Organization (WHO) classification recommends that pancreatic neuroendocrine tumors (PanNETs) be graded on the basis of the mitotic rate and Ki67 index, with grade 2 (G2) PanNETs defined as having a mitotic rate of 2 to 20 mitotic figures/10 high-power fields or a Ki67 index of 3% to 20%. Grade 3 (G3) pancreatic neuroendocrine carcinoma (NEC) is defined as having >20 mitotic figures/10 high-power fields or a Ki67 index of >20%. However, some PanNETs show discordance between the mitotic rate and Ki67 index, usually having a Ki67 index in the G3 range but a mitotic rate suggesting G2, prompting us to examine the clinical significance of the Ki67 index in a large series of clinically well-characterized mitotic G2 PanNETs. Mitotic G2 well differentiated PanNETs, surgically resected at our institutions were reviewed. Of those, 19 cases had a Ki67>20% and were selected as the study group of grade-discordant (mitotic count G2/Ki67 index G3) PanNETs. For comparison, 53 grade-concordant (both mitotic count and Ki67 index G2) PanNETs matched for presenting stage with the discordant group as well as 43 morphologically poorly differentiated (either small cell or large cell type) pancreatic NECs were also included. The percentage of Ki67-positive neoplastic cells was quantified by manual counting of at least 500 cells on printed photographic images of "hot spots." The mean Ki67 index for grade-concordant and grade-discordant PanNETs and poorly differentiated NECs were 8.1% (range, 3% to 20%), 40% (range, 24% to 80%), and 70% (range, 40% to 98%), respectively. Overall, patients with grade-discordant PanNETs had significantly longer survival time compared with the patients with poorly differentiated NEC (median survival of 54.1 vs. 11 mo and 5 y survival of 29.1% vs. 16.1%; P=0.002). In addition, the survival time of the patients with grade-discordant PanNETs was shorter than that of the patients with grade-concordant PanNETs (median survival of 67.8 mo and 5

  20. CD200 Expression in Neuroendocrine Neoplasms.

    PubMed

    Love, Jason E; Thompson, Kimberly; Kilgore, Mark R; Westerhoff, Maria; Murphy, Claire E; Papanicolau-Sengos, Antonios; McCormick, Kinsey A; Shankaran, Veena; Vandeven, Natalie; Miller, Faith; Blom, Astrid; Nghiem, Paul T; Kussick, Steven J

    2017-09-01

    CD200 expression has been well studied in hematopoietic malignancies; however, CD200 expression has not been well-characterized in neuroendocrine neoplasms. We examined CD200 expression in 391 neuroendocrine neoplasms from various anatomic sites. Tissue blocks containing pulmonary small cell carcinoma, pulmonary carcinoid, large cell neuroendocrine carcinoma, pancreatic neuroendocrine tumor, gastrointestinal carcinoid, and Merkel cell carcinoma were evaluated for CD200 expression by immunohistochemistry. A set of nonneuroendocrine carcinomas was stained for comparison. CD200 was expressed in 87% of the neuroendocrine neoplasms studied, including 60 of 72 (83%) pulmonary small cell carcinomas, 15 of 22 (68%) pulmonary carcinoids, three of four (75%) pulmonary large cell neuroendocrine carcinomas, 125 of 146 (86%) Merkel cell carcinomas, 79 of 83 (95%) gastrointestinal luminal carcinoids, and 56 of 60 (93%) pancreatic neuroendocrine tumors. Thirty-two of 157 (20%) nonneuroendocrine carcinomas expressed CD200. In gastrointestinal carcinoid and pancreatic neuroendocrine neoplasms, CD200 negativity correlated with higher grade. CD200 is a relatively sensitive marker of neuroendocrine neoplasms and represents a potential therapeutic target in these difficult-to-treat malignancies.

  1. Gastrointestinal carcinoid tumours. Histogenetic, histochemical, immunohistochemical, clinical and therapeutic aspects.

    PubMed

    Wilander, E; Lundqvist, M; Oberg, K

    1989-01-01

    The increased knowledge of the pathobiology of gastrointestinal carcinoid (neuroendocrine) tumours and the improved therapeutic possibilities have brought a demand for more precise diagnosis. Although the carcinoid tumours can often be tentatively recognized in routinely processed microscopic slides, their more accurate identification requires additional diagnostic procedures. General neuroendocrine markers such as the argyrophil reaction of Grimelius and immunohistochemistry with application of antibodies against chromogranin A and of neuron-specific enolase are discriminatory staining methods which are used to reveal the neuroendocrine origin of almost all highly differentiated carcinoid tumours of the gastrointestinal tract. Mid-gut carcinoids, which predominate among these tumours almost unexceptionally contain serotonin. This biogenic amine can be demonstrated by the argentaffin reaction of Masson, serotonin immunoreactively or by formalin-induced fluorescence. The characteristic staining pattern of mid-gut carcinoids is almost invariably preserved in the metastatic deposits and consequently the staining methods for identifying serotonin can also be used on metastases to reveal a primary mid-gut carcinoid. The enterochromaffin-like (ECL) cell carcinoids of the body and fundic area of the stomach often seen in association with pernicious anaemia are argyrophil with the Sevier-Munger silver stain. Other neuroendocrine tumours, viz. antral, duodenal and rectal carcinoids should be studied by a battery of relevant peptide hormone antisera for adequate diagnosis. During the last decade new peptide hormones have been found in circulation in patients with carcinoid tumours, but serotonin and urinary 5-HIAA are still the most important markers for carcinoids of the mid-gut origin. Other clinically useful tumour markers are chromogranin A + B, pancreatic polypeptide, human chorionic gonadotropin alpha and beta subunits. For localizing procedures, angiography is the

  2. Gene expression profiles of progressive pancreatic endocrine tumours and their liver metastases reveal potential novel markers and therapeutic targets.

    PubMed

    Capurso, G; Lattimore, S; Crnogorac-Jurcevic, T; Panzuto, F; Milione, M; Bhakta, V; Campanini, N; Swift, S M; Bordi, C; Delle Fave, G; Lemoine, N R

    2006-06-01

    The intrinsic nature of tumour behaviour (stable vs progressive) and the presence of liver metastases are key factors in determining the outcome of patients with a pancreatic endocrine tumour (PET). Previous expression profile analyses of PETs were limited to non-homogeneous groups or to primary lesions only. The aim of this study was to investigate the gene expression profiles of a more uniform series of sporadic, non-functioning (NF) PETs with progressive disease and, for the first time, their liver metastases, on the Affymetrix human genome U133A and B GeneChip set. Thirteen NF PET samples (eight primaries and five liver metastases) from ten patients with progressive, metastatic disease, three cell lines (BON, QGP and CM) and four purified islet samples were analysed. The same samples were employed for confirmation of candidate gene expression by means of quantitative RT-PCR, while a further 37 PET and 15 carcinoid samples were analysed by immunohistochemistry. Analysis of genes differentially expressed between islets and primaries and metastases revealed 667 up- and 223 down-regulated genes, most of which have not previously been observed in PETs, and whose gene ontology molecular function has been detailed. Overexpression of bridging integrator 1 (BIN1) and protein Z dependent protease inhibitor (SERPINA10) which may represent useful biomarkers, and of lymphocyte specific protein tyrosine kinase (LCK) and bone marrow stromal cell antigen (BST2) which could be used as therapeutic targets, has been validated. When primary tumours were compared with metastatic lesions, no significantly differentially expressed genes were found, in accord with cluster analysis which revealed a striking similarity between primary and metastatic lesions, with the cell lines clustering separately. We have provided a comprehensive list of differentially expressed genes in a uniform set of aggressive NF PETs. A number of dysregulated genes deserve further in-depth study as potentially

  3. 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.

  4. Deletion at 3p25.3-p23 is frequently encountered in endocrine pancreatic tumours and is associated with metastatic progression.

    PubMed

    Barghorn, A; Komminoth, P; Bachmann, D; Rütimann, K; Saremaslani, P; Muletta-Feurer, S; Perren, A; Roth, J; Heitz, P U; Speel, E J

    2001-08-01

    For several reasons, chromosome 3p is thought to be involved in the pathogenesis of sporadic endocrine pancreatic tumours (EPTs): von Hippel-Lindau's disease (VHL gene at 3p25.5) is associated with EPTs; 3p is frequently involved in solid human tumours; and comparative genomic hybridization has identified frequent losses at 3p in EPTs. This study investigated 99 benign and malignant tumours, including 20 metastases, from 82 patients, by microsatellite loss of heterozygosity (LOH) analysis and fluorescence in situ hybridization (FISH) in order to evaluate the importance of chromosome 3p deletions in the molecular pathogenesis and biological behaviour of EPTs, to elaborate a common region of deletion, and to narrow down putative tumour suppressor gene loci. Allelic losses of 3p were found in 58/99 (58.6%) of tumours in 45/82 (54.9%) patients; analysis of seven microsatellite markers (3p26-p21) revealed a common region of LOH at 3p25.3-p23. The LOH frequency was significantly higher in malignant than in benign neoplasms (70.2% versus 28.0%; p=0.001). In addition, a strong correlation was found between the loss of alleles on chromosome 3p and clinically metastatic disease (LOH of 73.7% in metastasizing versus 41.5% in non-metastasizing tumours; p=0.008). EPTs from these patients showed a tendency towards losing large parts or the entire short arm of chromosome 3 with tumour progression. Furthermore, FISH analysis revealed complete loss of chromosome 3 in ten out of 37 EPTs (27%). These results indicate that a putative tumour suppressor gene at 3p25.3-p23 may play a role in the oncogenesis of sporadic EPTs and that losses of larger centromeric regions are associated with metastatic progression.

  5. PTCH 1 staining of pancreatic neuroendocrine tumor (PNET) samples from patients with and without multiple endocrine neoplasia (MEN-1) syndrome reveals a potential therapeutic target.

    PubMed

    Gurung, Buddha; Hua, Xianxin; Runske, Melissa; Bennett, Bonita; LiVolsi, Virginia; Roses, Robert; Fraker, Douglas A; Metz, David C

    2015-01-01

    Pancreatic neuroendocrine tumors (PNETs) are rare, indolent tumors that may occur sporadically or develop in association with well-recognized hereditary syndromes, particularly multiple endocrine neoplasia type 1 (MEN-1). We previously demonstrated that the hedgehog (HH) signaling pathway was aberrantly up-regulated in a mouse model that phenocopies the human MEN-1 syndrome, Men1l/l;RipCre, and that inhibition of this pathway suppresses MEN-1 tumor cell proliferation. We hypothesized that the HH signaling pathway is similarly upregulated in human PNETs. We performed immunohistochemical (IHC) staining for PTCH1 in human fresh and archival PNET specimens to examine whether human sporadic and MEN-1-associated PNETs revealed similar abnormalities as in our mouse model and correlated the results with clinical and demographic factors of the study cohort. PTCH1 staining was positive in 12 of 22 PNET patients (55%). Four of 5 MEN-1 patients stained for PTCH1 (p = 0.32 as compared with sporadic disease patients). Nine of 16 patients with metastatic disease stained for PTCH1 as compared with zero of 3 with localized disease only (p = 0.21). No demographic or clinical features appeared to be predictive of PTCH 1 positivity and PTCH 1 positivity per se was not predictive of clinical outcome. PTCH1, a marker of HH pathway up regulation, is detectable in both primary and metastatic tumors in more than 50% of PNET patients. Although no clinical or demographic factors predict PTCH1 positivity and PTCH1 positivity does not predict clinical outcome, the frequency of expression alone indicates that perturbation of this pathway with agents such as Vismodegib, an inhibitor of Smoothened (SMO), should be examined in future clinical trials.

  6. The FGFR4-G388R single-nucleotide polymorphism alters pancreatic neuroendocrine tumor progression and response to mTOR inhibition therapy.

    PubMed

    Serra, Stefano; Zheng, Lei; Hassan, Manal; Phan, Alexandria T; Woodhouse, Linda J; Yao, James C; Ezzat, Shereen; Asa, Sylvia L

    2012-11-15

    Pancreatic neuroendocrine tumors (pNET), also known as islet cell tumors, exhibit a wide range of biologic behaviors ranging from long dormancy to rapid progression. Currently, there are few molecular biomarkers that can be used to predict recurrence/metastasis or response to therapy. This study examined the predictive and prognostic value of a single nucleotide polymorphism substituting an arginine (R) for glycine (G) in codon 388 of the FGFR4 transmembrane domain. We established the FGFR4 genotype of 71 patients with pNETs and correlated genotype with biologic behavior. We created an in vivo model of pNET with BON1 cells and transfected them with either FGFR4-G388 or FGFR4-R388 to determine the mechanism of action and to examine response to the mTOR inhibitor everolimus. We then validated the predictive results of experimental studies in a group of patients treated with everolimus. FGFR4-R388 is associated with more aggressive clinical behavior in patients with pNETs with a statistically significant higher risk of advanced tumor stage and liver metastasis. Using an orthotopic mouse xenograft model, we show that FGFR4-R388 promotes tumor progression by increasing intraperitoneal spread and metastatic growth within the liver. Unlike FGFR4-G388, FGFR4-R388 BON1 tumors exhibited diminished responsiveness to everolimus. Concordantly, there was a statistically significant reduction in response to everolimus in patients with FGFR4-R388. Our findings highlight the importance of the FGFR4 allele in pNET progression and identify a predictive marker of potential therapeutic importance in this disease.

  7. Long-term Prognosis of Resected Pancreatic Neuroendocrine Tumors in von Hippel-Lindau Disease Is Favorable and Not Influenced by Small Tumors Left in Place.

    PubMed

    de Mestier, Louis; Gaujoux, Sébastien; Cros, Jérôme; Hentic, Olivia; Vullierme, Marie-Pierre; Couvelard, Anne; Cadiot, Guillaume; Sauvanet, Alain; Ruszniewski, Philippe; Richard, Stéphane; Hammel, Pascal

    2015-08-01

    Management of pancreatic neuroendocrine tumors (PNETs) associated with von Hippel-Lindau disease (VHL) is challenging because of the malignant potential and difficulty in predicting prognosis. Compare the long-term outcome of resected VHL-PNET and sporadic PNET. Data of all patients with VHL (n = 23) operated on for nonmetastatic PNET were reviewed. Patient characteristics and recurrence-free survival rates were compared with those in patients operated on for sporadic PNET, matched for tumor size, stage, and Ki-67 index. Patients in both groups had similar demographic characteristics, except that patients with VHL were younger (36 vs 56 years, P < 0.0001). Median tumor size was 30 mm. Median Ki-67 index was 3% and 4% in the VHL and sporadic groups (P = 0.95), respectively, and lymph node metastases were present in 43% and 30% of cases, respectively (P = 0.45). Sixteen (70%) patients with VHL had multiple PNET; lesions less than 15 mm were left in place in 11 patients. Median postoperative follow-up was 107 months (interquartile range, 57-124 months) and 71 months (interquartile range, 58-131 months) in the VHL and control groups, respectively. Median recurrence-free survival could not have been estimated in the VHL group due to the low number of events (hazard ratio, 5.6; 95% confidence interval, 1.4-22.6; P = 0.013). Five patients with VHL died (3 from VHL-related tumors including 1 from PNET), whereas only one control patient died due to unrelated causes. The long-term outcome of resected VHL-PNET is better than that of sporadic PNET. PNET less than 15 mm left in place did not progress. A parenchyma-sparing surgical strategy seems appropriate in patients with VHL-PNET, who may develop more life-threatening tumors of other organs.

  8. Combination therapy with gemcitabine (GEM) and erlotinib (E) in exocrine pancreatic cancer under special reference to RASH and the tumour marker CA19-9.

    PubMed

    Klapdor, R; Klapdor, S; Bahlo, M

    2012-05-01

    We report on the results of a prospective treatment of 30 proven metastatic pancreatic cancer patients with the recently described combination of gemcitabine and erlotinib (GEM+E) (24× 1st line therapy, 8× 2nd line therapy). Eight of these patients received GEM+E for treatment of metastastic tumour recurrence after previous resective surgery, followed by adjuvant chemotherapy with gemcitabine. In 2 patients GEM+E was given as 1st line treatment and later, after complete response which was followed by a new recurrence, also as a second line therapy. The evaluation of RASH severity grades, the course of the serum tumour marker CA19-9 were determined every 14 days and the evaluation of the imaging methods CT or MRT, evaluated every 6-8 weeks, revealed the following results: there was a tendency for RASH grades to correlate with the tumour response, however, with observed exceptions. The decision for interruption or maintenance of GEM+E, therefore, should not be based on the RASH phenomenon, but on a detailed follow-up with imaging methods and the relevant tumour markers as in the follow-up before erlotinib introduction into pancreatic cancer therapy. As known from previous studies tumour markers represent more sensitive parameters compared to the imaging methods. GEM+E was active in the whole group of patients, mainly given as 1st line therapy (34% PD, 29% SD, 47% MR, PR, CR), but also in the 2 subgroups: in the patients with GEM+E as 2nd line therapy, as well as in patients after previous adjuvant gemcitabine therapy after tumour resection. In the 2 patients with transient-CR after 1st line therapy with GEM+E the 2nd line therapy also resulted in a CR with long lasting remission. These data should motivate clinicians to focus their interest not only to 1st line therapy regimens with erlotinib, but also to 2nd and 3rd line strategies within the previously published concept of an efficacy-orientated sequential polychemotherapy or multimodal-therapy for pancreatic

  9. hERG1 channels drive tumour malignancy and may serve as prognostic factor in pancreatic ductal adenocarcinoma

    PubMed Central

    Lastraioli, E; Perrone, G; Sette, A; Fiore, A; Crociani, O; Manoli, S; D'Amico, M; Masselli, M; Iorio, J; Callea, M; Borzomati, D; Nappo, G; Bartolozzi, F; Santini, D; Bencini, L; Farsi, M; Boni, L; Di Costanzo, F; Schwab, A; Onetti Muda, A; Coppola, R; Arcangeli, A

    2015-01-01

    Background: hERG1 channels are aberrantly expressed in human cancers. The expression, functional role and clinical significance of hERG1 channels in pancreatic ductal adenocarcinoma (PDAC) is lacking. Methods: hERG1 expression was tested in PDAC primary samples assembled as tissue microarray by immunohistochemistry using an anti-hERG1 monoclonal antibody (α-hERG1-MoAb). The functional role of hERG1 was studied in PDAC cell lines and primary cultures. ERG1 expression during PDAC progression was studied in Pdx-1-Cre,LSL-KrasG12D/+,LSL-Trp53R175H/+ transgenic (KPC) mice. ERG1 expression in vivo was determined by optical imaging using Alexa-680-labelled α-hERG1-MoAb. Results: (i) hERG1 was expressed at high levels in 59% of primary PDAC; (ii) hERG1 blockade decreased PDAC cell growth and migration; (iii) hERG1 was physically and functionally linked to the Epidermal Growth Factor-Receptor pathway; (iv) in transgenic mice, ERG1 was expressed in PanIN lesions, reaching high expression levels in PDAC; (v) PDAC patients whose primary tumour showed high hERG1 expression had a worse prognosis; (vi) the α-hERG1-MoAb could detect PDAC in vivo. Conclusions: hERG1 regulates PDAC malignancy and its expression, once validated in a larger cohort also comprising of late-stage, non-surgically resected cases, may be exploited for diagnostic and prognostic purposes in PDAC either ex vivo or in vivo. PMID:25719829

  10. The role of the AMOP domain in MUC4/Y-promoted tumour angiogenesis and metastasis in pancreatic cancer.

    PubMed

    Tang, Jie; Zhu, Yi; Xie, Kunling; Zhang, Xiaoyu; Zhi, Xiaofei; Wang, Weizhi; Li, Zheng; Zhang, Qun; Wang, Linjun; Wang, Jiwei; Xu, Zekuan

    2016-06-10

    MUC4 is a high molecular weight membrane protein that is overexpressed in pancreatic cancer (PC) and is associated with the development and progression of this disease. However, the exact mechanisms through which MUC4 domains promote these biological processes have rarely been studied, partly because of its high molecular weight, difficulty to overexpress it. Here, we use MUC4/Y, one of the MUC4 transcript variants, as a model molecule to investigate the AMOP-domain of MUC4(MUC/Y). We used cell proliferation, migration, invasion and tube formation assays in vitro to explore the abilities of AMOP domain in PC. In vivo, the matrigel plug assay, orthotopic implantation and Kaplan-Meier survival curves were used to check the results we observed in vitro. Finally, we discovered the underlying mechanism through western blot and immunofluorescence. We found that MUC4/Y overexpression could enhance the angiogenic and metastatic properties of PC cells, both in vitro and in vivo. However, the deletion of AMOP domain could cutback these phenomena. Additionally, Kaplan-Meier survival curves showed that mice injected with MUC4/Y overexpressed cells had shorter survival time, compared with empty-vector-transfected cells (MUC4/Y-EV), or cells expressing MUC4/Y without the AMOP domain (MUC4/Y-AMOP(△)). Our data also showed that overexpression of MUC4/Y could activate NOTCH3 signaling, increasing the expression of downstream genes: VEGF-A, MMP-9 and ANG-2. The AMOP domain had an important role in MUC4/Y (MUC4)-mediated tumour angiogenesis and metastasis of PC cells; and the NOTCH3 signaling was involved. These findings provided new insights into PC therapies. Our study also supplies a new method to study other high molecular membrane proteins.

  11. Neuroendocrine tumor targeting: study of novel gallium-labeled somatostatin radiopeptides in a rat pancreatic tumor model.

    PubMed

    Froidevaux, Sylvie; Eberle, Alex N; Christe, Martine; Sumanovski, Lazar; Heppeler, Axel; Schmitt, Jörg S; Eisenwiener, Klaus; Beglinger, Christoph; Mäcke, Helmut R

    2002-04-20

    Somatostatin analogs labeled with radionuclides are of considerable interest in the diagnosis and therapy of SSTR-expressing tumors, such as gastroenteropancreatic, small cell lung, breast and frequently nervous system tumors. In view of the favorable physical characteristics of the Ga isotopes (67)Ga and (68)Ga, enabling conventional tumor scintigraphy, PET and possibly internal radiotherapy, we focused on the development of a Ga-labeled somatostatin analog suitable for targeting SSTR-expressing tumors. For this purpose, 3 somatostatin analogs, OC, TOC and TATE were conjugated to the metal chelator DOTA and labeled with the radiometals (111)In, (90)Y and (67)Ga. They were then evaluated for their performance in the AR4-2J pancreatic tumor model by testing SSTR2-binding affinity, internalization/externalization in isolated cells and biodistribution in tumor-bearing nude mice. Surprisingly, we found that, compared to (111)In or (90)Y, labeling with (67)Ga considerably improved the biologic performance of the tested somatostatin analogs with respect to SSTR2 affinity and tissue distribution. (67)Ga-labeled DOTA-somatostatin analogs were rapidly excreted from nontarget tissues, leading to excellent tumor-to-nontarget tissue uptake ratios. Of interest for radiotherapeutic application, [(67)Ga]DOTATOC was strongly internalized by AR4-2J cells. Furthermore, our results suggest a link between the radioligand charge and its kidney retention. The excellent tumor selectivity of Ga-DOTA somatostatin analogs together with the different applications of Ga in nuclear oncology suggests that Ga-DOTA somatostatin analogs will become an important tool in the management of SSTR-positive tumors. Copyright 2002 Wiley-Liss, Inc.

  12. Pancreatitis

    MedlinePlus

    ... removal is sometimes performed along with a sphincterotomy. Stent placement. Using the endoscope, the doctor places a ... a narrowed pancreatic or bile duct. A temporary stent may be placed for a few months to ...

  13. Small pancreatic insulinoma: Successful endoscopic ultrasound-guided radiofrequency ablation in a single session, using a 22G fine needle.

    PubMed

    Bas-Cutrina, Francesc; Bargalló, Domingo; Gornals, Joan B

    2017-03-14

    A 63-year-old woman, morbidly obese, with clinical symptoms of periodic hypoglycemic episodes, was diagnosed with an insulinoma in pancreatic body that had not been detected by previous computed tomography and magnetic resonance. This neuroendocrine tumour was identified by EUS as a hypoechoic lesion with some iso-hyperechoic tracts, measuring 9 x 10 mm, and 4-5 mm from splenic vessels (Figure 1a). This article is protected by copyright. All rights reserved.

  14. Rationale and protocol of the MetNET-1 trial, a prospective, single center, phase II study to evaluate the activity and safety of everolimus in combination with octreotide LAR and metformin in patients with advanced pancreatic neuroendocrine tumors.

    PubMed

    Pusceddu, Sara; de Braud, Filippo; Concas, Laura; Bregant, Cristina; Leuzzi, Livia; Formisano, Barbara; Buzzoni, Roberto

    2014-01-01

    Abnormal PI3K-AKT-mTOR pathway signalling and autocrine activation of the mTOR pathway, mediated through insulin-like growth factor-1, have been implicated in the proliferation of pancreatic neuroendocrine tumor (pNET) cells. Everolimus, an mTOR inhibitor, has shown antitumor benefit in pNETs alone and in combination with octreotide LAR in RADIANT-1 and RADIANT-3 studies. Although everolimus-based phase II/III trials have improved progression-free survival for pNET, its use has not impacted on prolonging overall survival. Metformin has recently shown some anti-cancer activity in both in vitro and in vivo studies by its indirect properties to decrease insulin and insulin-like growth factor-1 (IGF-1) levels and by its antitumour effect to promote AMPK activation and consequently inhibition to TSC1-2/mTOR complex. In light of even more retrospective evidence of metformin's anticancer activity, a prospective evaluation is required to either confirm or discard these preliminary findings. With the aim to evaluate the antiproliferative effect of metformin in combination with everolimus and octreotide LAR in pancreatic well-differentiated neuroendocrine tumor patients, a single arm, prospective, single center phase II study was designed (MetNET-1 trial, NCT 02294006). Forty-three patients are expected to be evaluated. The study is ongoing, and recruitment is estimated to be completed in August 2016. The results will be anticipated in 2017.

  15. Calcium-dependent photodynamic action of di- and tetrasulphonated aluminium phthalocyanine on normal and tumour-derived rat pancreatic exocrine cells.

    PubMed Central

    al-Laith, M.; Matthews, E. K.

    1994-01-01

    Important differences exist in the responses to photodynamic agents of normal and tumour-derived pancreatic acinar cells. In the present study amylase release has been used to assess the mechanisms by which the photodynamic drugs tetra- and disulphonated aluminium phthalocyanine (A1PcS4, A1PcS2) act on pancreatic cells via energy and calcium-dependent activation and transduction pathways. The photodynamic release of amylase was found to be energy dependent and inhibited by the chelation of free cytoplasmic calcium but not by the removal of extracellular calcium. In contrast to their effects on normal acinar cells, the photodynamic action of A1PcS4 and A1PcS2 was to inhibit amylase secretion from pancreatoma AR4-2J cells. Removal of extracellular calcium reversed this inhibitory effect on AR4-2J cells and produced a significant increase in amylase release, but chelation of free cytoplasmic calcium did not affect the inhibitory photodynamic action of the phthalocyanines on amylase release from the tumour cells. Overall, these results demonstrate further important distinctions between the photodynamic action of sulphonated aluminium phthalocyanines on normal versus tumour exocrine cells of the pancreas and indicate that calcium plays an important role in photodynamic drug action, since these agents affected intracellular calcium mobilisation at some distal point in the membrane signal transduction pathway for regulated secretion. Furthermore, the photodynamic inhibition of constitutive secretion in tumour cells may involve a calcium-dependent membrane target site or modulation of membrane calcium channels by activation of protein kinase C. PMID:7524603

  16. (18)F-FDG PET/CT Volumetric Parameters are Associated with Tumor Grade and Metastasis in Pancreatic Neuroendocrine Tumors in von Hippel-Lindau Disease.

    PubMed

    Satoh, Kei; Sadowski, Samira M; Dieckmann, William; Quezado, Martha; Nilubol, Naris; Kebebew, Electron; Patel, Dhaval

    2016-12-01

    Approximately 8-17 % of patients with von Hippel-Lindau (VHL) syndrome develop pancreatic neuroendocrine tumors (PNETs), with 11-20 % developing metastases. Tumor grade is predictive of prognosis. The aim of this study was to determine if preoperative metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were associated with metastatic disease and tumor grade. Sixty-two patients with VHL-associated PNETs prospectively underwent (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT). MTV, TLG, and maximum standardized uptake value (SUVmax) were measured using a semi-automatic method. Surgically resected PNETs were classified according to 2010 World Health Organization tumor grade classification. MTV, TLG, and SUVmax were analyzed by metastatic disease and tumor grade using the Mann-Whitney test. A total of 88 PNETs were identified by CT and (18)F-FDG PET/CT, 10 of which were non-FDG-avid. Histologic grading was available for 20 surgical patients. Patients with metastatic PNETs had a higher TLG (median 25.9 vs. 7.7 mean SUV [SUVmean]*mL; p = 0.0092) compared with patients without metastasis, while patients with grade 2 PNETs had a higher MTV (median 6.9 vs. 2.6 mL; p = 0.034) and TLG (median 41.2 vs. 13.1 SUVmean*mL; p = 0.0035) compared with patients with grade 1 PNETs. No difference in tumor size or SUVmax was observed between the groups. Patients with metastatic PNETs have a higher TLG compared with patients without metastasis. Grade 2 PNETs have a higher MTV and TLG compared with grade 1 PNETs. Tumor size and SUVmax were not associated with grade. Volumetric parameters on (18)F-FDG PET/CT may be useful in detecting higher grade PNETs with a higher malignant potential that may need surgical intervention.

  17. Prospective Study of 68Ga-DOTATATE Positron Emission Tomography/Computed Tomography for Detecting Gastro-Entero-Pancreatic Neuroendocrine Tumors and Unknown Primary Sites

    PubMed Central

    Sadowski, Samira M.; Neychev, Vladimir; Millo, Corina; Shih, Joanna; Nilubol, Naris; Herscovitch, Peter; Pacak, Karel; Marx, Stephen J.

    2016-01-01

    Purpose Gastro-entero-pancreatic neuroendocrine tumors (GEPNETs) are increasing in incidence, and accurate staging is important for selecting the appropriate treatment. 68Ga-DOTATATE imaging is a promising approach for detecting GEPNETs and could help in selecting optimal therapeutic strategies. The aim of this study was to prospectively determine the clinical utility of 68Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) in detecting unknown primary and metastatic GEPNETs. Patients and Methods One hundred thirty-one patients were enrolled in a prospective study of patients undergoing 68Ga-DOTATATE PET/CT, 111In-pentetreotide single-photon emission computed tomography (SPECT)/CT and multiphasic CT scan, and/or magnetic resonance imaging in a blinded fashion with comprehensive biochemical testing. The primary outcome measure was the detection of lesions by each imaging study. Results 68Ga-DOTATATE PET/CT imaging detected 95.1% of lesions (95% CI, 92.4% to 96.8%) with an average maximum standardized uptake value of 65.4 ± 47 (range, 6.9 to 244), anatomic imaging detected 45.3% of lesions (95% CI, 37.9% to 52.9%), and 111In-pentetreotide SPECT/CT detected 30.9% of lesions (95% CI, 25.0% to 37.5%), with a significant difference between imaging modalities (P < .001). In four of 14 patients (28.6%), 68Ga-DOTATATE PET/CT found a previously unknown primary tumor, and detected primary GEPNET, lymph node, and distant metastases correctly in 72 of 113 lesions (63.7%) when compared with histopathology, with 22.1% and 38.9% detected by using 111In-pentetreotide SPECT/CT and anatomic imaging, respectively. On the basis of findings with 68Ga-DOTATATE PET/CT, 43 of 131 patients (32.8%) had a change in management recommendation. In patients with carcinoid symptoms but negative biochemical testing, 68Ga-DOTATATE PET/CT detected lesions in 65.2% of patients, 40% of which were detected neither by anatomic imaging nor by 111In-pentetreotide SPECT/CT. Conclusion

  18. Grading of well-differentiated pancreatic neuroendocrine tumors is improved by the inclusion of both Ki67 proliferative index and mitotic rate.

    PubMed

    McCall, Chad M; Shi, Chanjuan; Cornish, Toby C; Klimstra, David S; Tang, Laura H; Basturk, Olca; Mun, Liew Jun; Ellison, Trevor A; Wolfgang, Christopher L; Choti, Michael A; Schulick, Richard D; Edil, Barish H; Hruban, Ralph H

    2013-11-01

    The grading system for pancreatic neuroendocrine tumors (PanNETs) adopted in 2010 by the World Health Organization (WHO) mandates the use of both mitotic rate and Ki67/MIB-1 index in defining the proliferative rate and assigning the grade. In cases when these measures are not concordant for grade, it is recommended to assign the higher grade, but specific data justifying this approach do not exist. Thus, we counted mitotic figures and immunolabeled, using the Ki67 antibody, 297 WHO mitotic grade 1 and 2 PanNETs surgically resected at a single institution. We quantified the Ki67 proliferative index by marking at least 500 cells in "hot spots" and by using digital image analysis software to count each marked positive/negative cell and then compared the results with histologic features and overall survival. Of 264 WHO mitotic grade 1 PanNETs, 33% were WHO grade 2 by Ki67 proliferative index. Compared with concordant grade 1 tumors, grade-discordant tumors were more likely to have metastases to lymph node (56% vs. 34%) (P<0.01) and to distant sites (46% vs. 12%) (P<0.01). Discordant mitotic grade 1 PanNETs also showed statistically significantly more infiltrative growth patterns, perineural invasion, and small vessel invasion. Overall survival was significantly different (P<0.01), with discordant mitotic grade 1 tumors showing a median survival of 12 years compared with 16.7 years for concordant grade 1 tumors. Conversely, mitotic grade 1/Ki67 grade 2 PanNETs showed few significant differences from tumors that were mitotic grade 2 and either Ki67 grade 1 or 2. Our data demonstrate that mitotic rate and Ki67-based grades of PanNETs are often discordant, and when the Ki67 grade is greater than the mitotic grade, clinical outcomes and histopathologic features are significantly worse than concordant grade 1 tumors. Patients with discordant mitotic grade 1/Ki67 grade 2 tumors have shorter overall survival and larger tumors with more metastases and more aggressive histologic

  19. Direct comparison of (68)Ga-DOTA-TOC and (18)F-FDG PET/CT in the follow-up of patients with neuroendocrine tumour treated with the first full peptide receptor radionuclide therapy cycle.

    PubMed

    Nilica, Bernhard; Waitz, Dietmar; Stevanovic, Vlado; Uprimny, Christian; Kendler, Dorota; Buxbaum, Sabine; Warwitz, Boris; Gerardo, Llanos; Henninger, Benjamin; Virgolini, Irene; Rodrigues, Margarida

    2016-08-01

    To determine the value of (68)Ga-DOTA-TOC and (18)F-FDG PET/CT for initial and follow-up evaluation of patients with neuroendocrine tumour (NET) treated with peptide receptor radionuclide therapy (PRRT). We evaluated 66 patients who had histologically proven NET and underwent both PRRT and three combined (68)Ga-DOTA-TOC and (18)F-FDG PET/CT studies. (68)Ga-DOTA-TOC PET/CT was performed before PRRT, 3 months after completion of PRRT and after a further 6 - 9 months. (18)F-FDG PET/CT was done within 2 months of (68)Ga-DOTA-TOC PET/CT. Follow-up ranged from 11.8 to 80.0 months (mean 34.5 months). All patients were (68)Ga-DOTA-TOC PET-positive initially and at follow-up after the first full PRRT cycle. Overall, 62 of the 198 (18)F-FDG PET studies (31 %) were true-positive in 38 of the 66 patients (58 %). Of the 66 patients, 28 (5 grade 1, 23 grade 2) were (18)F-FDG-negative initially and during follow-up (group 1), 24 (5 grade 1, 13 grade 2, 6 grade 3) were (18)F-FDG-positive initially and during follow-up (group 2), 9 patients (2 grade 1, 6 grade 2, 1 grade 3) were (18)F-FDG-negative initially but (18)F-FDG-positive during follow-up (group 3), and 5 patients (all grade 2) were (18)F-FDG-positive initially but (18)F-FDG-negative during follow-up (group 4).(18)F-FDG PET showed more and/or larger metastases than (68)Ga-DOTA-TOC PET in five patients of group 2 and four patients of group 3, all with progressive disease. In three patients with progressive disease who died during follow-up tumour SUVmax increased by 41 - 82 % from the first to the last follow-up investigation. In NET patients, the presence of (18)F-FDG-positive tumours correlates strongly with a higher risk of progression. Initially, patients with (18)F-FDG-negative NET may show (18)F-FDG-positive tumours during follow-up. Also patients with grade 1 and grade 2 NET may have (18)F-FDG-positive tumours. Therefore, (18)F-FDG PET/CT is a complementary tool to (68)Ga-DOTA-TOC PET/CT with clinical

  20. 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.

  1. Clinical experience in appendiceal neuroendocrine neoplasms

    PubMed Central

    Ozcelik, Caglar K.; Bozdogan, Nazan; Dibekoglu, Cengiz

    2015-01-01

    Aim of the study To analyse the incidence of appendiceal neuroendocrine neoplasms in appendectomy specimens and establish the epidemiological and histopathological features, treatment, and clinical course. Material and methods Between 2004 and 2013, 975 patients who underwent appendectomy in Ankara Oncology Education and Research Hospital were retrospectively analysed. Results Neuroendocrine neoplasm was detected in the nine of 975 (0.9%) patients. Neuroendocrine neoplasms were diagnosed in eight patients by appendectomy, which was performed because of the prediagnosis of acute appendicitis, and in one patient by the suspicious mass detection during surgical procedures that were done in the appendix for a different reason. Eight of the patients’ tumours were in the tip of the appendix, and one of the patients’ tumours was at the base of appendix. Tumour size in 77.8% of patients was equal or less than 1 cm, in 22.2% patients it was 1–2 cm. There was tumour invasion in the muscularis propria layer in four patients, in the serosa layer in three patients, and in the deep mesoappendix in two patients. Patients were followed for a median of 78 months. In the follow-up of patients who were operated because of colon cancer, metachronous colon tumour evolved. This patient died due to progressive disease. Other patients are still disease-free. Conclusions The diagnosis of neuroendocrine neoplasm is often incidentally done after appendectomy. Tumour size is important in determining the extent of disease and in the selection of the surgical method during operation. PMID:26793027

  2. Stages of Pancreatic Neuroendocrine Tumors

    MedlinePlus

    ... endoscope is used to bounce high-energy sound waves ( ultrasound ) off internal tissues or organs and make echoes. The echoes ... ultrasound : A procedure that uses high-energy sound waves (ultrasound) to create images of internal organs or tissues during surgery. A transducer placed ...

  3. Pancreatic endocrine tumours: mutational and immunohistochemical survey of protein kinases reveals alterations in targetable kinases in cancer cell lines and rare primaries

    PubMed Central

    Corbo, V.; Beghelli, S.; Bersani, S.; Antonello, D.; Talamini, G.; Brunelli, M.; Capelli, P.; Falconi, M.; Scarpa, A.

    2012-01-01

    Background: Kinases represent potential therapeutic targets in pancreatic endocrine tumours (PETs). Patients and methods: Thirty-five kinase genes were sequenced in 36 primary PETs and three PET cell lines: (i) 4 receptor tyrosine kinases (RTK), epithelial growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), tyrosine-protein kinase KIT (KIT), platelet-derived growth factor receptor alpha (PDGFRalpha); (ii) 6 belonging to the Akt/mTOR pathway; and (iii) 25 frequently mutated in cancers. The immunohistochemical expression of the four RTKs and the copy number of EGFR and HER2 were assessed in 140 PETs. Results: Somatic mutations were found in KIT in one and ATM in two primary neoplasms. Among 140 PETs, EGFR was immunopositive in 18 (13%), HER2 in 3 (2%), KIT in 16 (11%), and PDGFRalpha in 135 (96%). HER2 amplification was found in 2/130 (1.5%) PETs. KIT membrane immunostaining was significantly associated with tumour aggressiveness and shorter patient survival. PET cell lines QGP1, CM and BON harboured mutations in FGFR3, FLT1/VEGFR1 and PIK3CA, respectively. Conclusions: Only rare PET cases, harbouring either HER2 amplification or KIT mutation, might benefit from targeted drugs. KIT membrane expression deserves further attention as a prognostic marker. ATM mutation is involved in a proportion of PET. The finding of specific mutations in PET cell lines renders these models useful for preclinical studies involving pathway-specific therapies. PMID:21447618

  4. Lung neuroendocrine tumours: deep sequencing of the four World Health Organization histotypes reveals chromatin-remodelling genes as major players and a prognostic role for TERT, RB1, MEN1 and KMT2D.

    PubMed

    Simbolo, Michele; Mafficini, Andrea; Sikora, Katarzyna O; Fassan, Matteo; Barbi, Stefano; Corbo, Vincenzo; Mastracci, Luca; Rusev, Borislav; Grillo, Federica; Vicentini, Caterina; Ferrara, Roberto; Pilotto, Sara; Davini, Federico; Pelosi, Giuseppe; Lawlor, Rita T; Chilosi, Marco; Tortora, Giampaolo; Bria, Emilio; Fontanini, Gabriella; Volante, Marco; Scarpa, Aldo

    2017-03-01

    Next-generation sequencing (NGS) was applied to 148 lung neuroendocrine tumours (LNETs) comprising the four World Health Organization classification categories: 53 typical carcinoid (TCs), 35 atypical carcinoid (ACs), 27 large-cell neuroendocrine carcinomas, and 33 small-cell lung carcinomas. A discovery screen was conducted on 46 samples by the use of whole-exome sequencing and high-coverage targeted sequencing of 418 genes. Eighty-eight recurrently mutated genes from both the discovery screen and current literature were verified in the 46 cases of the discovery screen, and validated on additional 102 LNETs by targeted NGS; their prevalence was then evaluated on the whole series. Thirteen of these 88 genes were also evaluated for copy number alterations (CNAs). Carcinoids and carcinomas shared most of the altered genes but with different prevalence rates. When mutations and copy number changes were combined, MEN1 alterations were almost exclusive to carcinoids, whereas alterations of TP53 and RB1 cell cycle regulation genes and PI3K/AKT/mTOR pathway genes were significantly enriched in carcinomas. Conversely, mutations in chromatin-remodelling genes, including those encoding histone modifiers and members of SWI-SNF complexes, were found at similar rates in carcinoids (45.5%) and carcinomas (55.0%), suggesting a major role in LNET pathogenesis. One AC and one TC showed a hypermutated profile associated with a POLQ damaging mutation. There were fewer CNAs in carcinoids than in carcinomas; however ACs showed a hybrid pattern, whereby gains of TERT, SDHA, RICTOR, PIK3CA, MYCL and SRC were found at rates similar to those in carcinomas, whereas the MEN1 loss rate mirrored that of TCs. Multivariate survival analysis revealed RB1 mutation (p = 0.0005) and TERT copy gain (p = 0.016) as independent predictors of poorer prognosis. MEN1 mutation was associated with poor prognosis in AC (p = 0.0045), whereas KMT2D mutation correlated with longer survival in SCLC

  5. GNAS mutation is a frequent event in pancreatic intraductal papillary mucinous neoplasms and associated adenocarcinomas.

    PubMed

    Hosoda, Waki; Sasaki, Eiichi; Murakami, Yoshiko; Yamao, Kenji; Shimizu, Yasuhiro; Yatabe, Yasushi

    2015-06-01

    In contrast to pancreatic ductal adenocarcinomas (PDAs), intraductal papillary mucinous neoplasms (IPMNs) frequently harbour GNAS mutations. To characterise GNAS-mutated pancreatic carcinomas, we examined mutations of GNAS and KRAS in 290 pancreatic adenocarcinomas and 77 pancreatic intraepithelial neoplasias (PanINs). In 64 % (39/61) of IPMNs and 37 % (11/30) of IPMN-associated adenocarcinomas, a GNAS mutation was found. GNAS mutations were frequent (78 %, 7/9) in mucinous carcinomas, with or without associated IPMN. In contrast, GNAS mutations were rarely observed in PDAs (1 %, 1/88) and PanINs (3 %, 2/77), and not at all in mucinous cystic neoplasms (MCNs) (0/10), neuroendocrine neoplasms (0/52), acinar cell neoplasms (0/16), serous cystadenomas (0/10), and solid-pseudopapillary neoplasms (0/14). We found GNAS mutations in 55/91 IPMNs with or without associated invasive carcinoma, solely in intestinal-type (78 %, 21/27) and gastric-type (62 %, 34/55) IPMNs. Of the IPMN-associated adenocarcinomas, mucinous-subtype tumours harboured GNAS mutations more frequently (83 %, 5/6) than tubular-subtype tumours (25 %, 6/24) (p = 0.02). We separately analysed GNAS in the adenocarcinoma and the IPMN component in the IPMN-associated adenocarcinomas. In all mucinous-subtype tumours, the two components exhibited identical genotypes. In contrast, the two components in 8 of 24 tubular-subtype tumours exhibited different genotypes, indicating intratumour heterogeneity. In conclusion, mucinous carcinomas with or without associated IPMN as well as IPMNs frequently harbour a GNAS mutation, reinforcing the notion that these constitute a spectrum of pancreatic tumours. Clinically and pathologically, these tumours are associated, but GNAS mutation sheds further light on this spectrum.

  6. 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

  7. Ga-68 DOTANOC PET/CT imaging in detection of primary site in patients with metastatic neuroendocrine tumours of unknown origin and its impact on clinical decision making: experience from a tertiary care centre in India

    PubMed Central

    Pankaj, Promila; Verma, Ritu; Jain, Anjali; Belho, Ethel S.; Mahajan, Harsh

    2016-01-01

    Background Neuroendocrine tumours (NETs) are rare, heterogeneous group of tumours which usually originate from small, occult primary sites and are characterized by over-expression of somatostatin receptors (SSTRs). Positron emission tomography/computed tomography (PET/CT) using Ga-68-labeled-somatostatin-analogues have shown superiority over other modalities for imaging of NETs. The objective of the study was to retrospectively evaluate the efficacy of Ga-68 DOTANOC PET/CT imaging in detecting the primary site in patients with metastatic NETs of unknown origin and its impact on clinical decision making in such patients. Methods Between December 2011 and September 2014, a total of 263 patients underwent Ga-68 DOTANOC PET/CT study in our department for various indications. Out of them, 68 patients (45 males, 23 females; mean age, 54.9±10.7 years; range, 31–78 years) with histopathologically proven metastatic NETs and unknown primary site (CUP-NET) on conventional imaging, who underwent Ga-68 DOTANOC PET/CT scan as part of their clinical work-up were included for analyses. Histopathology (wherever available) and/or follow-up imaging were taken as reference standard. Quantitative estimation of SSTR expression in the form of maximal standardized uptake value (SUVmax) of detected primary and metastatic sites was calculated. Follow-up data of individual patients was collected through careful survey of hospital medical records and telephonic interviews. Results Maximum patients presented to our department with hepatic metastasis (50 out of 68 patients) and grade I NETs (>50%). Ga-68 DOTANOC PET/CT scan identified primary sites in 40 out of these 68 patients i.e., in approximately 59% patients. Identified primary sites were: small intestine [19], rectum [8], pancreas [7], stomach [4], lung [1] and one each in rare sites in kidney and prostate. In one patient, 2 primary sites were identified (one each in stomach and duodenum). Mean SUVmax of the detected primary sites was

  8. Ga-68 DOTANOC PET/CT imaging in detection of primary site in patients with metastatic neuroendocrine tumours of unknown origin and its impact on clinical decision making: experience from a tertiary care centre in India.

    PubMed

    Pruthi, Ankur; Pankaj, Promila; Verma, Ritu; Jain, Anjali; Belho, Ethel S; Mahajan, Harsh

    2016-06-01

    Neuroendocrine tumours (NETs) are rare, heterogeneous group of tumours which usually originate from small, occult primary sites and are characterized by over-expression of somatostatin receptors (SSTRs). Positron emission tomography/computed tomography (PET/CT) using Ga-68-labeled-somatostatin-analogues have shown superiority over other modalities for imaging of NETs. The objective of the study was to retrospectively evaluate the efficacy of Ga-68 DOTANOC PET/CT imaging in detecting the primary site in patients with metastatic NETs of unknown origin and its impact on clinical decision making in such patients. Between December 2011 and September 2014, a total of 263 patients underwent Ga-68 DOTANOC PET/CT study in our department for various indications. Out of them, 68 patients (45 males, 23 females; mean age, 54.9±10.7 years; range, 31-78 years) with histopathologically proven metastatic NETs and unknown primary site (CUP-NET) on conventional imaging, who underwent Ga-68 DOTANOC PET/CT scan as part of their clinical work-up were included for analyses. Histopathology (wherever available) and/or follow-up imaging were taken as reference standard. Quantitative estimation of SSTR expression in the form of maximal standardized uptake value (SUVmax) of detected primary and metastatic sites was calculated. Follow-up data of individual patients was collected through careful survey of hospital medical records and telephonic interviews. Maximum patients presented to our department with hepatic metastasis (50 out of 68 patients) and grade I NETs (>50%). Ga-68 DOTANOC PET/CT scan identified primary sites in 40 out of these 68 patients i.e., in approximately 59% patients. Identified primary sites were: small intestine [19], rectum [8], pancreas [7], stomach [4], lung [1] and one each in rare sites in kidney and prostate. In one patient, 2 primary sites were identified (one each in stomach and duodenum). Mean SUVmax of the detected primary sites was 25.1±18.0 (median: 16

  9. 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

  10. 177Lu-octreotate, alone or with radiosensitising chemotherapy, is safe in neuroendocrine tumour patients previously treated with high-activity 111In-octreotide.

    PubMed

    Hubble, Daniel; Kong, Grace; Michael, Michael; Johnson, Val; Ramdave, Shakher; Hicks, Rodney John

    2010-10-01

    The aim of this retrospective study was to determine whether patients with previous peptide receptor radionuclide therapy using high-activity (111)In-pentetreotide can be safely treated with (177)Lu-octreotate and whether addition of radiosensitising chemotherapy increases the toxicity of this agent. Records of 27 patients (aged 17-75) who received 69 (median 3 per patient) (177)Lu-octreotate administrations, including 29 in conjunction with radiosensitising infusional 5-fluorouracil (5-FU) (n = 27), or capecitabine (n = 2), between October 2005 and July 2007 subsequent to 1-8 prior cycles of (111)In-pentetreotide therapy were analysed. Toxicity was assessed during and at 8-12 weeks post-treatment, with further long-term assessments including survival status reviewed till death or study close-out date of 1 November 2009. Reduction in blood counts was most marked following the first dose of (177)Lu-octreotate but at early follow-up the only major haematological toxicity was a single case of grade 4 lymphopaenia. Both the presence of bone metastases and the administration of chemotherapy tended to result in greater reduction in blood counts, but these differences did not reach statistical significance. On long-term follow-up, 16 patients (59%) are alive with median overall survival of 36 months (32-44 months from first (177)Lu-octreotate therapy). None of the recorded deaths was directly related to treatment toxicity. One patient had late grade 4 anaemia and thrombocytopaenia secondary to bone marrow failure from progressive infiltration by tumour. No other significant long-term haematological toxicities were recorded and no leukaemia was observed. No renal toxicity was observed on serial serum creatinine or radionuclide glomerular filtration rate (GFR) determination on initial or long-term follow-up. (177)Lu-octreotate is a safe and well-tolerated therapy for patients who have previously been treated with (111)In-pentetreotide and can be safely combined with

  11. Clinical utility of indigenously formulated single-vial lyophilized HYNIC-TOC kit in evaluating Gastro-entero Pancreatic neuro endocrine tumours.

    PubMed

    Shinto, Ajit S; Kamaleshwaran, K; Vyshak, K; Sudhakar, Natarajan; Banerjee, Sharmila; Korde, Aruna; Samuel, Grace; Mallia, Madhav

    2014-01-01

    The objective of this study was to evaluate the performance and utility of (99m)Tc HYNIC-TOC planar scintigraphy and SPECT/CT in the diagnosis, staging and management of gastroenteropancreatic neuroendocrine tumors (GPNETs). 22 patients (median age, 46 years) with histologically proven gastro- entero- pancreatic NETs underwent (99m)Tc HYNIC-TOC whole body scintigraphy and regional SPECT/CT as indicated. Scanning was performed after injection of 370-550 MBq (10-15 mCi) of (99m)Tc HYNIC-TOC intravenously. Images were evaluated by two experienced nuclear medicine physicians both qualitatively as well as semi quantitatively (tumor to background and tumor to normal liver ratios on SPECT -CT images). Results of SPECT/CT were compared with the results of conventional imaging. Histopathology results and follow-up somatostatin receptor scintigraphy with (99m)Tc HYNIC TOC or conventional imaging with biochemical markers were considered to be the reference standards. (99m)Tc HYNIC TOC showed sensitivity and specificity of 87.5% and 85.7%, respectively, for primary tumor and 100% and 86% for metastases. It was better than conventional imaging modalities for the detection of both primary tumor (P<0.001) and metastases (P<0.0001). It changed the management strategy in 6 patients (31.8%) and supported management decisions in 8 patients (36.3%). (99m)Tc HYNIC TOC SPECT/CT appears to be a highly sensitive and specific modality for the detection and staging of GPNETs. It is better than conventional imaging for the evaluation of GPNETs and can have a significant impact on patient management and planning further therapeutic options.

  12. Clinical utility of indigenously formulated single-vial lyophilized HYNIC-TOC kit in evaluating Gastro-entero Pancreatic neuro endocrine tumours

    PubMed Central

    Shinto, Ajit S; Kamaleshwaran, K; Vyshak, K; Sudhakar, Natarajan; Banerjee, Sharmila; Korde, Aruna; Samuel, Grace; Mallia, Madhav

    2014-01-01

    Objective(s): The objective of this study was to evaluate the performance and utility of 99mTc HYNIC-TOC planar scintigraphy and SPECT/CT in the diagnosis, staging and management of gastroenteropancreatic neuroendocrine tumors (GPNETs). Methods: 22 patients (median age, 46 years) with histologically proven gastro- entero- pancreatic NETs underwent 99mTc HYNIC-TOC whole body scintigraphy and regional SPECT/CT as indicated. Scanning was performed after injection of 370-550 MBq (10-15 mCi) of 99mTc HYNIC-TOC intravenously. Images were evaluated by two experienced nuclear medicine physicians both qualitatively as well as semi quantitatively (tumor to background and tumor to normal liver ratios on SPECT -CT images). Results of SPECT/CT were compared with the results of conventional imaging. Histopathology results and follow-up somatostatin receptor scintigraphy with 99mTc HYNIC TOC or conventional imaging with biochemical markers were considered to be the reference standards. Results: 99mTc HYNIC TOC showed sensitivity and specificity of 87.5% and 85.7%, respectively, for primary tumor and 100% and 86% for metastases. It was better than conventional imaging modalities for the detection of both primary tumor (P<0.001) and metastases (P<0.0001). It changed the management strategy in 6 patients (31.8%) and supported management decisions in 8 patients (36.3%). Conclusion: 99mTc HYNIC TOC SPECT/CT appears to be a highly sensitive and specific modality for the detection and staging of GPNETs. It is better than conventional imaging for the evaluation of GPNETs and can have a significant impact on patient management and planning further therapeutic options. PMID:27408857

  13. Estimating prognosis and palliation based on tumour marker CA 19-9 and quality of life indicators in patients with advanced pancreatic cancer receiving chemotherapy

    PubMed Central

    Bernhard, J; Dietrich, D; Glimelius, B; Hess, V; Bodoky, G; Scheithauer, W; Herrmann, R

    2010-01-01

    Background: To investigate the prognostic value of quality of life (QOL) relative to tumour marker carbohydrate antigen (CA) 19-9, and the role of CA 19-9 in estimating palliation in patients with advanced pancreatic cancer receiving chemotherapy. Methods: CA 19-9 serum concentration was measured at baseline and every 3 weeks in a phase III trial (SAKK 44/00–CECOG/PAN.1.3.001). Patients scored QOL indicators at baseline, and before each administration of chemotherapy (weekly or bi-weekly) for 24 weeks or until progression. Prognostic factors were investigated by Cox models, QOL during chemotherapy by mixed-effect models. Results: Patient-rated pain (P<0.02) and tiredness (P<0.03) were independent predictors for survival, although less prognostic than CA 19-9 (P<0.001). Baseline CA 19-9 did not predict QOL during chemotherapy, except for a marginal effect on pain (P<0.05). Mean changes in physical domains across the whole observation period were marginally correlated with the maximum CA 19-9 decrease. Patients in a better health status reported the most improvement in QOL within 20 days before maximum CA 19-9 decrease. They indicated substantially less pain and better physical well-being, already, early on during chemotherapy with a maximum CA 19-9 decrease of ⩾50% vs <50%. Conclusion: In advanced pancreatic cancer, pain and tiredness are independent prognostic factors for survival, although less prognostic than CA 19-9. Quality of life improves before best CA 19-9 response but the maximum CA 19-9 decrease has no impact on subsequent QOL. To estimate palliation by chemotherapy, patient's perception needs to be taken into account. PMID:20877359

  14. A novel long non-coding RNA ENST00000480739 suppresses tumour cell invasion by regulating OS-9 and HIF-1α in pancreatic ductal adenocarcinoma

    PubMed Central

    Sun, Y-W; Chen, Y-F; Li, J; Huo, Y-M; Liu, D-J; Hua, R; Zhang, J-F; Liu, W; Yang, J-Y; Fu, X-L; Yan, T; Hong, J; Cao, H

    2014-01-01

    Background: Invasion and metastasis are the distinct biologic characteristics of cancer, resulting in an exceptionally low 5-year survival rate in pancreatic ductal adenocarcinoma (PDAC). Understanding in detail the mechanisms underlying PDAC metastasis is critical for prevention and effective interventions. Long non-coding RNAs (lncRNAs) have been documented as having a critical role in cancer development and progression. Methods: We examined the expression levels of lncRNA ENST00000480739 and osteosarcoma amplified-9 (OS-9) mRNA in a cohort of 35 PDAC patients. Cell proliferation, invasion and migration were examined with and without ENST00000480739 overexpression in PDAC cells. Results: We determined that the ENST00000480739 expression level was remarkably decreased in tumorous tissues compared with their corresponding non-tumorous tissues. The expression of ENST00000480739 was negatively associated with tumour node metastasis stage and lymph node metastasis. In addition, ENST0000048073 was an independent prognostic factor of survival time in PDAC patients following surgery. Besides, enforced expression of ENST00000480739 suppressed PDAC cells' invasion in vitro. Overexpression of ENST00000480739 significantly increased both mRNA and protein levels of OS-9, and the luciferase assays confirmed that ENST00000480739 positively regulates OS-9 by activating the transcription level of the OS-9 promoter. We further found that ENST00000480739 may target hypoxia-inducible factor-1α (HIF-1α) expression by upregulating OS-9. Conclusions: These findings suggest that the frequently downregulated ENST00000480739 in PDAC contributes to tumour metastasis and progression by regulating HIF-1α. Long non-coding RNA ENST00000480739 may provide not only a therapeutic potential to suppress metastasis but it may also be a novel biomarker for risk prognostication and personal therapy screening of PDAC patients. PMID:25314054

  15. A novel long non-coding RNA ENST00000480739 suppresses tumour cell invasion by regulating OS-9 and HIF-1α in pancreatic ductal adenocarcinoma.

    PubMed

    Sun, Y-W; Chen, Y-F; Li, J; Huo, Y-M; Liu, D-J; Hua, R; Zhang, J-F; Liu, W; Yang, J-Y; Fu, X-L; Yan, T; Hong, J; Cao, H

    2014-11-25

    Invasion and metastasis are the distinct biologic characteristics of cancer, resulting in an exceptionally low 5-year survival rate in pancreatic ductal adenocarcinoma (PDAC). Understanding in detail the mechanisms underlying PDAC metastasis is critical for prevention and effective interventions. Long non-coding RNAs (lncRNAs) have been documented as having a critical role in cancer development and progression. We examined the expression levels of lncRNA ENST00000480739 and osteosarcoma amplified-9 (OS-9) mRNA in a cohort of 35 PDAC patients. Cell proliferation, invasion and migration were examined with and without ENST00000480739 overexpression in PDAC cells. We determined that the ENST00000480739 expression level was remarkably decreased in tumorous tissues compared with their corresponding non-tumorous tissues. The expression of ENST00000480739 was negatively associated with tumour node metastasis stage and lymph node metastasis. In addition, ENST0000048073 was an independent prognostic factor of survival time in PDAC patients following surgery. Besides, enforced expression of ENST00000480739 suppressed PDAC cells' invasion in vitro. Overexpression of ENST00000480739 significantly increased both mRNA and protein levels of OS-9, and the luciferase assays confirmed that ENST00000480739 positively regulates OS-9 by activating the transcription level of the OS-9 promoter. We further found that ENST00000480739 may target hypoxia-inducible factor-1α (HIF-1α) expression by upregulating OS-9. These findings suggest that the frequently downregulated ENST00000480739 in PDAC contributes to tumour metastasis and progression by regulating HIF-1α. Long non-coding RNA ENST00000480739 may provide not only a therapeutic potential to suppress metastasis but it may also be a novel biomarker for risk prognostication and personal therapy screening of PDAC patients.

  16. Acute Disseminated Intravascular Coagulation in Neuroendocrine Carcinoma

    PubMed Central

    Teh, Ru-Wen; Tsoi, Daphne T.

    2012-01-01

    Malignancy is a common cause of disseminated intravascular coagulation and usually presents as a chronic disorder in solid organ tumours. We present a rare case of recurrent acute disseminated intravascular coagulation in neuroendocrine carcinoma after manipulation, firstly, by core biopsy and, later, by cytotoxic therapy causing a release of procoagulants and cytokines from lysed tumour cells. This is reminiscent of tumour lysis syndrome where massive quantities of intracellular electrolytes and nucleic acid are released, causing acute metabolic imbalance and renal failure. This case highlights the potential complication of acute disseminated intravascular coagulation after trauma to malignant cells. PMID:23139666

  17. Veliparib, Capecitabine, and Temozolomide in Patients With Advanced, Metastatic, and Recurrent Neuroendocrine Tumor

    ClinicalTrials.gov

    2017-09-26

    Functional Pancreatic Neuroendocrine Tumor; Malignant Somatostatinoma; Merkel Cell Carcinoma; Metastatic Adrenal Gland Pheochromocytoma; Metastatic Carcinoid Tumor; Multiple Endocrine Neoplasia Type 1; Multiple Endocrine Neoplasia Type 2A; Multiple Endocrine Neoplasia Type 2B; Neuroendocrine Neoplasm; Non-Functional Pancreatic Neuroendocrine Tumor; Pancreatic Glucagonoma; Pancreatic Insulinoma; Recurrent Adrenal Cortex Carcinoma; Recurrent Adrenal Gland Pheochromocytoma; Recurrent Merkel Cell Carcinoma; Somatostatin-Producing Neuroendocrine Tumor; Stage III Adrenal Cortex Carcinoma; Stage III Thyroid Gland Medullary Carcinoma; Stage IIIA Merkel Cell Carcinoma; Stage IIIB Merkel Cell Carcinoma; Stage IV Adrenal Cortex Carcinoma; Stage IV Merkel Cell Carcinoma; Stage IVA Thyroid Gland Medullary Carcinoma; Stage IVB Thyroid Gland Medullary Carcinoma; Stage IVC Thyroid Gland Medullary Carcinoma; Thymic Carcinoid Tumor; VIP-Producing Neuroendocrine Tumor; Well Differentiated Adrenal Cortex Carcinoma; Zollinger Ellison Syndrome

  18. Tumour-derived Interleukin 35 promotes pancreatic ductal adenocarcinoma cell extravasation and metastasis by inducing ICAM1 expression

    PubMed Central

    Huang, Chongbiao; Li, Na; Li, Zengxun; Chang, Antao; Chen, Yanan; Zhao, Tiansuo; Li, Yang; Wang, Xiuchao; Zhang, Wei; Wang, Zhimin; Luo, Lin; Shi, Jingjing; Yang, Shengyu; Ren, He; Hao, Jihui

    2017-01-01

    Interleukin 35 (IL-35) is a novel member of the IL-12 family, consisting of an EBV-induced gene 3 (EBI3) subunit and a P35 subunit. IL-35 is an immune-suppressive cytokine mainly produced by regulatory T cells. However, the role of IL-35 in cancer metastasis and progression is not well understood. Here we demonstrate that IL-35 is overexpressed in human pancreatic ductal adenocarcinoma (PDAC) tissues, and that IL-35 overexpression is associated with poor prognosis in PDAC patients. IL-35 has critical roles in PDAC cell extravasation and metastasis by facilitating the adhesion to endothelial cells and transendothelial extravasation. Mechanistically, IL-35 promotes ICAM1 overexpression through a GP130-STAT1 signalling pathway, which facilitates endothelial adhesion and transendothelial migration via an ICAM1–fibrinogen–ICAM1 bridge. In an orthotopic xenograft model, IL-35 promotes spontaneous pancreatic cancer metastasis in an ICAM1-dependent manner. Together, our results indicate additional functions of IL-35 in promoting PDAC metastasis through mediating ICAM1 expression. PMID:28102193

  19. Neuroendocrine Adenoma of the Middle Ear: A Rare Histopathological Diagnosis

    PubMed Central

    McGinness, Sam; Coleman, Hedley; Varikatt, Winny; da Cruz, Melville

    2016-01-01

    Neuroendocrine tumours occur throughout the body but are rare in the head and neck region and particularly rare in the middle ear. Clinical findings are often nonspecific and therefore pose a diagnostic challenge. Furthermore, the nomenclature of neuroendocrine tumours of the middle ear is historically controversial. Herein a case is presented of a middle ear adenoma in a 33-year-old patient who presented with otalgia, hearing loss, and facial nerve palsy. A brief discussion is included regarding the histopathological features of middle ear adenomas and seeks to clarify the correct nomenclature for these tumours. PMID:27429819

  20. [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.

  1. Influence of tumour size on the efficacy of targeted alpha therapy with (213)Bi-[DOTA(0),Tyr(3)]-octreotate.

    PubMed

    Chan, Ho Sze; Konijnenberg, Mark W; de Blois, Erik; Koelewijn, Stuart; Baum, Richard P; Morgenstern, Alfred; Bruchertseifer, Frank; Breeman, Wouter A; de Jong, Marion

    2016-12-01

    Targeted alpha therapy has been postulated to have great potential for the treatment of small clusters of tumour cells as well as small metastases. (213)Bismuth, an α-emitter with a half-life of 46 min, has shown to be effective in preclinical as well as in clinical applications. In this study, we evaluated whether (213)Bi-[DOTA(0), Tyr(3)]-octreotate ((213)Bi-DOTATATE), a (213)Bi-labelled somatostatin analogue with high affinity for somatostatin receptor subtype 2 (SSTR2), is suitable for the treatment of larger neuroendocrine tumours overexpressing SSTR2 in comparison to its effectiveness for smaller tumours. We performed a preclinical targeted radionuclide therapy study with (213)Bi-DOTATATE in animals bearing tumours of different sizes (50 and 200 mm(3)) using two tumour models: H69 (human small cell lung carcinoma) and CA20948 (rat pancreatic tumour). Pharmacokinetics was determined for calculation of dosimetry in organs and tumours. H69- or CA20948-xenografted mice with tumour volumes of approximately 120 mm(3) were euthanized at 10, 30, 60 and 120 min post injection of a single dose of (213)Bi-DOTATATE (1.5-4.8 MBq). To investigate the therapeutic efficacy of (213)Bi-DOTATATE, xenografted H69 and CA20948 tumour-bearing mice with tumour sizes of 50 and 200 mm(3) were administered daily with a therapeutic dose of (213)Bi-DOTATATE (0.3 nmol, 2-4 MBq) for three consecutive days. The animals were followed for 90 days after treatment. At day 90, mice were injected with 25 MBq (99m)Tc-DMSA and imaged by SPECT/CT to investigate possible renal dysfunction due to (213)Bi-DOTATATE treatment. Higher tumour uptakes were found in CA20948 tumour-bearing animals compared to those in H69 tumour-bearing mice with the highest tumour uptake of 19.6 ± 6.6 %IA/g in CA20948 tumour-bearing animals, while for H69 tumour-bearing mice, the highest tumour uptake was found to be 9.8 ± 2.4 %IA/g. Nevertheless, as the anti-tumour effect was more pronounced in H69

  2. [Anorectal neuroendocrine carcinoma: observations on a case and review of the literature].

    PubMed

    Messinetti, S; Giacomelli, L; Drudi, F M; Innocenzi, D; Porcelli, C; Fabrizio, G; Finizio, R; Manno, A; Granai, A V

    1994-01-01

    Carcinoid tumours of the anorectum are rare (0.7% of malignant rectal tumours). Because of this rarity several aspects of the management of these tumours remain controversial. Diagnosis may be delayed because of failure to recognize their morphological characteristics and histological appearance may not reflect their biological behaviour. Immunocytochemistry for neuroendocrine-cells are essential to identify different types of carcinoid tumours and to do differential diagnosis from other malignant tumours. All that allow an exact therapeutic approach to these tumours. The tumours less than cm 1 in diameter can be safely treated by local excision; the tumours more than cm 1 in diameter are treated by radical surgery (AAP).

  3. Targeting the tumour microenvironment with an enzyme-responsive drug delivery system for the efficient therapy of breast and pancreatic cancers† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc00472a Click here for additional data file.

    PubMed Central

    Renoux, Brigitte; Raes, Florian; Legigan, Thibaut; Péraudeau, Elodie; Eddhif, Balkis; Poinot, Pauline; Tranoy-Opalinski, Isabelle; Alsarraf, Jérôme; Koniev, Oleksandr; Kolodych, Sergii; Lerondel, Stéphanie; Le Pape, Alain; Clarhaut, Jonathan

    2017-01-01

    The development of novel therapeutic strategies allowing the destruction of tumour cells while sparing healthy tissues is one of the main challenges of cancer chemotherapy. Here, we report on the design and antitumour activity of a low-molecular-weight drug delivery system programmed for the selective release of the potent monomethylauristatin E in the tumour microenvironment of solid tumours. After intravenous administration, this compound binds covalently to plasmatic albumin through Michael addition, thereby enabling its passive accumulation in tumours where extracellular β-glucuronidase initiates the selective release of the drug. This targeting device produces outstanding therapeutic efficacy on orthotopic triple-negative mammary and pancreatic tumours in mice (50% and 33% of mice with the respective tumours cured), leading to impressive reduction or even disappearance of tumours without inducing side effects. PMID:28507714

  4. Phase I study of olaparib plus gemcitabine in patients with advanced solid tumours and comparison with gemcitabine alone in patients with locally advanced/metastatic pancreatic cancer.

    PubMed

    Bendell, J; O'Reilly, E M; Middleton, M R; Chau, I; Hochster, H; Fielding, A; Burke, W; Burris, H

    2015-04-01

    Olaparib (Lynparza) is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor that induces synthetic lethality in cancers with homologous recombination defects. In this phase I, dose-escalation trial, patients with advanced solid tumours received olaparib (50-200 mg capsules b.i.d.) continuously or intermittently (days 1-14, per 28-day cycle) plus gemcitabine [i.v. 600-800 mg/m(2); days 1, 8, 15, and 22 (cycle 1), days 1, 8, and 15 (subsequent cycles)] to establish the maximum tolerated dose. A separate dose-escalation phase evaluated olaparib in tablet formulation (100 mg o.d./b.i.d.; days 1-14) plus gemcitabine (600 mg/m(2)). In an expansion phase, patients with genetically unselected locally advanced or metastatic pancreatic cancer were randomised 2 : 1 to the tolerated olaparib capsule combination dose or gemcitabine alone (1000 mg/m(2)). Sixty-six patients were treated [dose-escalation phase, n = 44 (tablet cohort, n = 12); dose-expansion phase, n = 22 (olaparib plus gemcitabine, n = 15; gemcitabine alone, n = 7)]. In the dose-escalation phase, four patients (6%) experienced dose-limiting toxicities (raised alanine aminotransferase, n = 2; neutropenia, n = 1; febrile neutropenia, n = 1). Grade ≥3 adverse events were reported in 38/47 patients (81%) treated with olaparib capsules plus gemcitabine; most common were haematological toxicities (55%). Tolerated combinations were olaparib 100 mg b.i.d. capsule (intermittently, days 1-14) plus gemcitabine 600 mg/m(2) and olaparib 100 mg o.d. tablet (intermittently, days 1-14) plus gemcitabine 600 mg/m(2). There were no differences in efficacy observed during the dose-expansion phase. Olaparib 100 mg b.i.d. (intermittent dosing; capsules) plus gemcitabine 600 mg/m(2) is tolerated in advanced solid tumour patients, with no unmanageable/unexpected toxicities. Continuous dosing of olaparib or combination with gemcitabine at doses >600 mg/m(2) was not considered to have an acceptable tolerability profile

  5. Neuroendocrine Tumor: Statistics

    MedlinePlus

    ... Tumor > Neuroendocrine Tumor: Statistics Request Permissions Neuroendocrine Tumor: Statistics Approved by the Cancer.Net Editorial Board , 11/ ... the body. It is important to remember that statistics on how many people survive this type of ...

  6. Evaluation of the Added Value of Diffusion-Weighted Imaging to Conventional Magnetic Resonance Imaging in Pancreatic Neuroendocrine Tumors and Comparison With 68Ga-DOTANOC Positron Emission Tomography/Computed Tomography.

    PubMed

    Farchione, Alessandra; Rufini, Vittoria; Brizi, Maria Gabriella; Iacovazzo, Donato; Larghi, Alberto; Massara, Roberto Maria; Petrone, Gianluigi; Poscia, Andrea; Treglia, Giorgio; De Marinis, Laura; Giordano, Alessandro; Rindi, Guido; Bonomo, Lorenzo

    2016-03-01

    The aims of this study were to investigate the added value of diffusion-weighted imaging (DWI) in pancreatic neuroendocrine tumor (pNET) evaluation and to compare magnetic resonance imaging (MRI) to Ga-DOTANOC positron emission tomography/computed tomography (PET/CT) results. Morphological MRI (T2-weighted [T2-w] + contrast-enhanced [CE] T1-w) and DWI (T2-w + DWI) and Ga-DOTANOC PET/CT in 25 patients/30 pNETs were retrospectively evaluated. Per-patient and per-lesion detection rates (pDR and lDR, respectively) were calculated. Apparent diffusion coefficient values were compared among pNET and surrounding and normal pancreas (control group, 18 patients). Apparent diffusion coefficient and standardized uptake value (SUV) values were compared among different grading and staging groups. No statistically significant differences in PET/CT and MRI session detection rates were found (morphological MRI and DW-MRI, 88% pDR and 87% lDR; combined evaluation, 92% pDR and 90% lDR; Ga-DOTANOC PET/CT, 88% pDR and 80% lDR). Consensus reading (morphological/DW-MRI + PET/CT) improved pDR and lDR (100%). Apparent diffusion coefficient mean value was significantly lower compared with surrounding and normal parenchyma (P < 0.01). The apparent diffusion coefficient and SUV values of pNETs among different grading and staging groups were not statistically different. Conventional MRI, DW-MRI + T2-w sequences, and Ga-DOTANOC PET/CT can be alternative tools in pNET detection. Diffusion-weighted MRI could be valuable in patients with clinical suspicion but negative conventional imaging findings. However, the consensus reading of the 3 techniques seems the best approach.

  7. A phase II study of tamoxifen plus melatonin in metastatic solid tumour patients.

    PubMed Central

    Lissoni, P.; Paolorossi, F.; Tancini, G.; Ardizzoia, A.; Barni, S.; Brivio, F.; Maestroni, G. J.; Chilelli, M.

    1996-01-01

    Preliminary data would suggest that the pineal hormone, melatonin (MLT), may enhance tamoxifen (TMX) anti-tumour efficacy. Both MLT and TMX have been used as single agents in the palliative treatment of metastatic neoplasms, other than the classical hormone-dependent tumours, without, however, any clear efficacy. On this basis, a phase II study with TMX plus MLT has been performed in untreatable metastatic solid tumour patients. The study included 25 metastatic solid tumour patients other than breast cancer and prostate cancer (six unknown primary tumour; four melanoma; four uterine cervix carcinoma; five pancreatic cancer; three hepatocarcinoma; two ovarian cancer; one non-small-cell lung cancer), for whom no other effective standard therapy was available, because of poor clinical conditions, no response to previous chemotherapies and/or chemotherapy-resistant tumours. Both drugs were given orally every day until disease progression (TMX, 20 mg day-1 at noon; MLT, 20 mg day-1 in the evening). Three patients had a partial response (PR) (12%; 95% confidence limits 2-24%) (one cervix carcinoma; one melanoma; one unknown primary tumour). A stable disease (SD) was achieved in 13 other patients, whereas the remaining nine patients progressed. Performance status (PS) improved in 9/25 patients, whose median score increased from 50% to 70%. Finally, a survival longer than 1 year was observed in 7/25 (28%) patients. This phase II study would suggest that the neuroendocrine combination with TMX plus MLT may have some benefit in untreatable metastatic solid tumour patients, either in controlling cancer cell proliferation or improving the PS. PMID:8912546

  8. Pancreatic Cancer Genetics

    PubMed Central

    Amundadottir, Laufey T.

    2016-01-01

    Although relatively rare, pancreatic tumors are highly lethal [1]. In the United States, an estimated 48,960 individuals will be diagnosed with pancreatic cancer and 40,560 will die from this disease in 2015 [1]. Globally, 337,872 new pancreatic cancer cases and 330,391 deaths were estimated in 2012 [2]. In contrast to most other cancers, mortality rates for pancreatic cancer are not improving; in the US, it is predicted to become the second leading cause of cancer related deaths by 2030 [3, 4]. The vast majority of tumors arise in the exocrine pancreas, with pancreatic ductal adenocarcinoma (PDAC) accounting for approximately 95% of tumors. Tumors arising in the endocrine pancreas (pancreatic neuroendocrine tumors) represent less than 5% of all pancreatic tumors [5]. Smoking, type 2 diabetes mellitus (T2D), obesity and pancreatitis are the most consistent epidemiological risk factors for pancreatic cancer [5]. Family history is also a risk factor for developing pancreatic cancer with odds ratios (OR) ranging from 1.7-2.3 for first-degree relatives in most studies, indicating that shared genetic factors may play a role in the etiology of this disease [6-9]. This review summarizes the current knowledge of germline pancreatic cancer risk variants with a special emphasis on common susceptibility alleles identified through Genome Wide Association Studies (GWAS). PMID:26929738

  9. Pancreatic Cancer Genetics.

    PubMed

    Amundadottir, Laufey T

    2016-01-01

    Although relatively rare, pancreatic tumors are highly lethal [1]. In the United States, an estimated 48,960 individuals will be diagnosed with pancreatic cancer and 40,560 will die from this disease in 2015 [1]. Globally, 337,872 new pancreatic cancer cases and 330,391 deaths were estimated in 2012 [2]. In contrast to most other cancers, mortality rates for pancreatic cancer are not improving; in the US, it is predicted to become the second leading cause of cancer related deaths by 2030 [3, 4]. The vast majority of tumors arise in the exocrine pancreas, with pancreatic ductal adenocarcinoma (PDAC) accounting for approximately 95% of tumors. Tumors arising in the endocrine pancreas (pancreatic neuroendocrine tumors) represent less than 5% of all pancreatic tumors [5]. Smoking, type 2 diabetes mellitus (T2D), obesity and pancreatitis are the most consistent epidemiological risk factors for pancreatic cancer [5]. Family history is also a risk factor for developing pancreatic cancer with odds ratios (OR) ranging from 1.7-2.3 for first-degree relatives in most studies, indicating that shared genetic factors may play a role in the etiology of this disease [6-9]. This review summarizes the current knowledge of germline pancreatic cancer risk variants with a special emphasis on common susceptibility alleles identified through Genome Wide Association Studies (GWAS).

  10. Paranasal Sinus Neuroendocrine Carcinoma: A Case Report and Review of the Literature

    PubMed Central

    Sirsath, Nagesh T.; Babu, K. Govind; Das, Umesh; Premlatha, C. S.

    2013-01-01

    Neuroendocrine neoplasms are defined as epithelial neoplasms with predominant neuroendocrine differentiation. They can arise in almost every organ of the body although they are most commonly found in the gastrointestinal tract and respiratory system. Nasal cavity and paranasal sinuses are a rare site for neuroendocrine carcinoma. In contrast to the other regions, neuroendocrine tumours of the sinuses have been reported to be recurrent and locally destructive. Very few cases of paranasal sinus neuroendocrine carcinoma have been reported till date. Difficulty in pathologic diagnosis and rarity of this malignancy have hindered the progress in understanding the clinical course and improving outcomes. We herein report a case of poorly differentiated neuroendocrine tumour of ethmoid and sphenoid sinus with invasion of orbit and intracranial extension. The patient had complete response at the end of chemoradiation and he was disease-free for 9 months duration after which he developed bone metastasis without regional recurrence. PMID:23476846

  11. Presence of sst5TMD4, a truncated splice variant of the somatostatin receptor subtype 5, is associated to features of increased aggressiveness in pancreatic neuroendocrine tumors

    PubMed Central

    Gahete, Manuel D.; Serrano-Somavilla, Ana; Villa-Osaba, Alicia; Adrados, Magdalena; Ibáñez-Costa, Alejandro; Martín-Pérez, Elena; Culler, Michael D.

    2016-01-01

    Purpose Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare and heterogeneous tumors, and their biological behavior is not well known. We studied the presence and potential functional roles of somatostatin receptors (sst1-5), focusing particularly on the truncated variants (sst5TMD4, sst5TMD5) and on their relationships with the angiogenic system (Ang/Tie-2 and VEGF) in human GEP-NETs. Experimental Design We evaluated 42 tumor tissue samples (26 primary/16 metastatic) from 26 patients with GEP-NETs, and 30 non-tumoral tissues (26 from adjacent non-tumor regions and 4 from normal controls) from a single center. Expression of sst1-5, sst5TMD4, sst5TMD5, Ang1-2, Tie-2 and VEGF was analyzed using real-time qPCR, immunofluorescence and immunohistochemistry. Expression levels were associated with tumor characteristics and clinical outcomes. Functional role of sst5TMD4 was analyzed in GEP-NET cell lines. Results sst1 exhibited the highest expression in GEP-NET, whilst sst2 was the most frequently observed sst-subtype (90.2%). Expression levels of sst1, sst2, sst3, sst5TMD4, and sst5TMD5 were significantly higher in tumor tissues compared to their adjacent non-tumoral tissue. Lymph-node metastases expressed higher levels of sst5TMD4 than in its corresponding primary tumor tissue. sst5TMD4 was also significantly higher in intestinal tumor tissues from patients with residual disease of intestinal origin compared to those with non-residual disease. Functional assays demonstrated that the presence of sst5TMD4 was associated to enhanced malignant features in GEP-NET cells. Angiogenic markers correlated positively with sst5TMD4, which was confirmed by immunohistochemical/fluorescence studies. Conclusions sst5TMD4 is overexpressed in GEP-NETs and is associated to enhanced aggressiveness, suggesting its potential value as biomarker and target in GEP-NETs. PMID:26673010

  12. Presence of sst5TMD4, a truncated splice variant of the somatostatin receptor subtype 5, is associated to features of increased aggressiveness in pancreatic neuroendocrine tumors.

    PubMed

    Sampedro-Núñez, Miguel; Luque, Raúl M; Ramos-Levi, Ana M; Gahete, Manuel D; Serrano-Somavilla, Ana; Villa-Osaba, Alicia; Adrados, Magdalena; Ibáñez-Costa, Alejandro; Martín-Pérez, Elena; Culler, Michael D; Marazuela, Mónica; Castaño, Justo P

    2016-02-09

    Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare and heterogeneous tumors, and their biological behavior is not well known. We studied the presence and potential functional roles of somatostatin receptors (sst1-5), focusing particularly on the truncated variants (sst5TMD4, sst5TMD5) and on their relationships with the angiogenic system (Ang/Tie-2 and VEGF) in human GEP-NETs. We evaluated 42 tumor tissue samples (26 primary/16 metastatic) from 26 patients with GEP-NETs, and 30 non-tumoral tissues (26 from adjacent non-tumor regions and 4 from normal controls) from a single center. Expression of sst1-5, sst5TMD4, sst5TMD5, Ang1-2, Tie-2 and VEGF was analyzed using real-time qPCR, immunofluorescence and immunohistochemistry. Expression levels were associated with tumor characteristics and clinical outcomes. Functional role of sst5TMD4 was analyzed in GEP-NET cell lines. sst1 exhibited the highest expression in GEP-NET, whilst sst2 was the most frequently observed sst-subtype (90.2%). Expression levels of sst1, sst2, sst3, sst5TMD4, and sst5TMD5 were significantly higher in tumor tissues compared to their adjacent non-tumoral tissue. Lymph-node metastases expressed higher levels of sst5TMD4 than in its corresponding primary tumor tissue. sst5TMD4 was also significantly higher in intestinal tumor tissues from patients with residual disease of intestinal origin compared to those with non-residual disease. Functional assays demonstrated that the presence of sst5TMD4 was associated to enhanced malignant features in GEP-NET cells. Angiogenic markers correlated positively with sst5TMD4, which was confirmed by immunohistochemical/fluorescence studies. sst5TMD4 is overexpressed in GEP-NETs and is associated to enhanced aggressiveness, suggesting its potential value as biomarker and target in GEP-NETs.

  13. Pathologic pancreatic endocrine cell hyperplasia

    PubMed Central

    Ouyang, Debra; Dhall, Deepti; Yu, Run

    2011-01-01

    Pathologic hyperplasia of various pancreatic endocrine cells is rare but has been long known. β cell hyperplasia contributes to persistent hyperinsulinemic hypoglycemia of infancy, which is commonly caused by mutations in the islet ATP-sensitive potassium channel, and to non-insulinoma pancreatogenous hypoglycemia in adults, which may or may not be associated with bariatric surgery. α cell hyperplasia may cause glucagonoma syndrome or induce pancreatic neuroendocrine tumors. An inactivating mutation of the glucagon receptor causes α cell hyperplasia and asymptomatic hyperglucagonemia. Pancreatic polypeptide cell hyperplasia has been described without a clearly-characterized clinical syndrome and hyperplasia of other endocrine cells inside the pancreas has not been reported to our knowledge. Based on morphological evidence, the main pathogenetic mechanism for pancreatic endocrine cell hyperplasia is increased endocrine cell neogenesis from exocrine ductal epithelium. Pancreatic endocrine cell hyperplasia should be considered in the diagnosis and management of hypoglycemia, elevated islet hormone levels, and pancreatic neuroendocrine tumors. Further studies of pathologic pancreatic endocrine cell hyperplasia will likely yield insights into the pathogenesis and treatment of diabetes and pancreatic neuroendocrine tumors. PMID:21245985

  14. The Impact of Phosphohistone-H3-Assisted Mitotic Count and Ki67 Score in the Determination of Tumor Grade and Prediction of Distant Metastasis in Well-Differentiated Pancreatic Neuroendocrine Tumors.

    PubMed

    Ozturk Sari, Sule; Taskin, Orhun Cig; Gundogdu, Gokcen; Yegen, Gulcin; Onder, Semen; Keskin, Metin; Saglam, Sezer; Ozluk, Yasemin; Gulluoglu, Mine; Mete, Ozgur

    2016-06-01

    This study investigated the impact of phosphohistone-H3 (PHH3)-assisted mitotic count by comparing its performance with conventional mitotic count and Ki67 score as well as the status of distant metastasis. A total of 43 surgically resected pancreatic neuroendocrine tumors (panNET) with complete follow-up information has been subjected to a standardized assessment with respect to mitotic count (both conventional and PHH3-assisted) and Ki67 score. Five participants assessed mitotic count and the time spent was recorded in both methods. All tumors were assigned to a G1 category of mitotic rate on conventional mitotic count that failed to identify three tumors with a G2 category of mitotic rate on PHH3. Near-perfect and fair agreements were achieved among observers when using PHH3 and conventional method, respectively. The mean time spent to determine mitotic count on PHH3-stained slides was significantly shorter (p < 0.001). The performance of PHH3-assisted mitotic grade category was significant as the three cases with a G2 mitotic category were associated with distant metastasis (p = 0.01). Despite its performance, the PHH3-assisted mitotic count downgraded 17 cases that were classified as G2 based on Ki67 scores in this series. The Ki67 grade category was either the same or higher than the mitotic grade category. Ten patients developed distant metastasis. Eleven tumors exhibited vascular invasion characterized by intravascular tumor cells admixed with thrombus. Our results indicate that PHH3-assisted mitotic count facilitates an accurate mitotic count with a perfect agreement among observers. The small size of this cohort is an important limitation of the current study, a G2 mitotic grade category based on PHH3 immunohistochemistry was one of the correlates of panNETs with distant metastasis. While the prognostic impact of PHH3-assisted mitotic count needs to be clarified in larger cohorts, Ki67 scores designated higher grade category in all cases; thus, it

  15. Small Cell Neuroendocrine Carcinoma of the Cervix: A Rare Entity

    PubMed Central

    V, Pavithra; Shalini, C.N. Sai; Priya, Shanmuga; Rani, Usha; Rajendiran, S; Joseph, Leena Dennis

    2014-01-01

    Small cell carcinoma of the cervix is a rare and a very aggressive tumour. Once being considered to be a rare type of squamous cell carcinoma, evidence has proven that most of the tumours express one or more markers of neuroendocrine differentiation. The behaviour of this rare malignancy is different from that of squamous cell carcinomas, with a high propensity for nodal and distant metastases. Hence, there is a need to highlight this histopathological entity. PMID:24701511

  16. Endoscopy-guided ablation of pancreatic lesions: Technical possibilities and clinical outlook

    PubMed Central

    Signoretti, Marianna; Valente, Roberto; Repici, Alessandro; Delle Fave, Gianfranco; Capurso, Gabriele; Carrara, Silvia

    2017-01-01

    Endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP)-guided ablation procedures are emerging as a minimally invasive therapeutic alternative to radiological and surgical treatments for locally advanced pancreatic cancer (LAPC), pancreatic neuroendocrine tumours (PNETs), and pancreatic cystic lesions (PCLs). The advantages of treatment under endoscopic control are the real-time imaging guidance and the possibility to reach a deep target like the pancreas. Currently, radiofrequency probes specifically designed for ERCP or EUS ablation are available as well as hybrid cryotherm probe combining radiofrequency with cryotechnology. To date, many reports and case series have confirmed the safety and feasibility of that kind of ablation technique in the pancreatic setting. Moreover, EUS-guided fine-needle injection is emerging as a method to deliver ablative and anti-tumoral agents inside the tumuor. Ethanol injection has been proposed mostly for the treatment of PCLs and for symptomatic functioning PNETs, and the use of gemcitabine and paclitaxel is also interesting in this setting. EUS-guided injection of chemical or biological agents including mixed lymphocyte culture, oncolytic viruses, and immature dendritic cells has been investigated for the treatment of LAPC. Data on the long-term efficacy of these approaches, and large prospective randomized studies are needed to confirm the real clinical benefits of these techniques for the management of pancreatic lesions. PMID:28250896

  17. Endoscopy-guided ablation of pancreatic lesions: Technical possibilities and clinical outlook.

    PubMed

    Signoretti, Marianna; Valente, Roberto; Repici, Alessandro; Delle Fave, Gianfranco; Capurso, Gabriele; Carrara, Silvia

    2017-02-16

    Endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP)-guided ablation procedures are emerging as a minimally invasive therapeutic alternative to radiological and surgical treatments for locally advanced pancreatic cancer (LAPC), pancreatic neuroendocrine tumours (PNETs), and pancreatic cystic lesions (PCLs). The advantages of treatment under endoscopic control are the real-time imaging guidance and the possibility to reach a deep target like the pancreas. Currently, radiofrequency probes specifically designed for ERCP or EUS ablation are available as well as hybrid cryotherm probe combining radiofrequency with cryotechnology. To date, many reports and case series have confirmed the safety and feasibility of that kind of ablation technique in the pancreatic setting. Moreover, EUS-guided fine-needle injection is emerging as a method to deliver ablative and anti-tumoral agents inside the tumuor. Ethanol injection has been proposed mostly for the treatment of PCLs and for symptomatic functioning PNETs, and the use of gemcitabine and paclitaxel is also interesting in this setting. EUS-guided injection of chemical or biological agents including mixed lymphocyte culture, oncolytic viruses, and immature dendritic cells has been investigated for the treatment of LAPC. Data on the long-term efficacy of these approaches, and large prospective randomized studies are needed to confirm the real clinical benefits of these techniques for the management of pancreatic lesions.

  18. Biology and Treatment of Metastatic Gastrointestinal Neuroendocrine Tumors

    PubMed Central

    Strosberg, Jonathan R.; Nasir, Aejaz; Kvols, Larry

    2008-01-01

    Neuroendocrine malignancies of the gastroenteropancreatic axis include carcinoid and pancreatic endocrine tumors. These heterogeneous neoplasms arise from the enterochromaffin cells of the gastrointestinal tract and the islet cells of the pancreas. Histologically, most well-differentiated endocrine tumors consist of small, round, monomorphic cells, arranged in islands or trabeculae, with a distinct “salt-and-pepper” pattern of nuclear chromatin. Chromogranin and synaptophysin are useful as immunohistochemical markers of neuroendocrine differentiation. Other common features include the capacity to secrete peptide hormones and biogenic amines. A relatively indolent growth rate is characteristic of most gastrointestinal neuroendocrine tumors, with the exception of poorly differentiated tumors which are usually aggressive. Treatment strategies are designed to limit tumor progression and palliate hormonal syndromes. This article reviews the diverse biologic characteristics of gastrointestinal neuroendocrine tumors and current treatment options for metastatic disease. PMID:19259290

  19. Angiogenesis: a prognostic determinant in pancreatic cancer?

    PubMed

    van der Zee, Jill A; van Eijck, Casper H J; Hop, Wim C J; van Dekken, Herman; Dicheva, Bilyana M; Seynhaeve, Ann L B; Koning, Gerben A; Eggermont, Alexander M M; ten Hagen, Timo L M

    2011-11-01

    Angiogenesis has been associated with disease progression in many solid tumours, however the statement that tumours need angiogenesis to grow, invade and metastasise seems no longer applicable to all tumours or to all tumour subtypes. Prognostic studies in pancreatic cancer are conflicting. In fact, pancreatic cancer has been suggested an example of a tumour in which angiogenesis is less essential for tumour progression. The aim of the present study was therefore to measure angiogenesis in two anatomically closely related however prognostically different types of pancreatic cancer, pancreatic head and periampullary cancer, and investigate its relation with outcome. Vessels were stained by CD31 on original paraffin embedded tissue from 206 patients with microscopic radical resection (R0) of pancreatic head (n=98) or periampullary cancer (n=108). Angiogenesis was quantified by microvessel density (MVD) and measured by computerised image analysis of three randomly selected fields and investigated for associations with recurrence free survival (RFS), cancer specific survival (CSS), overall survival (OS) and conventional prognostic factors. MVD was heterogeneous both between and within tumours. A higher MVD was observed in periampullary cancers compared with pancreatic head cancers (p<.01). Furthermore, MVD was associated with lymph node involvement in pancreatic head (p=.014), but not in periampullary cancer (p=.55). Interestingly, MVD was not associated with RFS, CSS or with OS. In conclusion, angiogenesis is higher in periampullary cancer and although associated with nodal involvement in pancreatic head cancer, pancreatic cancer prognosis seems indeed angiogenesis independent.

  20. Multimodal management of neuroendocrine liver metastases

    PubMed Central

    Frilling, Andrea; Sotiropoulos, Georgios C; Li, Jun; Kornasiewicz, Oskar; Plöckinger, Ursula

    2010-01-01

    Background: The incidence of neuroendocrine tumours (NET) has increased over the past three decades. Hepatic metastases which occur in up to 75% of NET patients significantly worsen their prognosis. New imaging techniques with increasing sensitivity enabling tumour detection at an early stage have been developed. The treatment encompasses a panel of surgical and non-surgical modalities. Methods: This article reviews the published literature related to management of hepatic neuroendocrine metastases. Results: Abdominal computer tomography, magnetic resonance tomography and somatostatin receptor scintigraphy are widely accepted imaging modalities. Hepatic resection is the only potentially curative treatment. Liver transplantation is justified in highly selected patients. Liver-directed interventional techniques and locally ablative measures offer effective palliation. Promising novel therapeutic options offering targeted approaches are under evaluation. Conclusions: The treatment of neuroendocrine liver metastases still needs to be standardized. Management in centres of expertise should be strongly encouraged in order to enable a multidisciplinary approach and personalized treatment. Development of molecular prognostic factors to select treatment according to patient risk should be attempted. PMID:20662787

  1. Prognostic impact of tumour size in completely resected thymic epithelial tumours.

    PubMed

    Fukui, Takayuki; Fukumoto, Koichi; Okasaka, Toshiki; Kawaguchi, Koji; Nakamura, Shota; Hakiri, Shuhei; Ozeki, Naoki; Hirakawa, Akihiro; Tateyama, Hisashi; Yokoi, Kohei

    2016-12-01

    The T descriptor of thymic epithelial tumours proposed by the International Association for the Study of Lung Cancer and the International Thymic Malignancy Interest Group as well as the Masaoka-Koga system is defined by the anatomical extent of primary tumours, regardless of their size. However, the prognostic significance of tumour size in thymic epithelial tumours has not been fully elucidated. We evaluated the prognostic significance of tumour size in 154 consecutive patients with thymic epithelial tumours including 124 thymomas, 21 thymic carcinomas and 9 neuroendocrine tumours, who underwent complete resection between 2001 and 2014. Among all tumours, the median tumour size was 4.9 cm. The median thymoma, thymic carcinoma and neuroendocrine tumour sizes were 4.8, 5.7 and 5.8, respectively, although the differences were not significant. In survival analysis, the 5- and 10-year overall survival (OS) and recurrence-free survival (RFS) rates for all patients were 91 and 81%, and 80 and 69%, respectively. Under the stratification of tumour size, no trend was observed for OS, whereas RFS showed stepwise deterioration as tumour size increased. For 119 patients with Stage I disease, RFS showed deterioration as tumour size increased. Multivariate analysis revealed that tumour size >4.0 cm was an independent prognostic factor for worsening RFS (P = 0.03). Patients with tumours >4.0 cm showed significantly worse outcomes in RFS compared with those with smaller tumours. This relationship was also noted in patients with Stage I disease. © The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

  2. [Biological aspects of pancreatic cancer].

    PubMed

    Tonel, E; Carbone, A; Scirelli, T; Bellone, G; Emanuelli, G

    2005-04-01

    Pancreatic ductal carcinoma still is an aggressive disease with a fatal prognosis due to late diagnosis and resistance to pharmacological and surgical treatments. Molecular investigations of pancreatic cancer are complicated by the restricted accessibility of the organ for biopsies. However, recent studies have indicated that pancreatic cancer is a multi-stage process resulting from the accumulation of genetic changes in the somatic DNA of normal cells. These molecular alterations, including overexpression of receptor-ligand systems, oncogene activation and loss of tumour suppressor genes, leads to a profound disturbance in cell cycle regulation and continuous growth. The molecular findings are now integrated in a pancreatic tumour progression model, with genetically and morphological defined precursor lesions. However, it remains unclear whether the initial target cells of this cancer develop from ductal or acinar cells. This review will present recent emerging questions on the biology of pancreatic cancer with particular emphasis on the cell origin and tumour microenvironment.

  3. Treatment Options for Pancreatic Neuroendocrine Tumors

    MedlinePlus

    ... endoscope is used to bounce high-energy sound waves ( ultrasound ) off internal tissues or organs and make echoes. The echoes ... ultrasound : A procedure that uses high-energy sound waves (ultrasound) to create images of internal organs or tissues during surgery. A transducer placed ...

  4. [Perineural pseudoinvasion in chronic pancreatitis].

    PubMed

    Hauptmann, K; Hauptmann, S

    2000-09-01

    The occurrence of perineural epithelial complexes within the pancreas cannot always be regarded as evidence of malignancy. Chronic pancreatitis can induce alterations in the anatomy of the organ with a histological picture comparable to that of neural invasion. The important criteria for differential diagnosis are neuroendocrine differentiation of these cells or their ductular morphology without atypia.

  5. Alteration of the exDNA profile in blood serum of LLC-bearing mice under the decrease of tumour invasion potential by bovine pancreatic DNase I treatment

    PubMed Central

    Brenner, Evgenyi V.; Kurilshikov, Alexander M.; Patutina, Olga A.; Zenkova, Marina A.

    2017-01-01

    Taking into account recently obtained data indicating the participation of circulating extracellular DNA (exDNA) in tumorigenesis, enzymes with deoxyribonucleic activity have again been considered as potential antitumour and antimetastatic drugs. Previously, using murine Lewis lung carcinoma and hepatocellular carcinoma A1 tumour models, we have shown the antimetastatic activity of bovine DNase I, which correlates with an increase of DNase activity and a decrease of exDNA concentration in the blood serum of tumour-bearing mice. In this work, using next-generation sequencing on the ABS SOLiD™ 5.500 platform, we performed a search for molecular targets of DNase I by comparing the exDNA profiles of healthy animals, untreated animals with Lewis lung carcinoma (LLC) and those with LLC treated with DNase I. We found that upon DNase I treatment of LLC-bearing mice, together with inhibition of metastasis, a number of strong alterations in the patterns of exDNA were observed. The major differences in exDNA profiles between groups were: i) the level of GC-poor sequences increased during tumour development was reduced to that of healthy mice; ii) levels of sequences corresponding to tumour-associated genes Hmga2, Myc and Jun were reduced in the DNase I-treated group in comparison with non-treated mice; iii) 224 types of tandem repeat over-presented in untreated LLC-bearing mice were significantly reduced after DNase I treatment. The most important result obtained in the work is that DNase I decreased the level of B-subfamily repeats having homology to human ALU repeats, known as markers of carcinogenesis, to the level of healthy animals. Thus, the obtained data lead us to suppose that circulating exDNA plays a role in tumour dissemination, and alteration of multiple molecular targets in the bloodstream by DNase I reduces the invasive potential of tumours. PMID:28222152

  6. A rectal neuroendocrine neoplasm.

    PubMed

    Varas Lorenzo, Modesto J; Muñoz Agel, Fernando

    2017-08-01

    The incidence of gastric and rectal carcinoids is increasing. This is probably due to endoscopic screening. The prognosis is primarily dependent upon tumor size, aggressiveness (pathology, Ki-67), metastatic disease and stage. However, neuroendocrine carcinoma usually behaves as an adenocarcinoma.

  7. Hereditary Pancreatitis

    MedlinePlus

    ... meals throughout the day that are high in carbohydrates and low in protein and fat. Pancreatic enzymes ... the Pancreas NPF Centers Pancreatitis Centers Pancreatitis Center Application Pancreatic Cancer Centers Diagnosis of Pancreatic Cancer Pancreas ...

  8. [Adrenal tumours in childhood].

    PubMed

    Martos-Moreno, G A; Pozo-Román, J; Argente, J

    2013-09-01

    This special article aims to summarise the current knowledge regarding the two groups of tumours with their origin in the adrenal gland: 1) adrenocortical tumours, derived from the cortex of the adrenal gland and 2) phaeochromocytomas and paragangliomas, neuroendocrine tumours derived from nodes of neural crest derived cells symmetrically distributed at both sides of the entire spine (paragangliomas [PG]). These PGs can be functioning tumors that secrete catecholamines, which confers their typical dark colour after staining with chromium salts (chromaffin tumors). Among these, the term phaeochromocytoma (PC) is restricted to those PGs derived from the chromaffin cells in the adrenal medulla (intra-adrenal PGs), whereas the term PG is used for those sympathetic or parasympathetic ones in an extra-adrenal location. We analyse the state of the art of their pathogenic and genetic bases, as well as their clinical signs and symptoms, the tests currently available for performing their diagnosis (biochemical, hormonal, imaging and molecular studies) and management (surgery, pre- and post-surgical medical treatment), considering the current and developing strategies in chemo- and radiotherapy.

  9. [Chronic pancreatitis, acute pancreatitis].

    PubMed

    Mabuchi, T; Katada, N; Nishimura, D; Hoshino, H; Shimizu, F; Suzuki, R; Sano, H; Kato, K

    1998-11-01

    MRCP has been recognized as a safe and noninvasive diagnostic method. In the present study we evaluated the usefulness of MRCP in diagnosis of chronic and acute pancreatitis. Two-dimensional fast asymmetric spin-echo (FASE) MRCP was performed in 40 patients with chronic pancreatitis and 13 with acute pancreatitis. In 29 patients (72.5%) with chronic pancreatitis and 9 (66.7%) with acute pancreatitis, main pancreatic duct (MPD) was visualized entirely. MRCP could demonstrate the characteristic findings of chronic pancreatitis such as dilatation and irregularity of MPD in most cases. In acute pancreatitis, MRCP indicated that MPD was normal in diameter, but irregular in configuration compared with that of the control group. MRCP may facilitate the diagnosis of chronic and acute pancreatitis.

  10. Atypical carcinoid presenting as dumb-bell-shaped tumour in the normal kidney.

    PubMed

    Verma, Ritu; Gupta, Pallav

    2013-09-24

    Carcinoid tumours are low-grade malignant neoplasms with neuroendocrine differentiation and occur frequently in the gastrointestinal and respiratory tracts. Primary carcinoid tumours of the kidney are rare and a majority of these tumours occur in anomalous kidney and exhibit typical renal carcinoid morphology. We reported a middle-aged man with primary atypical carcinoid tumour occurring in a normal kidney. The patient was diagnosed as having renal cell carcinoma owing to a lack of neuroendocrinal clinical features. Immunohistochemical staining of the nephrectomy specimen helped in the diagnosis of atypical renal carcinoid.

  11. Neuroendocrine hormone amylin in diabetes

    PubMed Central

    Zhang, Xiao-Xi; Pan, Yan-Hong; Huang, Yan-Mei; Zhao, Hai-Lu

    2016-01-01

    The neuroendocrine hormone amylin, also known as islet amyloid polypeptide, is co-localized, co-packaged and co-secreted with insulin from adult pancreatic islet β cells to maintain glucose homeostasis. Specifically, amylin reduces secretion of nutrient-stimulated glucagon, regulates blood pressure with an effect on renin-angiotensin system, and delays gastric emptying. The physiological actions of human amylin attribute to the conformational α-helix monomers whereas the misfolding instable oligomers may be detrimental to the islet β cells and further transform to β-sheet fibrils as amyloid deposits. No direct evidence proves that the amylin fibrils in amyloid deposits cause diabetes. Here we also have performed a systematic review of human amylin gene changes and reported the S20G mutation is minor in the development of diabetes. In addition to the metabolic effects, human amylin may modulate autoimmunity and innate inflammation through regulatory T cells to impact on both human type 1 and type 2 diabetes. PMID:27162583

  12. Pancreatitis - discharge

    MedlinePlus

    Chronic pancreatitis - discharge; Pancreatitis - chronic - discharge; Pancreatic insufficiency - discharge; Acute pancreatitis - discharge ... fluids through an intravenous (IV) tube in your vein and nutrition through a feeding tube or IV. ...

  13. Hereditary Pancreatitis

    MedlinePlus

    ... Donate E-News Sign-Up Home Hereditary Pancreatitis Hereditary Pancreatitis Hereditary Pancreatitis (HP) is a rare genetic condition characterized ... at least 1,000 individuals are affected with hereditary pancreatitis. HP has also been linked to an ...

  14. Insulinoma--a deceptive endocrine tumour.

    PubMed

    Rehman, Abdul

    2011-09-01

    Insulinoma is a deceptive endocrine tumour that can easily mislead even an astute clinician because of its bizarre and nonspecific symptom complex. A 45 year old woman presented with altered behaviour, seizures and spells of coma and was being treated as a case of hysterical neurosis. Biochemical and radiological investigations revealed fasting hypoglycaemia, endogenous hyperinsulinism, and a pancreatic parenchymal lesion. Removal of the pancreatic lesion resulted in abrupt restoration of euglycaemia and complete disappearance of patients' symptoms.

  15. Nine cases of Merkel cell tumour.

    PubMed Central

    Bose, A

    1997-01-01

    Merkel cell tumour is an aggressive neuroendocrine neoplasm arising in the dermis. Although only a few hundred cases have been reported worldwide, nine were seen in Nottingham between 1985 and early 1994. The patients were five women and four men age 63-88. One was the first Afro-Caribbean reported to have such a tumour. In no case was the diagnosis made clinically; histological and histochemical examination was necessary. Three of the patients died quickly with metastatic disease. The primary treatment is surgical excision. For advanced disease, radiotherapy is commonly beneficial. Images Figure 1 Figure 2 Figure 3 PMID:9306997

  16. Neuroendocrine mechanisms in athletes.

    PubMed

    Misra, Madhusmita

    2014-01-01

    Athletic activity may be associated with alterations in various neuroendocrine axes depending on the state of energy availability. In addition, genetic factors and an underlying predilection for polycystic ovarian syndrome (PCOS) may predispose some athletes to develop functional hypothalamic amenorrhea earlier than other athletes. In conditions of low energy availability associated with athletic activity, changes that occur in various neuroendocrine axes are primarily adaptive, and aim to either conserve energy for the most essential functions, or allow the body to draw on its reserves to meet energy needs. These hormonal changes, however, then lead to changes in body composition and bone metabolism. Impaired bone accrual in younger athletes and low bone density in older athletes constitutes the major pathologic consequence of neuroendocrine changes associated with low energy availability. The female athlete triad of low energy availability, menstrual dysfunction, and low bone density is prevalent in certain kinds of sports and activities, particularly endurance sports, gymnastics, and ballet. It is essential to screen for this condition in athletes at every preparticipation physical and during office visits, and to put in place an effective treatment team to manage the triad early, in order to optimize outcomes.

  17. Neuroendocrine Role for VGF

    PubMed Central

    Lewis, Jo E.; Brameld, John M.; Jethwa, Preeti H.

    2015-01-01

    The vgf gene (non-acronymic) is highly conserved and was identified on the basis of its rapid induction in vitro by nerve growth factor, although can also be induced by brain-derived neurotrophic factor, and glial-derived growth factor. The VGF gene gives rise to a 68 kDa precursor polypeptide, which is induced robustly, relatively selectively and is synthesized exclusively in neuronal and neuroendocrine cells. Post-translational processing by neuroendocrine specific prohormone convertases in these cells results in the production of a number of smaller peptides. The VGF gene and peptides are widely expressed throughout the brain, particularly in the hypothalamus and hippocampus, in peripheral tissues including the pituitary gland, the adrenal glands, and the pancreas, and in the gastrointestinal tract in both the myenteric plexus and in endocrine cells. VGF peptides have been associated with a number of neuroendocrine roles, and in this review, we aim to describe these roles to highlight the importance of VGF as therapeutic target for a number of disorders, particularly those associated with energy metabolism, pain, reproduction, and cognition. PMID:25699015

  18. Endoscopic mucosal resection of early stage colon neuroendocrine carcinoma

    PubMed Central

    Yamasaki, Yasushi; Uedo, Noriya; Ishihara, Ryu; Tomita, Yasuhiko

    2015-01-01

    Early stage colorectal neuroendocrine carcinoma is rare. A small colon tumour was found in a 56-year-old man during diagnostic colonoscopy performed after a positive faecal occult blood test, and he was referred for treatment. A slightly reddish superficial elevated lesion with a shallow depression 10 mm in size was found in the transverse colon. Magnifying narrow-band imaging revealed disrupted irregular microvessels and the absence of a surface pattern in the depressed area. En bloc endoscopic mucosal resection (EMR) of the tumour was undertaken. The tumour was positive for chromogranin A and synaptophysin, and had a mitotic rate of >20/10 high-power fields and a Ki-67 proliferative index of >50%; it was diagnosed as a neuroendocrine carcinoma. The tumour minimally invaded the submucosa (300 μm) without lymphovascular involvement. The patient was followed up carefully, and at 1 year after EMR, no recurrence was found using colonoscopy and CT scans. PMID:25737221

  19. [Various neuroendocrine tumors in a family with multiple endocrine neoplasia type 1].

    PubMed

    Sepp, Krisztián; Valkusz, Zsuzsanna

    2013-12-22

    When multiple endocrine tumors are detected more tests are required to diagnose endocrine tumor syndromes. The authors report the case history of a patient with clinical manifestation of multiplex endocrine neoplasia type 1 (parathyroid adenoma, pancreatic neuroendocrine tumor, pituitary tumor, adrenal gland tumors and thymic neuroendocrine carcinoma). Genetic screening proved a novel stop codon mutation of the MEN1 gene in the patient and in two other members of the family. The son of the index patient showed clinical symptoms of pancreatic neuroendocrine tumor (insulinoma) and parathyroid adenoma. One of the two daughters was also positive for the same mutation, however, she had no clinical symptoms. The authors review current knowledge on the genetic background of multiple endocrine syndrome type 1, the role of menin and the usefulness of gene mutation screening.

  20. Duodenal leiomyosarcoma mimicking a pancreatic pseudocyst.

    PubMed

    Sperti, C; Pasquali, C; Di Prima, F; Baffa, R; Pedrazzoli, S

    1994-01-01

    A case of duodenal leiomyosarcoma presenting as a cystic mass is reported. Amylase, tumour markers levels in the cyst fluid and radiological findings suggested an inflammatory pancreatic pseudocyst. Exploratory laparotomy and frozen section examination showed a smooth muscle tumour of the duodenum. Pancreatoduodenectomy with pylorus-preser vation was performed and the patient remained symptom-free at 8 months follow-up.

  1. [Intestinal carcinoid tumour: Case report].

    PubMed

    Mussan-Chelminsky, Gil; Vidal-González, Pablo; Núñez-García, Edgar; Valencia-García, Luis César; Márquez-Ugalde, Miguel Ángel

    2015-01-01

    Carcinoid of the small intestine, is a well-differentiated neuroendocrine tumor that rarely presents with clinical signs. This tumour can be associated with other conditions, such as inflammatory bowel disease, presenting a wide range of symptoms. In some cases they have an aggressive and highly symptomatic behaviour; thus, clinical suspicion must be high to make an early diagnosis. A 60 year-old male patient with Crohn's disease and gastrointestinal symptoms attributed to this disease within the last year. He presented with intestinal obstruction initially treated with conservative management with no improvement. Exploratory laparotomy was performed finding a mesenteric tumour that caused the bowel obstruction. Bowel resection with primary anastomosis was performed. The pathology report showed an intestinal carcinoid tumour with lymph node metastases. The patient recovered well, and was discharged without complications to continue medical treatment and follow-up by the Oncology department. In almost 42% of the cases, the most common site of carcinoid tumours is the small intestine, and of these, 41% are presented as locoregional disease. Patients with Crohn's disease present a higher incidence. In these cases, the most common presentation is an acute intestinal obstruction (90%). Surgery is usually curative, and follow up is important as the symptoms of Crohn's disease can hide any recurrence. Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

  2. [A rare case of coexistence of pancreatic cystadenoma and adenocarcinoma of the rectum].

    PubMed

    Ostapiuk, H; Kemona, A; Sulkowski, S; Sobaniec-Lotowska, M; Ostapiuk, W

    1989-05-01

    A rare coexistence is reported of a benign pancreatic tumour--cystadenoma--with anal adenocarcinoma. A particular attention is called to the histological structure of the tumour and differential diagnosis. Photographic documentation is enclosed.

  3. Neuroendocrine Tumors of the Lung

    PubMed Central

    Fisseler-Eckhoff, Annette; Demes, Melanie

    2012-01-01

    Neuroendocrine tumors may develop throughout the human body with the majority being found in the gastrointestinal tract and bronchopulmonary system. Neuroendocrine tumors are classified according to the grade of biological aggressiveness (G1–G3) and the extent of differentiation (well-differentiated/poorly-differentiated). The well-differentiated neoplasms comprise typical (G1) and atypical (G2) carcinoids. Large cell neuroendocrine carcinomas as well as small cell carcinomas (G3) are poorly-differentiated. The identification and differentiation of atypical from typical carcinoids or large cell neuroendocrine carcinomas and small cell carcinomas is essential for treatment options and prognosis. Pulmonary neuroendocrine tumors are characterized according to the proportion of necrosis, the mitotic activity, palisading, rosette-like structure, trabecular pattern and organoid nesting. The given information about the histopathological assessment, classification, prognosis, genetic aberration as well as treatment options of pulmonary neuroendocrine tumors are based on own experiences and reviewing the current literature available. Most disagreements among the classification of neuroendocrine tumor entities exist in the identification of typical versus atypical carcinoids, atypical versus large cell neuroendocrine carcinomas and large cell neuroendocrine carcinomas versus small cell carcinomas. Additionally, the classification is restricted in terms of limited specificity of immunohistochemical markers and possible artifacts in small biopsies which can be compressed in cytological specimens. Until now, pulmonary neuroendocrine tumors have been increasing in incidence. As compared to NSCLCs, only little research has been done with respect to new molecular targets as well as improving the classification and differential diagnosis of neuroendocrine tumors of the lung. PMID:24213466

  4. Neuroendocrine tumor of the pancreas in a patient with tuberous sclerosis: a case report and review of the literature.

    PubMed

    Díaz Díaz, Delissa; Ibarrola, Carolina; Goméz Sanz, Ramón; Pérez Hurtado, Bladimir; Salazar Tabares, Johny; Colina Ruizdelgado, Francisco

    2012-08-01

    A rare case of pancreatic neuroendocrine neoplasm in a patient with tuberous sclerosis complex is described. The patient was a 31-year-old man who had multiple congenital subependymal nodules, bilateral cortical tubers, and seizures of difficult control. A 2.3 cm × 2 cm well-delimitated solid tumor in the tail of the pancreas was discovered during a monitoring abdominal computed tomography. A distal pancreatectomy was performed. Histologically, the tumor was formed by uniform cells with moderated cytoplasm arranged in a combined trabecular and nested pattern. The nuclear features were bland, and mitosis was infrequent. There was no vascular invasion. Immunoreactivity for cytokeratine AE1/AE3, chromogranin A, and synaptophysin confirmed the neuroendocrine nature of this neoplasia. Pancreatic hormones were negatives. One of the 5 lymph nodes isolated from the peripancreatic adipose tissue was positive for metastases. Small series and case reports have documented that in tuberous sclerosis many endocrine system alterations might occur, affecting the function of the pituitary, parathyroid, and other neuroendocrine tissue, including islet cells of the pancreas. However, the true association of these pathological conditions remains uncertain. As far as we know, there are 10 cases reported of pancreatic neuroendocrine tumors in a setting of tuberous sclerosis complex, in which 2 cases resulted in malignant, nonfunctioning pancreatic neuroendocrine tumors.

  5. Pancreatic pseudocyst

    MedlinePlus

    ... More Acute pancreatitis Chronic pancreatitis Pancreatic abscess Shock Review Date 10/27/2015 Updated by: Subodh K. ... gastroenterologist with Gastrointestinal Specialists of Georgia, Austell, GA. Review provided by VeriMed Healthcare Network. Also reviewed by ...

  6. Pancreatic Cysts

    MedlinePlus

    ... triggering pancreatitis, you may need to have your gallbladder removed. If your pancreatitis is due to alcohol ... www.mayoclinic.org/diseases-conditions/pancreatic-cysts/basics/definition/CON-20024331 . Mayo Clinic Footer Legal Conditions and ...

  7. Pancreatic Cancer

    MedlinePlus

    ... hormones that help control blood sugar levels. Pancreatic cancer usually begins in the cells that produce the juices. Some risk factors for developing pancreatic cancer include Smoking Long-term diabetes Chronic pancreatitis Certain ...

  8. ACTH-producing neuroendocrine tumor of the pancreas: a case report and literature review

    PubMed Central

    Byun, Justin; Kim, Sung Hyun; Jeong, Hyang Sook; Rhee, Yumie; Lee, Woo Jung

    2017-01-01

    Tumors that arise from the endocrine pancreas, or the islets of pancreas, are called pancreatic neuroendocrine tumors (NETs). Pancreatic NET have an incidence of <0.1 per one million persons, and can lead to secretion of ectopic adrenocorticotropic hormone (ACTH). Herein, we presented a case of patient with Cushing's syndrome as a result of ACTH-producing pancreatic NET, who underwent successful laparoscopic distal pancreatosplenectomy. A 40-year-old Korean female patient with ophthalmologic discomfort, osteoporosis, and unexplained hypokalemia was admitted to our hospital. Under the suspicion of ACTH producing pancreatic NET after the diagnostic workup, we decided to perform surgical resection. Laparoscopic distal pancreatosplenectomy was performed; and the pathological examination revealed a 1.5 cm-sized grade 2 neuroendocrine tumor of the pancreas, which was encapsulated within the pancreatic parenchyma. After the operation, the patient no longer displayed cushingoid features. ACTH-producing pancreatic NET is rare, but can be one of the causes of Cushing's syndrome. Surgical resection is a feasible option in treating ACTH-producing pancreatic NET. PMID:28317048

  9. Immunoglobulin G4, autoimmune pancreatitis and pancreatic cancer.

    PubMed

    Bojková, Martina; Dítě, Petr; Dvořáčková, Jana; Novotný, Ivo; Floreánová, Katarina; Kianička, Bohuslav; Uvírová, Magdalena; Martínek, Arnošt

    2015-01-01

    Immunoglobulin G4 (IgG4)-related diseases are a group of diseases characterized by enlargement of the affected organs, elevation of serum IgG4, massive infiltration of affected organs with lymphocytes and plasma cells with IgG4 positivity and tissue fibrosis. Type I autoimmune pancreatitis is one form of IgG4-related disease. For IgG4-related diseases, various localizations are described for up to 10% of malignancies. The aim of our study was to examine IgG4 serum levels and pancreatic tissue with respect to the simultaneous presence of autoimmune pancreatitis in patients with pancreatic cancer. IgG4 serum levels were examined In 106 patients with histologically confirmed pancreatic cancer. The level of 135 mg/dl was considered as the normal value. Pancreatic tissue was histologically examined with respect to the presence of markers of autoimmune pancreatitis. A higher IgG4 level than the cut-off value of 135 mg/dl was proven in 11 patients with pancreatic cancer. Of these 11 patients, 7 had levels twice the normal limit (65.6%). Autoimmune pancreatitis was diagnosed in these individuals. In the case of 1 patient, it was basically an unexpected finding; another patient was initially diagnosed with autoimmune pancreatitis. Repeated biopsy of the pancreas at the time of diagnosis did not confirm the presence of tumour structures, therefore steroid therapy was started. At a check-up 6 months after starting steroid therapy, the condition of the patient improved subjectively and IgG4 levels decreased. However, endosonographically, malignancy was suspected, which was subsequently confirmed histologically. This patient also demonstrated an IgG4 level twice the normal limit. IgG4-related diseases can be accompanied by the simultaneous occurrence of malignancies, which also applies to autoimmune pancreatitis. Chronic pancreatitis is considered a risk factor for pancreatic cancer. It cannot be reliably confirmed whether this also applies to autoimmune pancreatitis. In

  10. [Clinical study on the relationship between pancreatic fistula and the degree of pancreatic fibrosis after pancreatic and duodenal resection].

    PubMed

    Yang, M W; Deng, Y; Huang, T; Zhang, L D

    2017-05-01

    Objective: To explore the risk factors of pancreatic fistula after pancreatoduodenectomy and its relationship with pancreatic fibrosis. Methods: Retrospective analysis was made including 408 patients who underwent pancreaticoduodenectomy from January 2013 to December 2015 in Department of Hepatobiliary Surgery of the First Affiliated Hospital of Third Military Medical University. There were 274 males and females, aging from 14 to 82 years with an average age of 54.6 years. Postoperative pathological diagnosis: 285 cases with pancreatic ductal adenocarcinoma, 81 cases with gastrointestinal tumors, 13 cases with neuroendocrine tumors, 16 cases with inflammatory changes, 8 cases with pancreatic papillary tumors, 4 cases with serous cystadenoma, 1 case with retroperitoneal liposarcoma.Univariate analysis using pearson's χ(2) test, multivariate analysis using binary Logistic regression analysis, correlation analysis using Spearman rank correlation analysis and the predictive value of pancreatic fibrosis in pancreatic fistula after pancreaticoduodenectomy was assessed using the area under the receiver operating characteristic(ROC) curve. Results: There were 123 cases (30.1%) with postoperative pancreatic fistula among 408 patients. Univariate analysis showed that body mass index(BMI)(P=0.005), preoperative gamma-glutamyltranspeptidase content(P=0.046), pancreatic duct diameter(P=0.001), CT value of pancreatic tissue(P=0.049), operation time(P=0.037), pancreatic stiffness (intraoperative judgment)(P=0.001) and percentage of pancreatic fibrosis(P=0.034) were the prognostic factors of pancreatic fistula. Multivariate analysis showed that BMI≥25 kg/m(2), pancreatic duct diameter ≤3 mm, pancreatic tissue CT value <40 Hu, pancreatic hardness (intraoperative judgments) for the soft and pancreatic lobular fibrosis percentage ≤25% of postoperative pancreatic fistula occurrence of high-risk factor(P<0.05). Pancreatic fistula's CT value and percentage of pancreatic fibrosis

  11. 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.

  12. Oral Tumours

    PubMed Central

    Lecavalier, D.R.; Main, J.H.P.

    1988-01-01

    The authors of this article review briefly the anatomy of the oral soft tissues and describe the more common benign and malignant tumours of the mouth, giving emphasis to their clinical features. ImagesFigure 1Figure 2Figure 3Figure 4Figure 5Figure 6Figure 7Figure 8 PMID:21253197

  13. Tumour angiogenesis.

    PubMed Central

    Arnold, F.

    1985-01-01

    Tumours induce the growth of host blood vessels to support their proliferation. This process of angiogenesis is evoked by specific chemical signals. Recognition of these angiogenic factors has led to experimental methods for cancer diagnosis and for inhibiting malignant growth by specifically blocking neovascularisation. The clinical potential of these techniques is discussed. PMID:2413796

  14. Acute Pancreatitis and Pregnancy

    MedlinePlus

    ... Pancreatitis Acute Pancreatitis and Pregnancy Acute Pancreatitis and Pregnancy Timothy Gardner, MD Acute pancreatitis is defined as ... pancreatitis in pregnancy. Reasons for Acute Pancreatitis and Pregnancy While acute pancreatitis is responsible for almost 1 ...

  15. 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.

  16. 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

  17. Pancreatic stellate cell: Pandora's box for pancreatic disease biology

    PubMed Central

    Bynigeri, Ratnakar R; Jakkampudi, Aparna; Jangala, Ramaiah; Subramanyam, Chivukula; Sasikala, Mitnala; Rao, G Venkat; Reddy, D Nageshwar; Talukdar, Rupjyoti

    2017-01-01

    Pancreatic stellate cells (PSCs) were identified in the early 1980s, but received much attention after 1998 when the methods to isolate and culture them from murine and human sources were developed. PSCs contribute to a small proportion of all pancreatic cells under physiological condition, but are essential for maintaining the normal pancreatic architecture. Quiescent PSCs are characterized by the presence of vitamin A laden lipid droplets. Upon PSC activation, these perinuclear lipid droplets disappear from the cytosol, attain a myofibroblast like phenotype and expresses the activation marker, alpha smooth muscle actin. PSCs maintain their activated phenotype via an autocrine loop involving different cytokines and contribute to progressive fibrosis in chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC). Several pathways (e.g., JAK-STAT, Smad, Wnt signaling, Hedgehog etc.), transcription factors and miRNAs have been implicated in the inflammatory and profibrogenic function of PSCs. The role of PSCs goes much beyond fibrosis/desmoplasia in PDAC. It is now shown that PSCs are involved in significant crosstalk between the pancreatic cancer cells and the cancer stroma. These interactions result in tumour progression, metastasis, tumour hypoxia, immune evasion and drug resistance. This is the rationale for therapeutic preclinical and clinical trials that have targeted PSCs and the cancer stroma. PMID:28210075

  18. Pancreatic stellate cell: Pandora's box for pancreatic disease biology.

    PubMed

    Bynigeri, Ratnakar R; Jakkampudi, Aparna; Jangala, Ramaiah; Subramanyam, Chivukula; Sasikala, Mitnala; Rao, G Venkat; Reddy, D Nageshwar; Talukdar, Rupjyoti

    2017-01-21

    Pancreatic stellate cells (PSCs) were identified in the early 1980s, but received much attention after 1998 when the methods to isolate and culture them from murine and human sources were developed. PSCs contribute to a small proportion of all pancreatic cells under physiological condition, but are essential for maintaining the normal pancreatic architecture. Quiescent PSCs are characterized by the presence of vitamin A laden lipid droplets. Upon PSC activation, these perinuclear lipid droplets disappear from the cytosol, attain a myofibroblast like phenotype and expresses the activation marker, alpha smooth muscle actin. PSCs maintain their activated phenotype via an autocrine loop involving different cytokines and contribute to progressive fibrosis in chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC). Several pathways (e.g., JAK-STAT, Smad, Wnt signaling, Hedgehog etc.), transcription factors and miRNAs have been implicated in the inflammatory and profibrogenic function of PSCs. The role of PSCs goes much beyond fibrosis/desmoplasia in PDAC. It is now shown that PSCs are involved in significant crosstalk between the pancreatic cancer cells and the cancer stroma. These interactions result in tumour progression, metastasis, tumour hypoxia, immune evasion and drug resistance. This is the rationale for therapeutic preclinical and clinical trials that have targeted PSCs and the cancer stroma.

  19. Tumour suppressor p16(INK4a) - anoikis-favouring decrease in N/O-glycan/cell surface sialylation by down-regulation of enzymes in sialic acid biosynthesis in tandem in a pancreatic carcinoma model.

    PubMed

    Amano, Maho; Eriksson, Hanna; Manning, Joachim C; Detjen, Katharina M; André, Sabine; Nishimura, Shin-Ichiro; Lehtiö, Janne; Gabius, Hans-Joachim

    2012-11-01

    Tumour suppressor p16(INK4a) is known to exert cell-cycle control via cyclin-dependent kinases. An emerging aspect of its functionality is the orchestrated modulation of N/O-glycosylation and galectin expression to induce anoikis in human Capan-1 pancreatic carcinoma cells. Using chemoselective N/O-glycan enrichment technology (glycoblotting) and product characterization, we first verified a substantial decrease in sialylation. Tests combining genetic (i.e. transfection with α2,6-sialyltransferase-specific cDNA) or metabolic (i.e. medium supplementation with N-acetylmannosamine to track down a bottleneck in sialic acid biosynthesis) engineering with cytofluorometric analysis of lectin binding indicated a role of limited substrate availability, especially for α2,6-sialylation, which switches off reactivity for anoikis-triggering homodimeric galectin-1. Quantitative MS analysis of protein level changes confirmed an enhanced galectin-1 presence along with an influence on glycosyltransferases (β1,4-galactosyltransferase-IV, α2,3-sialyltransferase-I) and detected p16(INK4a) -dependent down-regulation of two enzymes in the biosynthesis pathway for sialic acid [i.e. the bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) and N-acetylneuraminic acid 9-phosphate synthase] (P < 0.001). By contrast, quantitative assessment for the presence of nuclear CMP-N-acetylneuraminic acid synthase (which is responsible for providing the donor for enzymatic sialylation that also acts as feedback inhibitor of the epimerase activity of GNE) revealed a trend for an increase. Partial restoration of sialylation in GNE-transfected cells supports the implied role of sialic acid availability for the glycophenotype. Fittingly, the extent of anoikis was reduced in double-transfected (p16(INK4a) /GNE) cells. Thus, a second means of modulating cell reactivity to the growth effector galectin-1 is established in addition to the common route of altering α2

  20. Neuroendocrine control of metabolism.

    PubMed

    Kuliczkowska-Plaksej, J; Milewicz, A; Jakubowska, J

    2012-03-01

    Metabolism is controlled through homeostatic system consisting of central centers, gut hormones, hormones from adipose tissue and the other hormonal axes. This cooperation is based on cross-talk between central and peripheral signals. Among them the hypothalamus plays a crucial role, with interconnected nuclei forming neuronal circuits. Other regions in the brain, such as the brain stem, the endocannabinoid system, the vagal afferents, are also involved in energy balance. The second component is peripheral source of signals--the gastrointestinal tract hormones. Additionally, adipokines from adipose tissue, thyrotropic, gonadotropic and somatotropic axes play a role in energy homeostasis. Knowledge about all components of this neuroendocrine circuit will be helpful in developing novel therapeutic approaches against the metabolic syndrome and its components.

  1. Endoscopic diagnosis and treatment of neuroendocrine tumors of the digestive system

    PubMed Central

    Telesca, Donato Alessandro; Ruggiero, Simona; Russo, Teresa; Amato, Maurizio; Bianco, Tommaso; Amato, Bruno; Formisano, Cesare; Avellino, Manuela; Napolitano, Vincenzo

    2016-01-01

    Abstract The authors evaluated the role of endoscopic techniques in the diagnosis and in the potential treatment of neuroendocrine tumors (NET) localized in the gastro-entero-pancreatic system, on the basis of their experience and of the international literature. NET are rare tumors that arise from neuroendocrine cells of the gastrointestinal tract and pancreas. It is a possibility that both the digestive endoscopy and EUS play an important role in the diagnosis, staging and surveillance of this disease. In some cases, especially in the early stages, surgical endoscopy allows the treatment of such tumors. PMID:28352822

  2. Expanding the Spectrum of Colonic Manifestations in Tuberous Sclerosis: L-Cell Neuroendocrine Tumor Arising in the Background of Rectal PEComa.

    PubMed

    Kolin, David L; Duan, Kai; Ngan, Bo; Gerstle, J Ted; Krzyzanowska, Monika K; Somers, Gino R; Mete, Ozgur

    2017-07-21

    Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous condition that predisposes to numerous proliferative lesions, including perivascular epithelioid cell tumors (PEComas), such as lymphangioleiomyomatosis (LAM) and angiomyolipomas, and rare neuroendocrine neoplasms. We describe herein a TSC2-harboring tuberous sclerosis patient manifesting with a synchronous well-differentiated L-cell rectal neuroendocrine tumor and leiomyomatosis-like LAM of the rectum. The background large bowel wall was thickened by confluent nodular areas comprising vessels and spindle-to-epithelioid cells, which are immunoreactive for myoid (smooth muscle actin, muscle specific actin, and desmin) and melanocytic markers (HMB45, Melan-A, microphthalmia transcription factor, and CD117). With the exception of TSC-related pancreatic neuroendocrine tumors, the association between tuberous sclerosis and neuroendocrine neoplasms remains largely unknown in the gastrointestinal tract. Neuroendocrine tumorigenesis in tuberous sclerosis is often linked to inactivating mutations of TSC2 leading to aberrant activation of mammalian target of rapamycin (mTOR) pathway. In this report, we document, for the first time, two foci of L-cell rectal neuroendocrine tumor arising in the setting of tuberous sclerosis, thus broadening the spectrum of TSC-associated endocrine disorders. Moreover, to our knowledge, this is only the second documented case of gastrointestinal leiomyomatosis-like LAM in a patient with tuberous sclerosis. The current case provides further evidence that, similar to pancreatic neuroendocrine tumors, neuroendocrine tumors of the luminal gastrointestinal tract may also be a feature of tuberous sclerosis and can be seen in association with PEComas.

  3. Neuroendocrine targets of endocrine disruptors.

    PubMed

    Gore, Andrea C

    2010-01-01

    The central neuroendocrine systems are responsible for the control of homeostatic processes in the body, including reproduction, growth, metabolism and energy balance, as well as stress responsiveness. These processes are initiated by signals in the central nervous system, specifically the hypothalamus, and are conveyed first by neural and then by endocrine effectors. The neuroendocrine systems, as the links between the brain and peripheral endocrine organs, play critical roles in the ability of an organism to respond to its environment under normal circumstances. When neuroendocrine homeostasis is disrupted by environmental endocrine-disrupting chemicals, a variety of perturbations can ensue, particularly when endocrine disruption occurs during critical developmental time periods. This article will discuss the evidence for environmental endocrine disruption of neuroendocrine systems and the effects on endocrine and reproductive functions.

  4. Advances in the diagnosis and treatment of gastric neuroendocrine neoplasms.

    PubMed

    Tan, Huangying

    2016-01-01

    Gastric neuroendocrine neoplasms (g-NENs) are a group of heterogeneous tumors arising from the endocrine cells of stomach. Most g-NENs progresses slowly and have a long disease course; however, some other g-NENs grow rapidly, similar to the progression of gastric adenocarcinoma. g-NENs have complex and diverse clinical manifestations and their prognosis and treatment strategies depend highly on clinical subtype, pathological grade, tumour stage, and other factors. Due to their low prevalence, most clinicians have limited knowledge about g-NENs. Missed diagnosis and excessive/inadequate treatment is common in clinical settings. Thus, the diagnosis and treatment of g-NENs needs to be further standardized.

  5. Neuroendocrine System of the Skin

    PubMed Central

    Slominski, Andrzej

    2005-01-01

    Evidence is accumulating that the skin can serve as a peripheral neuroendocrine organ. The skin neuroendocrine activities are predominantly independent of regulation from the central level (which controls classical hormone secretion) but are rather regulated by local cutaneous factors. These endocrine factors would represent an exquisite regulatory layer addressed at restricting maximally the effect of noxious agents in the skin to preserve local and consequently global homeostasis. PMID:16205064

  6. Neuroendocrine Immunoregulation in Multiple Sclerosis

    PubMed Central

    Lee, Wai-Ping; Berneman, Zwi N.

    2013-01-01

    Currently, it is generally accepted that multiple sclerosis (MS) is a complex multifactorial disease involving genetic and environmental factors affecting the autoreactive immune responses that lead to damage of myelin. In this respect, intrinsic or extrinsic factors such as emotional, psychological, traumatic, or inflammatory stress as well as a variety of other lifestyle interventions can influence the neuroendocrine system. On its turn, it has been demonstrated that the neuroendocrine system has immunomodulatory potential. Moreover, the neuroendocrine and immune systems communicate bidirectionally via shared receptors and shared messenger molecules, variously called hormones, neurotransmitters, or cytokines. Discrepancies at any level can therefore lead to changes in susceptibility and to severity of several autoimmune and inflammatory diseases. Here we provide an overview of the complex system of crosstalk between the neuroendocrine and immune system as well as reported dysfunctions involved in the pathogenesis of autoimmunity, including MS. Finally, possible strategies to intervene with the neuroendocrine-immune system for MS patient management will be discussed. Ultimately, a better understanding of the interactions between the neuroendocrine system and the immune system can open up new therapeutic approaches for the treatment of MS as well as other autoimmune diseases. PMID:24382974

  7. Focal autoimmune pancreatitis and chronic sclerosing sialadenitis mimicking pancreatic cancer and neck metastasis.

    PubMed

    Sun, Li; Zhou, Qiang; Brigstock, David R; Yan, Su; Xiu, Ming; Piao, Rong-Li; Gao, Yan-Hang; Gao, Run-Ping

    2014-12-14

    Type 1 autoimmune pancreatitis (AIP) or chronic sclerosing sialadenitis (Küttner's tumour) is an uncommon disorder that has recently been confirmed as an IgG4-related disease. Here, we describe a rare case of a 53-year-old male patient who primarily presented with pancreatic body mass, left neck mass and several lumps in his lower lip mimicking pancreatic cancer (PC) and neck metastasis. The patient underwent pancreatic body mass and labial gland lumps resection as well as an ultrasound-guided biopsy of the left neck mass. He was diagnosed with IgG4-related focal type of AIP (f-AIP) and Küttner's tumour by immunohistochemistry. The patient responded well to corticosteroid therapy and remains healthy with no signs of recurrence at one year follow-up. The differentiation of f-AIP from PC is very important to avoid unnecessary pancreatic resection.

  8. [Biotherapy of neuroendocrine tumors].

    PubMed

    Chanson, Philippe; Ducreux, Michel

    2002-02-01

    The somatostatin analogues have an excellent symptomatic therapeutic effect (60-90% responses in carcinoid syndrome) which permits an amelioration in the quality of life, particularly in patients with metastatic tumours. The availability of long-acting somatostatin analogues assuring stable plasma concentrations over several weeks (thanks to progressive liberation) further facilitates the use of these medications by allowing a reduction in the number of injections. Interferon also has an anti-secretory effect, albeit inferior to that of the somatostatin analogues, but potentially of interest in the case of resistance to these products.

  9. Urogenital tumours in childhood

    PubMed Central

    Swinson, S.

    2011-01-01

    Abstract The commonest urogenital tumours in childhood are Wilms tumour of the kidney and rhabdomyosarcoma in the pelvis. We review these tumours along with other primary renal tumours and less common ovarian and testicular tumours in childhood. Current clinical concepts, relevant staging investigations and imaging features are described. PMID:22187115

  10. Chronic Pancreatitis in Children

    MedlinePlus

    ... Chronic Pancreatitis in Children Childhood Inherited Disorders Pancreatic Cancer Pancreatic Cancer Risks and Symptoms Staging of Pancreatic Cancer Treatment of Pancreatic Cancer Whipple Procedure Complementary Therapies Pancreatic Cancer Support ...

  11. Acute Pancreatitis in Children

    MedlinePlus

    ... Chronic Pancreatitis in Children Childhood Inherited Disorders Pancreatic Cancer Pancreatic Cancer Risks and Symptoms Staging of Pancreatic Cancer Treatment of Pancreatic Cancer Whipple Procedure Complementary Therapies Pancreatic Cancer Support ...

  12. Acute Pancreatitis and Pregnancy

    MedlinePlus

    ... Chronic Pancreatitis in Children Childhood Inherited Disorders Pancreatic Cancer Pancreatic Cancer Risks and Symptoms Staging of Pancreatic Cancer Treatment of Pancreatic Cancer Whipple Procedure Complementary Therapies Pancreatic Cancer Support ...

  13. Neuroendocrine control of satiation.

    PubMed

    Asarian, Lori; Bächler, Thomas

    2014-09-01

    Abstract Eating is a simple behavior with complex functions. The unconscious neuroendocrine process that stops eating and brings a meal to its end is called satiation. Energy homeostasis is mediated accomplished through the control of meal size via satiation. It involves neural integrations of phasic negative-feedback signals related to ingested food and tonic signals, such as those related to adipose tissue mass. Energy homeostasis is accomplished through adjustments in meal size brought about by changes in these satiation signals. The best understood meal-derived satiation signals arise from gastrointestinal nutrient sensing. Gastrointestinal hormones secreted during the meal, including cholecystokinin, glucagon-like peptide 1, and PYY, mediate most of these. Other physiological signals arise from activation of metabolic-sensing neurons, mainly in the hypothalamus and caudal brainstem. We review both classes of satiation signal and their integration in the brain, including their processing by melanocortin, neuropeptide Y/agouti-related peptide, serotonin, noradrenaline, and oxytocin neurons. Our review is not comprehensive; rather, we discuss only what we consider the best-understood mechanisms of satiation, with a special focus on normally operating physiological mechanisms.

  14. Morphological and functional investigations of neuroendocrine tumors of the pancreas.

    PubMed

    Pereira, Philippe L; Wiskirchen, Jakub

    2003-09-01

    Neuroendocrine tumors of the pancreas are rare neoplasms arising predominantly from the pancreatic islets of Langerhans and are thus known as islet cell tumors. More than the half of all neuroendocrine tumors are called functioning islet cell tumors because they secrete one or more biologically active peptides that may produce clinical symptoms. Clinical diagnosis of non-functioning, i.e., biologically inactive, tumors is often delayed and patients tend to present with advanced tumors (size greater than 5 cm) that are easily localized by using conventional imaging modalities. On the other hand, symptoms of functioning islet cell tumors usually appear early in the clinical course, rendering the preoperative localization of these small hormone-producing tumors (size less than 2 cm) difficult with non-invasive methods. Since functioning islet cell tumors can often be cured by surgical resection, invasive procedures are warranted when necessary for localization diagnosis. Failure to search for, detect, and resect these small tumors will invariably result in persistent symptoms. Regarding the unsatisfactory results of morphological imaging methods, functional studies, especially arterial stimulation with hepatic venous samplings, may provide a preoperative regionalization of the pancreatic adenoma, regardless of its size.

  15. 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

  16. 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.

  17. Imaging and localization of islet-cell tumours of the pancreas on CT and MRI.

    PubMed

    Noone, Tara C; Hosey, Jason; Firat, Zeynep; Semelka, Richard C

    2005-06-01

    Islet-cell tumours are neuroendocrine tumours that arise from the endocrine pancreas. They may be associated with a variety of syndromes and are subclassified into functioning and non-functioning tumours. They range from benign to malignant. They demonstrate characteristic features when imaged with both computed tomography (CT) and magnetic resonance imaging (MRI). Sensitivity and specificity, as well as detection of extrapancreatic extension, are generally superior with MRI. However, CT is currently still more readily available to patients. Multiphase, post-contrast series are commended for the evaluation of islet-cell tumours with either modality.

  18. Adjuvant therapy in pancreatic cancer.

    PubMed

    Jones, Owain Peris; Melling, James Daniel; Ghaneh, Paula

    2014-10-28

    Pancreatic cancer remains one of the leading causes of cancer related death worldwide with an overall five-year survival of less than 5%. Potentially curative surgery, which alone can improve 5-year survival to 10%, is an option for only 10%-20% of patients at presentation owing to local invasion of the tumour or metastatic disease. Adjuvant chemotherapy has been shown to improve 5-year survival to 20%-25% but conflicting evidence remains with regards to chemoradiation. In this article we review the current evidence available from published randomised trials and discuss ongoing phase III trials in relation to adjuvant therapy in pancreatic cancer.

  19. Neuroendocrine effects of light

    NASA Astrophysics Data System (ADS)

    Reiter, Russel J.

    1991-09-01

    The light/dark cycle to which animals, and possibly humans, are exposed has a major impact on their physiology. The mechanisms whereby specific tissues respond to the light/dark cycle involve the pineal hormone melatonin. The pineal gland, an end organ of the visual system in mammals, produces the hormone melatonin only at night, at which time it is released into the blood. The duration of elevated nightly melatonin provides every tissue with information about the time of day and time of year (in animals that are kept under naturally changing photoperiods). Besides its release in a circadian mode, melatonin is also discharged in a pulsatile manner; the physiological significance, if any, of pulsatile melatonin release remains unknown. The exposure of animals including man to light at night rapidly depresses pineal melatonin synthesis and, therefore, blood melatonin levels drop precipitously. The brightness of light at night required to depress melatonin production is highly species specific. In general, the pineal gland of nocturnally active mammals, which possess rod-dominated retinas, is more sensitive to inhibition by light than is the pineal gland of diurnally active animals (with cone-dominated retinas). Because of the ability of the light/dark cycle to determine melatonin production, the photoperiod is capable of influencing the function of a variety of endocrine and non-endocrine organs. Indeed, melatonin is a ubiquitously acting pineal hormone with its effects on the neuroendocrine system having been most thoroughly investigated. Thus, in nonhuman photoperiodic mammals melatonin regulates seasonal reproduction; in humans also, the indole has been implicated in the control of reproductive physiology.

  20. Biomarker discovery for neuroendocrine cervical cancer.

    PubMed

    Lin, Li-Hsun; Chang, Shing-Jyh; Hu, Ren-Yu; Lin, Meng-Wei; Lin, Szu-Ting; Huang, Shun-Hong; Lyu, Ping-Chiang; Chou, Hsiu-Chuan; Lai, Zih-Yin; Chuang, Yung-Jen; Chan, Hong-Lin

    2014-07-01

    Neuroendocrine cervical cancer is an aggressive but rare form of cervical cancer. The majority of neuroendocrine cervical cancer patients present with advanced-stage diseases. However, the limited numbers of neuroendocrine tumor markers are insufficient for clinical purposes. Thus, we used a proteomic approach combining lysine labeling 2D-DIGE and MALDI-TOF MS to investigate the biomarkers for neuroendocrine cervical cancer. By analyzing the global proteome alteration between the neuroendocrine cervical cancer line (HM-1) and non-neuroendocrine cervical cancer lines (CaSki cells, ME-180 cells, and Hela cells), we identified 82 proteins exhibiting marked changes between HM-1 and CaSki cells, and between ME-180 and Hela cells. Several proteins involved in protein folding, cytoskeleton, transcription control, signal transduction, glycolysis, and redox regulation exhibited significant changes in abundance. Proteomic and immunoblot analyses indicated respective 49.88-fold and 25-fold increased levels of transgelin in HM-1 cells compared with that in other non-neuroendocrine cervical cancer cell lines, implying that transgelin is a biomarker for neuroendocrine cervical cancer. In summary, we used a comprehensive neuroendocrine/non-neuroendocrine cervical cancer model based proteomic approach for identifying neuroendocrine cervical cancer markers, which might contribute to the prognosis and diagnosis of neuroendocrine cervical cancer.

  1. Combined endocrine and exocrine tumours of the pancreas.

    PubMed

    Alzaraa, Ahmed; Udom, Valeri; Mousa, Husam; Alzein, Abdulhalem; Benhamida, Abduljalil; Dalal, Neha

    2007-09-14

    Cystic neoplasms of the pancreas comprise 10%-15% of pancreatic cystic lesions, with the serous cystadenoms being the commonest. The association of exocrine and endocrine tumours of the pancreas unrelated to Von Hipple Lindau disease is very rare. Very few cases have been reported in the literature. We present another case of both these tumours in one patient. A female patient was seen in the surgical clinic for a pain in the right groin. Clinical examination and investigations confirmed a diagnosis of combined endocrine and exocrine tumours of the pancreas. She underwent surgery and is under regular follow-up in the surgical clinic. Biphasic differentiation of pancreatic stem cell during embryological development could happen and may result in combined endocrine and exocrine tumours of the pancreas. Imaging studies are excellent in diagnosing theses lesions. Surgery has a central role and could be curative.

  2. Combined endocrine and exocrine tumours of the pancreas

    PubMed Central

    Alzaraa, Ahmed; Udom, Valeri; Mousa, Husam; Alzein, Abdulhalem; Benhamida, Abduljalil; Dalal, Neha

    2007-01-01

    Background Cystic neoplasms of the pancreas comprise 10%–15% of pancreatic cystic lesions, with the serous cystadenoms being the commonest. The association of exocrine and endocrine tumours of the pancreas unrelated to Von Hipple Lindau disease is very rare. Very few cases have been reported in the literature. We present another case of both these tumours in one patient. Case presentation A female patient was seen in the surgical clinic for a pain in the right groin. Clinical examination and investigations confirmed a diagnosis of combined endocrine and exocrine tumours of the pancreas. She underwent surgery and is under regular follow-up in the surgical clinic. Conclusion Biphasic differentiation of pancreatic stem cell during embryological development could happen and may result in combined endocrine and exocrine tumours of the pancreas. Imaging studies are excellent in diagnosing theses lesions. Surgery has a central role and could be curative. PMID:17868437

  3. The poor prognosis factors in G2 neuroendocrine tumor.

    PubMed

    Poiană, Cătălina; Neamţu, M C; Avramescu, Elena Taina; Carşote, Mara; Trifănescu, Raluca; Terzea, Dana; Neamţu, Oana Maria; Ferechide, D; Dănciulescu Miulescu, Rucsandra

    2013-01-01

    The G2 neuroendocrine tumors (NET) or well-differentiated neuroendocrine carcinomas (2010 WHO Classification of Tumours of the Digestive System) embrace different types of evolution despite the fact that they actually are included in the same group of prognosis based on mitotic count and the Ki-67 proliferation index. We studied the pathological and clinical aspects in patients with G2 NET. This is a retrospective pilot observational study in patients admitted between January 2008 and January 2013 in "Constantin I. Parhon" National Institute of Endocrinology, Bucharest, Romania. They were evaluated based on the pathological report, imagistic scan, and neuroendocrine markers. Nine patients (female/male ratio: 5/4) with G2 NET were included (mean age at diagnosis 54.11 years). Surgery was performed in 66.66% of cases. 44.44% of tumors had unknown origin. 22.22% of patients had negative immunostain for chromogranin A. Synaptophysin was positive in all cases. Neuronal specific enolase (NSE) was performed in 44.44% of cases and it was positive in all these situations. 88.88% of patients had high neuroendocrine markers. Multiple tumors were found in two cases (follicular thyroid adenoma, and a carcinoma of the port vein, respective bilaterally pheochromocytomas). The youngest patient (39-year-old) had atypical onset with bilateral adrenal tumors (positive for CHROMO, EMA, CK-19, CK-20, negative for SOMATO, CK-7, S-100, glucagon, CD57, and a Ki-67 of 15%). Death was registered in two cases, both with bone metastases. Some poor prognosis factors may be taken into account as lack of CHROMO immunostain, young age at diagnosis, genetic background, and lack of therapy options as surgery. Larger databases will provide more information. It is possible that the G2 NET group of tumors actually includes some different subtypes or in fact, a late diagnosis of the tumor might be associated with a poor diagnosis.

  4. Primary Neuroendocrine Carcinoma of the Breast Metastatic to the Bones, Which Chemotherapy?

    PubMed

    Soe, Aye M; Joseph, Gardith; Guevara, Elizabeth; Xiao, Philip

    2017-09-01

    The primary neuroendocrine carcinoma (NEC) of the breast is defined as immunohistochemical expression of neuroendocrine markers (chromogranin and synoptophysin) in more than 50% of the neoplastic cells according to World Health Organization (WHO) classification of tumors in 2003 (Tumours of the Breast and Female Genital Organs, 2003, Lyon: IARC Press). It accounts for less than 5% of all cancers arising from the breast (Tumours of the Breast and Female Genital Organs, 2003, Lyon, France: IARC Press). However, based on the study conducted by Wang et al., the primary NEC of breast comprises less than 0.1% of all mammary carcinomas (Frankf Z Pathol, 73, 1963, 24). Because of the rarity of the disease and absence of the prospective trials, there is no standard treatment for primary NEC of the breast. Herein, we report the case of a middle age woman with primary NEC with bone metastasis. © 2017 Wiley Periodicals, Inc.

  5. Comparison of metastatic neuroendocrine neoplasms to the breast and primary invasive mammary carcinomas with neuroendocrine differentiation.

    PubMed

    Mohanty, Sambit K; Kim, Stacey A; DeLair, Deborah F; Bose, Shikha; Laury, Anna R; Chopra, Shefali; Mertens, Richard B; Dhall, Deepti

    2016-08-01

    Metastatic neuroendocrine neoplasms to the breast may show considerable morphologic overlap with primary mammary carcinomas, particularly those showing evidence of neuroendocrine differentiation, and may be misdiagnosed as such. Accurate distinction between these two entities is crucial for determination of appropriate clinical management. The histologic and immunohistochemical features of metastatic neuroendocrine neoplasms to the breast were studied and compared with the features of primary invasive mammary carcinomas with neuroendocrine differentiation, which served as controls. Of the metastatic neuroendocrine neoplasms, 15 were well-differentiated neuroendocrine tumors with carcinoid tumor-type morphology and 7 were poorly differentiated/high-grade neuroendocrine carcinomas with small-cell or large-cell neuroendocrine carcinoma morphology. The majority of the metastatic neoplasms originated in the lung and gastrointestinal tract. There were histologic similarities between metastatic neuroendocrine neoplasms and invasive mammary carcinomas with neuroendocrine differentiation, both of which exhibited neuroendocrine histologic features (nested and trabecular architecture, minimal tubular differentiation, and characteristic nuclear features). Only one case of the invasive mammary carcinomas with neuroendocrine differentiation was modified Bloom-Richardson grade 1 (largely due to minimal tubular differentiation on most such tumors), and the invasive mammary carcinomas with neuroendocrine differentiation were often associated with in situ carcinoma. Immunohistochemistry was helpful in distinguishing metastatic neuroendocrine neoplasms from invasive mammary carcinomas with neuroendocrine differentiation. Whereas the majority of invasive mammary carcinomas with neuroendocrine differentiation were positive for estrogen receptor and GATA3, metastatic