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Sample records for colorectal neuroendocrine tumors

  1. Molecular characteristics of colorectal neuroendocrine carcinoma; similarities with adenocarcinoma rather than neuroendocrine tumor.

    PubMed

    Takizawa, Nobuyoshi; Ohishi, Yoshihiro; Hirahashi, Minako; Takahashi, Shunsuke; Nakamura, Kazuhiko; Tanaka, Masao; Oki, Eiji; Takayanagi, Ryoichi; Oda, Yoshinao

    2015-12-01

    To further clarify the molecular features of colorectal neuroendocrine carcinomas (NECs), we immunohistochemically examined tumor samples from 25 NECs, including 9 small cell NECs (SCNECs) and 16 large cell NECs (LCNECs), 20 neuroendocrine tumors (NETs), and 21 poorly differentiated adenocarcinomas (PDCs) for the expression of several biomarkers (p53, β-catenin, Bcl-2, Rb, p16, p21, cyclin D1, and cyclin E) and used sequencing analysis to identify gene alterations of TP53, APC, CTNNB1, KRAS, and BRAF. The frequencies of aberrant p53 expression (88%), β-catenin nuclear expression (48%), and high expression of cyclin E (84%) were significantly higher in NECs than in NETs (0%, 5%, and 5%, P < .01, respectively). The immunohistochemical results of NECs and PDCs were similar. TP53, APC, KRAS, and BRAF gene mutations were variously detected in NECs and PDCs but not in any NETs. The frequencies of decreased expression of Rb (56%) and high expression of p16 (56%) and Bcl-2 (64%) were significantly higher in NECs than in PDCs (5%, 19%, and 5%, P < .05, respectively) or NETs (10%, 5%, and 5%, P < .01, respectively). Such immunohistochemical characteristics of NECs were more evident in SCNECs than in large cell NECs (P < .01). In conclusion, the molecular features of colorectal NECs are similar to those of adenocarcinomas and not to those of NETs. Decreased expression of Rb and high expression of p16 and Bcl-2 are characteristics of NECs, suggesting that Rb-p16 pathway disruption may contribute to the promotion of proliferative activity in colorectal NECs. SCNECs may be a prototype of NECs. PMID:26434631

  2. INSL5 may be a unique marker of colorectal endocrine cells and neuroendocrine tumors

    SciTech Connect

    Mashima, Hirosato; Ohno, Hideki; Yamada, Yumi; Sakai, Toshitaka; Ohnishi, Hirohide

    2013-03-22

    Highlights: ► INSL5 is expressed in enteroendocrine cells along the colorectum. ► INSL5 is expressed increasingly from proximal colon to rectum. ► INSL5 co-localizes rarely with chromogranin A. ► All rectal neuroendocrine tumors examined expressed INSL5. -- Abstract: Insulin-like peptide 5 (INSL5) is a member of the insulin superfamily, and is a potent agonist for RXFP4. We have shown that INSL5 is expressed in enteroendocrine cells (EECs) along the colorectum with a gradient increase toward the rectum. RXFP4 is ubiquitously expressed along the digestive tract. INSL5-positive EECs have little immunoreactivity to chromogranin A (CgA) and might be a unique marker of colorectal EECs. CgA-positive EECs were distributed normally along the colorectum in INSL5 null mice, suggesting that INSL5 is not required for the development of CgA-positive EECs. Exogenous INSL5 did not affect the proliferation of human colon cancer cell lines, and chemically-induced colitis in INSL5 null mice did not show any significant changes in inflammation or mucosal healing compared to wild-type mice. In contrast, all of the rectal neuroendocrine tumors examined co-expressed INSL5 and RXFP4. INSL5 may be a unique marker of colorectal EECs, and INSL5–RXFP4 signaling might play a role in an autocrine/paracrine fashion in the colorectal epithelium and rectal neuroendocrine tumors.

  3. Roles of miR-186 and PTTG1 in colorectal neuroendocrine tumors

    PubMed Central

    Wang, Maonan; Xia, Xin; Chu, Wenxiang; Xia, Liyan; Meng, Tao; Liu, Lintao; Liu, Yushi

    2015-01-01

    Objectives: This work aims to investigate the expression of miRNA-186 in patients with colorectal cancer tissues, blood and feces and its roles in regulating the infiltration and invasion in colorectal cancer. Methods: Totally 39 patients with surgical resection were included from August 2012 to February 2015 in Jilin Province People’s Hospital as the Colorectal Neuroendocrine tumor (CNET). Peripheral blood, stool, and resected tumor tissues with adjacent normal of each patient was collected. In the same period, the blood and stool from 25 patients with hemorrhoids or other non-neoplastic diseases were collected and these samples used as clinical control group. MiR-186 expression and PTTG1 (pituitary tumor-transforming 1) expression were detected by quantitative Real-Time PCR (qRT-PCR). The PTTG1 protein expression in tumor samples were detected by Western Blot, while its expression in blood and stool were detected by Elisa. Results: Compared with the control group, the expression of PTTG1 mRNA and protein was significantly up-regulated in tumor samples, blood, and stool of patients with CNET, while the expression of miR-186 was down-regulated (P < 0.05). Conclusion: PTTG1 expression was significantly up-regulated in patients with CNET, which was induced by the down-regulated miR-186. MiR-186 may participate in the regulation of infiltration and invasion in CNET patients through targeting PTTG1 expression. PMID:26885189

  4. Neuroendocrine Tumor: Statistics

    MedlinePlus

    ... Tumor > Neuroendocrine Tumor - Statistics Request Permissions Neuroendocrine Tumor - Statistics Approved by the Cancer.Net Editorial Board , 04/ ... the body. It is important to remember that statistics on how many people survive this type of ...

  5. Neuroendocrine differentiation: The mysterious fellow of colorectal cancer

    PubMed Central

    Kleist, Britta; Poetsch, Micaela

    2015-01-01

    Neuroendocrine differentiation in sporadic colorectal cancer has been recognized since decades, but its clinical impact is still controversially discussed. Detailed parameter analyses hint at the possibility that probably not neuroendocrine differentiation itself, but its association with poor grade of tumor differentiation, lymph node metastases, distant metastases and other unfavorable features contribute to worse clinical outcome. However, other studies deny a relationship between neuroendocrine differentiation and prognosis of colorectal cancer. This review elucidates, whether new insights into the origin of neuroendocrine differentiation in the intestinal epithelium, its regulation by mTOR pathway components and its possible link to the intestinal stem cell compartment could determine a role of neuroendocrine cells as prognostic marker and putative therapeutic target in sporadic colorectal cancer. PMID:26556999

  6. [Grading of neuroendocrine tumors].

    PubMed

    Saeger, W; Schnabel, P A; Komminoth, P

    2016-07-01

    The current WHO classification of neuroendocrine tumors (NET) differentiates between typical carcinoids (low grade NET), atypical carcinoids (intermediate grade NET) and small cell and large cell carcinomas (high grade NET) according to the prognosis. Neuroendocrine neoplasms (NEN) of the gastrointestinal tract and the pancreas are graded in an identical way. Together with the TNM system this enables a preoperative estimation of the prognosis in biopsies and fine needle aspirates. Well-differentiated tumors are graded into G1 tumors by the number of mitoses, <2 per 10 high-power fields (HPF) and the Ki-67 (index <3 %) and G2 tumors (2-20 mitoses/10 HPF, Ki-67 3-20 %). Discrepancies between the number of mitoses and the Ki-67 index are not uncommon and in these cases the higher value of the two should be applied. The more differentiated tumors of the G3 type have to be differentiated from undifferentiated carcinomas of the small cell type and large cell type with a much poorer prognosis. Prognosis relevant grading of thyroid cancers is achieved by special subtyping so that the G1-G3 system is not applicable. The rare cancers of the parathyroid gland and of the pituitary gland are not graded. Adrenal tumors also have no grading system. The prognosis is dependent on the Ki-67 index and with some reservations on the established scoring systems. PMID:27379621

  7. Expanding Therapy for Neuroendocrine Tumors.

    PubMed

    2016-03-01

    Results from two phase III studies suggest that everolimus, an mTOR inhibitor, and (177)Lutetium-DOTATATE, a radiopharmaceutical, may be effective new options for patients with advanced neuroendocrine tumors of the gastrointestinal tract. Both therapies were well tolerated and significantly prolonged progression-free survival. PMID:26826165

  8. Notch Signaling in Neuroendocrine Tumors

    PubMed Central

    Crabtree, Judy S.; Singleton, Ciera S.; Miele, Lucio

    2016-01-01

    Carcinoids and neuroendocrine tumors (NETs) are a heterogeneous group of tumors that arise from the neuroendocrine cells of the GI tract, endocrine pancreas, and the respiratory system. NETs remain significantly understudied with respect to molecular mechanisms of pathogenesis, particularly the role of cell fate signaling systems such as Notch. The abundance of literature on the Notch pathway is a testament to its complexity in different cellular environments. Notch receptors can function as oncogenes in some contexts and tumor suppressors in others. The genetic heterogeneity of NETs suggests that to fully understand the roles and the potential therapeutic implications of Notch signaling in NETs, a comprehensive analysis of Notch expression patterns and potential roles across all NET subtypes is required. PMID:27148486

  9. Molecular Imaging of Neuroendocrine Tumors

    PubMed Central

    Carrasquillo, Jorge A.; Chen, Clara C.

    2014-01-01

    Neuroendocrine tumors (NET) are a heterogeneous group of tumors that arise from neuroendocrine cells. These tumors may arise from various organs, including lung, thymus, thyroid, stomach, duodenum, small bowel, large bowel, appendix, pancreas, adrenal, and skin. Most are well differentiated and have the ability to produce biogenic amines and various hormones. NET usually occur sporadically but they also be associated with various familial syndromes. For the vast majority of NET, surgical resection is the treatment of choice whenever feasible. Localization of NET prior to surgery and for staging and follow-up relies on both anatomic and functional imaging modalities. In fact, the unique secretory characteristics of these tumors lend themselves to imaging by molecular imaging modalities, which can target specific metabolic pathways or receptors. Neuroendocrine cells have a variety of such target receptors and pathways for which radiopharmaceuticals have been developed, including [123I/131I]-metaiodobenzylguanidine (MIBG), [ 111In]pentetreotide, [68Ga] somatostatin analogs, [18F] fluorodeoxyglucose (FDG), [11C/18F] dihydroxyphenylalanine (DOPA), [11C] 5-hydroxytryptophan (5-HTP) 99mTc pentavalent dimercaptosuccinic acid ([99mTc] (V) DMSA, and [18F] fluorodopamine (FDA). Here, we review the molecular imaging approaches for NET using various radiopharmaceuticals. PMID:21167384

  10. Update on pancreatic neuroendocrine tumors

    PubMed Central

    McKenna, Logan R.

    2014-01-01

    Pancreatic neuroendocrine tumors (pNETs) are relatively rare tumors comprising 1-2% of all pancreas neoplasms. In the last 10 years our understanding of this disease has increased dramatically allowing for advancements in the treatment of pNETs. Surgical excision remains the primary therapy for localized tumors and only potential for cure. New surgical techniques using laparoscopic approaches to complex pancreatic resections are a major advancement in surgical therapy and increasingly possible. With early detection being less common, most patients present with metastatic disease. Management of these patients requires multidisciplinary care combining the best of surgery, chemotherapy and other targeted therapies. In addition to surgical advances, recently, there have been significant advances in systemic therapy and targeted molecular therapy. PMID:25493258

  11. Primary Neuroendocrine Tumor in Brain

    PubMed Central

    Tamura, Ryota; Kuroshima, Yoshiaki; Nakamura, Yoshiki

    2014-01-01

    The incidence of brain metastases for neuroendocrine tumor (NET) is reportedly 1.5~5%, and the origin is usually pulmonary. A 77-year-old man presented to our hospital with headache and disturbance of specific skilled motor activities. Computed tomography (CT) showed a massive neoplastic lesion originating in the left temporal and parietal lobes that caused a mass edematous effect. Grossly, total resection of the tumor was achieved. Histological examination revealed much nuclear atypia and mitotic figures. Staining for CD56, chromogranin A, and synaptophysin was positive, indicating NET. The MIB-1 index was 37%. Histopathologically, the tumor was diagnosed as NET. After surgery, gastroscopy and colonoscopy were performed, but the origin was not seen. After discharge, CT and FDG-PET (fluoro-2-deoxy-d-glucose positron emission tomography) were performed every 3 months. Two years later we have not determined the origin of the tumor. It is possible that the brain is the primary site of this NET. To our knowledge, this is the first reported case of this phenomenon. PMID:25506006

  12. General Information about Pancreatic Neuroendocrine Tumors (Islet Cell Tumors)

    MedlinePlus

    ... Islet Cell Tumors) Treatment (PDQ®)–Patient Version General Information About Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Go ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  13. 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

  14. Duodenal Neuroendocrine Tumors: Location Matters!

    PubMed

    Sheikh, Mohd Raashid; Osman, Houssam; Cheek, Susannah; Hunter, Shanee; Jeyarajah, Dhiresh Rohan

    2016-05-01

    Duodenal neuroendocrine tumors (NETs) are rare. Historically, when feasible a less aggressive surgical approach is considered. The aim of this study was to identify factors associated with prognosis and the necessity for more aggressive surgical procedures. All patients who underwent surgery for duodenal NETs between September 2005 and June 2014 were identified retrospectively. Data collected included clinical presentation, operative findings, and histopathological data. Eighteen patients underwent surgical management for duodenal NETs. Two patients underwent transduodenal excision (11%), two patients had partial duodenal resection (11%), two patients had antrectomy including 1st part of duodenum (D1) resection (33%), and eight underwent pancreaticoduodenectomy [PD (44%)]. On analysis, 2nd part of duodenum (D2) location was the most common site of duodenal NETs (n = 9, 50%). The odds of having a PD were 10 times higher when the lesion was in D2 location. The odds of having a positive lymph node are nine times higher when the lesion is in D2 region. The odds of having a positive lymph node are three times higher when lesion is greater than T1. D2 location of NETs is associated with higher odds of lymph node positivity and need for more extensive procedures like PD. PMID:27215716

  15. 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.

  16. Neuroendocrine tumors: common presentations of uncommon diseases.

    PubMed

    Kirkwood, K S; Debas, H T

    1995-12-01

    In recent decades, isolation of the peptides secreted by gastrointestinal neuroendocrine tumors has greatly advanced our understanding of the pathophysiology of the syndromes resulting from over-production of these biologically active compounds. Early detection of these lesions permits localization and surgical extirpation prior to the development of mestastatic disease. In 1995, early detection of gastrointestinal neuroendocrine tumors hinges on an appropriate index of suspicion on the part of the primary care physician. The prompt recognition of the typical clinical constellations of symptoms associated with these tumors is essential to their timely diagnosis and management. PMID:8789136

  17. Skin manifestations of endocrine and neuroendocrine tumors.

    PubMed

    Leventhal, Jonathan S; Braverman, Irwin M

    2016-06-01

    The skin signs of benign and malignant endocrine and neuroendocrine tumors are manifold and early identification of these dermatologic features is crucial in initiating timely diagnosis and management. This article reviews the salient cutaneous features of these tumors that arise in the classic endocrine glands, lung and gastrointestinal tract either as individual neoplasms or as part of a syndrome. PMID:27178685

  18. Medical Treatment of Gastroenteropancreatic Neuroendocrine Tumors

    PubMed Central

    Rinke, Anja; Michl, Patrick; Gress, Thomas

    2012-01-01

    Treatment of the clinically and prognostically heterogeneous neuroendocrine neoplasms (NEN) should be based on a multidisciplinary approach, including surgical, interventional, medical and nuclear medicine-based therapeutic options. Medical therapies include somatostatin analogues, interferon-α, mTOR inhibitors, multikinase inhibitors and systemic chemotherapy. For the selection of the appropriate medical treatment the hormonal activity, primary tumor localization, tumor grading and growth behaviour as well as the extent of the disease must be considered. Somatostatin analogues are mainly indicated in hormonally active tumors for symptomatic relief, but antiproliferative effects have also been demonstrated, especially in well-differentiated intestinal NET. The efficacy of everolimus and sunitinib in patients with pancreatic neuroendocrine tumors (pNET) has been demonstrated in large placebo-controlled clinical trials. pNETs are also chemosensitive. Streptozocin-based chemotherapeutic regimens are regarded as current standard of care. Temozolomide in combination with capecitabine is an alternative that has shown promising results that need to be confirmed in larger trials. Currently, no comparative studies and no molecular markers are established that predict the response to medical treatment. Therefore the choice of treatment for each pNET patient is based on individual parameters taking into account the patient’s preference, expected side effects and established response criteria such as proliferation rate and tumor load. Platin-based chemotherapy is still the standard treatment for poorly differentiated neuroendocrine carcinomas. Clearly, there is an unmet need for new systemic treatment options in patients with extrapancreatic neuroendocrine tumors. PMID:24213230

  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. Biochemical diagnosis of neuroendocrine GEP tumor.

    PubMed Central

    Oberg, K.

    1997-01-01

    Neuroendocrine gut and pancreatic tumors are known to contain and secret different peptide hormones and amines. During the last two decades, many radioimmunoassays and Elizas have been developed to analyze these substances in blood and urine, which has enabled clinicians to improve the diagnosis and monitoring of patients with various neuroendocrine tumors. Due to cost constraints in medical care, it is important to try to define the most useful biochemical markers from the clinical point of view. The glycoprotein chromogranin A has been shown to be a useful marker for diagnosing various neuroendocrine tumors, both by histopathology and circulating tumor markers. In patients with demonstrable endocrine tumors, about 90 percent of the patients present high circulating levels of chromogranin A. A hundred-fold increase of plasma chromogranin is seen in patients with midgut carcinoid tumors and liver metastases. The plasma levels of chromogranin A reflect the tumor mass and can be used for monitoring the patient during treatment and follow-up, although the day-to-day variation might be 30-40 percent. High circulating levels of the chromogranin A might be an indicator of bad prognosis in patients with malignant carcinoid tumors. Besides analyzing plasma chromogranin A, specific analyses such as urinary 5-HIAA in midgut carcinoid patients, serum gastrin in patients with Zollinger-Ellison syndrome and insulin/proinsulin in patients with hypoglycemia should be performed. In patients with small tumor masses or intermittent symptoms, provocative tests such as a meal stimulation test, secretin test or pentagastrin stimulation of tachykinin release can supplement the basal measurements of peptides and amines. To fully evaluate the growth potential in neuroendocrine tumors, traditional biochemical markers should be supplemented with indicators of growth proliferation (Ki-67, PCNA) and immunohistochemical staining for the adhesion molecule CD44 and the PDGF-alpha receptor

  1. Neuroendocrine Tumors of the Female Reproductive Tract: A Literature Review

    PubMed Central

    Chun, Yi Kyeong

    2015-01-01

    Neuroendocrine tumors of the female reproductive tract are a heterogeneous group of neoplasms that display various histologic findings and biologic behaviors. In this review, the classification and clinicopathologic characteristics of neuroendocrine tumors of the female reproductive tract are described. Differential diagnoses are discussed, especially for non-neuroendocrine tumors showing high-grade nuclei with neuroendocrine differentiation. This review also discusses recent advances in our pathogenetic understanding of these disorders. PMID:26459408

  2. Gastroenteropancreatic neuroendocrine tumors: diagnosis and treatment

    PubMed Central

    Díez, Marc; Teulé, Alexandre; Salazar, Ramon

    2013-01-01

    Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are relatively rare and complex neoplasms that present many clinical challenges. Most GEP-NETs are sporadic, but they can be multiple and a component of a familial syndrome. Assessment of the location and extent of GEP-NETs is crucial for management and a number of novel imaging modalities are under evaluation with the principal goal of increasing sensitivity for the detection of micro-metastases while retaining specificity. The appropriate diagnosis and treatment of neuroendocrine tumors often involves collaboration between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Management strategies include surgery, radiological intervention, cytotoxic chemotherapies, somatostatin analogs and novel biological agents such as sunitinib and everolimus. Other biological agents, new chemoteraphy regimens and somatostatin-tagged radionuclide therapies are also under investigation. In spite of this, comparison between therapeutic modalities is currently difficult. Further studies are warranted to individualize and optimize the diagnosis and treatment of these tumors. PMID:24714698

  3. [Neuroendocrine tumors: Peptide receptors radionuclide therapy (PRRT)].

    PubMed

    Papamichail, Dimitris G; Exadaktylou, Paraskevi E; Chatzipavlidou, Vasiliki D

    2016-01-01

    Neuroendocrine tumors (neuroendocrine tumors-NET) are a heterogeneous group of neoplasms with a common embryological origin and diverse biological behavior, derived from cells of the neuroendocrine system, the system APUD (amine precursor uptake and decarboxylation). They are characterized by overexpression of all five somatostatin receptors (SSTR1-SSTR5), particularly type 2 (SST2). Surgical resection of the tumor is the treatment option, with a possibility of complete remission in patients with limited disease. Somatostatin analogs (octreotide and lanreotide) are the treatment of choice in patients with residual disease, particularly when it comes to NET non-pancreatic origin. Systemic chemotherapy is administered primarily to patients with poorly differentiated carcinomas. PRRT treatment is recommended in case of non-responsiveness of the disease. The ideal candidates for PRRT are patients with unresectable disease of high and intermediate differentiation. Somatostatine analogs radiolabelled with Indium-111 ((111)In), Yttrium-90 ((90)Y), Lutetium-177 ((177)Lu) and Bismuth-213 ((213)Bi), are selectively concentrated in the tumor cells, causing maximum tissue damage to tumors and with fewer effects on healthy tissue and the immune system. In the current review, it was demonstrated that patients with unresectable grade 1 or 2 disease showed increased PFS (progression free survival) and OS (overall survival), while quality of life was improved after PRRT treatment as compared to somatostatin analogs, chemotherapy and other targeted therapies. PMID:27035909

  4. GEP- NETS UPDATE: Genetics of neuroendocrine tumors.

    PubMed

    Crona, Joakim; Skogseid, Britt

    2016-06-01

    Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms, arising from neuroendocrine cells that are dispersed throughout the body. Around 20% of NETs occur in the context of a genetic syndrome. Today there are at least ten recognized NET syndromes. This includes the classical syndromes: multiple endocrine neoplasias types 1 and 2, and von Hippel-Lindau and neurofibromatosis type 1. Additional susceptibility genes associated with a smaller fraction of NETs have also been identified. Recognizing genetic susceptibility has proved essential both to provide genetic counseling and to give the best preventive care. In this review we will also discuss the knowledge of somatic genetic alterations in NETs. At least 24 genes have been implicated as drivers of neuroendocrine tumorigenesis, and the overall rates of genomic instability are relatively low. Genetic intra-tumoral, as well as inter-tumoral heterogeneity in the same patient, have also been identified. Together these data point towards the common pathways in NET evolution, separating early from late disease drivers. Although knowledge of specific mutations in NETs has limited impact on actual patient management, we predict that in the near future genomic profiling of tumors will be included in the clinical arsenal for diagnostics, prognostics and therapeutic decisions. PMID:27165966

  5. Surgical management of pancreatic neuroendocrine tumors.

    PubMed

    Kimura, Wataru; Tezuka, Koji; Hirai, Ichiro

    2011-10-01

    This study outlines the surgical management and clinicopathological findings of pancreatic neuroendocrine tumors (P-NETs). There are various surgical options, such as enucleation of the tumor, spleen-preserving distal pancreatectomy, distal pancreatectomy with splenectomy, pancreatoduodenectomy, and duodenum-preserving pancreas head resection. Lymph node dissection is performed for malignant cases. New guidelines and classifications have been proposed and are now being used in clinical practice. However, there are still no clear indications for organ-preserving pancreatic resection or lymph node dissection. Hepatectomy is the first choice for liver metastases of well-differentiated neuroendocrine carcinoma without extrahepatic metastases. On the other hand, cisplatin-based combination therapy is performed as first-line chemotherapy for metastatic poorly differentiated neuroendocrine carcinoma. Other treatment options are radiofrequency ablation, transarterial chemoembolization/embolization, and liver transplantation. Systematic chemotherapy and biotherapy, such as that with somatostatin analogue and interferon-α, are used for recurrence after surgery. The precise surgical techniques for enucleation of the tumor and spleen-preserving distal pancreatectomy are described. PMID:21922354

  6. Colorectal poorly differentiated neuroendocrine carcinomas frequently exhibit BRAF mutations and are associated with poor overall survival.

    PubMed

    Olevian, Dane C; Nikiforova, Marina N; Chiosea, Simon; Sun, Weijing; Bahary, Nathan; Kuan, Shih-Fan; Pai, Reetesh K

    2016-03-01

    The molecular alterations in colorectal poorly differentiated neuroendocrine carcinoma remain incompletely characterized, particularly with respect to mutations in BRAF and KRAS. We analyzed 32 colorectal poorly differentiated neuroendocrine carcinomas and 40 colorectal poorly differentiated conventional adenocarcinomas for mutations in KRAS and BRAF and for DNA mismatch repair protein abnormalities to correlate histopathology with molecular alterations and survival. Compared with poorly differentiated conventional adenocarcinoma, poorly differentiated neuroendocrine carcinoma frequently harbored BRAF mutations (59% versus 5%; P < .001) and less frequently demonstrated KRAS codon 12 or 13 mutations (17% versus 43%; P = .03). BRAF mutations were identified in both pure poorly differentiated neuroendocrine carcinoma (60%) and poorly differentiated neuroendocrine carcinoma associated with a signet ring cell adenocarcinoma component (82%). Most (93%) poorly differentiated neuroendocrine carcinomas demonstrated proficient DNA mismatch repair by either microsatellite instability polymerase chain reaction or DNA mismatch repair immunohistochemistry. Patients with poorly differentiated neuroendocrine carcinoma had a significantly worse overall survival compared with patients with poorly differentiated conventional adenocarcinoma (P < .001). There was no significant difference in overall survival between patients with pure poorly differentiated neuroendocrine carcinoma and patients with both poorly differentiated neuroendocrine carcinoma and adenocarcinoma components (P = .5). In conclusion, colorectal poorly differentiated neuroendocrine carcinomas frequently harbor BRAF mutations and are associated with poor overall survival. PMID:26826419

  7. Canine neuroendocrine carcinoma. A tumor resembling histiocytoma.

    PubMed

    Nickoloff, B J; Hill, J; Weiss, L M

    1985-12-01

    The clinical and light- and electron microscopic features of 20 cases of canine neuroendocrine carcinoma, initially classified as atypical histiocytomas, are reported. The locally expansile well-circumscribed dermal tumor nodules were composed of solid masses of cells with high mitotic index and multinucleation, arranged in a trabecular pattern with prominent fibrovascular connective tissue stroma rich in reticulin fibers that outlined compact cell nests. Ultrastructural studies revealed evenly dispersed chromatin, focally indented nuclei and abundant cytoplasm with perinuclear filaments, membrane-bound dense core granules, and prominent interdigitating plasma membrane projections with primitive intercellular junctions. Clinical and pathological comparisons between canine neuroendocrine carcinoma, canine histiocytomas, and human Merkel cell neoplasms are discussed. PMID:4091229

  8. [Update of pathological diagnosis of pulmonary neuroendocrine tumor].

    PubMed

    Xiaodong, Teng; Ming, Zhao; Maode, Lai

    2016-05-25

    Pulmonary neuroendocrine tumors are common in pathological practice and its pathological classification and histological grading are not exactly the same as that of those in the digestive tract and pancreas. In 2015 edition of World Health Organization classification, pulmonary neuroendocrine tumors are classified as carcinoid tumors (including typical carcinoid and atypical carcinoid), small cell lung carcinoma, large cell neuroendocrine carcinoma, and precursor lesion diffuse idiopathic neuroendocrine cell hyperplasia; each category has distinctive morphological and immunohistochemical features. The morphologic features including growth patterns and cytological appearances are keys for the diagnosis of neuroendocrine tumor, and immunohistochemical findings are also critical for its diagnosis. Furthermore, the diagnostic criteria vary for different types of specimen. In this article, we present a concise review and summary of the update of clinicopathological characterizations of pulmonary neuroendocrine tumor, with an emphasis on its diagnostic criteria and differential diagnosis. PMID:27045239

  9. Octreotide and Lanreotide in Gastroenteropancreatic Neuroendocrine Tumors.

    PubMed

    Pokuri, Venkata K; Fong, Mei Ka; Iyer, Renuka

    2016-01-01

    Neuroendocrine tumors are heterogeneous, rare malignancies that arise most commonly in the gastrointestinal tract and pancreas. They often secrete vasoactive substances resulting in carcinoid syndrome and the tumor cells exclusively express somatostatin receptors. Octreotide and lanreotide are the two synthetic somatostatin analogs used for the control of carcinoid symptoms and tumor progression in advanced inoperable disease. Recent pivotal trials (PROMID and CLARINET studies) established their antitumor activity. We discuss the available data to support their use as symptom controlling and antiproliferative agents. This article also reviews the guidelines (National Comprehensive Cancer Network and North American Neuro Endocrine Tumor Society), cost-analysis (suggesting the cost-effectiveness of lanreotide autogel compared to higher doses of octreotide long acting release formulation in refractory patients), and future directions of somatostatin analogs in the management of patients refractory to conventional doses of octreotide and lanreotide. PMID:26743514

  10. Pulmonary neuroendocrine tumors with nuclear inclusion.

    PubMed

    Kobayashi, Saori; Tsuta, Koji; Sekine, Shigeki; Yoshida, Akihiko; Sasaki, Naoshi; Shibuki, Yasuo; Sakurai, Hiroyuki; Watanabe, Shun-Ichi; Asamura, Hisao; Tsuda, Hitoshi

    2013-09-01

    Nuclear inclusion or pseudoinclusion is a peculiar cytological feature, and its recognition in appropriate clinicopathological settings can aid in the diagnosis of several disease entities. To the best of our knowledge, only 1 case of pulmonary neuroendocrine tumor (NET) with nuclear pseudoinclusion has been reported. A review of 227 patients who had undergone surgical resection for pulmonary NETs revealed 2 tumors with different mechanisms of nuclear inclusion. To explore the cause of nuclear inclusion, NET with nuclear inclusion was characterized immunohistochemically and ultrastructurally. Nuclear inclusions were observed in 2 of the 227 (0.9%) patients with pulmonary NETs. The first patient was a 46-year-old woman with small cell carcinoma. Tumor cells with nuclear inclusions were distributed focally. Ultrastructural analysis showed that these inclusions were pseudoinclusions. The second patient was a 62-year-old man with large-cell neuroendocrine carcinoma. Nuclear inclusions were observed in the focal area of the tumor. Immunohistochemical analysis revealed that the intra-nuclear materials consisted of biotin and aberrant cytoplasmic and nuclear accumulation of β-catenin. Mutational analysis revealed a CTNNB1 gene mutation. Although very rare, diagnostic errors may be observed in cases of pulmonary NETs with nuclear inclusions. The mechanisms of nuclear inclusion differed, with one due to herniation of the cytoplasm into the nucleus (pseudoinclusion) and the other due to accumulation of biotin resulting from a CTNNB1 gene mutation. PMID:23896262

  11. Therapy for metastatic pancreatic neuroendocrine tumors

    PubMed Central

    Massironi, Sara; Conte, Dario; Peracchi, Maddalena

    2014-01-01

    Background Pancreatic neuroendocrine tumors (pNETs) are frequently malignant (50-80%, except for insulinoma) and may show an aggressive course with metastases to the liver as well as more distant sites. These heterogeneous neoplasms include functioning tumors, which secrete a variety of peptide hormones, and non-functioning tumors (up to 90% of pNETs), which often show metastases at the time of diagnosis. Methods A PubMed search was performed for English-language publications from 1995 through December 2012. Reference lists from studies selected were manually searched to identify further relevant reports. Manuscripts comparing different therapeutic options and advances for metastatic pNETs were selected. Results The therapeutic options for metastatic pNETs are expanding and include surgery, which remains the only curative approach, liver-directed therapies, and medical therapy. In selected cases also liver transplantation (OLT) may be considered. The option of OLT for metastatic disease is unique to neuroendocrine tumors. Recently, novel promising targeted therapies have been proposed for progressive well-differentiated pNETs. Conclusions The best therapeutic approach for pNETs is still matter of debating. However, since pNETs often show a more indolent behavior compared to other malignancies, the preservation of the quality of life of the patient and the personalization of the therapy according to tumor’s and patient’s features are mandatory. PMID:25332984

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

    ClinicalTrials.gov

    2016-03-18

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

  13. Management of gastric and duodenal neuroendocrine tumors

    PubMed Central

    Sato, Yuichi; Hashimoto, Satoru; Mizuno, Ken-ichi; Takeuchi, Manabu; Terai, Shuji

    2016-01-01

    Gastrointestinal neuroendocrine tumors (GI-NETs) are rare neoplasms, like all NETs. However, the incidence of GI-NETS has been increasing in recent years. Gastric NETs (G-NETs) and duodenal NETs (D-NETs) are the common types of upper GI-NETs based on tumor location. G-NETs are classified into three distinct subgroups: type I, II, and III. Type I G-NETs, which are the most common subtype (70%-80% of all G-NETs), are associated with chronic atrophic gastritis, including autoimmune gastritis and Helicobacter pylori associated atrophic gastritis. Type II G-NETs (5%-6%) are associated with multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome (MEN1-ZES). Both type I and II G-NETs are related to hypergastrinemia, are small in size, occur in multiple numbers, and are generally benign. In contrast, type III G-NETs (10%-15%) are not associated with hypergastrinemia, are large-sized single tumors, and are usually malignant. Therefore, surgical resection and chemotherapy are generally necessary for type III G-NETs, while endoscopic resection and follow-up, which are acceptable for the treatment of most type I and II G-NETs, are only acceptable for small and well differentiated type III G-NETs. D-NETs include gastrinomas (50%-60%), somatostatin-producing tumors (15%), nonfunctional serotonin-containing tumors (20%), poorly differentiated neuroendocrine carcinomas (< 3%), and gangliocytic paragangliomas (< 2%). Most D-NETs are located in the first or second part of the duodenum, with 20% occurring in the periampullary region. Therapy for D-NETs is based on tumor size, location, histological grade, stage, and tumor type. While endoscopic resection may be considered for small nonfunctional D-NETs (G1) located in the higher papilla region, surgical resection is necessary for most other D-NETs. However, there is no consensus regarding the ideal treatment of D-NETs. PMID:27570419

  14. Management of gastric and duodenal neuroendocrine tumors.

    PubMed

    Sato, Yuichi; Hashimoto, Satoru; Mizuno, Ken-Ichi; Takeuchi, Manabu; Terai, Shuji

    2016-08-14

    Gastrointestinal neuroendocrine tumors (GI-NETs) are rare neoplasms, like all NETs. However, the incidence of GI-NETS has been increasing in recent years. Gastric NETs (G-NETs) and duodenal NETs (D-NETs) are the common types of upper GI-NETs based on tumor location. G-NETs are classified into three distinct subgroups: type I, II, and III. Type I G-NETs, which are the most common subtype (70%-80% of all G-NETs), are associated with chronic atrophic gastritis, including autoimmune gastritis and Helicobacter pylori associated atrophic gastritis. Type II G-NETs (5%-6%) are associated with multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome (MEN1-ZES). Both type I and II G-NETs are related to hypergastrinemia, are small in size, occur in multiple numbers, and are generally benign. In contrast, type III G-NETs (10%-15%) are not associated with hypergastrinemia, are large-sized single tumors, and are usually malignant. Therefore, surgical resection and chemotherapy are generally necessary for type III G-NETs, while endoscopic resection and follow-up, which are acceptable for the treatment of most type I and II G-NETs, are only acceptable for small and well differentiated type III G-NETs. D-NETs include gastrinomas (50%-60%), somatostatin-producing tumors (15%), nonfunctional serotonin-containing tumors (20%), poorly differentiated neuroendocrine carcinomas (< 3%), and gangliocytic paragangliomas (< 2%). Most D-NETs are located in the first or second part of the duodenum, with 20% occurring in the periampullary region. Therapy for D-NETs is based on tumor size, location, histological grade, stage, and tumor type. While endoscopic resection may be considered for small nonfunctional D-NETs (G1) located in the higher papilla region, surgical resection is necessary for most other D-NETs. However, there is no consensus regarding the ideal treatment of D-NETs. PMID:27570419

  15. Recurrent gastric neuroendocrine tumors treated with total gastrectomy

    PubMed Central

    Jung, Myounghwa; Kim, Jung-Wook; Jang, Jae-Young; Chang, Young Woon; Park, Sun Hee; Kim, Yong Ho; Kim, Youn Wha

    2015-01-01

    Gastric neuroendocrine tumors are rare; however, the incidence has recently increased due to the increasing use of upper endoscopy. Neuroendocrine tumors arise from the excess proliferation of enterochromaffin-like (ECL) cells. The proliferative changes of enterochromaffin cells evolve through a hyperplasia-dysplasia-neoplasia sequence that is believed to underlie the pathogenesis of gastric neuroendocrine tumors. Endoscopic resection is recommended as the initial treatment if the tumor is not in an advanced stage. However, there is no definite guideline for the treatment of recurrent gastric neuroendocrine tumors following endoscopic resection. Here, we report a rare case of gastric neuroendocrine tumors in a 56-year-old male who experienced two recurrences within 11 years after endoscopic resection. The patient finally underwent a total gastrectomy. The pathological features of the resected stomach exhibited the full hyperplasia-dysplasia-neoplasia sequence of the ECL cells in a single specimen. PMID:26675502

  16. Endoscopic Ultrasound in Gastroenteropancreatic Neuroendocrine Tumors

    PubMed Central

    2012-01-01

    Endoscopic ultrasound (EUS) is an advanced endoscopic technique currently used in the staging and diagnosis of many gastrointestinal neoplasms. The proximity of the echoendoscope to the gastrointestinal tract lends itself to a detailed view of the luminal pathology and the pancreas. This unique ability enables endoscopists to use EUS in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Diagnostic EUS allows previously unidentified NETs to be localized. EUS also determines tumor management by staging the GEP-NETS, enabling the clinicians to choose the appropriate endoscopic or surgical management. The ability to obtain a tissue diagnosis with EUS guidance enables disease confirmation. Finally, recent developments suggest that EUS may be used to deliver therapeutic agents for the treatment of NETs. This review will highlight the advances in our knowledge of EUS in the clinical management of these tumors. PMID:23170141

  17. Primary Neuroendocrine Tumors of the Ureter: A Short Review.

    PubMed

    Acosta, Andres M; Kajdacsy-Balla, Andre

    2016-07-01

    Neuroendocrine tumors represent 0.05% of urinary tract malignancies, and most originate in the bladder. Their pathogenesis is debated, since ureters are thought to lack neuroendocrine cells. Morphologically, most ureteral neuroendocrine tumors demonstrate the typical small cell neuroendocrine appearance, are immunohistochemically positive for synaptophysin/chromogranin A/CD56, and show electron-dense granules by electron microscopy. Clinical presentation is similar to that of other more common ureteral neoplasms. Prognosis is usually dismal, but a multimodal treatment approach including platinum-based adjuvant or neoadjuvant chemotherapy seems to be beneficial. PMID:27362572

  18. TNM Staging of Pancreatic Neuroendocrine Tumors

    PubMed Central

    Yang, Min; Zeng, Lin; Zhang, Yi; Wang, Wei-guo; Wang, Li; Ke, Neng-wen; Liu, Xu-bao; Tian, Bo-le

    2015-01-01

    Abstract We aimed to analyze the clinical characteristics and compare the surgical outcome of pancreatic neuroendocrine tumors (p-NETs) using the 2 tumor-node-metastasis (TNM) systems by both the American Joint Committee on Cancer (AJCC) Staging Manual (seventh edition) and the European Neuroendocrine Tumor Society (ENETS). Moreover, we sought to validate the prognostic value of the new AJCC criterion. Data of 145 consecutive patients who were all surgically treated and histologically diagnosed as p-NETs from January 2002 to June 2013 in our single institution were retrospectively collected and analyzed. The 5-year overall survival (OS) rates for AJCC classifications of stages I, II, III, and IV were 79.5%, 63.1%, 15.0%, and NA, respectively, (P < 0.005). As for the ENETS system, the OS rates at 5 years for stages I, II, III, and IV were 75.5%, 72.7%, 29.0%, and NA, respectively, (P < 0.005). Both criteria present no statistically notable difference between stage I and stage II (P > 0.05) but between stage I and stages III and IV (P < 0.05), as well as those between stage II and stages III and IV (P < 0.05). Difference between stage III and IV by ENETS was significant (P = 0.031), whereas that by the AJCC was not (P = 0.144). What's more, the AJCC Staging Manual (seventh edition) was statistically significant in both uni- and multivariate analyses by Cox regression (P < 0.005 and P = 0.025, respectively). Our study indicated that the ENETS TNM staging system might be superior to the AJCC Staging Manual (seventh edition) for the clinical practice of p-NETs. Together with tumor grade and radical resection, the new AJCC system was also validated to be an independent predictor for p-NETs. PMID:25816036

  19. Genomic landscape of pancreatic neuroendocrine tumors

    PubMed Central

    Gebauer, Niklas; Schmidt-Werthern, Christian; Bernard, Veronica; Feller, Alfred C; Keck, Tobias; Begum, Nehara; Rades, Dirk; Lehnert, Hendrik; Brabant, Georg; Thorns, Christoph

    2014-01-01

    AIM: To investigate the prognostic role of genomic stability and copy number alterations (CNAs) pancreatic neuroendocrine tumors (PanNETs). METHODS: A high-resolution array-based comparative genomic hybridization approach was utilized in order to investigate and quantify chromosomal aberrations in a panel of 37 primary PanNET and 11 metastatic samples. DNA samples were extracted from formalin-fixed and paraffin-embedded tumor specimen. Genomic findings were correlated with histopathological and immunohistochemical data. Moreover, the dataset was subjected to employing an unsupervised hierarchical clustering analysis approach utilizing Euclidean distance and average linkage and associations between genomically defined tumor groups and recurrent CNAs or clinicopathological features of the study group were assessed. RESULTS: Numerous chromosomal aberrations were recurrently detected in both, primary tumor samples and metastases. Copy number gains were most frequently observed at 06p22.2-p22.1 (27.1%), 17p13.1 (20.8%), 07p21.3-p21.2 (18.8%), 09q34.11 (18.8%). Genomic losses were significantly less frequent and the only recurrent aberration affected 08q24.3 (6.3%). Moreover, we detected a high degree of genomic heterogeneity between primary tumors and metastatic lesions. Unsupervised hierarchical clustering of loci affected by CNAs in more than 3 primary tumor samples revealed two genetically distinct tumor groups as well as two chromosomal clusters of genomic imbalances indicating a small subset of tumors with common molecular features (13.5%). Aberrations affecting 6p22.2-22.1, 8q24.3, 9q34.11 and 17p13.1 (P = 0.011; 0.003; 0.003; 0.001), were significantly associated with a poorer survival prognosis. CONCLUSION: This study suggests that several frequent CNAs in numerous candidate regions are involved in the pathogenesis and metastatic progression of PanNET. PMID:25516664

  20. [Tumor markers for colorectal cancer].

    PubMed

    Yamamoto, H; Miyake, Y; Noura, S; Ogawa, M; Yasui, M; Ikenaga, M; Sekimoto, M; Monden, M

    2001-09-01

    CEA and CA19-9 are the two most common tumor markers for colorectal cancer that are currently utilized clinically. The positive rate of CEA is 40-60% and that of CA19-9 is 30-50%. Simultaneous use of the two markers is useful in evaluating the therapeutic effect and monitoring the recurrence of advanced colorectal cancer. Surgical specimens may also provide useful information for the appropriate treatment of patients. Using surgically resected lymph nodes, we examined micrometastasis to assess the spread of the cancer cells and the malignant potential of colorectal cancer. Immunohistochemical analysis using anti-cytokeratin antibody revealed no significant impact of micrometastasis on patient prognosis, while RT-PCR assay using CEA as a genetic marker suggested a positive value in predicting a rapid recurrence. Among various molecular markers, we found that CDC25B phosphatase was a powerful prognostic factor for colorectal cancer. Diagnosis of the existence and malignant potential of cancer cells, together with serum tumor marker levels, may help to construct a more useful system for the better treatment of colorectal cancer. PMID:11579645

  1. Diagnosis of functioning pancreaticoduodenal neuroendocrine tumors.

    PubMed

    Imamura, Masayuki; Nakamoto, Yuji; Uose, Suguru; Komoto, Izumi; Awane, Masaaki; Taki, Yoshiro

    2015-08-01

    Functioning pancreaticoduodenal neuroendocrine tumors (PD-NETs) are popular in a textbook, but they are still unfamiliar to a general clinician, and delay of diagnosis or misdiagnosis has been reported even today. It is a consensus that sporadic functioning PD-NET is cured only by surgical resection. So, early detection and early resection is the gold standard for the treatment of functioning PD-NET. Functioning PD-NETs in patients with multiple endocrine neoplasia type 1 (MEN 1) are often multiple. You should check about MEN 1 whenever you encountered multiple PD-NET. They are diagnosed in younger age than sporadic cases. In most cases they are accompanied with numerous microscopic or macroscopic nonfunctioning P-NETs, which are potentially metastatic and the most common cause of death in MEN 1 patients. PMID:25624017

  2. Multidisciplinary management of advanced lung neuroendocrine tumors

    PubMed Central

    Ferolla, Piero; Guerrera, Francesco; Ruffini, Enrico; Travis, William D.; Rossi, Giulio; Lausi, Paolo Olivo; Oliaro, Alberto

    2015-01-01

    The optimal clinical management of aggressive/advanced lung neuroendocrine tumors (NETs) is still debated, due to their rarity and the lack of prospective randomized studies. Results derive from retrospective mono-Institutional series, and few dedicated prospective trials, recently designed, are still ongoing. In low-grade tumors [bronchial carcinoids (BCs)] surgery, whenever feasible, remains the mainstay of treatment, and chemo/radiotherapy (RT) should be reserved to progressive diseases (PD). In case of resected N1-N2 BCs, a “watch and see” policy associated with a close clinical/radiological follow-up is recommended. Somatostatin analogs (SSA) seem to be effective in controlling BCs associated endocrine syndromes, while SSA antiproliferative effect has also been reported in the past. Targeted therapy with new drugs (Everolimus) seems to be very promising, but further trials are needed. Surgery alone is not sufficient to treat high-grade NETs: adjuvant CT is required also in early stages. Platinum-Etoposide regimen demonstrated to be the most effective; irinotecan and other biological drugs are considered very promising. In conclusion, the management of advanced lung NETs should be individualized by multidisciplinary teams which include Medical and Radiation Oncologists, Surgeons, Pathologists, Pulmonologists, Endocrinologists, Interventional Radiologists, and the prognosis is mainly dependent on tumor grade and its anatomical extent. PMID:25984363

  3. [Management of metabolic disorders induced by everolimus in patients with differentiated neuroendocrine tumors: expert proposals].

    PubMed

    Lombard-Bohas, Catherine; Cariou, Bertrand; Vergès, Bruno; Coriat, Romain; N'guyen, Thierry; François, Eric; Hammel, Pascal; Niccoli, Patricia; Hentic, Olivia

    2014-02-01

    Medical management of pancreatic neuroendocrine tumors has recently been improved by new molecules of which the mTOR inhibitor everolimus. If digestive neuroendocrine tumors are rare, the incidence is in constant increase and the prevalence in digestive cancers put them right behind colorectal cancers. Everolimus has demonstrated efficacy in unresectable and progressive pancreatic neuroendocrine tumors, by doubling the median progression free survival (11 versus 4.6 months), with a median time of exposure to everolimus of nine months. Everolimus is generally maintained until progression or intolerance and some patients are treated during several years. Potential metabolic disorders induced by everolimus (dyslipidemia, hyperglycemia) in patients with life expectancy of several years, justify monitoring of these parameters and accurate treatment management algorithm. These will avoid worsening patient's prognostic, but also prematurely discontinue potentially effective treatment or contraindicate other therapeutic weapons, in a pathology in which there are multiple therapeutic options in metastatic phase. We propose a standard practice in terms of initial assessment, monitoring, care threshold, and therapeutic objectives to manage metabolic disorders, fitted to our patients with advanced pancreatic neuroendocrine tumors. PMID:24557872

  4. A case of rectal neuroendocrine tumor presenting as polyp

    PubMed Central

    RAKICI, Halil; AKDOGAN, Remzi Adnan; YURDAKUL, Cüneyt; CANTURK, Neşe

    2015-01-01

    Neuroendocrine tumor (NET) is detected in the examination of polypectomy material, presenting as rectal polyp. Since this is a rare case, we aimed to summarize the approach to rectal NET’s. PMID:25625492

  5. Octreoscan SPET evaluation in the diagnosis of pancreas neuroendocrine tumors.

    PubMed

    Briganti, V; Matteini, M; Ferri, P; Vaggelli, L; Castagnoli, A; Pieroni, C

    2001-12-01

    The study describes the results of Octreoscan SPET (OCTSPET) qualitative and semi-quantitative evaluation in 38 patients with suspected pancreatic neuroendocrine tumors. SPET studies were acquired at 4 and 24 hours after the injection of 111-220 MBq of 111-In-pentetreotide (Octreoscan). Qualitative and semi-quantitative evaluations were performed. The semi-quantitative approach was based on the time course of Tumor/Non Tumor ratios (TNTinc) from 4 and 24 hours. The OCTSPET results were true positive in 18 of 19 patients (10 gastrinoma, 5 insulinoma, 1 neuroendocrine tumor, 1 glucagonoma and 1 carcinoid) and false negative in one insulinoma. Besides, 20 of 38 patients (52%) had clinical plans modified after OCTSPET; OCTSPET was the only positive diagnostic test in 14 of 19 patients (73%) and guided the surgery decision in 14 of 25 patients (56%). In conclusion, these data indicate that Octreoscan represents an excellent tool for the diagnosis of pancreatic neuroendocrine tumors. PMID:11789028

  6. Nonlinear optical microscopy for label-free detection of gastrointestinal neuroendocrine tumors.

    PubMed

    Li, Lianhuang; Jiang, Liwei; Chen, Zhifen; Kang, Deyong; Yang, Zhenrong; Liu, Xing; Jiang, Weizhong; Zhuo, Shuangmu; Guan, Guoxian; Zhou, Yongjian; Chen, Jianxin

    2016-09-01

    Neuroendocrine tumors (NETs), which are rare and slow-growing neoplasms, pose a diagnostic challenge as they are clinically silent at the time of presentation. Here, gastrointestinal neuroendocrine tumors were researched by nonlinear microscopy, and results demonstrate that this technique has the capability to identify neuroendocrine tumors in the absence of labels and can, in particular, detect rare neuroendocrine tumor cells, vascular invasion, desmoplastic reaction, and fibroelastosis induced by neuroendocrine tumors. These conclusions highlight the possibility of nonlinear optical microscopy as a diagnostic tool for label-freely differentiating neuroendocrine tumors by these histopathologic features. PMID:27299572

  7. Molecular characteristics and predictors of survival in patients with malignant neuroendocrine tumors

    PubMed Central

    Arnold, Christian N.; Nagasaka, Takeshi; Goel, Ajay; Scharf, Iris; Grabowski, Patricia; Sosnowski, Andrea; Schmitt-Gräff, Annette; Boland, C. Richard; Arnold, Rudolf; Blum, Hubert E.

    2010-01-01

    To better understand the molecular pathogenesis of neuroendocrine tumors (NET), we investigated the molecular and clinical characteristics of malignant poorly differentiated colorectal NET and compared these findings with sporadic CRC and well-differentiated benign and malignant fore-/midgut NET. Tumors were analyzed and correlated for microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP). NET were scored for proliferation using Ki-67. A total of 34 malignant poorly differentiated colorectal NET, 38 well-differentiated benign and malignant fore-/midgut-NET and 150 sporadic colorectal cancers (CRC) with known MSI status were investigated. Among the sporadic CRC, CIMP was significantly correlated with MSI-high (MSI-H) (p < 0.001). Of the 34 colorectal NET, 0/1 of the MSI-H, 3/5 (60%) of the MSI-L and 13/19 (68%) of the MSS tumors were CIMP+ (p = 0.17). Of the fore-/midgut-NET, none was MSI-H. 20/34 (59%) colorectal NET vs. 11/38 (29%) fore-/midgut-NET were CIMP+ (p = 0.01). The Ki-67 index was significantly higher in poorly differentiated colorectal NET compared to the less malignant fore-/midgut-NET (p < 0.0001). Besides the location in the colon, Ki-67 predicted poor outcome in NET (p < 0.0001). CIMP status did not affect survival. In NET, p16 methylation predicted a poor outcome (p = 0.0004). We conclude that molecular pathogenesis in sporadic CRC and poorly differentiated colorectal NET is different despite some similarities. Main differences between malignant well-differentiated and poorly differentiated NET are the Ki-67 proliferation rate and differential methylation in tumor-associated genes. Predictors of a poor outcome in patients with NET are poor differentiation, a high Ki-67 index and p16 methylation. PMID:18646189

  8. [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. PMID:23009947

  9. Primary hepatic neuroendocrine tumor: A case report and literature review.

    PubMed

    Song, Jeong Eun; Kim, Byung Seok; Lee, Chang Hyeong

    2016-08-16

    Primary hepatic neuroendocrine tumors (PHNETs) are extremely rare and difficult to distinguish from other liver tumors, such as hepatocellular carcinoma (HCC) and cholangiocarcinoma, based on medical imaging findings. A 70-year-old man was referred for evaluation of liver mass incidentally discovered on abdominal computed tomography. The characteristic finding from dynamic liver magnetic resonance imaging led to a diagnosis of HCC. The patient underwent right hepatectomy. Histopathological and immunohistochemical examination revealed grade 2 neuroendocrine tumor. The postoperative 24-h urinary excretion of 5-hydroxy-indolacetic acid was within the normal range. Further imaging investigations were performed. No other lesions were found making probable the diagnosis of PHNET. This case shows that the diagnosis of PHNET is a medical challenge, requiring differentiation of PHNETs other hepatic masses and exclusion of occult primary neuroendocrine tumors. The diagnosis of PHNET can be ascertained after long term follow-up to exclude another primary origin. PMID:27574614

  10. Primary hepatic neuroendocrine tumor: A case report and literature review

    PubMed Central

    Song, Jeong Eun; Kim, Byung Seok; Lee, Chang Hyeong

    2016-01-01

    Primary hepatic neuroendocrine tumors (PHNETs) are extremely rare and difficult to distinguish from other liver tumors, such as hepatocellular carcinoma (HCC) and cholangiocarcinoma, based on medical imaging findings. A 70-year-old man was referred for evaluation of liver mass incidentally discovered on abdominal computed tomography. The characteristic finding from dynamic liver magnetic resonance imaging led to a diagnosis of HCC. The patient underwent right hepatectomy. Histopathological and immunohistochemical examination revealed grade 2 neuroendocrine tumor. The postoperative 24-h urinary excretion of 5-hydroxy-indolacetic acid was within the normal range. Further imaging investigations were performed. No other lesions were found making probable the diagnosis of PHNET. This case shows that the diagnosis of PHNET is a medical challenge, requiring differentiation of PHNETs other hepatic masses and exclusion of occult primary neuroendocrine tumors. The diagnosis of PHNET can be ascertained after long term follow-up to exclude another primary origin. PMID:27574614

  11. Imaging in neuroendocrine tumors: an update for the clinician

    PubMed Central

    Maxwell, Jessica E; Howe, James R

    2015-01-01

    Neuroendocrine tumors are a heterogeneous group of neoplasms that are best worked up and managed using a variety of clinical and imaging studies. They are often diagnosed after they have already metastasized, though this does not necessarily preclude an attempt at curative surgical treatment or surgical debulking. Tumor burden assessment often requires use of multiple imaging modalities including computed tomography, magnetic resonance imaging and ultrasound. Somatostatin receptor-based imaging is also of great utility in looking for primaries and determining the extent of metastatic disease. This paper will review the most common imaging modalities used in the diagnosis and treatment of neuroendocrine tumors. PMID:26257863

  12. Rectal neuroendocrine tumor with uncommon metastatic spread: A case report and review of literature

    PubMed Central

    Tsoukalas, Nikolaos; Galanopoulos, Michail; Tolia, Maria; Kiakou, Maria; Nakos, Georgios; Papakostidi, Aristoula; Koumakis, Georgios

    2016-01-01

    Neuroendocrine tumors of the gastrointestinal tract are rare neoplasms. Rectal neuroendocrine tumors consist approximately the 5%-14% of all neuroendocrine neoplasms in Europe. These tumors are diagnosed in relatively young patients, with a mean age at diagnosis of 56 years. Distant metastases from rectal neuroendocrine tumors are not very common. Herein we describe a case of a rectal neuroendocrine tumor which metastasized to the lung, mediastinum and orbit. This case underscores the importance of early identification and optimal management to improve patient’s prognosis. Therefore, the clinical significance of this case is the necessity of physicians’ awareness and education regarding neuroendocrine tumors’ diagnosis and management. PMID:26909138

  13. Future Directions in the Biology of Neuroendocrine Tumors.

    PubMed

    Halperin, Daniel M; Dasari, Arvind; Yao, James C

    2016-07-01

    The neuroendocrine field is experiencing an ever-accelerating expansion of data about the makeup of these tumors whose biology has long been opaque. Genome sequencing and epigenetic data regarding copy number variations, methylation events, and expression profiling are increasingly available for small bowel and pancreatic neuroendocrine tumors. However, in addition to building larger and more robust genetic and epigenetic datasets, the remaining challenge is moving beyond the data toward meaningful information, knowledge, and wisdom. Herein, we will offer perspectives on the existing data and thoughts on future directions. PMID:27295529

  14. Neuroendocrine tumors involving the gastroenteropancreatic tract: a clinicopathological evaluation of 773 cases

    PubMed Central

    Estrozi, Bruna; Bacchi, Carlos E

    2011-01-01

    OBJECTIVE: Description of some of the clinical pathological characteristics of neuroendocrine tumors of the gastroenteropancreatic tract in Brazilian patients. INTRODUCTION: Neuroendocrine tumors arise in many organs and share common pathological features. In 2010, the World Health Organization published a new classification for neuroendocrine tumors using a three-tiered system that applies the terms neuroendocrine tumor Grade 1, neuroendocrine tumor Grade 2, and neuroendocrine carcinoma. The tumor grades are based on their mitotic rate and the Ki-67 index. In Brazil, information on neuroendocrine tumors of gastroenteropancreatic tract is scarce. METHODS: This study investigated clinicopathological features of 773 Brazilian gastroenteropancreatic neuroendocrine tumor cases from all the geographic regions of Brazil. All of the cases emerged from the files of a single institution (a large pathology reference laboratory) between 1997 and 2009. In addition, the gastroenteropancreatic neuroendocrine tumors were graded according to the new 2010 World Health Organization classification. RESULTS: Overall there were a higher number of neuroendocrine tumors in female over male. The lower ages were seen in patients with appendiceal tumors. The most common anatomic location involved was stomach followed by small and large intestines. All cases involving the appendix were of grade 1 and 92.1% of the neuroendocrine tumors of the esophagus were neuroendocrine carcinomas (grade 3). CONCLUSIONS: In this series, the proportion of NET cases in the total number of surgical pathology cases at our institution over the past 12 years is increasing. PMID:22012036

  15. Genomic Aberrations Drive Clonal Evolution of Neuroendocrine Tumors.

    PubMed

    Kaushik, Akash Kumar; Sreekumar, Arun

    2016-05-01

    Molecular features of castration-resistant neuroendocrine prostate cancer (CRPC-NE) are not well characterized. A recent study that investigated genomic aberrations of CRPC-NE tumors suggests their clonal evolution from CRPC adenocarcinoma. Furthermore, the existence of a distinct DNA methylation profile in CRPC-NE implicates a critical role for epigenetic modification in the development of CRPC-NE. PMID:27037211

  16. Capnocytophaga Lung Abscess in a Patient with Metastatic Neuroendocrine Tumor

    PubMed Central

    Thirumala, Raghu; Babady, N. Esther; Kamboj, Mini; Chawla, Mohit

    2012-01-01

    Capnocytophaga species are known commensals of the oral cavity of humans and animals (mainly dogs and cats) and are a rare cause of respiratory tract infections. We report a case of cavitary lung abscess caused by a Capnocytophaga species in a patient with a metastatic neuroendocrine tumor. PMID:22075586

  17. Neuroendocrine tumor of the gallbladder with spectral CT.

    PubMed

    Du, Hai; Zhang, Haoliang; Xu, Yandong; Wang, Li

    2014-12-01

    Neuroendocrine tumors (NETs) are neoplasms that arise from neural crest argyrophil cells, and often occur to the elderly, female and patients with cholelithiasis. In this case, the female patient was 38 years old and admitted into the hospital for interrupted right upward abdominal pain for 2 years plus aggravated with nausea and anorexia for 1 week. Ultrasound showed gallbladder space-occupying lesions and spectral computed tomography (CT) suggested of retroperitoneal lymph node metastasis. The patient was diagnosed with gallbladder neuroendocrine carcinoma after the surgery. PMID:25525590

  18. Neuroendocrine tumor of the gallbladder with spectral CT

    PubMed Central

    Du, Hai; Xu, Yandong; Wang, Li

    2014-01-01

    Neuroendocrine tumors (NETs) are neoplasms that arise from neural crest argyrophil cells, and often occur to the elderly, female and patients with cholelithiasis. In this case, the female patient was 38 years old and admitted into the hospital for interrupted right upward abdominal pain for 2 years plus aggravated with nausea and anorexia for 1 week. Ultrasound showed gallbladder space-occupying lesions and spectral computed tomography (CT) suggested of retroperitoneal lymph node metastasis. The patient was diagnosed with gallbladder neuroendocrine carcinoma after the surgery. PMID:25525590

  19. Familial neuroendocrine tumor syndromes: from genetics to clinical practice.

    PubMed

    Sakurai, Akihiro; Katai, Miyuki; Hashizume, Kiyoshi; Fukushima, Yoshimitsu

    2006-01-01

    Thanks to recent developments in molecular biology and cancer genetics, genetic testing has become widely available and useful in several kinds of familial tumor syndrome. However, the impact of genetic testing on medical management is not always straightforward. Clinicians have to consider the psychological impact and ethical complexities of communicating hereditary cancer risk information to families. This review notes some points on genetic counseling before and after genetic testing for familial neuroendocrine tumor syndromes. PMID:17001463

  20. Establishment and Characterization of a Human Neuroendocrine Tumor Xenograft.

    PubMed

    Yang, Zhaoying; Zhang, Le; Serra, Stefano; Law, Calvin; Wei, Alice; Stockley, Tracy L; Ezzat, Shereen; Asa, Sylvia L

    2016-06-01

    Neuroendocrine tumors (NETs) are increasing in incidence yet the cause of these tumors remains unknown. Familial associations have shed light on the genetic basis of some of these tumors, but sporadic tumors seem to have primarily epigenetic dysregulation. The rarity of cell lines and animal models has been a barrier to studies of treatment modalities. We set out to develop a xenograft model of gastrointestinal NETs. Primary human NETs were collected at the time of surgery under sterile conditions and xenografted into the flanks of immunodeficient mice. Tumor growth was measured and when tumors reached 1500 mm(3), they were excised and half was re-xenografted through multiple generations. The other half was bisected; a part was frozen and a part was fixed for morphologic and immunohistochemical characterization as well as molecular validation of fidelity of a successful xenograft. Of 106 human NETs, seven were successfully engrafted of which only one tumor was successfully propagated for eight passages. Two years later, the tumor retains its neuroendocrine features and similarity to the original primary human tumor. It has retained expression of keratin as well as chromogranin A reactivity. The establishment of a NET xenograft provides a model for further study of the biological behavior of these tumors and can be used to examine the in vivo effects of various medical and targeted radiotherapeutic agents on tumor growth. PMID:27067082

  1. Drug therapy in metastatic neuroendocrine tumors of the gastroenteropancreatic system.

    PubMed

    Faiss, S; Scherübl, H; Riecken, E O; Wiedenmann, B

    1996-01-01

    Successful treatment of neuroendocrine tumor disease of the gastroenteropancreatic system requires a multimodal approach. Radical tumor surgery is required before other therapies are initiated. So far, only surgery has proven to be curative. If surgical intervention is not possible or a tumor-free state cannot be achieved, biotherapy with the somatostatin analogues octreotide or lanreotide should then be preferably carried out in patients with functional tumors. Interferon-alpha can alternatively be given. In patients with gastrinoma, therapy with proton pump inhibitors (e.g., omeprazol) is the initial treatment of choice. In patients with nonfunctional tumors, indication for treatment is only given in cases of documented tumor progress. In case of progressive tumor disease or functionality under the above-mentioned therapies, treatment with somatostatin analogues can be intensified by dose escalation or alternatively by a combination therapy with interferon-alpha and a somatostatin analogue. On the basis of the less favorable response of neuroendocrine foregut tumors to biotherapy, chemotherapy should be initiated after failure of biotherapy in documented tumor progression. A combination of streptozotocin and 5-fluorouracil, possibly combined with D,L-folinic acid, is the treatment of choice, considering the response and side effect rates. In case of predominantly anaplastic neuroendocrine tumors in advanced stages, good tumor response rates with a chemotherapeutic scheme consisting of cisplatin and etoposide can be achieved. Since the chemotherapy scheme is less effective in patients with midgut or hindgut tumors, chemoembolization of liver metastases should follow biotherapy. The response to chemoembolization may be increased by simultaneous systemic chemotherapy. Attention should always be paid to an adequate analgesic drug administration. PMID:8893342

  2. The Tumor Microenvironment in Colorectal Carcinogenesis

    PubMed Central

    Peddareddigari, Vijay G.; Wang, Dingzhi

    2010-01-01

    Colorectal cancer is the second leading cause of cancer-related mortality in the United States. Therapeutic developments in the past decade have extended life expectancy in patients with metastatic disease. However, metastatic colorectal cancers remain incurable. Numerous agents that were demonstrated to have significant antitumor activity in experimental models translated into disappointing results in extending patient survival. This has resulted in more attention being focused on the contribution of tumor microenvironment to the progression of a number of solid tumors including colorectal cancer. A more complete understanding of interactions between tumor epithelial cells and their stromal elements will enhance therapeutic options and improve clinical outcome. Here we will review the role of various stromal components in colorectal carcinogenesis and discuss the potential of targeting these components for the development of future therapeutic agents. PMID:21209781

  3. Multidisciplinary management of nonfunctional neuroendocrine tumor of the pancreas

    PubMed Central

    Folkert, Ian W; Hernandez, Paul; Roses, Robert E

    2016-01-01

    Pancreatic neuroendocrine tumors (PNETs) are a rare and diverse group of tumors; nonfunctional (NF) PNETs account for the majority of cases. Most patients with NF-PNETs have metastatic disease at the time of presentation. A variety of treatment modalities exist, including medical, liver directed, and surgical treatments. Aggressive surgical management is associated with prolonged survival, however available data are limited by selection bias and the frequent combination of PNETs with carcinoid tumors. Although few patients with metastatic disease will be cured, application of currently available therapies in a multidisciplinary setting can lead to excellent outcomes with prolonged patient survival. PMID:27003988

  4. Clinicopathological features of small nonfunctioning pancreatic neuroendocrine tumors

    PubMed Central

    Furukori, Mariko; Imai, Koji; Karasaki, Hidenori; Watanabe, Kenji; Oikawa, Kensuke; Miyokawa, Naoyuki; Taniguchi, Masahiko; Furukawa, Hiroyuki

    2014-01-01

    AIM: To present our experiences in studying the clinicopathological features of small nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs). METHODS: The subjects included 9 patients with NF-pNETs who underwent pancreatectomy between April 1996 and September 2012. The surgical procedure, histopathological findings, and prognosis were assessed. RESULTS: All tumors were incidentally detected by computed tomography. The median diameter was 10 mm (5-32 mm). One patient was diagnosed with von Hippel-Lindau disease, and the others were sporadic cases. For the histopathological findings, 7 patients were G1; 1 patient was G2; and 1 patient, whose tumor was 22 mm, had neuroendocrine carcinoma (NEC). One patient who had a tumor that was 32 mm had direct invasion to a regional lymph node and 1 patient with NEC, had regional lymph node metastases. Six of the 7 patients with sporadic NF-pNETs, excluding the patient with NEC, had tumors that were smaller than 10 mm. Tumors smaller than 10 mm showed no malignancy and lacked lymph node metastasis. CONCLUSION: Sporadic NF-pNETs smaller than 10 mm tend to have less malignant potential. These findings suggest that lymphadenectomy may be omitted for small NF-pNETs after further investigation. PMID:25548493

  5. Hepatic-directed Therapies in Patients with Neuroendocrine Tumors.

    PubMed

    Kennedy, Andrew S

    2016-02-01

    Neuroendocrine tumors (NETs) of the gastrointestinal (GI) tract have a propensity for producing hepatic metastases. Most GI NETs arise from the foregut or midgut, are malignant, and can cause severe debilitating symptoms adversely affecting quality of life. Aggressive treatments to reduce symptoms have an important role in therapy. Patients with GI NETs usually present with inoperable metastatic disease and severe symptoms from a variety of hormones and biogenic amines. This article describes intra-arterial hepatic-directed therapies for metastases from NETs, a group of treatments in which the therapeutic and/or embolic agents are released intra-arterially in specific hepatic vessels to target tumors. PMID:26614377

  6. Secondary neuroendocrine tumor after allogeneic bone marrow transplantation.

    PubMed

    Tamura, Shinichi; Ishida, Hiroyuki; Naito, Takeshi; Kondo, Osamu; Inoue, Masami; Kawa, Keisei; Kawabata, Kenji; Hojo, Hiroshi; Ouchi, Kazutaka; Imamura, Toshihiko

    2015-12-01

    Here we report a case of aggressive neuroendocrine tumor (NET), which is an extremely rare secondary solid tumor that occurs after allogeneic hematopoietic cell transplantation (allo-HSCT). A patient with chronic active Epstein-Barr virus infection received allo-HSCT from an HLA-DR two allele-mismatched unrelated donor. Four years later, he developed NET with multiple metastases. He received thoraco-abdominal irradiation as a conditioning regimen, and developed repeated episodes of intestinal graft-versus-host disease, for which he received long-term immunosuppressive therapy. Although these factors may be potential contributing factors to the development of secondary NET, the exact pathogenesis remains unclear. PMID:26711919

  7. Advances in the treatment of gastroenteropancreatic neuroendocrine tumors

    PubMed Central

    Kunz, Pamela L; Fisher, George A

    2010-01-01

    Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a rare and heterogeneous class of neoplasms. While surgical resection is the mainstay of treatment, non-surgical therapies play a role in the setting of unresectable and metastatic disease. The goals of medical therapy are directed both at alleviating symptoms of peptide release and shrinking tumor mass. Biotherapies such as somatostatin analogs and interferon can decrease the secretion of peptides and inhibit their end-organ effects. A second objective for treatment of unresectable GEP-NETs is limiting tumor growth. Options for limiting tumor growth include somatostatin analogs, systemic chemotherapy, locoregional therapies, ionizing radiation, external beam radiation, and newer targeted agents. In particular, angiogenesis inhibitors, tyrosine kinase inhibitors, and mTOR inhibitors have shown early promising results. The rarity of these tumors, their resistance to standard chemotherapy, and the excellent performance status of most of these patients, make a strong argument for consideration of novel therapeutic trials. PMID:21694850

  8. Neuroendocrine Tumors of the Large Intestine: Clinicopathological Features and Predictive Factors of Lymph Node Metastasis

    PubMed Central

    Kojima, Motohiro; Ikeda, Koji; Saito, Norio; Sakuyama, Naoki; Koushi, Kenichi; Kawano, Shingo; Watanabe, Toshiaki; Sugihara, Kenichi; Ito, Masaaki; Ochiai, Atsushi

    2016-01-01

    A new histological classification of neuroendocrine tumors (NETs) was established in WHO 2010. ENET and NCCN proposed treatment algorithms for colorectal NET. Retrospective study of NET of the large intestine (colorectal and appendiceal NET) was performed among institutions allied with the Japanese Society for Cancer of the Colon and Rectum, and 760 neuroendocrine tumors from 2001 to 2011 were re-assessed using WHO 2010 criteria to elucidate the clinicopathological features of NET in the large intestine. Next, the clinicopathological relationship with lymph node metastasis was analyzed to predict lymph node metastasis in locally resected rectal NET. The primary site was rectum in 718/760 cases (94.5%), colon in 30/760 cases (3.9%), and appendix in 12/760 cases (1.6%). Patients were predominantly men (61.6%) with a mean age of 58.7 years. Tumor size was <10 mm in 65.4% of cases. Proportions of NET G1, G2, G3, and mixed adeno-neuroendocrine carcinoma (MANEC) were 88.4, 6.3, 3.9, and 1.3%, respectively. Of the 760 tumors, 468 were locally resected, and 292 were surgically resected with lymph node dissection. Rectal NET showed a higher proportion of NET G1, and colonic and appendiceal NET was more commonly G3 and MANEC. Of the 292 surgically resected cases, 233 NET G1 and G2 located in the rectum were used for the prediction of lymph node metastasis. Lymphatic and blood vessel invasion were independent predictive factors of lymph node metastasis. NET G2 cases showed more frequent lymph node metastasis than that seen in NET G1 cases, but this was not an independent predictor of lymph node metastasis. Of the 98 surgically resected cases <10 mm in size, we found 9 cases with lymph node metastasis (9.2%). All cases were NET G1, and eight of the nine cases were positive either for lymphatic invasion or blood vessel invasion. Using the WHO classification, we found NET in the large intestine showed a tumor-site-dependent variety of histological and clinicopathological

  9. Neuroendocrine Tumors of the Large Intestine: Clinicopathological Features and Predictive Factors of Lymph Node Metastasis.

    PubMed

    Kojima, Motohiro; Ikeda, Koji; Saito, Norio; Sakuyama, Naoki; Koushi, Kenichi; Kawano, Shingo; Watanabe, Toshiaki; Sugihara, Kenichi; Ito, Masaaki; Ochiai, Atsushi

    2016-01-01

    A new histological classification of neuroendocrine tumors (NETs) was established in WHO 2010. ENET and NCCN proposed treatment algorithms for colorectal NET. Retrospective study of NET of the large intestine (colorectal and appendiceal NET) was performed among institutions allied with the Japanese Society for Cancer of the Colon and Rectum, and 760 neuroendocrine tumors from 2001 to 2011 were re-assessed using WHO 2010 criteria to elucidate the clinicopathological features of NET in the large intestine. Next, the clinicopathological relationship with lymph node metastasis was analyzed to predict lymph node metastasis in locally resected rectal NET. The primary site was rectum in 718/760 cases (94.5%), colon in 30/760 cases (3.9%), and appendix in 12/760 cases (1.6%). Patients were predominantly men (61.6%) with a mean age of 58.7 years. Tumor size was <10 mm in 65.4% of cases. Proportions of NET G1, G2, G3, and mixed adeno-neuroendocrine carcinoma (MANEC) were 88.4, 6.3, 3.9, and 1.3%, respectively. Of the 760 tumors, 468 were locally resected, and 292 were surgically resected with lymph node dissection. Rectal NET showed a higher proportion of NET G1, and colonic and appendiceal NET was more commonly G3 and MANEC. Of the 292 surgically resected cases, 233 NET G1 and G2 located in the rectum were used for the prediction of lymph node metastasis. Lymphatic and blood vessel invasion were independent predictive factors of lymph node metastasis. NET G2 cases showed more frequent lymph node metastasis than that seen in NET G1 cases, but this was not an independent predictor of lymph node metastasis. Of the 98 surgically resected cases <10 mm in size, we found 9 cases with lymph node metastasis (9.2%). All cases were NET G1, and eight of the nine cases were positive either for lymphatic invasion or blood vessel invasion. Using the WHO classification, we found NET in the large intestine showed a tumor-site-dependent variety of histological and clinicopathological

  10. Working formulation of neuroendocrine tumors of the skin and breast.

    PubMed

    Asioli, Sofia; Foschini, Maria Pia; Masetti, Riccardo; Eusebi, Vincenzo

    2014-06-01

    In the skin and breast, endocrine tumors are composed of a heterogeneous mixture of endocrine and exocrine cells. The definition of "pure" endocrine carcinomas is a matter for debate, and as a consequence, there is lack of uniform diagnostic criteria. There are no significant clinical differences in either overall or disease-free survival between matched neoplasms with endocrine and without endocrine differentiation nor between the degree of endocrine differentiation and tumor size, stage, or prevalence of vascular invasion for both sites (skin and breast). Here, endocrine tumors of the skin and breast are grouped respectively into three categories that include most of the neuroendocrine tumors of the skin and breast as seen in routine practice. It was felt that the number of different types of neuroendocrine tumors is so conspicuous that it is impossible to organize them in an orderly classification. It has been proposed therefore, for practical diagnostic routine purposes, to arrange these neoplasms into a working formulation. The latter includes heterogeneous lesions respectively of the skin and breast within the same group that have clinical features in common. PMID:24729037

  11. MRI-guided laser ablation of neuroendocrine tumor hepatic metastases

    PubMed Central

    Perälä, Jukka; Klemola, Rauli; Kallio, Raija; Li, Chengli; Vihriälä, Ilkka; Salmela, Pasi I; Tervonen, Osmo

    2014-01-01

    Background Neuroendocrine tumors (NET) represent a therapeutically challenging and heterogeneous group of malignancies occurring throughout the body, but mainly in the gastrointestinal system. Purpose To describe magnetic resonance imaging (MRI)-guided laser ablation of NET liver metastases and assess its role within the current treatment options and methods. Material and Methods Two patients with NET tumor hepatic metastases were treated with MRI-guided interstitial laser ablation (LITT). Three tumors were treated. Clinical follow-up time was 10 years. Results Both patients were successfully treated. There were no local recurrences at the ablation site during the follow-up. Both patients had survived at 10-year follow-up. One patient is disease-free. Conclusion MRI-guided laser ablation can be used to treat NET tumor liver metastases but combination therapy and a rigorous follow-up schedule are recommended. PMID:24778794

  12. Small bowel neuroendocrine tumors: From pathophysiology to clinical approach.

    PubMed

    Xavier, Sofia; Rosa, Bruno; Cotter, José

    2016-02-15

    Neuroendocrine tumors (NETs), defined as epithelial tumors with predominant neuroendocrine differentiation, are among the most frequent types of small bowel neoplasm. They represent a rare, slow-growing neoplasm with some characteristics common to all forms and others attributable to the organ of origin. The diagnosis of this subgroup of neoplasia is not usually straight-forward for several reasons. Being a rare form of neoplasm they are frequently not readily considered in the differential diagnosis. Also, clinical manifestations are nonspecific lending the clinician no clue that points directly to this entity. However, the annual incidence of NETs has risen in the last years to 40 to 50 cases per million probably not due to a real increase in incidence but rather due to better diagnostic tools that have become progressively available. Being a rare malignancy, investigation regarding its pathophysiology and efforts toward better understanding and classification of these tumors has been limited until recently. Clinical societies dedicated to this matter are emerging (NANETS, ENETS and UKINETS) and several guidelines were published in an effort to standardize the nomenclature, grading and staging systems as well as diagnosis and management of NETs. Also, some investigation on the genetic behavior of small bowel NETs has been recently released, shedding some light on the pathophysiology of these tumors, and pointing some new directions on the possible treating options. In this review we focus on the current status of the overall knowledge about small bowel NETs, focusing on recent breakthroughs and its potential application on clinical practice. PMID:26909234

  13. Small bowel neuroendocrine tumors: From pathophysiology to clinical approach

    PubMed Central

    Xavier, Sofia; Rosa, Bruno; Cotter, José

    2016-01-01

    Neuroendocrine tumors (NETs), defined as epithelial tumors with predominant neuroendocrine differentiation, are among the most frequent types of small bowel neoplasm. They represent a rare, slow-growing neoplasm with some characteristics common to all forms and others attributable to the organ of origin. The diagnosis of this subgroup of neoplasia is not usually straight-forward for several reasons. Being a rare form of neoplasm they are frequently not readily considered in the differential diagnosis. Also, clinical manifestations are nonspecific lending the clinician no clue that points directly to this entity. However, the annual incidence of NETs has risen in the last years to 40 to 50 cases per million probably not due to a real increase in incidence but rather due to better diagnostic tools that have become progressively available. Being a rare malignancy, investigation regarding its pathophysiology and efforts toward better understanding and classification of these tumors has been limited until recently. Clinical societies dedicated to this matter are emerging (NANETS, ENETS and UKINETS) and several guidelines were published in an effort to standardize the nomenclature, grading and staging systems as well as diagnosis and management of NETs. Also, some investigation on the genetic behavior of small bowel NETs has been recently released, shedding some light on the pathophysiology of these tumors, and pointing some new directions on the possible treating options. In this review we focus on the current status of the overall knowledge about small bowel NETs, focusing on recent breakthroughs and its potential application on clinical practice. PMID:26909234

  14. Practical management and treatment of pancreatic neuroendocrine tumors

    PubMed Central

    Ikeda, Yasuharu

    2014-01-01

    Pancreatic neuroendocrine tumors (NETs) are uncommon disease, about which little is known. Pancreatic NETs are usually slow growing and their malignant potential are often underestimated. The management of this disease poses a challenge because of the heterogeneous clinical presentation and varying degrees of aggressiveness. Recently, several guidelines for the management of pancreatic NETs have been established and help to devise clinical strategy. In the treatment algorithms, however, a lot of uncertain points are included. Practical treatment decisions of pancreatic NETs are still sometimes made in a patient- and/or physicians-oriented manner. The tumor grading system proposed by the European Neuroendocrine Tumor Society (ENETS) gives important prognostic information, however, the implication of grading regarding medical treatment strategies to choose has not yet been clarified. Moreover, the place of surgical treatment is unclear in the overall management course of advanced pancreatic NETs. In some cases, practical management and treatment have to be individualized depending on predominant symptoms, tumor spread, and general health of the patients. Current issues and a few points to make a strategy in the management of pancreatic NETs would be reviewed. PMID:25493259

  15. Veliparib, Capecitabine, and Temozolomide in Patients With Advanced, Metastatic, and Recurrent Neuroendocrine Tumor

    ClinicalTrials.gov

    2016-07-10

    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

  16. Functional-anatomical image fusion in neuroendocrine tumors.

    PubMed

    Schillaci, Orazio

    2004-02-01

    Nuclear medicine provides physiologic and functional data for normal and pathologic organs but often the clear definition of the sites of radiotracers' uptake are difficult. Radiological methods are able to identify structural changes in a detailed way, but do not give precise information on function of organs or pathologic lesions. The registration and fusion of nuclear medicine studies with structural information obtained by radiological exams allows the precise correlation of functional and anatomical data. Software-based fusion of independently performed nuclear medicine and morphologic studies is uncertain of success and the alignment procedures are labor intensive. Recently, a new imaging device combining a dual-head, variable angle gamma camera with a low-dose x-ray tube has been introduced; the acquired single-photon emission computed tomography (SPECT) and x-ray computed tomography (CT) images are coregistered by means of the hardware in the same session. This new technology can be particularly useful when applied to scintigraphic procedures in neuroendocrine tumors. In-111 pentetreotide and radiolabeled MIBG play an important role in the study of patients with these tumors; the addition of anatomical maps provides a precise localization of SPECT findings and allows the exclusion of disease in sites of physiologic tracer uptake. SPECT/CT fused images are able to provide additional information that improves the accuracy of SPECT interpretation and leads to changes in therapeutic options, so enhancing the clinical role of nuclear medicine in evaluating patients with neuroendocrine tumors. PMID:15068621

  17. Synchronous collision neuroendocrine tumor and rectal adenocarcinoma: a case report.

    PubMed

    Zhu, Jie-Gao; Zhang, Zhong-Tao; Wu, Guo-Cong; Han, Wei; Wang, Kang-Li

    2015-04-01

    Collision tumors are thought to arise from the accidental meeting of two independent tumors. Adenocarcinoma is the most common malignant rectal tumor, while neuroendocrine tumor (NET) is relatively rare. Due to the endoscopy and reporting, the overall incidence of NETs was increasing recently but still less than 1 per 100,000. This means that a combination of an adenocarcinoma and NET is a very rare finding and an actual collision of these tumors even more so. We report here a highly unusual case of a 64-year-old woman who had collision tumors composed of a primary rectal adenocarcinoma and NET showing a "side by side" pattern. Resection margins are free of both the tumors. The postoperative course was uneventful. The patient underwent a protocol CT scan at 3 months after surgery, which did not show any recurrence. Both the malignant adenocarcinoma and the NET would make a great influence in the rest lifetime and a follow up will be continued, although the CT did not show any recurrence until now. To the best of our knowledge, this is the first reported case of such an occurrence. PMID:25972691

  18. Endoscopic imaging in the management of gastroenteropancreatic neuroendocrine tumors.

    PubMed

    Pellicano, Rinaldo; Fagoonee, Sharmila; Altruda, Fiorella; Bruno, Mauro; Saracco, Giorgio M; De Angelis, Claudio

    2016-12-01

    Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of tumors deriving from the gastrointestinal (GI) neuroendocrine system. Since these neoplasms are usually very small, located deeply within the retroperitoneum or into an extramucosal site of the GI tract and, lastly, because they may be multi-sited, radiological imaging modalities, in combination with endoscopy, are the diagnostic workhorses in patients with GEP-NETs. Endoscopic approach is useful for detection, bioptic diagnosis and curative resection of small GEP-NETs of stomach, duodenum, jejuno-ileum, and colon-rectum. Moreover, endoscopic ultrasonography (EUS), associated with high frequency miniprobes, is a valuable procedure in regional staging of lesions of the GI wall and can provide information which has a remarkable impact on therapeutic choices. EUS is still the sole technique, in a substantial number of cases, providing a definitive diagnosis of pancreatic insulinoma and it detects and follows small lesions of the pancreas in patients with Multiple Endocrine Neoplasia type 1 syndrome. EUS should be performed in those cases in which morphological or molecular imaging modalities need to be supported because of negative or dubious results. In this review we describe the applications of endoscopic procedures in the management of GEP-NETs. PMID:27600643

  19. Recent developments in imaging of pancreatic neuroendocrine tumors

    PubMed Central

    Kartalis, Nikolaos; Mucelli, Raffaella Maria Pozzi; Sundin, Anders

    2015-01-01

    Pancreatic neuroendocrine tumors (PNETs) are very rare, accounting for 1-2% of all pancreatic neoplasms. They are classified into functioning and non-functioning and their behavior varies widely from benign to highly malignant. For their investigation, a variety of anatomical and functional imaging methods are available. Anatomical methods include computed tomography (CT), magnetic resonance imaging, and ultrasonography. Functional methods include scintigraphy and positron emission tomography (PET). A combination of anatomical and morphological methods results in the so-called hybrid imaging, such as PET/CT. We herein discuss the currently available imaging modalities for the investigation of PNETs and, more specifically, their applications in tumor detection and staging as well as in choice of therapy, imaging follow up and prediction of response, with emphasis on the recent developments. PMID:25830417

  20. Irreversible electroporation for the treatment of pancreatic neuroendocrine tumors

    PubMed Central

    Papamichail, Michail; Ali, Amir; Pizanias, Michail; Peddu, Praveen; Karani, John

    2016-01-01

    Backgrounds/Aims Resection or enucleation is currently the treatment of choice for small pancreatic neuroendocrine tumors (NETs). Irreversible electroporation is a novel ablative method that is used for locally advanced pancreatic adenocarcinoma, but little data exists for its use for pancreatic NETs. We report an early experience of IRE for early pancreatic NETs. Methods Between April 2014 and March 2015, 3 patients with small (<2 cm) pancreatic NETs were treated with percutaneous IRE. Results There were no adverse effects during the procedure. Mean hospital stay was 2.6 days. All patients remained disease free on 12-19 months follow up. One patient developed recurrent pancreatitis with pseudocyst formation. Conclusions IRE for small tumors of the pancreas is practical and may offer advantages over other thermal ablative techniques, since it preserves vital structures such as blood vessels, bile and pancreatic ducts. Further data regarding the long term disease free interval is required to establish efficacy. PMID:27621748

  1. Pancreatic neuroendocrine tumor accompanied with multiple liver metastases

    PubMed Central

    Hori, Tomohide; Takaori, Kyoichi; Uemoto, Shinji

    2014-01-01

    Pancreatic neuroendocrine tumor (P-NET) is rare and slow-growing. Current classifications predict its prognosis and postoperative recurrence. Curative resection is ideal, although often difficult, because over 80% of patients have unresectable multiple liver metastases and extrahepatic metastasis. Aggressive surgery for liver metastases is important to improve survival. Aggressive or cytoreductive surgery for liver metastases is indicated to reduce hormone levels and improve symptoms and prognosis. Liver transplantation was originally conceived as an ideal therapy for unresectable liver metastases. Unfortunately, there is no clear consensus on the role and timing of surgery for primary tumor and liver metastases. Surgeons still face questions in deciding the best surgical scenario in patients with P-NET with unresectable liver metastases. PMID:25232452

  2. New horizons for targeted treatment of neuroendocrine tumors.

    PubMed

    Mangano, Alberto; Lianos, Georgios D; Roukos, Dimitrios H; Mason, Sam E; Kim, Hoon Yub; Dionigi, Gianlorenzo

    2016-04-01

    Neuroendocrine tumors (NETs) are rare and heterogeneous tumors and there is a paucity of randomized clinical trials evaluating the different therapeutic strategies. Over recent years, some important molecular aspects have been investigated and multiple targeted therapies are currently available. One of the most promising targets for the therapy of NETs are the mTOR and angiogenic growth factor receptors. The advent of the inhibitors of the mTOR pathway, tyrosine kinase inhibitors and of somatostatin analogs have shown their efficacy in randomized clinical trials in terms of implementing clinical hormone-induced syndromes and progression-free survival of advanced NETs. This article summarizes the standard therapies and new perspectives in NET's treatment, which remains still very heterogeneous and little known entity. PMID:26916705

  3. Genetic associations with neuroendocrine tumor risk: results from a genome-wide association study.

    PubMed

    Du, Yeting; Ter-Minassian, Monica; Brais, Lauren; Brooks, Nichole; Waldron, Amanda; Chan, Jennifer A; Lin, Xihong; Kraft, Peter; Christiani, David C; Kulke, Matthew H

    2016-08-01

    The etiology of neuroendocrine tumors remains poorly defined. Although neuroendocrine tumors are in some cases associated with inherited genetic syndromes, such syndromes are rare. The majority of neuroendocrine tumors are thought to be sporadic. We performed a genome-wide association study (GWAS) to identify potential genetic risk factors for sporadic neuroendocrine tumors. Using germline DNA from blood specimens, we genotyped 909,622 SNPs using the Affymetrix 6.0 GeneChip, in a cohort comprising 832 neuroendocrine tumor cases from Dana-Farber Cancer Institute and Massachusetts General Hospital and 4542 controls from the Harvard School of Public Health. An additional 241 controls from Dana-Farber Cancer Institute were used for quality control. We assessed risk associations in the overall cohort, and in neuroendocrine tumor subgroups. We identified no potential risk associations in the cohort overall. In the small intestine neuroendocrine tumor subgroup, comprising 293 cases, we identified risk associations with three SNPs on chromosome 12, all in strong LD. The three SNPs are located upstream of ELK3, a transcription factor implicated in angiogenesis. We did not identify clear risk associations in the bronchial or pancreatic neuroendocrine subgroups. This large-scale study provides initial evidence that presumed sporadic small intestine neuroendocrine tumors may have a genetic etiology. Our results provide a basis for further exploring the role of genes implicated in this analysis, and for replication studies to confirm the observed associations. Additional studies to evaluate potential genetic risk factors for sporadic pancreatic and bronchial neuroendocrine tumors are warranted. PMID:27492634

  4. Diagnostic Imaging of Primary Hepatic Neuroendocrine Tumors: A Case and Discussion of the Literature

    PubMed Central

    Tuong, Betty; Harris, Alison C.; Yoshida, Eric

    2014-01-01

    Neuroendocrine tumors (NETs) are derived from neuroendocrine cells that are capable of producing functional peptide hormones. These tumors occur most frequently in the GI tract and lungs. GI NETs frequently metastasize into the liver, though NETs of primary hepatic origin are extremely rare. Ultrasound, CT, and MRI are typically all employed for characterization of these lesions but their appearance on diagnostic imaging can be highly variable. Reported here is an interesting case of a primary hepatic neuroendocrine tumor (PHNET), along with a discussion of the imaging characteristics of these tumors. Additionally, the current standards for definitive diagnosis and treatment of PHNETs are discussed. PMID:25258691

  5. Biotherapy of pancreatic neuroendocrine tumors using somatostatin analogs.

    PubMed

    Igarashi, Hisato; Hijioka, Masayuki; Lee, Lingaku; Ito, Tetsuhide

    2015-08-01

    Basically, pancreatic neuroendocrine tumor (PNET) should be treated surgically; however, in unresectable cases, a treatment that aims to improve the prognosis by inhibiting the growth of the tumor and control the clinical symptoms becomes necessary. In the case of functional tumors, the quality of life of patients is decreased by not only the symptoms with tumor invasion and/or metastasis but also by the symptoms of hormone excess. The efficacy of somatostatin analogs against the latter has been previously reported, and their sustained release formulations have been developed. Somatostatin analogs are recommended to treat the endocrine symptoms of functional PNET; however, in case they can cause hypoglycemia in patients with insulinoma. On the other hand, results from the PROMID study demonstrated a tumor-stabilizing effect when octreotide LAR (long acting repeatable) was used to treat patients with advanced midgut NET; however, there has been no consensus regarding its antitumor effect for PNET. Additionally, a recent result from the CLARINET study suggests that lanreotide autogel has an antitumor effect against nonfunctional NET including PNET. Further clinical study results are awaited. PMID:25689143

  6. Pancreatic body adenocarcinoma with neuroendocrine tumor characteristics: A case report

    PubMed Central

    TAJIMA, HIDEHIRO; KITAGAWA, HIROHISA; SHOJI, MASATOSHI; WATANABE, TOSHIFUMI; NAKANUMA, SHINICHI; OKAMOTO, KOICHI; SAKAI, SEISHO; KINOSHITA, JUN; MAKINO, ISAMU; FURUKAWA, HIROYUKI; NAKAMURA, KEISHI; HAYASHI, HIRONORI; OYAMA, KATSUNOBU; INOKUCHI, MASAFUMI; NAKAGAWARA, HISATOSHI; MIYASHITA, TOMOHARU; ITOH, HIROSHI; TAKAMURA, HIROYUKI; NINOMIYA, ITASU; FUSHIDA, SACHIO; FUJIMURA, TAKASHI; OHTA, TETSUO; SATOH, HIROHIDE; IKEDA, HIROKO; HARADA, KENICHI; NAKANUMA, YASUNI

    2014-01-01

    A 61-year-old female with pancreatic body cancer underwent a distal pancreatectomy. The tumor was a moderately- to poorly-differentiated adenocarcinoma. Tumor growth filled the dilated main pancreatic duct (MPD) and infiltrated the surrounding area. Six months later, metastases to the left diaphragm and MPD of the remnant pancreatic head were detected. Chemoradiotherapy was administered, but the patient succumbed 22 months after surgery. An autopsy demonstrated that a moderately- to poorly-differentiated adenocarcinoma had arisen from the pancreatic head and infiltrated the duodenum and bile duct. Huge liver metastases and multiple peritoneal disseminations were also present. Microscopically, a portion of the tumor had a pseudo-rosette appearance in the adenocarcinoma component, while another section showed characteristics of a neuroendocrine tumor (NET) immunohistochemically. The original surgically-resected tumor also showed NET characteristics immunohistochemically. It is therefore necessary to search for NET components in pancreatic cancer with atypical growth and metastases, even when adenocarcinoma has been diagnosed histologically. PMID:24944667

  7. PROX1 is involved in progression of rectal neuroendocrine tumors, NETs.

    PubMed

    Jernman, Juha; Kallio, Pauliina; Hagström, Jaana; Välimäki, Matti J; Haapasalo, Hannu; Alitalo, Kari; Arola, Johanna; Haglund, Caj

    2015-09-01

    PROX1 is a homeobox transcription factor involved in the development of the lens, liver and heart and found upregulated in colorectal cancers. We studied PROX1 expression by immunohistochemistry in rectal neuroendocrine tumors (NETs). Approximately 10 to 15 % of gastroenteropancreatic NETs occur in the rectum, and some may metastasize. Yet little is known about the molecular pathogenesis of rectal NETs or their metastasis propensity. The objectives were to find out whether PROX1 plays a role in progression of rectal NETs and whether it has value as prognostic marker. In grading of rectal NETs, we applied the WHO 2010 classification. We carried out immunohistochemical staining of PROX1 on 72 primary tumors and six metastases and evaluated nuclear positivity in each tumor. Correlation between PROX1 expression, metastasis and patient survival was then assessed. Annexin A1, a downstream target of PROX1, was immunohistochemically assessed in 18 tumors. PROX1 protein was detected in about half of the tumors, with stronger expression in metastasized cases. PROX1 expression correlated with tumor metastasis and patient prognosis. Annexin A1 was negative in most of the high-grade tumors correlating strongly with grade and metastatic potential. Our results indicate that immunohistochemical detection of PROX1 correlates with a more malignant phenotype in rectal NETs. High PROX1 expression was associated with increased metastatic potential and poor patient survival but not as strongly as grade by the WHO 2010 classification. PROX1 may be involved in progression of rectal NETs as a part of the Wnt pathway. PMID:26063416

  8. Management of pancreatic neuroendocrine tumors in patients with MEN 1

    PubMed Central

    Sadowski, Samira M.

    2015-01-01

    Pancreatic neuroendocrine tumors (PNETs) are frequent and can be non-functional (NF) in patients with multiple endocrine neoplasia type 1 (MEN1). Their identification is of clinical importance because malignant PNETs are reported to be the most common cause of death in patients with MEN1. Once the diagnosis of MEN1 is established in an individual based on clinical manifestations and/or genetic testing results, an active surveillance program is instituted for early detection and treatment of MEN1-associated disease. Ultrasonography, endoscopic ultrasonography (EUS), CT, MRI, selective arterial angiography and somatostatin receptor scintigraphy are all used for localization of tumors. Managing PNETs can be challenging and includes diagnosis, surveillance, adequate staging, and interdisciplinary, multimodal treatments to optimize patient outcome. Treatment includes surgical resection for loco-regional disease, as well as liver directed and targeted chemotherapies for advanced progressive disease. To date, the recommendation for surgical resection in NF-PNETs is based on tumor size, as a higher rate of metastases was found in patients with larger tumors. This review summarizes key concepts in managing PNETs in patients with MEN1. PMID:25713781

  9. Hepatic arterial embolization in patients with neuroendocrine tumors

    PubMed Central

    2014-01-01

    Liver metastases occur in 46-93% of patients with neuroendocrine neoplasms (NENs). Presence and extension of liver metastases are considered important prognostic factors, as they may significantly impair the patient’s quality of life, because of either tumor bulk or hormonal hypersecretion. Therapies for NEN liver metastases include surgical resection, liver transplantation, chemotherapy and biotherapy. Surgery is the gold standard for curative therapy, but in most of NEN patients with liver metastases, when surgery can not be applied, minimally invasive therapeutic approaches are adopted. They include trans-arterial embolization (TAE), trans-arterial chemoembolization (TACE), radiofrequency thermal ablation and new emerging techniques. TAE is based on selective infusion of particles in the branch of the hepatic artery supplying the tumor lesions. The goal of TAE is to occlude tumor blood vessels resulting in ischemia and necrosis. Many reports have shown that TAE can reduce tumor size and hormone output, resulting in palliation of symptoms without the use of cytotoxic drugs, resulting in better tolerability. This review will focus on TAE performance and safety in NEN patients with liver metastases. PMID:24887262

  10. Endoscopic resection of colorectal granular cell tumors

    PubMed Central

    Take, Iri; Shi, Qiang; Qi, Zhi-Peng; Cai, Shi-Lun; Yao, Li-Qing; Zhou, Ping-Hong; Zhong, Yun-Shi

    2015-01-01

    AIM: To determine the feasibility and effectiveness of endoscopic resection for the treatment of colorectal granular cell tumors (GCTs). METHODS: This was a retrospective study performed at a single institution. From January 2008 to April 2015, we examined a total of 11 lesions in 11 patients who were treated by an endoscopic procedure for colorectal GCTs in the Endoscopy Center, Zhongshan Hospital of Fudan University, Shanghai, China. Either endoscopic mucosal resection or endoscopic submucosal dissection (ESD) was performed by three surgeons with expertise in endoscopic treatment. The pre- and post-operative condition and follow-up of these patients were evaluated by colonoscopy and endoscopic ultrasonography (EUS). RESULTS: Of these 11 lesions, 2 were located in the cecum, 3 were in the ileocecal junction, 5 were in the ascending colon, and 1 was in the rectum. The median maximum diameter of the tumors was 0.81 cm (range 0.4-1.2 cm). The en bloc rate was 100%, and the complete resection rate was 90.9% (10/11). Post-operative pathology in one patient showed a tumor at the cauterization margin. However, during ESD, this lesion was removed en bloc, and no tumor tissue was seen in the wound. No perforations or delayed perforations were observed and emergency surgery was not required for complications. All patients were followed up to May 2015, and none had recurrence, metastasis, or complaints of discomfort. CONCLUSION: Endoscopic treatment performed by endoscopists with sufficient experience appears to be feasible and effective for colorectal GCTs. PMID:26730166

  11. 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. PMID:27353036

  12. Somatostatin receptor imaging of neuroendocrine tumors with indium-111 pentetreotide (Octreoscan).

    PubMed

    Olsen, J O; Pozderac, R V; Hinkle, G; Hill, T; O'Dorisio, T M; Schirmer, W J; Ellison, E C; O'Dorisio, M S

    1995-07-01

    Somatostatin, a naturally occurring 14-amino acid peptide, can be thought of as an anti-growth hormone and functional down-regulator of sensitive tissue. Most neuroendocrine tumors seem to possess somatostatin receptors in sufficient abundance to allow successful scintigraphic imaging with radiolabeled somatostatin congeners. Several of these, including Indium-III-DTPA Pentetreotide (Octreoscan [Mallinckrodt Medical, St. Louis, MO]), which was approved for clinical use by the Food and Drug Administration in June 1994, have been of considerable value in scintigraphically identifying various neuroendocrine tumors. The Octreoscan compares favorably with other imaging modalities. The success of somatostatin receptor imaging in evaluating patients with suspected neuroendocrine tumors, including identifying otherwise radiographically occult lesions, has resulted in ranking somatostatin receptor imaging as the prime imaging procedure in patients with suspected neuroendocrine tumors at The Ohio State University. PMID:7570044

  13. Une angiocholite secondaire à un thrombus tumoral d'une tumeur neuroendocrine primitive du foie

    PubMed Central

    Baba, Hicham; Allaoui, Mohamed; Elfahssi, Mohammed; Bounaim, Ahmed; Ali, Abdelmounaim Ait; Oukabli, Mohamed; Sair, Khalid; Zentar, Aziz

    2015-01-01

    Nous rapportons le cas exceptionnel d'une patiente de 54 ans prise en charge pour une angiocholite due à un thrombus tumoral, d'une tumeur neuroendocrine primitive (TNE Ive) du foie, dans la voie biliaire principale. PMID:26966504

  14. Neuroendocrine tumor arising de novo in the left upper thigh: a case report.

    PubMed

    Păun, Ion; Costin, Andrei; Păun, Mariana; Ţenovici, Mihaela; Georgescu, Claudia Valentina; Georgescu, Corneliu Cristian; Constantin, Vlad Denis

    2015-01-01

    Neuroendocrine tumors (NETs) originate in the neuroendocrine cells of the neural crest (Kulchitsky cells). If neuroendocrine tumors arising in the digestive tract or lung may occasionally result in skin metastases, primary soft tissue or skin NETs are infrequent. The current paper presents the case of an elderly woman patient with neuroendocrine tumors arising de novo in the left upper thigh, accompanied by lymph nodes metastases in the left groin and in the left pelvic sidewall, in close vicinity of the iliac vessels. The diagnosis of NET was performed based on immunohistochemical tests. Such tumors show a slow growth and, generally, have a good prognosis. It is emphasized that complete surgical excision, in some cases associated with adjuvant external radiotherapy is the optimal therapeutic modality in dealing with such lesions. PMID:26429186

  15. Neuroendocrine Differentiation Is a Prognostic Factor for Stage II Poorly Differentiated Colorectal Cancer

    PubMed Central

    Liu, Yue; Xu, Jinghong; Jiao, Yurong; Hu, Yeting; Yi, Chenghao; Li, Qiong; Tong, Zhou; Wang, Xiaowei; Hu, Lifeng; Li, Jun; Ding, Kefeng

    2014-01-01

    Neuroendocrine differentiation (NED) in colorectal cancer is an indistinct phenomenon and may define a new cancer subtype, especially in the poorly differentiated colorectal cancer (PDCRC). The clinical features of PDCRC with NED remain controversial, thus confusing the implementation of individualized treatment. This study included 171 patients who underwent surgery from 2000 to 2011 and had pathology-confirmed PDCRC. Each sample was examined by immunohistochemistry for the biological markers of NED, synaptophysin (Syn), and chromogranin (CgA). Patients with Syn(+) and/or CgA(+) cells were classified as NED(+); otherwise, they were NED(−). Data were collected for patients who were followed up for at least two years. NED(+) staining was present in 71 (41.5%) patients. The median survival time was 36.9 months. No survival differences existed between the NED(−) and NED(+) groups (P > 0.05). However, stage II NED(+) patients had a significantly worse prognosis than NED(−) patients (P = 0.018). For the NED(+) group, the median survival was 38.56 months, and the 5-year survival was 65%. For the NED(−) group, the median survival was 53.18 months, and the 5-year survival was 90%. NED is a common event in primary PDCRC. For stage II PDCRC, NED(+) indicates a poor prognosis. PMID:25093184

  16. Sentinel node navigation surgery for gastroduodenal neuroendocrine tumors

    PubMed Central

    Arigami, Takaaki; Uenosono, Yoshikazu; Yanagita, Shigehiro; Okubo, Keishi; Kijima, Takashi; Matsushita, Daisuke; Amatatsu, Masahiko; Hagihara, Takahiko; Haraguchi, Naoto; Mataki, Yuko; Ehi, Katsuhiko; Ishigami, Sumiya; Natsugoe, Shoji

    2016-01-01

    Abstract The percentage of gastroduodenal neuroendocrine tumors (NETs) among all gastroenteropancreatic (GEP) NETs has gradually increased worldwide. Sentinel node navigation surgery (SNNS) has been developed as a personalized approach in the surgical strategy for early gastrointestinal tract cancers. We herein report 2 cases of gastroduodenal NETs treated with SNNS. 99m Technetium-tin colloid including indocyanine green was endoscopically injected into the submucosa around a tumor the day before surgery. Basin dissection including the sentinel nodes (SNs), which were identified by Navigator GPS and near-infrared fluorescence imaging, was performed during laparoscopic surgery. SNs were intraoperatively examined using hematoxylin–eosin (HE) staining. SNs were detected in 2 patients. Lymph node metastasis was intraoperatively identified in 1 of the 2 patients. Consequently, 1 patient with metastatic SNs underwent laparoscopic gastrectomy with lymphadenectomy. Pathological findings identified submucosal NET measuring 6.0 mm × 5.0 mm. Our results suggest that SNNS is a promising surgical tool for detecting subclinical lymph node metastasis in patients with gastroduodenal NETs. PMID:27368046

  17. Toppling high-grade pulmonary neuroendocrine tumors with a DLL3-targeted trojan horse.

    PubMed

    Dylla, Scott J

    2016-03-01

    Delta-like protein 3 (DLL3) is a novel and tractable tumor-initiating cell-associated target for the antibody-drug conjugate SC16LD6.5 in high-grade pulmonary neuroendocrine tumors. Elevated expression of DLL3, an inhibitor of Notch pathway activation, marks the second recent observation that impairment of Notch receptor signaling may play a critical role in neuroendocrine tumorigenesis. PMID:27308627

  18. A phase II study of axitinib in advanced neuroendocrine tumors

    PubMed Central

    Strosberg, J R; Cives, M; Hwang, J; Weber, T; Nickerson, M; Atreya, C E; Venook, A; Kelley, R K; Valone, T; Morse, B; Coppola, D; Bergsland, E K

    2016-01-01

    Neuroendocrine tumors (NETs) are highly vascular neoplasms overexpressing vascular endothelial growth factor (VEGF) as well as VEGF receptors (VEGFR). Axitinib is a potent, selective inhibitor of VEGFR-1, -2 and -3, currently approved for the treatment of advanced renal cell carcinoma. We performed an open-label, two-stage design, phase II trial of axitinib 5 mg twice daily in patients with progressive unresectable/metastatic low-to-intermediate grade carcinoid tumors. The primary end points were progression-free survival (PFS) and 12-month PFS rate. The secondary end points included time to treatment failure (TTF), overall survival (OS), overall radiographic response rate (ORR), biochemical response rate and safety. A total of 30 patients were enrolled and assessable for toxicity; 22 patients were assessable for response. After a median follow-up of 29 months, we observed a median PFS of 26.7 months (95% CI, 11.4–35.1), with a 12-month PFS rate of 74.5% (±10.2). The median OS was 45.3 months (95% CI, 24.4–45.3), and the median TTF was 9.6 months (95% CI, 5.5–12). The best radiographic response was partial response (PR) in 1/30 (3%) and stable disease (SD) in 21/30 patients (70%); 8/30 patients (27%) were unevaluable due to early withdrawal due to toxicity. Hypertension was the most common toxicity that developed in 27 patients (90%). Grade 3/4 hypertension was recorded in 19 patients (63%), leading to treatment discontinuation in six patients (20%). Although axitinib appears to have an inhibitory effect on tumor growth in patients with advanced, progressive carcinoid tumors, the high rate of grade 3/4 hypertension may represent a potential impediment to its use in unselected patients. PMID:27080472

  19. Genetic reconstruction of individual colorectal tumor histories

    PubMed Central

    Tsao, Jen-Lan; Yatabe, Yasushi; Salovaara, Reijo; Järvinen, Heikki J.; Mecklin, Jukka-Pekka; Aaltonen, Lauri A.; Tavaré, Simon; Shibata, Darryl

    2000-01-01

    It is difficult to observe human tumor progression as precursor lesions are systematically removed. Alternatives to direct observations, commonly used to reveal the hidden past of species and populations, are sequence comparisons or molecular clocks. Noncoding microsatellite (MS) loci were employed as molecular tumor clocks in 13 human mutator phenotype (MSI+) colorectal tumors. Quantitative analysis revealed that specific patterns of somatic MS mutations accumulate with division after loss of mismatch repair (MMR). Tumors had unique patterns of MS mutation, and, therefore, based on this model, each tumor had its own unique history. Loss of MMR occurred very early relative to terminal clonal expansion, with an estimated average of 2,300 divisions since loss of MMR and 280 divisions since expansion. Contrary to the classical adenoma-cancer sequence, MSI+ adenomas were nearly as old as cancers (2,000 versus 2,400 divisions since loss of MMR). Negative clinical examinations preceded six tumors, independently documenting an absence of visible precursors during early MSI+ adenoma or cancer progression. These findings further extend a window beyond visible progression since loss of MMR appears to start a genetic phase involving clone sizes or phenotypes below a threshold of clinical detection. This previously occult prologue before visible neoplasia is longer and therefore likely more important than generally appreciated. PMID:10655514

  20. Co-expression of TTF-1 and neuroendocrine markers in the human fetal lung and pulmonary neuroendocrine tumors.

    PubMed

    Miskovic, Josip; Brekalo, Zdrinko; Vukojevic, Katarina; Miskovic, Helena Radic; Kraljevic, Daniela; Todorovic, Jelena; Soljic, Violeta

    2015-01-01

    The expression pattern of thyroid transcription factor 1 (TTF-1) and neuroendocrine markers, neuron cell adhesion molecule (NCAM; CD56), chromogranin A (CgA) and synaptophysin (Syp), of different lung cell lineages was histologically analyzed in 15 normal human fetal lungs and 12 neuroendocrine tumors (NETs) using immunohistochemical methods. During pseudoglandular phase strong nuclear TTF-1 staining was detected in the columnar nonciliated epithelial cells, while NCAM, CgA and Syp had a moderate expression in the proximal airways and mild expression in the distal airways. Neuroendocrine cells (NECs) in proximal lung airway were co-localizing TTF-1 and other neuroendocrine markers while neuroendocrine bodies (NEBs) exhibit only staining with NCAM and Syp. In the canalicular phase TTF-1 nuclear staining was expressed only in several epithelial cells in proximal airways, while budding airways epithelium showed strong TTF-1 expression. Expression of NCAM, CgA and Syp in this phase equals the one in pseudoglandular phase. NEBs cells were co-localizing TTF-1 and NCAM in proximal airways and few NECs in distal airway were co-localizing TTF-1 and Syp. TTF-1 staining in the saccular phase was limited to subsets of epithelial cells in the proximal airways with stronger positivity in the distal airways. NCAM expression is moderate only in proximal airways, while Syp and CgA show mild expression in proximal and distal airways. NECs were co-localizing TTF-1 and NCAM in proximal lung airway. With regard to NECs, all small cell lung cancer (SCLC) cells had strong TTF-1, NCAM, Syp and CgA positivity and TTF-1 co-localized with other neuroendocrine markers. All pulmonary typical carcinoids were TTF-1 negative, while pulmonary atypical carcinoids were focal positive for TTF-1 and some neoplastic cells co-localized TTF-1 with neuroendocrine markers. Our results indicate that TTF-1 expression in NECs suggests a possible role in their normal development and differentiation. Our

  1. Surgical Treatment and Clinical Outcome of Nonfunctional Pancreatic Neuroendocrine Tumors

    PubMed Central

    Yang, Min; Zeng, Lin; Zhang, Yi; Su, An-ping; Yue, Peng-ju; Tian, Bo-le

    2014-01-01

    Abstract Our primary aim of the present study was to analyze the clinical characteristics and surgical outcome of nonfunctional pancreatic neuroendocrine tumors (non-F-P-NETs), with an emphasis on evaluating the prognostic value of the newly updated 2010 grading classification of the World Health Organization (WHO). Data of 55 consecutive patients who were surgically treated and pathologically diagnosed as non-F-P-NETs in our single institution from January 2000 to December 2013 were retrospectively collected. This entirety comprised of 55 patients (31 males and 24 females), with a mean age of 51.24 ± 12.95 years. Manifestations of non-F-P-NETs were nonspecific. Distal pancreatectomy, pancreaticoduodenectomy, and local resection of pancreatic tumor were the most frequent surgical procedures, while pancreatic fistula was the most common but acceptable complication (30.3%). The overall 5-year survival rate of this entire cohort was 41.0%, with a median survival time of 60.4 months. Patients who underwent R0 resections obtained a better survival than those who did not (P < 0.005). As for the prognostic analysis, tumor size and lymph invasion were only statistically significant in univariate analysis (P = 0.046 and P < 0.05, respectively), whereas the newly updated 2010 grading classification of WHO (G1 and G2 vs G3), distant metastasis, and surgical margin were all meaningful in both univariate and multivariate analysis (P = 0.045, 0.001, and 0.042, respectively). Non-F-P-NETs are a kind of rare neoplasm, with mostly indolent malignancy. Patients with non-F-P-NETs could benefit from the radical resections. The new WHO criteria, distant metastasis and surgical margin, might be independent predictors for the prognosis of non-F-P-NETs. PMID:25396335

  2. Ileal neuroendocrine tumors and heart: not only valvular consequences.

    PubMed

    Calissendorff, Jan; Maret, Eva; Sundin, Anders; Falhammar, Henrik

    2015-04-01

    Ileal neuroendocrine tumors (NETs) often progress slowly, but because of their generally nonspecific symptoms, they have often metastasized to local lymph nodes and to the liver by the time the patient presents. Biochemically, most of these patients have increased levels of whole blood serotonin, urinary 5-hydroxyindoleacetic acid, and chromogranin A. Imaging work-up generally comprises computed tomography or magnetic resonance imaging and somatostatin receptor scintigraphy, or in recent years positron emission tomography with 68Ga-labeled somatostatin analogs, allowing for detection of even sub-cm lesions. Carcinoid heart disease with affected leaflets, mainly to the right side of the heart, is a well-known complication and patients routinely undergo echocardiography to diagnose and monitor this. Multitasking surgery is currently recognized as first-line treatment for ileal NETs with metastases and carcinoid heart disease. Open heart surgery and valve replacement are advocated in patients with valvular disease and progressive heart failure. When valvulopathy in the tricuspid valve results in right-sided heart failure, a sequential approach, performing valve replacement first before intra-abdominal tumor-reductive procedures are conducted, reduces the risk of bleeding. Metastases to the myocardium from ileal NETs are seen in <1-4.3% of patients, depending partly on the imaging technique used, and are generally discovered in those affected with widespread disease. Systemic treatment with somatostatin analogs, and sometimes alpha interferon, is first-line medical therapy in metastatic disease to relieve hormonal symptoms and stabilize the tumor. This treatment is also indicated when heart metastases are detected, with the addition of diuretics and fluid restriction in cases of heart failure. Myocardial metastases are rarely treated by surgical resection. PMID:25319177

  3. Neuroendocrine Tumors of the Prostate: Emerging Insights from Molecular Data and Updates to the 2016 World Health Organization Classification.

    PubMed

    Priemer, David S; Montironi, Rodolfo; Wang, Lisha; Williamson, Sean R; Lopez-Beltran, Antonio; Cheng, Liang

    2016-06-01

    Neuroendocrine neoplasms of the prostate represent a multifarious group of tumors that exist both in pure forms and associated with prostatic adenocarcinoma. Morphologically, neuroendocrine cells in prostate neoplasms can range from being indistinguishable from surrounding prostate adenocarcinoma cells to having high-grade neuroendocrine appearances similar to neuroendocrine malignancies of other organs. On the molecular level, neuroendocrine malignancies arising in the setting of prostate adenocarcinoma have been the subject of a large amount of recent research, most of which has supported the conclusion that neuroendocrine malignancy within the prostate develops as a transdifferentiation from prostate adenocarcinoma. There has not, however, been substantial investigation into rare, pure neuroendocrine malignancies and the possibility that these tumors may have a different cell of origin and molecular genesis. Here, we discuss the morphologic spectrum of malignant neuroendocrine prostate neoplasms and review the most recent molecular data on the subject of malignant neuroendocrine differentiation in prostatic adenocarcinoma. In reflection of the most recent data, we also discuss diagnostic classification of prostate neuroendocrine tumors with reference to the 2016 World Health Organization (WHO) classification. We discuss the reporting of these tumors, placing emphasis on the differentiation between pure and mixed neuroendocrine malignancies so that, in the least, they can be easily identified for the purposes of future clinical and laboratory-based investigation. Finally, we suggest a designation for an unclassifiable (or not otherwise specified) high-grade neuroendocrine prostate malignancy whose features do not easily place it into one of the WHO diagnostic entities. PMID:26885643

  4. Site-Specific Epithelial-Mesenchymal Interactions in Digestive Neuroendocrine Tumors

    PubMed Central

    Dumortier, Jérôme; Ratineau, Christelle; Scoazec, Jean-Yves; Pourreyron, Céline; Anderson, Wena; Jacquier, Marie-France; Blanc, Martine; Bernard, Christine; Bellaton, Claire; Remy, Lionel; Chayvialle, Jean-Alain; Roche, Colette

    2000-01-01

    Little is known about the functional interactions between digestive neuroendocrine tumor cells and their stromal microenvironment. The focus of our study is whether mesenchymal cells modulate peptide expression, cell proliferation, and invasiveness in digestive neuroendocrine tumor cells. We designed an experimental in vivo and in vitro study using the mouse enteroendocrine cell line STC-1. In vivo, STC-1 cells were injected subcutaneously in 18 immunosuppressed newborn rats. At day 21, all animals presented poorly differentiated neuroendocrine tumors with lung metastases. Subcutaneous tumors were usually limited by a capsule containing basement membrane components and myofibroblasts that presented a low mitotic index. Lung tumors were devoid of capsule and poor in myofibroblasts, and their mitotic index was high. The profile of peptide expression in STC-1 tumors was different from that of cultured STC-1 cells. In vitro, STC-1 cells were cultured with fibroblasts of different origins, including dermis, lung, digestive tract, and liver. Based on their origin, myofibroblasts differentially modulated hormone synthesis, proliferation, spreading, and adhesion of STC-1 cells. In conclusion, our results show that site-specific functional interactions between mesenchymal and neuroendocrine cells may contribute to modulating the behavior of digestive neuroendocrine tumors, depending on their growth site. PMID:10666396

  5. Peptide receptor radionuclide therapy with somatostatin analogues in neuroendocrine tumors.

    PubMed

    Giovacchini, Giampiero; Nicolas, Guillaume; Forrer, Flavio

    2012-06-01

    Neuroendocrine tumors (NETs) are rare tumors with variable malignant behavior. The majority of NETs express increased levels of somatostatin (SST) receptors, particularly SST2 receptors. Radiolabeled peptides specific for the SST2 receptors may be used for diagnosis of NETs and for peptide receptor radionuclide therapy (PRRT). [(111)In-DTPA(0)]-octreotide has been the first peptide used for PRRT. This radiolabeled peptide, emitting Auger electrons, often induced symptomatic relief, but objective morphological responses were rarely documented. After the introduction of the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) other peptides, primarily [DOTA(0),Tyr(3)]octreotate (DOTATATE) and [DOTA(0),Tyr(3)]octreotide (DOTATOC) were labeled with (90)Y or (177)Lu and used for therapy applications. The rate of objective response obtained with these radiolabeled peptides ranges between 6% and 46%, owing to differences in inclusion criteria adopted in different studies, length and type of therapy, and criteria of evaluation of the response. The present data in the literature do not allow defining the most suitable peptide and radionuclide for the treatment of NETs. Instead emerging evidence indicates that a combination of nuclides with different physical characteristics might be more effective than the use of a single nuclide. Kidney and bone marrow toxicity are the limiting factors for PRRT. Mild toxicity is often encountered while severe toxicity is rarer. Toxicity could be reduced and therapeutic efficacy enhanced by patient-specific dosimetry. Future directions include different issues of PRRT, such as defining the most suitable treatment scheme, evaluation of new peptides with different affinity profiles to other SST receptor subtypes, and reduction of toxicity. PMID:22292758

  6. Effectiveness of Endoscopic Treatment for Gastrointestinal Neuroendocrine Tumors

    PubMed Central

    Sun, Weili; Wu, Siyuan; Han, Xiao; Yang, Chuanhua

    2016-01-01

    Abstract Several recent studies have explored efficacy and safety of different endoscopic treatments for gastrointestinal neuroendocrine tumors (GI-NETs). However, there is no definitive consensus regarding the best endoscopic approach for GI-NETs treatment. Therefore, the present study was conducted to investigate the application of various endoscopic techniques for the treatment of GI-NETs according to the previous conclusions and to summarize the optimal endoscopic modalities for GI-NETs. Ninety-eight patients with 100 GI-NETs removed by endoscopic therapies were reviewed. The pathological complete resection rate (PCRR), complication, local recurrence, and factors possibly associated with the pathological complete resection were analyzed. Twenty-two patients were treated by conventional polypectomy (including 6 cold biopsy forceps polypectomy and 16 snare polypectomy with electrocauterization), 41 by endoscopic mucosal resection (EMR), and 35 by endoscopic submucosal dissection (ESD). The PCRRs of conventional polypectomy, EMR, and ESD were 86.4%, 75.6%, and 85.7%, respectively. Sixteen GI-NETs that had a polypoid appearance, with a mean tumor size of 5.2 mm, were removed by snare polypectomy (PCRR 93.8%). The complication rates of conventional polypectomy, EMR, and ESD were 0.0% (0/22), 2.4% (1/41), and 2.9% (1/35), respectively. There were 2 local recurrences after cold biopsy forceps polypectomy treatment and no local recurrences in the EMR and ESD groups (P = 0.049). The results showed that PCRR was only associated with the depth of invasion (P = 0.038). Endoscopic resection of GI-NETs is safe and effective in properly selected patients. For submucosal GI-NETs, ESD was a feasible modality, with a higher PCRR compared with EMR. For ≤5 mm polypoid-like NETs, snare polypectomy with electrocauterization was a simple procedure with a high PCRR. PMID:27082572

  7. Localization of Neuroendocrine Tumors Using Somatostatin Receptor Imaging With Indium-111-Pentetreotide (OctreoScan).

    PubMed

    Ellison; Schirmer; Olsen; Pozderac; Hinkle; Hill; O'Dorisio; O'Dorisio

    1997-01-01

    BACKGROUND: Many imaging methods have been used to detect neuroendocrine tumors of the gastrointestinal system. There is no gold standard for identifying the location of primary tumors and their potential metastases, and most conventional imaging techniques cannot detect tumors less than 1.0 cm in size. METHODS: The authors have investigated the use of 111-In-pentetreotide as an imaging agent for abdominal neuroendocrine tumors. RESULTS: The agent is cleared rapidly by the kidneys and is primarily excreted intact with a biologic half-life of six hours. The largest radiation burden is to the spleen and kidneys. A nine-center study conducted in Europe involved 365 patients with gastroenteropancreatic neuroendocrine tumors that were also imaged by other methods. The results of 111-In-pentetreotide were in agreement with those obtained by other methods for 79% of tumor locations. An additional 110 tumor localizations were detected that were not seen with conventional methods. The smallest gastrinoma imaged by 111-In-pentetreotide was a 4-mm duodenal tumor. CONCLUSIONS: Scintigraphy with 111-In-pentetreotide is effective in visualizing various somatostatin receptors characteristic of neuroendocrine tumors of the gastrointestinal tract. Insulinomas, however, are not well imaged. Concurrent computed tomography scanning is advised to minimize the risk of missing liver metastases. PMID:10763002

  8. Regorafenib in Treating Patients With Advanced or Metastatic Neuroendocrine Tumors

    ClinicalTrials.gov

    2015-08-29

    Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Pancreatic Polypeptide Tumor; Pulmonary Carcinoid Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Somatostatinoma

  9. Sigmoid colon carcinoma with focal neuroendocrine differentiation associated with ulcerative colitis: A case report

    PubMed Central

    Rifu, Kazuma; Koinuma, Koji; Horie, Hisanaga; Morimoto, Mitsuaki; Kono, Yoshihiko; Tahara, Makiko; Sakuma, Yasunaru; Hosoya, Yoshinori; Kitayama, Joji; Lefor, Alan Kawarai; Sata, Naohiro; Suzuki, Tsukasa; Fukushima, Noriyoshi

    2016-01-01

    Introduction Neuroendocrine tumors of the colon and rectum are relatively rare compared to sporadic colorectal carcinoma. There are few reports of neuroendocrine tumors of the colon and rectum in patients with ulcerative colitis. Presentation of case A patient with sigmoid colon carcinoma with focal neuroendocrine features is presented. A 32-year-old man, who had been followed for ulcerative colitis for 14 years, was found to have carcinoma of the sigmoid colon on routine annual colonoscopy, and he underwent laparoscopic total colectomy. Pathologic examination showed sigmoid colon adenocarcinoma with focal neuroendocrine features. Discussion Most colorectal carcinomas associated with inflammatory bowel disease are histologically similar to the sporadic type, and tumors with neuroendocrine features are very unusual. Conclusion Very rare case of sigmoid colon carcinoma with neuroendocrine features arising in a patient with UC was described. PMID:27136202

  10. Calcitonin-negative neuroendocrine tumor of thyroid gland mimicking anaplastic carcinoma: an unusual entity

    PubMed Central

    Arpaci, Rabia Bozdogan; Berkesoglu, Mustafa; Dag, Ahmet; Sezer, Emel; Bal, Kemal Koray; Vayısoğlu, Yusuf

    2015-01-01

    Medullary thyroid cancer is the neuroendocrine tumor (NET) of thyroid with mostly both secreting calcitonin and immunohistochemically showing calcitonin positivity. Occasionally; NETs of thyroid may have little or no calcitonin expression. We present a case of serum calcitonin negative and immunohistochemically calcitonin-negative staining tumor with positive reaction to neuroendocrine markers synaptophysin and chromogranin-A. The patient’s right vocal cord was paralytic and thyroid mass was huge with descending to thorax till hilar region. We discussed diagnostic difficulties and way of treatment about NETs of thyroid with the light of current literature with this case. PMID:26312221

  11. Everolimus and Octreotide Acetate With or Without Bevacizumab in Treating Patients With Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors That Cannot Be Removed by Surgery

    ClinicalTrials.gov

    2016-06-20

    Gastrin-Producing Neuroendocrine Tumor; Malignant Pancreatic Gastrinoma; Malignant Pancreatic Glucagonoma; Malignant Pancreatic Insulinoma; Malignant Pancreatic Somatostatinoma; Pancreatic Alpha Cell Adenoma; Pancreatic Beta Cell Adenoma; Pancreatic Delta Cell Adenoma; Pancreatic G-Cell Adenoma; Pancreatic Glucagonoma; Pancreatic Insulinoma; Pancreatic Polypeptide Tumor; Recurrent Pancreatic Carcinoma; Recurrent Pancreatic Neuroendocrine Carcinoma; Somatostatin-Producing Neuroendocrine Tumor; Stage III Pancreatic Cancer; Stage IV Pancreatic Cancer

  12. Well Differentiated Neuroendocrine Tumors with a Morphologically Apparent High Grade Component: A Pathway Distinct from Poorly Differentiated Neuroendocrine Carcinomas

    PubMed Central

    Tang, Laura H.; Untch, Brian R.; Reidy, Diane L.; O'Reilly, Eileen; Dhall, Deepti; Jih, Lily; Basturk, Olca; Allen, Peter J.; Klimstra, David S.

    2016-01-01

    Purpose Most well-differentiated neuroendocrine tumors (WD-NETs) of the enteropancreatic system are low-intermediate grade (G1,G2). Elevated proliferation demonstrated by either a brisk mitotic rate (>20/10 high power fields) or high Ki67 index (>20%) defines a group of aggressive neoplasms designated as high grade (G3) neuroendocrine carcinoma (NEC). High grade NEC is equated with poorly-differentiated NEC (PD-NEC) and is associated with a dismal outcome. Progression of WD-NETs to a high grade neuroendocrine neoplasm very rarely occurs and their clinicopathologic and molecular features need to be characterized. Methods We investigated the 31 cases of WD-NETs with evidence of component of a high grade neoplasm. The primary sites included pancreas, small bowel, bile duct, and rectum. Histopathology of the cases was retrospectively reviewed and selected immunohistochemistry and gene mutation analyses performed. Results The high grade component occurred either within the primary tumor (48%) or at metastatic sites (52%). The clinical presentation, radiographic features, biomarkers, and the genotype of these WD-NETs with high grade component remained akin to those of G1-G2 WD-NETs. The median disease specific survival (DSS) was 55 months (16-119 months), and 2-year and 5-year DSS was 88% and 49%, respectively – significantly better than that of a comparison group of true PD-NEC (DSS 11 months). Conclusion Mixed grades can occur in WD-NETs, which are distinguished from PDNECs by their unique phenotype, proliferative indices, and the genotype. This phenomenon of mixed grade in WD-NET provides additional evidence to the growing recognition that the current WHO G3 category contains both WD-NETs as well as PDNECs. PMID:26482044

  13. Neuroendocrine Tumors of the Urinary Bladder According to the 2016 World Health Organization Classification: Molecular and Clinical Characteristics.

    PubMed

    Kouba, Erik; Cheng, Liang

    2016-09-01

    Neuroendocrine neoplasms of the urinary bladder are a rare type of tumor that account for a small percentage of urinary bladder neoplasms. These tumors of the urinary bladder range from well-differentiated neuroendocrine neoplasms (carcinoids) to the more aggressive subtypes such as small cell carcinoma. Despite the rarity of the neuroendocrine tumors of the bladder, there has been substantial investigation into the underlying genomic, molecular, and the cellular alterations within this group of neoplasms. Accordingly, these findings are increasingly incorporated into the understanding of clinical aspects of these neoplasms. In this review, we provide an overview of recent literature related to the 2016 World Health Organization Classification of Neuroendocrine Tumors of the Urinary Bladder. Particular emphasis is placed on molecular alterations and recently described gene expression. The neuroendocrine tumors of the urinary bladder are subdivided into four subtypes. Similar to their pulmonary and other extrapulmonary site counterparts, these have different degrees of neuroendocrine differentiation and morphological features. The clinical aspects of four subtypes of neuroendocrine tumor are discussed with emphasis of the most recent developments in diagnosis, treatment, and prognosis. An understanding of molecular basis of neuroendocrine tumors will provide a base of knowledge for future investigations into this group of unusual bladder neoplasms. PMID:27334654

  14. Somatostatin Analogs and Tumor Localization Do Not Influence Vitamin D Concentration in Patients with Neuroendocrine Tumors.

    PubMed

    Motylewska, Ewelina; Gawronska, Joanna; Niedziela, Agata; Melen-Mucha, Gabriela; Lawnicka, Hanna; Komorowski, Jan; Swietoslawski, Jacek; Stepien, Henryk

    2016-04-01

    Patients with neuroendocrine tumors (NETs), malignancies of rare but still rising incidence, may be a group at higher risk of vitamin D insufficiency. The gastrointestinal tumor prevalence and somatostatin analog (SSA) therapy may cause vitamin D malabsorption. The aim of this study was to evaluate the serum level of vitamin D in NET patients. A total of 36 NET patients were enrolled into the experimental group and 16 individuals were enrolled into the control group. All patients were further classified into subgroups according to primary tumor localization (gastropancreatic, lung, and other NETs) or therapy (with or without SSA treatment). The concentrations of total 25(OH)D were assayed with Electrochemiluminescence immunoassay (ECLIA). Serum concentration of 25(OH)D in NET patients did not differ significantly from that of the control group. However, the average level of 25(OH)D in both groups met the criteria of vitamin D deficiency. Importantly, SSA therapy did not aggravate vitamin D deficiency. Moreover, the concentration of 25(OH)D in the studied group was not significantly influenced by primary tumor localization, patient age, or season. Vitamin D deficiency is a widespread disorder affecting both NET patients and individuals without other health problems, and SSA and gastrointestinal tumor localization do not exacerbate this condition. PMID:27028957

  15. Gefitinib in Treating Patients With Progressive Metastatic Neuroendocrine Tumors

    ClinicalTrials.gov

    2013-06-03

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

  16. The Contrasting Role of p16Ink4A Patterns of Expression in Neuroendocrine and Non-Neuroendocrine Lung Tumors: A Comprehensive Analysis with Clinicopathologic and Molecular Correlations

    PubMed Central

    Fusco, Nicola; Guerini-Rocco, Elena; Del Gobbo, Alessandro; Franco, Renato; Zito-Marino, Federica; Vaira, Valentina; Bulfamante, Gaetano; Ercoli, Giulia; Nosotti, Mario; Palleschi, Alessandro; Bosari, Silvano; Ferrero, Stefano

    2015-01-01

    Lung cancer encompasses a constellation of malignancies with no validated prognostic markers. p16Ink4A expression has been reported in different subtypes of lung cancers; however, its prognostic value is controversial. Here, we sought to investigate the clinical significance of p16Ink4A immunoexpression according to specific staining patterns and its operational implications. A total of 502 tumors, including 277 adenocarcinomas, 84 squamous cell carcinomas, 22 large cell carcinomas, 47 typical carcinoids, 12 atypical carcinoids, 28 large cell neuroendocrine carcinomas, and 32 small cell carcinomas were reviewed and subjected to immunohistochemical analysis for p16Ink4A and Ki67. The spectrum of p16Ink4A expression was annotated for each case as negative, sporadic, focal, or diffuse. Expression at immunohistochemical level showed intra-tumor homogeneity, regardless tumor histotype. Enrichments in cells expressing p16Ink4A were observed from lower- to higher-grade neuroendocrine malignancies, whereas a decrease was seen in poorly and undifferentiated non-neuroendocrine carcinomas. Tumor proliferation indices were higher in neuroendocrine tumors expressing p16Ink4A while non-neuroendocrine malignancies immunoreactive for p16Ink4A showed a decrease in Ki67-positive cells. Quantitative statistical analyses including each histotype and the p16Ink4A status confirmed the independent prognostic role of p16Ink4A expression, being a high-risk indicator in neuroendocrine tumors and a marker of good prognosis in non-neuroendocrine lung malignancies. In this study, we provide circumstantial evidence to suggest that the routinary assessment of p16Ink4A expression using a three-tiered scoring algorithm, even in a small biopsy, may constitute a reliable, reproducible, and cost-effective substrate for a more accurate risk stratification of each individual patient. PMID:26674347

  17. 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. PMID:9448967

  18. Assessment of intracranial metastases from neuroendocrine tumors/carcinoma

    PubMed Central

    Ragab Shalaby, Ahmed M.; Kazuei, Hoshi; Koichi, Honma; Naguib, Saeed; Al-Menawei, Lubna A.

    2016-01-01

    Background: The most common sites of origin for neuroendocrine carcinoma are gastrointestinal tract and its accessory glands, and lungs. Materials and Methods: One-hundred fifty cases diagnosed with metastatic brain lesions were retrieved from hospital records within 5 years. For these cases, the primary neoplasm, histopathological classification, metastasis, treatment, and fate all were studied. Results: Intracranial deposits were detected in 10%. The primary lesion was in the lungs in 87% of patients, and 1 patient in the breast and 1 in esophagus. Pathological classification of the primary lesion was Grade 2 (MIB-1: 3–20%) in 1 patient and neuroendocrine carcinoma (MIB-1: ≥21%) in 14 patients. The median period from onset of the primary lesion up to diagnosis of brain metastasis was 12.8 months. About 33% of patients had a single metastasis whereas 67% patients had multiple metastases. Brain metastasis was extirpated in 33% of patients. Stereotactic radiotherapy alone was administered in 20% of patients, and brain metastasis was favorably controlled in most of the patients with coadministration of cranial irradiation as appropriate. The median survival period from diagnosis of brain metastasis was 8.1 months. Conclusion: Most of patients with brain metastasis from neuroendocrine carcinoma showed the primary lesion in the lungs, and they had multiple metastases to the liver, lymph nodes, bones, and so forth at the time of diagnosis of brain metastasis. The guidelines for accurate diagnosis and treatment of neuroendocrine carcinoma should be immediately established based on further analyses of those patients with brain metastasis. PMID:27365963

  19. PHLDA3 is a novel tumor suppressor of pancreatic neuroendocrine tumors.

    PubMed

    Ohki, Rieko; Saito, Kozue; Chen, Yu; Kawase, Tatsuya; Hiraoka, Nobuyoshi; Saigawa, Raira; Minegishi, Maiko; Aita, Yukie; Yanai, Goichi; Shimizu, Hiroko; Yachida, Shinichi; Sakata, Naoaki; Doi, Ryuichiro; Kosuge, Tomoo; Shimada, Kazuaki; Tycko, Benjamin; Tsukada, Toshihiko; Kanai, Yae; Sumi, Shoichiro; Namiki, Hideo; Taya, Yoichi; Shibata, Tatsuhiro; Nakagama, Hitoshi

    2014-06-10

    The molecular mechanisms underlying the development of pancreatic neuroendocrine tumors (PanNETs) have not been well defined. We report here that the genomic region of the PHLDA3 gene undergoes loss of heterozygosity (LOH) at a remarkably high frequency in human PanNETs, and this genetic change is correlated with disease progression and poor prognosis. We also show that the PHLDA3 locus undergoes methylation in addition to LOH, suggesting that a two-hit inactivation of the PHLDA3 gene is required for PanNET development. We demonstrate that PHLDA3 represses Akt activity and Akt-regulated biological processes in pancreatic endocrine tissues, and that PHLDA3-deficient mice develop islet hyperplasia. In addition, we show that the tumor-suppressing pathway mediated by MEN1, a well-known tumor suppressor of PanNETs, is dependent on the pathway mediated by PHLDA3, and inactivation of PHLDA3 and MEN1 cooperatively contribute to PanNET development. Collectively, these results indicate the existence of a novel PHLDA3-mediated pathway of tumor suppression that is important in the development of PanNETs. PMID:24912192

  20. The Treatment of Liver Metastases in Patients with Neuroendocrine Tumors in 2012

    PubMed Central

    Amaral, Teresa; Fernandes, Isabel; Sousa, Ana Rita; Costa, Ana Lúcia; Távora, Isabel; Quintela, António; Cortes, Paulo; Costa, Luís

    2013-01-01

    Neuroendocrine tumors (NETs) comprise a heterogeneous group of tumors that form a distinct entity. Approximately 75–80% of patients present with liver metastases at the time of their diagnosis, and 20%–25% will develop these lesions in the course of their disease. The presence of secondary deposits in the liver significantly increases the morbidity and mortality in these patients. The only potentially curative treatment is the surgical resection of the primary tumor and hepatic lesions. However, only 10% of patients presents under ideal conditions for that approach. Several techniques aimed at localized liver lesions have been applied also with interesting results in terms of survival and symptom control. The same has been demonstrated with new systemic therapies (target therapies). However, these are still under study, in order to define their true role in the management of these patients. This paper intends to address, in a general way, the various treatment options in patients with liver metastases from neuroendocrine tumors. PMID:27335831

  1. Tumor-derived circulating endothelial cell clusters in colorectal cancer.

    PubMed

    Cima, Igor; Kong, Say Li; Sengupta, Debarka; Tan, Iain B; Phyo, Wai Min; Lee, Daniel; Hu, Min; Iliescu, Ciprian; Alexander, Irina; Goh, Wei Lin; Rahmani, Mehran; Suhaimi, Nur-Afidah Mohamed; Vo, Jess H; Tai, Joyce A; Tan, Joanna H; Chua, Clarinda; Ten, Rachel; Lim, Wan Jun; Chew, Min Hoe; Hauser, Charlotte A E; van Dam, Rob M; Lim, Wei-Yen; Prabhakar, Shyam; Lim, Bing; Koh, Poh Koon; Robson, Paul; Ying, Jackie Y; Hillmer, Axel M; Tan, Min-Han

    2016-06-29

    Clusters of tumor cells are often observed in the blood of cancer patients. These structures have been described as malignant entities for more than 50 years, although their comprehensive characterization is lacking. Contrary to current consensus, we demonstrate that a discrete population of circulating cell clusters isolated from the blood of colorectal cancer patients are not cancerous but consist of tumor-derived endothelial cells. These clusters express both epithelial and mesenchymal markers, consistent with previous reports on circulating tumor cell (CTC) phenotyping. However, unlike CTCs, they do not mirror the genetic variations of matched tumors. Transcriptomic analysis of single clusters revealed that these structures exhibit an endothelial phenotype and can be traced back to the tumor endothelium. Further results show that tumor-derived endothelial clusters do not form by coagulation or by outgrowth of single circulating endothelial cells, supporting a direct release of clusters from the tumor vasculature. The isolation and enumeration of these benign clusters distinguished healthy volunteers from treatment-naïve as well as pathological early-stage (≤IIA) colorectal cancer patients with high accuracy, suggesting that tumor-derived circulating endothelial cell clusters could be used as a means of noninvasive screening for colorectal cancer. In contrast to CTCs, tumor-derived endothelial cell clusters may also provide important information about the underlying tumor vasculature at the time of diagnosis, during treatment, and throughout the course of the disease. PMID:27358499

  2. Clinicopathological Characteristics of Laterally Spreading Colorectal Tumor

    PubMed Central

    Xiang, Li; Wang, Yadong; Wang, Xianfei; Li, Aimin; Liu, Side

    2014-01-01

    Background and Aims Laterally spreading tumor (LST) is a colorectal pre-cancerous lesion. Previous studies have demonstrated distinct LST clinicopathological characteristics in different populations. This study evaluated clinicopathological characteristics of LST in a Chinese population. Methods A total of 259 Chinese LST patients with 289 lesions were recruited for endoscopic and clinicopathological analyses. Results Among these 289 lesions, 185 were granular type (LST-G), whereas 104 were non-granular type (LST-NG). LST-G lesions were further classified into homogeneous G-type and nodular mixed G-type, while LST-NG lesions were further classified into flat elevated NG-type and pseudo-depressed NG-type. Clinically, these four LST subtypes showed distinct clinicopathological characteristics, e.g., lesion size, location, or histopathological features (high-grade intraepithelial neoplasia and submucosal carcinoma). The nodular mixed G-type showed larger tumor size and higher incidence of high-grade intraepithelial neoplasia compared to the other three subtypes, while pseudo-depressed NG-type lesions showed the highest incidence of submucosal carcinoma. Noticeably, no diffidence was detected between the lesions of homogeneous G-type and flat elevated NG-type with regard to the histopathological features. Histology of the malignancy potential was associated with nodular mixed G-type [OR = 2.41, 95% CI (1.09–5.29); P = 0.029], flat elevated NG-type [OR = 3.49, 95% CI (1.41–8.22); P = 0.007], Diameter ≥30 mm [OR = 2.56, 95% CI (1.20–5.20); P = 0.009], Villous adenoma [OR = 2.76, 95% CI (1.01–7.58); P = 0.048] and serrated adenoma [OR = 6.99, 95% CI (1.81–26.98); P = 0.005]. Conclusion Chinese LSTs can be divided into four different subtypes, which show distinct clinicopathological characteristics. Morphology, size and pathological characteristics are all independent predictors of advanced histology. PMID:24751926

  3. Novel interferon-{lambda}s induce antiproliferative effects in neuroendocrine tumor cells

    SciTech Connect

    Zitzmann, Kathrin; Brand, Stephan; Baehs, Sebastian; Goeke, Burkhard; Meinecke, Jennifer; Spoettl, Gerald; Meyer, Heinrich; Auernhammer, Christoph J. . E-mail: Christoph.Auernhammer@med.uni-muenchen.de

    2006-06-16

    Interferon-{alpha} (IFN-{alpha}) is used for biotherapy of neuroendocrine carcinomas. The interferon-{lambda}s (IL-28A/B and IL-29) are a novel group of interferons. In this study, we investigated the effects of the IFN-{lambda}s IL-28A and IL-29 on human neuroendocrine BON1 tumor cells. Similar to IFN-{alpha}, incubation of BON1 cells with IL-28A (10 ng/ml) and IL-29 (10 ng/ml) induced phosphorylation of STAT1, STAT2, and STAT3, significantly decreased cell numbers in a proliferation assay, and induced apoptosis as demonstrated by poly(ADP-ribose) polymerase (PARP)-cleavage, caspase-3-cleavage, and DNA-fragmentation. Stable overexpression of suppressor of cytokine signaling proteins (SOCS1 and SOCS3) completely abolished the aforementioned effects indicating that SOCS proteins act as negative regulators of IFN-{lambda} signaling in BON1 cells. In conclusion, the novel IFN-{lambda}s IL-28A and IL-29 potently induce STAT signaling and antiproliferative effects in neuroendocrine BON1 tumor cells. Thus, IFN-{lambda}s may hint a promising new approach in the antiproliferative therapy of neuroendocrine tumors.

  4. High VEGF serum values are associated with locoregional spread of gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

    PubMed

    Cigrovski Berković, Maja; Čačev, Tamara; Catela Ivković, Tina; Marout, Jasminka; Ulamec, Monika; Zjačić-Rotkvić, Vanja; Kapitanović, Sanja

    2016-04-15

    Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are highly vascularized neoplasms, capable of synthethisizing VEGF-A, a key mediator of angiogenesis. In pancreatic neuroendocrine tumors (pNETs) VEGF expression is higher in benign and low-grade tumors and associated with good prognosis (neuroendocrine paradox) while the VEGF role in gastrointestinal NETs (GI-NETs) is still unclear. In this study, we examined the VEGF-1154A/G polymorphism in 145 GEP-NET patients and 150 controls. Next, we measured VEGF serum levels and VEGF tumor protein expression, comparing it with Ki67 and tumor grade. Patients' VEGF serum levels were compared with VEGF -1145A/G genotypes and metastatic status as well as with chromogranin A (CgA) and 5-hydroxyindolacetic acid (5-HIAA) in case of GI-NET patients. In this study GEP-NET patients had elevated VEGF serum values when compared to healthy controls (p = 0.0013). VEGF-1145G allele correlated with higher VEGF serum levels (p = 0.002). Patients with metastatic tumors had higher VEGF serum values when compared to patients without metastases (p = 0.033), and highest levels were observed in case of lymph node metastases (p = 0.008). VEGF-1145G allele was more frequent in non-functional GI-NET patients than in healthy controls (p = 0.041). CgA was superior to VEGF in tumor detection, while VEGF was superior to 5-HIAA. A correlation was observed between VEGF immunohistochemical staining and Ki-67 (p = 0.028). Tumours with weaker VEGF protein expression were more aggressive than tumours with stronger VEGF expression, confirming a "neuroendocrine paradox" in GI-NETs. Our results suggest the role of VEGF in GI-NETs locoregional spread. PMID:26805636

  5. The axon guidance molecule semaphorin 3F is a negative regulator of tumor progression and proliferation in ileal neuroendocrine tumors

    PubMed Central

    Vercherat, Cécile; Blanc, Martine; Lepinasse, Florian; Gadot, Nicolas; Couderc, Christophe; Poncet, Gilles; Walter, Thomas; Joly, Marie-Odile; Hervieu, Valérie; Scoazec, Jean-Yves; Roche, Colette

    2015-01-01

    Gastro-intestinal neuroendocrine tumors (GI-NETs) are rare neoplasms, frequently metastatic, raising difficult clinical and therapeutic challenges due to a poor knowledge of their biology. As neuroendocrine cells express both epithelial and neural cell markers, we studied the possible involvement in GI-NETs of axon guidance molecules, which have been shown to decrease tumor cell proliferation and metastatic dissemination in several tumor types. We focused on the role of Semaphorin 3F (SEMA3F) in ileal NETs, one of the most frequent subtypes of GI-NETs. SEMA3F expression was detected in normal neuroendocrine cells but was lost in most of human primary tumors and all their metastases. SEMA3F loss of expression was associated with promoter gene methylation. After increasing endogenous SEMA3F levels through stable transfection, enteroendocrine cell lines STC-1 and GluTag showed a reduced proliferation rate in vitro. In two different xenograft mouse models, SEMA3F-overexpressing cells exhibited a reduced ability to form tumors and a hampered liver dissemination potential in vivo. This resulted, at least in part, from the inhibition of mTOR and MAPK signaling pathways. This study demonstrates an anti-tumoral role of SEMA3F in ileal NETs. We thus suggest that SEMA3F and/or its cellular signaling pathway could represent a target for ileal NET therapy. PMID:26447612

  6. Hypercalcemia from metastatic pancreatic neuroendocrine tumor secreting 1,25-dihydroxyvitamin D

    PubMed Central

    Zhu, Viola; de las Morenas, Antonio; Janicek, Milos

    2014-01-01

    Malignant hypercalcemia occurs in about 20-30% of patients with cancer, both solid tumors and hematologic malignancies. The secretion of parathyroid hormone-related protein (PTH-rP) is the most common cause and has been shown to be the etiology of hypercalcemia associated with neuroendocrine tumors. Here we report the case of a patient with metastatic pancreatic neuroendocrine tumor who developed hypercalcemia more than 4 years after the initial diagnosis as a result of secretion of 1,25-dihydroxyvitamin D, a mechanism only commonly seen in lymphomas. The successful control of the patient’s disease with capecitabine and temozolomide led to the alleviation of this paraneoplastic syndrome. PMID:25083313

  7. 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

  8. Neuroendocrine Cancer of Rectum Metastasizing to Ovary.

    PubMed

    Amin, Sapna Vinit; Kumaran, Aswathy; Bharatnur, Sunanda; Vasudeva, Akhila; Udupa, Kartik; Venkateshiah, Dinesh Bangalore; Bhat, Shaila T

    2016-01-01

    Neuroendocrine carcinomas (NECs) are rare malignancies that originate from the hormone-producing cells of the body's neuroendocrine system. Rectal high grade NEC (HG-NEC) constituting less than 1% of colorectal cancers can cause large ovarian metastasis that may be the initial presenting complaint. Ovarian Krukenberg tumor from a primary rectal HG-NEC is a very unusual and exceedingly uncommon differential diagnosis for secondary ovarian malignancy. This case report describes one such extremely rare case of a woman who had presented to the gynecology department with features suggestive of ovarian malignancy and was ultimately diagnosed to have Krukenberg tumor originating from neuroendocrine cancer of rectum. We felt this is a good opportunity to spread more light on neuroendocrine neoplasms that are very rare in gynecological practice. PMID:27293931

  9. Neuroendocrine Cancer of Rectum Metastasizing to Ovary

    PubMed Central

    Amin, Sapna Vinit; Kumaran, Aswathy; Bharatnur, Sunanda; Vasudeva, Akhila; Udupa, Kartik; Venkateshiah, Dinesh Bangalore; Bhat, Shaila T.

    2016-01-01

    Neuroendocrine carcinomas (NECs) are rare malignancies that originate from the hormone-producing cells of the body's neuroendocrine system. Rectal high grade NEC (HG-NEC) constituting less than 1% of colorectal cancers can cause large ovarian metastasis that may be the initial presenting complaint. Ovarian Krukenberg tumor from a primary rectal HG-NEC is a very unusual and exceedingly uncommon differential diagnosis for secondary ovarian malignancy. This case report describes one such extremely rare case of a woman who had presented to the gynecology department with features suggestive of ovarian malignancy and was ultimately diagnosed to have Krukenberg tumor originating from neuroendocrine cancer of rectum. We felt this is a good opportunity to spread more light on neuroendocrine neoplasms that are very rare in gynecological practice. PMID:27293931

  10. Pancreatic neuroendocrine tumors: Challenges in an underestimated disease.

    PubMed

    Viúdez, A; De Jesus-Acosta, A; Carvalho, F L; Vera, R; Martín-Algarra, S; Ramírez, N

    2016-05-01

    Pancreatic neuroendocrine tumours (PanNETs) are considered a relatively unusual oncologic entity. Due to its relative good prognosis, surgery remains the goal standard therapy not only in localized disease but also in the setting of locally or metastatic disease. Most of the patients are diagnosed in metastatic scenario, where multidisciplinary approach based on surgery, chemotherapies, liver-directed and/or molecular targeted therapies are commonly used. Owing to a deeper molecular knowledge of this disease, these targeted therapies are nowadays widely implemented, being the likely discovery of predictive biomarkers that would allow its use in other settings. This review is focused on describing the different classifications, etiology, prognostic biomarkers and multidisciplinary approaches that are typically used in PanNET. PMID:27021395

  11. Full-thickness excision using transanal endoscopic microsurgery for treatment of rectal neuroendocrine tumors

    PubMed Central

    Chen, Wei-Jie; Wu, Nan; Zhou, Jiao-Lin; Lin, Guo-Le; Qiu, Hui-Zhong

    2015-01-01

    AIM: To assess the efficacy of full-thickness excision using transanal endoscopic microsurgery (TEM) in the treatment of rectal neuroendocrine tumors. METHODS: We analyzed the data of all rectal neuroendocrine tumor patients who underwent local full-thickness excision using TEM between December 2006 and December 2014 at our department. Data collected included patient demographics, tumor characteristics, operative details, postoperative outcomes, pathologic findings, and follow-ups. RESULTS: Full-thickness excision using TEM was performed as a primary excision (n = 38) or as complete surgery after incomplete resection by endoscopic polypectomy (n = 21). The mean size of a primary tumor was 0.96 ± 0.21 cm, and the mean distance of the tumor from the anal verge was 8.4 ± 1.4 cm. The mean duration of the operation was 57.6 ± 13.7 min, and the mean blood loss was 13.5 ± 6.6 mL. No minor morbidities, transient fecal incontinence, or wound dehiscence was found. Histopathologically, all tumors showed typical histology without lymphatic or vessel infiltration, and both deep and lateral surgical margins were completely free of tumors. Among 21 cases of complete surgery after endoscopic polypectomy, 9 were histologically shown to have a residual tumor in the specimens obtained by TEM. No additional radical surgery was performed. No recurrence was noted during the median of 3 years’ follow-up. CONCLUSION: Full-thickness excision using TEM could be a first surgical option for complete removal of upper small rectal neuroendocrine tumors. PMID:26290641

  12. Cardiac metastases of neuroendocrine tumors treated with 177Lu DOTATATE peptide receptor radionuclide therapy or 131I-MIBG therapy.

    PubMed

    Makis, William; McCann, Karey; Bryanton, Mark; McEwan, Alexander J B

    2015-12-01

    Neuroendocrine tumors have a propensity to metastasize to the heart, although the reason for this remains unknown. A review of 251 neuroendocrine tumor patients treated with Lu DOTATATE peptide receptor radionuclide therapy or I-MIBG therapy at our institution since 2003 revealed 2 patients with cardiac metastases (incidence, 0.8%), one treated with Lu DOTATATE and one with I-MIBG. We present the imaging findings of these 2 patients, as well as their management and responses to therapy. PMID:26359563

  13. Perianal neuroendocrine tumor with suspected lymph node metastasis causing colonic compression and subsequent megacolon

    PubMed Central

    Joudrey, Scott D.; Robinson, Duane A.; Blair, Robert; McLaughlin, Leslie D.; Gaschen, Lorrie

    2015-01-01

    An 8-year-old spayed female domestic shorthair cat was presented with a 4- to 5-month history of a progressively growing mass above her anus and an inability to defecate for 3 to 4 wk. External perianal and internal regional masses were subsequently identified and diagnosed as tumors of neuroendocrine origin through surgical excision and histopathologic evaluation. The cat was treated with 2 courses of chemotherapy and radiation therapy. PMID:25750442

  14. Small Bowel Neuroendocrine Tumors with Inguinal Metastases: A Diagnostic and Therapeutic Dilemma

    PubMed Central

    Daly, Kevin P; Askarian, Farhad; Saif, Muhammad W

    2016-01-01

    Small bowel neuroendocrine tumors (NETs) are frequently characterized by a strong propensity to metastasize to the liver, mesentery, and peritoneum. However, only a few extra-abdominal metastatic sites have been reported in the published literature. The present paper implicates that primary small bowel NETs may unusually metastasize to the inguinal lymph nodes. Furthermore, we discuss the formidable diagnostic and therapeutic challenges associated with the metastatic NETs. PMID:27555990

  15. Urology pertinent neuroendocrine tumors: focusing on renal pelvis, bladder, prostate located sympathetic functional paragangliomas

    PubMed Central

    ALBERTI, C.

    2016-01-01

    Urology pertinent neuroendocrine neoplasias are more and more driving to research attractive contributions mainly as regards the urinary tract paragangliomas, besides the prostate cancer neuroendocrine differentiation. About such visceral sympathetic paragangliomas, a considerable attention is aroused by those concerning the renal pelvis, urinary bladder and, particularly, the prostate gland. Essential catecholamine/adrenergic signal-mediated pathophysiological implications and outlined diagnostic approaches are here taken into consideration. Particularly, to reach an accurate functional diagnostic assessment, both plasma and urine catecholamine level tests are required together with 123I or 131I-meta-iodobenzylguanidine (MIBG) scan while 131I-, instead of 123I-, labeled MIBG, proving to be also useful to targeted radionuclide therapy of sympathetic paragangliomas. Nevertheless, a thorough diagnostic confirmation should be obtained by a proper histologic/immunohistochemical study, so that it respectively highlighting the typical “zellballen” cell setting and neuroendocrine tumor cell specific bio-markers such as chromogranin-A, synaptophysin, neuron-specific enolase. Open/laparoscopic/robot-assisted surgical procedures are performed under α1 (doxazosin, prazosin) - and β(propranolol)-adrenergic blockade to avoid the risk of an intraoperative adrenergic signal-triggered hypertensive crisis, what moreover may occur also during cystoscopy and biopsy in case of bladder or prostate paraganglioma. Given a conceivable likeness, about some adrenergic-mediated pathophysiological implications, between prostate paraganglioma and prostate cancer neuroendocrine transdifferentiation – although as regards two obviously different diseases – a reliable pathogenetic matter concerning prostate paraganglioma is requiring novel research approaches. PMID:27381689

  16. Neuroendocrine tumors of the gallbladder: a case report and review of the literature

    PubMed Central

    2011-01-01

    Introduction Primary gallbladder neuroendocrine tumors are extremely rare, representing 0.2% of all neuroendocrine tumors. The diagnosis is incidental in most cases. Case presentation We describe the case of a 57-year-old Caucasian man who underwent laparoscopic cholecystectomy for the evaluation of a gallbladder polyp that had been incidentally detected by ultasonography. Histologically, his lesion was composed of monomorphic cells that contained small round nuclei and that were organized in small nodular, trabecular, and acinar structures. His cells were positive for chromogranin A and synaptophysin, and a diagnosis of "typical" carcinoid of the gallbladder was made. His post-operative computerized axial tomography, 111In-pentetreotide scintigraphy, and hormone-specific marker results were negative. He is disease-free 45 months after surgical treatment. Conclusions Characteristic pathological findings of the gallbladder neuroendocrine tumors predict the prognosis. Whereas classical carcinoids of the gallbladder only rarely have a metastatic or invasive phenotype, the "atypical" variants are more aggressive and are associated with a poorer prognosis. Given the difficulty in distinguishing between benign and malignant lesions in the pre-surgical setting, we tend to consider each polypoid-like lesion of the gallbladder to be a high-risk lesion if it is larger than 1 cm and, as a result, to emphasize the need for cholecystectomy in all cases, relying on the pathological and immunohistochemistry analyses for the final diagnosis. PMID:21801379

  17. Nicotine, acetylcholine and bombesin are trophic growth factors in neuroendocrine cell lines derived from experimental hamster lung tumors

    SciTech Connect

    Schueller, H.M.; Nylen, E.; Park, P.; Becker, K.L. George Washington Univ., Washington, DC )

    1990-01-01

    Neuroendocrine hamster lung tumors, induced by exposure to 60% hyperoxia and subcutaneous administration of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) for 12 weeks, were placed in cell culture. By subsequent selective transfer of epithelial cells and maintenance in an atmosphere of 8% CO{sub 2}, cell lines with characteristics of neuroendocrine cells were established. The neuroendocrine markers expressed by these cell lines included electron dense neuroendocrine secretion granules as well as secretion of calcitonin and mammalian bombesin. In keeping with data previously reported for a human neuroendocrine lung tumor cell line, nicotine, acetylcholien, and mammalian bombesin (MB) acted as strongrowth factors in these neuroendocrine hamster tumor lines. The mitogenic effect of nicotine an acetylcholine was abolished by nicotinic receptor inhibition while the effects of mammalian bombesin were inhibited by an antagonist of MB receptors. Our data suggest that a receptor-mediated mitogenic effect of nicotine on neuroendocrine lung cells may be instrumental in the induction of smoking-associated small cell lung cancer.

  18. Small cell neuroendocrine tumor of the breast in a 40 year-old woman: a case report

    PubMed Central

    2010-01-01

    Introduction Small cell neuroendocrine cancer of the breast is a rare tumor with less than 30 cases reported in the literature. The morphological and immunohistochemical patterns of this tumor are similar to small cell neuroendocrine cancer of the lung. For this reason, it is often difficult to distinguish a primary small cell neuroendocrine cancer of the breast from a metastatic lesion from other sites. Case presentation We report and characterize with immunohistochemical techniques a case of primary small cell neuroendocrine cancer of the breast occurring in a 40-year-old Caucasian woman. A palpable and mobile 3.0 cm tumor was located in the upper-outer quadrant of her right breast. Lumpectomy and subsequent radical mastectomy with axillary lymph node resection were performed. Microscopically, the tumor consisted predominantly of a diffuse proliferation of small oat cells. The tumor cells were positive for neuroendocrine markers chromogranin A and synaptophysin. One of 16 lymph nodes was metastatic. A correct treatment needs to be chosen. Conclusions It has recently been demonstrated that early small cell neuroendocrine cancer of the breast shows a good prognosis with adjuvant treatments with high disease free survival. Our patient is alive and well without disease eight years after treatment. We performed an adjuvant therapy with the classic scheme doxorubicin and cyclophosphamide, followed by carboplatin and etoposide. A more extensive review is required to define a standard treatment protocol for this rare neoplasm. PMID:20591162

  19. Primary ovarian neuroendocrine tumor arising in association with a mature cystic teratoma: A case report.

    PubMed

    Orsi, Nicolas M; Menon, Mini

    2016-08-01

    Primary ovarian carcinoid tumors are exceptionally rare entities accounting for approximately 0.1% of all ovarian neoplasms. This report describes a primary ovarian neuroendocrine tumor arising in association with a mature cystic teratoma in a 65 year-old woman. Macroscopically, the unilateral adnexal tumor was composed of cystic, solid and mucinous elements which resolved into a dual component lesion histologically. The majority of the tumor displayed an organoid architecture with mild to moderate pleomorphism and no discernible mitotic activity, while approximately 10% consisted of sheets and groups of cells with highly pleomorphic nuclei, necrosis and occasional mitoses. Features of a mature cystic teratoma were seen very focally. Immunohistochemistry revealed strong, diffuse positivity for CD56 and synaptophysin. Chromogranin immunonegativity was noted and there was an absence of nuclear β-catenin accumulation. Ki-67 index was 10-12%. Although there is no established diagnostic framework for primary ovarian carcinoid tumors, this case was diagnosed as a well-differentiated neuroendocrine tumor, Grade 2 (intermediate grade), arising in association with a mature cystic teratoma/dermoid cyst. This case highlights the need to develop ovarian diagnostic criteria in this area. PMID:27508272

  20. An Integrated Framework for Automatic Ki-67 Scoring in Pancreatic Neuroendocrine Tumor

    PubMed Central

    Xing, Fuyong; Su, Hai; Yang, Lin

    2015-01-01

    The Ki-67 labeling index is a valid and important biomarker to gauge neuroendocrine tumor cell progression. Automatic Ki-67 assessment is very challenging due to complex variations of cell characteristics. In this paper, we propose an integrated learning-based framework for accurate Ki-67 scoring in pancreatic neuroendocrine tumor. The main contributions of our method are: a novel and robust cell detection algorithm is designed to localize both tumor and non-tumor cells; a repulsive deformable model is applied to correct touching cell segmentation; a two stage learning-based scheme combining cellular features and regional structure information is proposed to differentiate tumor from non-tumor cells (such as lymphocytes); an integrated automatic framework is developed to accurately assess the Ki-67 labeling index. The proposed method has been extensively evaluated on 101 tissue microarray (TMA) whole discs, and the cell detection performance is comparable to manual annotations. The automatic Ki-67 score is very accurate compared with pathologists’ estimation. PMID:24505696

  1. Endoscopic Ultrasonography-Guided Ethanol Ablation for Small Pancreatic Neuroendocrine Tumors: Results of a Pilot Study

    PubMed Central

    Choi, Jun-Ho; Oh, Dongwook; Lee, Sang Soo; Seo, Dong-Wan; Lee, Sung Koo; Kim, Myung-Hwan

    2015-01-01

    Background/Aims Endoscopic ultrasonography (EUS)-guided ethanol ablation is gaining popularity for the treatment of focal pancreatic lesions. The aim of this study was to evaluate the safety, feasibility, and treatment response after EUS-guided ethanol injection for small pancreatic neuroendocrine tumors (p-NETs). Methods This was a retrospective analysis of a prospectively collected database including 11 consecutive patients with p-NETs who underwent EUS-guided ethanol injection. Results EUS-guided ethanol injection was successfully performed in 11 patients with 14 tumors. The final diagnosis was based on histology and clinical signs as follows: 10 non-functioning neuroendocrine tumors and four insulinomas. During follow-up (median, 370 days; range, 152 to 730 days), 10 patients underwent clinical follow-up after treatment, and one patient was excluded because of loss to follow-up. A single treatment session with an injection of 0.5 to 3.8 mL of ethanol resulted in complete responses (CRs) at the 3-month radiologic imaging for seven of 13 tumors (response rate, 53.8%). Multiple treatment sessions performed in three tumors with residual viable enhancing tissue increased the number of tumors with CRs to eight of 13 (response rate, 61.5%). Mild pancreatitis occurred in three of 11 patients. Conclusions EUS-guided ethanol injection appears to be a safe, feasible, and potentially effective method for treating small p-NETs in patients who are poor surgical candidates. PMID:25844345

  2. Neuroendocrine tumors of the lung: hystological classification, diagnosis, traditional and new therapeutic approaches.

    PubMed

    Cueto, A; Burigana, F; Nicolini, A; Lugnani, F

    2014-01-01

    Lung neuroendocrine tumors are neoplasms originating from bronchopulmonary neuroendocrine cells, usually Kulchitsky cells, loaded with argentaffin granules. They account for 20-25% of all primitive lung tumors, the most common being the small-cell undifferentiated carcinoma. They include different tumors, from tumors of low-grade malignancy, especially the typical carcinoids, with high survival rates after surgical therapy, to the high-grade malignancy tumors, especially small-cell undifferentiated carcinomas. The latter have very few indications for surgical treatment with a low survival rate, even after multimodal therapy. The aim of this review is to describe the present knowledge and discuss possible new developments in the management of pulmonary neuroendocrine tumors. The authors examine and discuss in particular the role that surgical techniques should have in the treatment of small-cell lung cancer in opposition to a nihilism position that has limited therapies to non-surgical approaches. The critical review of this attitude opens the door to a more aggressive approach. In the meantime the review shows that it might be possible to include the new minimally invasive percutaneous ablative techniques as cryosurgery, thermotherapy and irreversible electroporation within a modern and flexible framework. The authors also present the hypothesis that cancer stem cells (CSC) are at the basis of recurrences of small-cell lung cancer (SCLC) and therefore that the issue is of difficult solution with the conventional oncologic approach considering the chemo-resistance of CSC to drugs. For these reasons an epigenetic therapy based on differentiation factors is proposed alongside the usual surgical and chemo-radiation protocols. PMID:24304279

  3. Efficacy and Safety of Endoscopic Ultrasound-guided Ethanol Ablation Therapy for Pancreatic Neuroendocrine Tumors.

    PubMed

    Matsumoto, Kazuyuki; Kato, Hironari; Tsutsumi, Koichiro; Mizukawa, Sho; Yabe, Syuntaro; Seki, Hiroyuki; Akimoto, Yutaka; Uchida, Daisuke; Tomoda, Takeshi; Yamamoto, Naoki; Horiguchi, Shigeru; Okada, Hiroyuki

    2016-08-01

    Recently, endoscopic ultrasonography (EUS)-guided ethanol ablation for small pancreatic neuroendocrine tumors (p-NETs) has been reported. However, the efficacy and safety of the technique remain unclear. We have launched a prospective pilot study of EUS-guided ethanol ablation for p-NETs. The major eligibility criteria are the presence of a pathologically diagnosed grade (G) 1 or G2 p-NET, a tumor size of 2cm, and being a poor candidate for surgery. A total of 5 patients will be treated. The primary endpoint will be the complete ablation rate at 1 month after treatment. PMID:27549680

  4. 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. PMID:27456058

  5. Radioembolization in the Treatment of Neuroendocrine Tumor Metastases to the Liver

    PubMed Central

    Vyleta, Martin; Coldwell, Douglas

    2011-01-01

    Surgical excision remains the preferred treatment for resectable hepatic metastases of neuroendocrine tumors. In cases of more disseminated hepatic disease, transarterial radioembolization with Yttrium-90- (90Y-) labeled microspheres has been demonstrated as a viable option for symptom and locoregional tumor control. On an outpatient basis, radioembolization can be utilized from early line to salvage phases, in various combinations with systemic therapies. Review of available data shows encouraging safety and efficacy profiles for the intraarterial application of 90Y for the treatment of mNETs of the liver. Symptom control and decrease in somatostatin analog use can be achieved, as well as prolonged survival. PMID:22235376

  6. Small Cell Type of Esophageal Neuroendocrine Carcinoma Resembling a Submucosal Tumor.

    PubMed

    Chino, Osamu; Makuuchi, Hiroyasu; Ozawa, Soji; Shimada, Hideo; Nishi, Takayuki; Kise, Yoshifumi; Hara, Tadashi; Yamamoto, Soichiro; Kazuno, Akihito; Kajiwara, Hiroshi

    2015-07-01

    We report a rare case of primary small cell type esophageal neuroendocrine carcinoma with a unusual endoscopic form similar to a submucosal tumor with the results of the histological and immunohistochemical analyses. A 57-year-old woman with dysphagia was referred to our hospital for further examination and treatment, and was diagnosed as type 1s esophageal carcinoma in the middle thoracic esophagus. Endoscopy revealed a protruding esophageal carcinoma resembling a submucosal tumor with an irregular and nodular surface covered by non-neoplastic epithelium stained with iodine. Analysis of the esophageal biopsy specimen revealed poorly differentiated squamous cell carcinoma. Based on a diagnosis of type 1s carcinoma in the middle thoracic esophagus that was 5 cm in size longitudinally, a radical esophagectomy with three-field lymph node dissection was performed. The pathological examination with histological and immunohistochemical analysis of the resected specimen revealed a small cell type neuroendocrine carcinoma overlaid by a non-neoplastic epithelium, extending into the adventitia without lymph node metastasis (T3, N0, M0, Stage II). However, multiple metastases in the brain and lung developed 3 months postoperatively, and the patient died of the cancer 7 months after the operation. This was a rare case of a highly malignant primary small cell type esophageal neuroendocrine carcinoma showing extremely rare form. PMID:26150181

  7. Ectopic insulin secreting neuroendocrine tumor of kidney with recurrent hypoglycemia: a diagnostic dilemma

    PubMed Central

    2014-01-01

    Background Hypoglycemia secondary to ectopic insulin secretion of non-pancreatic tumors is rare. Case presentation We describe a middle aged woman with recurrent hypoglycemia. On evaluation, she was detected to have hyperinsulinemic hypoglycemia and right sided renal mass lesion. 68Ga-Dotanoc and 99mTc-HYNICTOC scans confirmed the intrarenal mass to be of neuroendocrine origin. Right nephrectomy was done and it turned out to be an insulin secreting neuroendocrine tumour. Neuroendocrine nature of this tumour was further confirmed by ultra-structural examination. Her hypoglycemia did not recur after resection of this tumour. Conclusion Few cases of ectopic insulin secretion have been reported though some are not proven convincingly. This case addresses all the issues raised in previous case reports and proves by clinical, laboratory, functional imaging and immunohistochemical analysis that ectopic origin of insulin by non-pancreatic tumors does occur. To our knowledge, this is the first reported case of ectopic insulinoma arising from the kidney. PMID:24741994

  8. Proposal for a Standardized Pathology Report of Gastroenteropancreatic Neuroendocrine Tumors: Prognostic Significance of Pathological Parameters

    PubMed Central

    Cho, Mee-Yon; Jin, So Young; Kim, Hyunki; Jung, Eun Sun; Kim, Mi-Jung; Kim, Kyoung-Mee; Kim, Woo Ho; Kim, Joon Mee; Kang, Yun Kyung; Choi, Joon Hyuk; Kang, Dae Young; Kim, Youn Wha; Choi, Eun Hee

    2013-01-01

    Background There is confusion in the diagnosis and biological behaviors of gastroenteropancreatic neuroendocrine tumors (GEP-NETs), because of independently proposed nomenclatures and classifications. A standardized form of pathology report is required for the proper management of patients. Methods We discussed the proper pathological evaluation of GEP-NET at the consensus conference of the subcommittee meeting for the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists. We then verified the prognostic significance of pathological parameters from our previous nationwide collection of pathological data from 28 hospitals in Korea to determine the essential data set for a pathology report. Results Histological classification, grading (mitosis and/or Ki-67 labeling index), T staging (extent, size), lymph node metastasis, and lymphovascular and perineural invasion were significant prognostic factors and essential for the pathology report of GEP-NET, while immunostaining such as synaptophysin and chromogranin may be optional. Furthermore, the staging system, either that of the 2010 American Joint Cancer Committee (AJCC) or the European Neuroendocrine Tumor Society (ENETS), should be specified, especially for pancreatic neuroendocrine neoplasms. Conclusions A standardized pathology report is crucial for the proper management and prediction of prognosis of patients with GEP-NET. PMID:23837015

  9. A study of pipeline drugs in neuroendocrine tumors

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Inhibition of neovessel development can stabilize tumor growth. A rapid in vitro method that can evaluate the effectiveness of anti-angiogenic drugs would aid in drug development. We tested a series of investigational agents to determine their ability to inhibit angiogenesis in our in vitro human a...

  10. Applications of a novel tumor-grading-metastasis staging system for pancreatic neuroendocrine tumors

    PubMed Central

    Yang, Min; Tan, Chun-Lu; Zhang, Yi; Ke, Neng-Wen; Zeng, Lin; Li, Ang; Zhang, Hao; Xiong, Jun-Jie; Guo, Zi-Heng; Tian, Bo-Le; Liu, Xu-Bao

    2016-01-01

    Abstract The ability to stratify patients with pancreatic neuroendocrine tumors (p-NETs) into prognostic groups has been hindered by the absence of a commonly accepted staging system. Both the 7th tumor-node-metastasis (TNM) staging guidelines by the American Joint Committee on Cancer (AJCC) and the 2010 grading classifications by the World Health Organization (WHO) were validated to be unsatisfactory. We aim to evaluate the feasibility of combining the latest AJCC and WHO criteria to devise a novel tumor-grading-metastasis (TGM) staging system. We also sought to examine the stage-specific survival rates and the prognostic value of this new TGM system for p-NETs. Data of 120 patients with surgical resection and histopathological diagnosis of p-NETs from January 2004 to February 2014 in our institution were retrospectively collected and analyzed. Based on the AJCC and WHO criteria, we replaced the stage N0 and N1 with stage Ga (NET G1 and NET G2) and Gb (NET G3 and MANEC) respectively, without changes of the definition of T or M stage. The present novel TGM staging system was grouped as follows: stage I was defined as T1–2, Ga, M0; stage II as T3, Ga, M0 or as T1–3, Gb, M0; stage III as T4, Ga–b, M0 and stage IV as any T, M1. The new TGM staging system successfully distributed 55, 42, 12, and 11 eligible patients in stage I to IV, respectively. Differences of survival compared stage I with III and IV for patients with p-NETs were both statistically significant (P < 0.001), as well as those of stage II with III and IV (P < 0.001). Patients in stage I showed better a survival than those in stage II, whereas difference between stages III and IV was not notable (P = 0.001, P = 0.286, respectively). In multivariate models, when the TGM staging system was evaluated in place of the individual T, G, and M variables, this new criteria were proven to be an independent predictor of survival for surgically resected p-NETs (P < 0.05). Stratifying patients well

  11. Identification of tumorigenic cells and therapeutic targets in pancreatic neuroendocrine tumors.

    PubMed

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

    2016-04-19

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

  12. Primary hepatic neuroendocrine tumor with multiple liver metastases: A case report with review of the literature.

    PubMed

    Yang, Kai; Cheng, Ying-Sheng; Yang, Ji-Jin; Jiang, Xu; Guo, Ji-Xiang

    2015-03-14

    We herein present a case involving a 41-year-old woman in whom ultrasound examination revealed multiple liver hemangiomas more than 3 years ago. Follow-up ultrasound examination revealed that the masses had significantly increased; the largest was located in the right lobe (about 8.2 cm × 7.4 cm × 6.0 cm). Abdominal multidetector computed tomography revealed multiple well-circumscribed, heterogeneous, hypodense masses (largest, 6.4 cm × 6.3 cm × 5.0 cm) with significant contrast enhancement during the arterial and portal phases and with contrast wash-out and peripheral enhancement during the delayed phases. Magnetic resonance images demonstrated multiple well-circumscribed, heterogeneous, hypointense hepatic masses with significant contrast enhancement (largest, 6.4 cm × 6.5 cm × 5.1 cm); multiple enlarged porta lymph nodes; and multiple slightly enlarged retroperitoneal lymph nodes. Histological and immunohistochemical examination of the right mass biopsy specimen suggested a malignant neoplasm that had originated from a neuroendocrine cell type (grade 2 well-differentiated neuroendocrine carcinoma). After performing a systemic examination to exclude metastasis from an extrahepatic primary site, we considered that the masses had arisen from a primary hepatic neuroendocrine tumor with multiple liver metastases. The patient underwent transcatheter arterial chemoembolization using a combination of oxaliplatin (150 mg) mixed with one bottle of gelatin sponge particles (560-710 μm) and lipiodol (6 mL). Primary neuroendocrine tumors of the liver are extremely rare. This case is interesting because of the rarity of this neoplasm and previous misdiagnosis as multiple liver hemangiomas. Previously reported cases in the literature are also reviewed. PMID:25780316

  13. 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. PMID:27081637

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

    PubMed Central

    Grande, Enrique

    2016-01-01

    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. PMID:27081637

  15. Acute appendicitis with a neuroendocrine tumor G1 (carcinoid): pitfalls of conservative treatment.

    PubMed

    Watanabe, Hiroyuki A; Fujimoto, Taketoshi; Kato, Yo; Sasaki, Mayumi; Ikusue, Toshikazu

    2016-08-01

    A man in his early thirties presented to our clinic with right lower abdominal pain. Computed tomography (CT) and ultrasonography (US) revealed a swollen appendix and an appendicolith. Abscess formation was not observed but ongoing appendiceal rupture was not ruled out. Three months after successful conservative therapy, the lumen of the apical portion was kept dilated and laparoscopic interval appendectomy was performed. No tumorous findings were observed macroscopically. However, histology revealed many tiny nests infiltrating the submucosa, muscular layer, and subserosa at the root of the appendix. An appendiceal neuroendocrine tumor G1 (NET G1; carcinoid) was diagnosed immunohistologically. Neither CT nor US visualized the tumor because of its non-tumor-forming but infiltrative growth. In conclusion, after successful conservative treatment, interval appendectomy should be considered to uncover a possible appendiceal NET G1 (carcinoid), particularly when dilatation of the distal lumen is kept under observation. PMID:27311320

  16. PET-Based Molecular Imaging in Designing Personalized Management Strategy in Gastroenteropancreatic Neuroendocrine Tumors.

    PubMed

    Basu, Sandip; Ranade, Rohit; Ostwal, Vikas; Shrikhande, Shailesh V

    2016-07-01

    In recent years, PET-based molecular functional imaging has been increasingly used in neuroendocrine tumors for tailoring of treatment strategies to the individual characteristics of each patient. For each particular patient, the relative tracer uptake by the dual-tracer PET imaging approach (with 68Ga-DOTANOC/TATE and 18F-FDG) frequently plays an important role along with the histopathologic tumor grades for selecting the optimal treatment approach for advanced/metastatic cases. Various tumor-specific parameters have resulted in development of such precision-medicine type model in this biologically heterogeneous group of tumors. The traditional advantages of PET/computed tomography in terms of disease staging are also applicable for personalization of management. From the medical oncologist's standpoint, multitracer PET-based information and staging is of significant importance (in addition to the histologic grades) in selecting the appropriate chemotherapy regimen and monitoring response on an individual basis in the course of treatment. PMID:27321028

  17. Personalized treatment approach to gastroenteropancreatic neuroendocrine tumors: a medical oncologist's perspective.

    PubMed

    Paul, Davinder; Ostwal, Vikas; Bose, Subhadeep; Basu, Sandip; Gupta, Sudeep

    2016-09-01

    The medical management of gastroenteropancreatic neuroendocrine tumors involves treatment of symptomatic disease related to hormone secretions or bulky unresectable metastatic disease. Combining gallium DOTA with fluorine-18 fluorodeoxyglucose-PET along with histopathological grading helps to determine tumor heterogeneity and seek reasons for poor response to therapy. In the light of adding chemotherapy in selected patients with intermediate-grade tumors, the newer scan helps in personalization of the therapy along with the biopsy. The tumor dedifferentiation over the particular time period leading to aggressive behavior, a well-known entity, is contrasted with the redifferentiation phenomenon in some patients as a result of chemotherapy or targeted drug therapy. This may support the basis for combining peptide receptor-targeted radiotherapy/octreotide therapy with chemotherapy or mTOR inhibitors such as everolimus. PMID:27257869

  18. Pancreatic neuroendocrine tumor with ectopic adrenocorticotropin production: a case report and review of literature.

    PubMed

    Patel, Forum B; Khagi, Simon; Daly, Kevin P; Lechan, Ronald M; Ummaritchot, Vorawan; Saif, Muhammad W

    2013-09-01

    Pancreatic neuroendocrine tumors (p-NETs) entail a vast array of tumors, which can vary from benign neoplastic growths to rapidly aggressive malignancies. Such is the case with ectopic adrenocorticotropic hormone (ACTH)-producing p-NETs. These tumors have been found to be quite aggressive and a challenge to treat, especially due to the occurrence of metastatic disease even after resection of the primary tumor. We discuss the case of a 44-year-old female who initially presented with vague, non-specific symptoms, in which a malignant p-NET was found to be the cause of her clinical presentation. Although resection of the pancreatic mass was performed, the patient presented again with metastatic disease to the liver. PMID:24023341

  19. Hepatic Arterial Chemoembolization Using Drug-Eluting Beads in Gastrointestinal Neuroendocrine Tumor Metastatic to the Liver

    SciTech Connect

    Gaur, Shantanu K.; Friese, Jeremy L.; Sadow, Cheryl A.; Ayyagari, Rajasekhara; Binkert, Christoph A.; Schenker, Matthew P.; Kulke, Matthew; Baum, Richard

    2011-06-15

    Purpose: This study was designed to evaluate short (<3 months) and intermediate-term (>3 months) follow-up in patients with metastatic neuroendocrine tumor to the liver who underwent hepatic arterial chemoembolization with drug-eluting beads at a single institution. Methods: Institutional review board approval was obtained for this retrospective review. All patients who were treated with 100-300 or 300-500 {mu}m drug-eluting LC Beads (Biocompatibles, UK) preloaded with doxorubicin (range, 50-100 mg) for GI neuroendocrine tumor metastatic to the liver from June 2004 to June 2009 were included. CT and MRI were evaluated for progression using Response Evaluation Criteria In Solid Tumors (RECIST) or European Association for the Study of the Liver (EASL) criteria. Short-term (<3 months) and intermediate-term (>3 months) imaging response was determined and Kaplan-Meier survival curves were plotted. Results: Thirty-eight drug-eluting bead chemoembolization procedures were performed on 32 hepatic lobes, comprising 21 treatment cycles in 18 patients. All procedures were technically successful with two major complications (biliary injuries). At short-term follow-up (<3 months), 22 of 38 (58%) procedures and 10 of 21 (48%) treatment cycles produced an objective response (OR) with the remainder having stable disease (SD). At intermediate-term follow-up (mean, 445 days; range, 163-1247), 17 of 26 (65%) procedures and 8 of 14 (57%) treatment cycles produced an OR. Probability of progressing was approximately 52% at 1 year with a median time to progression of 419 days. Conclusions: Drug-eluting bead chemoembolization is a reasonable alternative to hepatic arterial embolization and chemoembolization for the treatment of metastatic neuroendocrine tumor to the liver.

  20. Netrin-4 delays colorectal cancer carcinomatosis by inhibiting tumor angiogenesis.

    PubMed

    Eveno, Clarisse; Broqueres-You, Dong; Feron, Jean-Guillaume; Rampanou, Aurore; Tijeras-Raballand, Annemilaï; Ropert, Stanislas; Leconte, Laurence; Levy, Bernard I; Pocard, Marc

    2011-04-01

    A close relationship between tumor angiogenesis, growth, and carcinomatosis has been observed. Netrin-4 (NT-4) has been shown to regulate angiogenic responses. We aimed to examine the effects of NT-4 on colon tumor angiogenesis, growth, and carcinomatosis. We showed that NT-4 was expressed in human colon cancer cells (LS174). A 20-fold increase in NT-4 expression was stably induced by NT-4 pcDNA in LS174 cells. In vivo, a Matrigel angiogenesis assay showed that NT-4 overexpression altered vascular endothelial growth factor (VEGF)/basic fibroblast growth factor-induced angiogenesis. In nude mice with LS174 xenografts, NT-4 overexpression inhibited tumor angiogenesis and growth. In addition, these NT-4-involved inhibitory effects were associated with decreased tumor cell proliferation and increased tumor cell apoptosis. Using an orthotopic peritoneal carcinomatosis model, we demonstrated that NT-4 overexpression decreased colorectal cancer carcinomatosis. Moreover, carcinomatosis-related ascites formation was significantly decreased in mice transplanted with NT-4 LS174 cells versus control LS174 cells. The antiangiogenic activity of NT-4 was probably mediated by binding to its receptor neogenin. Netrin-4 had a direct effect on neither in vitro apoptosis and proliferation of cultured LS174 cells nor the VEGF-induced acute increase in vascular permeability in vivo. We propose that NT-4 overexpression decreases tumor growth and carcinomatosis, probably via an antiangiogenic effect, underlying the potential therapeutic interest in NT-4 in the treatment of colorectal cancer growth and carcinomatosis. PMID:21406174

  1. A Big Bang model of human colorectal tumor growth.

    PubMed

    Sottoriva, Andrea; Kang, Haeyoun; Ma, Zhicheng; Graham, Trevor A; Salomon, Matthew P; Zhao, Junsong; Marjoram, Paul; Siegmund, Kimberly; Press, Michael F; Shibata, Darryl; Curtis, Christina

    2015-03-01

    What happens in early, still undetectable human malignancies is unknown because direct observations are impractical. Here we present and validate a 'Big Bang' model, whereby tumors grow predominantly as a single expansion producing numerous intermixed subclones that are not subject to stringent selection and where both public (clonal) and most detectable private (subclonal) alterations arise early during growth. Genomic profiling of 349 individual glands from 15 colorectal tumors showed an absence of selective sweeps, uniformly high intratumoral heterogeneity (ITH) and subclone mixing in distant regions, as postulated by our model. We also verified the prediction that most detectable ITH originates from early private alterations and not from later clonal expansions, thus exposing the profile of the primordial tumor. Moreover, some tumors appear 'born to be bad', with subclone mixing indicative of early malignant potential. This new model provides a quantitative framework to interpret tumor growth dynamics and the origins of ITH, with important clinical implications. PMID:25665006

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

    PubMed

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

    2016-04-01

    Meckel diverticulum is the most common abnormality of the gastrointestinal tract arising from an incomplete obliteration of the vitelline duct during the intrauterine life. Although tumor development in Meckel diverticulum is not a common situation, it can occur due to the persistence of cellular islets with gastric, pancreatic or intestinal origin. The presence of a neuroendocrine tumor arising from Meckel diverticulum is even scarcer. We present the case of a 59-year-old patient in whom a Meckel diverticulum was found during surgery for inguinal hernia; the histopathological and immunohistochemical studies revealed the presence of a well-differentiated neuroendocrine tumor with low mitotic index. PMID:27069171

  3. Diagnostic imaging of pancreatic neuroendocrine neoplasms (pNEN): tumor detection, staging, prognosis, and response to treatment.

    PubMed

    Baur, Alexander D J; Pavel, Marianne; Prasad, Vikas; Denecke, Timm

    2016-03-01

    Pancreatic neuroendocrine neoplasms (pNEN) are rare malignancies arising from neuroendocrine cells of the pancreas. Functional tumors can present with specific clinical syndromes due to hormonal secretion. These tumors can present as incidental findings on imaging performed for unrelated purposes or they are diagnosed when workup is initiated in patients with specific syndromes or metastases. This article presents an overview of available imaging techniques focusing on computed tomography and magnetic resonance imaging. Recommendations regarding examination protocols are given. Typical imaging features of pNEN and metastases are described. Their potential value for the evaluation of prognosis as well as tumor response under treatment is discussed. PMID:25855665

  4. A Calcitonin-Negative Neuroendocrine Tumor Derived from Follicular Lesions of the Thyroid

    PubMed Central

    Kim, Ga Young; Park, Chul Yun; Cho, Chang Ho; Park, June Sik; Jung, Eui Dal

    2015-01-01

    Neuroendocrine lesions of the thyroid are rare. The most common types are medullary thyroid carcinomas (MTCs) and C-cell hyperplasia. MTCs originate from thyroid parafollicular cells that secrete calcitonin which serves as a serum marker of MTCs. Here, the rare case of a calcitonin-negative neuroendocrine tumor (NET) derived from follicular lesions of the thyroid is described. A 34-year-old man presented at our hospital for the surgical management of an incidental thyroid nodule that was observed on an ultrasound sonography (USG) of the neck. Initially, USG-guided aspiration cytology was performed, and a MTC was suspected. The expressions of thyroglobulin and thyroid transcription factor-1, which are thyroid follicular cell markers, and synaptophysin and chromogranin A, which are neuroendocrine markers, was confirmed following surgical pathology. However, the staining of calcitonin, a marker of MTCs, was not observed. A nonmedullary NET of the thyroid is uncommon, and the distinction between calcitonin-negative NETs and MTCs of the thyroid may be important due to differences in their clinical courses and management. PMID:25491784

  5. A Rare Case of Mixed Neuroendocrine Tumor and Adenocarcinoma of the Pancreas.

    PubMed

    Xenaki, Sofia; Lasithiotakis, Konstantinos; Andreou, Alexandros; Aggelaki, Sofia; Tzardi, Maria; Daskalaki, Anna; Chalkiadakis, George; Chrysos, Emmanuel

    2016-01-01

    Introduction. Neuroendocrine carcinoma (NEC) of pancreas is a rare tumor with aggressive progression and poor prognosis. Its coexistence with adenocarcinoma poses significant clinical problems and has not been addressed in the literature. Methods. We describe a case of a 51-year-old male who underwent pancreatoduodenectomy due to pancreatic head tumor 1.5 × 1 × 1.4 cm. Histological examination of the specimen revealed a mixed neoplasm: (1) a well differentiated adenocarcinoma, neoplastic blasts of which are extended focally to the submucosa without invading the muscular layer, and (2) a low differentiated NEC consisting of solid clusters and pagetoid formations. All 18 lymph nodes of the specimen were free of neoplastic disease and the surgical margins of the specimen were tumor-free. No adjuvant treatment was administered and two months after the operation the patient developed liver metastasis. FNA cytology of the hepatic lesions revealed low grade carcinoma with neuroendocrine characteristics. Five lines of chemotherapy were administered: VP + CDDP, paclitaxel + ifosfamide + Mesna + CDDP, Folfox + Avastin, Folfiri + Avastin, and CAV. During his treatment he revealed PD and succumbed to his disease 13 months after the operation. Conclusion. Coexistence of NEC with adenocarcinoma of the pancreas is a very rare entity presenting significant challenges regarding its adjuvant treatment and the treatment of distant relapse. PMID:27610261

  6. 18F-FDG PET/CT Imaging of Primary Hepatic Neuroendocrine Tumor

    PubMed Central

    Mitamura, Katsuya; Yamamoto, Yuka; Tanaka, Kenichi; Sanomura, Takayuki; Murota, Makiko; Nishiyama, Yoshihiro

    2015-01-01

    Primary hepatic neuroendocrine tumors (PHNETs) are extremely rare neoplasms. Herein, we report a case of a 70- year-old man with a hepatic mass. The non-contrast computed tomography (CT) image showed a low-density mass, and dynamic CT images indicated the enhancement of the mass in the arterial phase and early washout in the late phase. F-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and fused PET/CT images showed increased uptake in the hepatic mass. Whole-body 18F-FDG PET images showed no abnormal activity except for the liver lesion. Presence of an extrahepatic tumor was also ruled out by performing upper gastrointestinal endoscopy, total colonoscopy, and chest and abdominal CT. A posterior segmentectomy was performed, and histologic examination confirmed a neuroendocrine tumor (grade 1). The patient was followed up for about 2 years after the resection, and no extrahepatic lesions were radiologically found. Therefore, the patient was diagnosed with PHNET. To the best of our knowledge, no previous case of PHNET have been detected by 18F-FDG PET imaging.

  7. (18)F-FDG PET/CT Imaging of Primary Hepatic Neuroendocrine Tumor.

    PubMed

    Mitamura, Katsuya; Yamamoto, Yuka; Tanaka, Kenichi; Sanomura, Takayuki; Murota, Makiko; Nishiyama, Yoshihiro

    2015-01-01

    Primary hepatic neuroendocrine tumors (PHNETs) are extremely rare neoplasms. Herein, we report a case of a 70- year-old man with a hepatic mass. The non-contrast computed tomography (CT) image showed a low-density mass, and dynamic CT images indicated the enhancement of the mass in the arterial phase and early washout in the late phase. F-18 fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) and fused PET/CT images showed increased uptake in the hepatic mass. Whole-body (18)F-FDG PET images showed no abnormal activity except for the liver lesion. Presence of an extrahepatic tumor was also ruled out by performing upper gastrointestinal endoscopy, total colonoscopy, and chest and abdominal CT. A posterior segmentectomy was performed, and histologic examination confirmed a neuroendocrine tumor (grade 1). The patient was followed up for about 2 years after the resection, and no extrahepatic lesions were radiologically found. Therefore, the patient was diagnosed with PHNET. To the best of our knowledge, no previous case of PHNET have been detected by (18)F-FDG PET imaging. PMID:27408882

  8. [Von Hippel-Lindau disease type 2-related pancreatic neuroendocrine tumor and adrenal myelolipoma].

    PubMed

    Dolzhansky, O V; Morozova, M M; Korostelev, S A; Kanivets, I V; Chardarov, N K; Shatveryan, G A; Pal'tseva, E M; Fedorov, D N

    2016-01-01

    The paper describes a case of von Hippel--Lindau-related pancreatic neuroendocrine tumor and adrenal myelolipoma in a 44-year-old woman. The pancreatic tumor and a left retroperitoneal mass were removed in the women in July 2014 and May 2015. Histological examination of the pancreatic tumor revealed that the latter consisted of clear cells forming tubular and tubercular structures showing the expression of chromogranin A, synaptophysin, and cytokeratins 18 and 19 and a negative response to CD10 and RCC. The adrenal medullary mass presented as clear-cell alveolar structures with inclusions of adipose tissue mixed with erythroid, myeloid, and lymphoid cells. The clear-cell component of the adrenal gland expressed neuroendocrine markers with a negative response to cytokeratins, CD10, and RCC. Molecular genetic examination yielded a signal corresponding to two copies of the VHL gene. No deletions or amplifications of the gene were detected. Cases of von Hippel--Lindau disease concurrent with adrenal pheochromocytoma and myelolipoma and simultaneous pancreatic involvement were not found in the literature. PMID:26978235

  9. Therapy of metastatic pancreatic neuroendocrine tumors (pNETs): recent insights and advances

    PubMed Central

    Ito, Tetsuhide; Igarashi, Hisato

    2013-01-01

    Neuroendocrine tumors (NETs) [carcinoids, pancreatic neuroendocrine tumors (pNETs)] are becoming an increasing clinical problem because not only are they increasing in frequency, but they can frequently present with advanced disease that requires diagnostic and treatment approaches different from those used in the neoplasms that most physicians are used to seeing and treating. In the past few years there have been numerous advances in all aspects of NETs including: an understanding of their unique pathogenesis; specific classification systems developed which have prognostic value; novel methods of tumor localization developed; and novel treatment approaches described. In patients with advanced metastatic disease these include the use of newer chemotherapeutic approaches, an increased understanding of the role of surgery and cytoreductive methods, the development of methods for targeted delivery of cytotoxic agents, and the development of targeted medical therapies (everolimus, sunitinib) based on an increased understanding of the disease biology. Although pNETs and gastrointestinal NETs share many features, recent studies show they differ in pathogenesis and in many aspects of diagnosis and treatment, including their responsiveness to different therapies. Because of limited space, this review will be limited to the advances made in the management and treatment of patients with advanced metastatic pNETs over the past 5 years. PMID:22886480

  10. A Rare Case of Mixed Neuroendocrine Tumor and Adenocarcinoma of the Pancreas

    PubMed Central

    Lasithiotakis, Konstantinos; Andreou, Alexandros; Aggelaki, Sofia; Tzardi, Maria; Chalkiadakis, George; Chrysos, Emmanuel

    2016-01-01

    Introduction. Neuroendocrine carcinoma (NEC) of pancreas is a rare tumor with aggressive progression and poor prognosis. Its coexistence with adenocarcinoma poses significant clinical problems and has not been addressed in the literature. Methods. We describe a case of a 51-year-old male who underwent pancreatoduodenectomy due to pancreatic head tumor 1.5 × 1 × 1.4 cm. Histological examination of the specimen revealed a mixed neoplasm: (1) a well differentiated adenocarcinoma, neoplastic blasts of which are extended focally to the submucosa without invading the muscular layer, and (2) a low differentiated NEC consisting of solid clusters and pagetoid formations. All 18 lymph nodes of the specimen were free of neoplastic disease and the surgical margins of the specimen were tumor-free. No adjuvant treatment was administered and two months after the operation the patient developed liver metastasis. FNA cytology of the hepatic lesions revealed low grade carcinoma with neuroendocrine characteristics. Five lines of chemotherapy were administered: VP + CDDP, paclitaxel + ifosfamide + Mesna + CDDP, Folfox + Avastin, Folfiri + Avastin, and CAV. During his treatment he revealed PD and succumbed to his disease 13 months after the operation. Conclusion. Coexistence of NEC with adenocarcinoma of the pancreas is a very rare entity presenting significant challenges regarding its adjuvant treatment and the treatment of distant relapse. PMID:27610261

  11. Neuroendocrine, immunohistochemical, and ultrastructural study of pineal region tumors.

    PubMed

    Grimoldi, N; Tomei, G; Stankov, B; Lucini, V; Masini, B; Caputo, V; Repetti, M L; Lazzarini, G; Gaini, S M; Lucarini, C; Fraschini, F; Villani, R

    1998-10-01

    Thirteen patients with tumors in the pineal region were submitted to pre- and post-operative blood sampling (08:00, 14:00, 20:00, and 02:00 hr) for three or four consecutive days. A single cerebrospinal fluid (CSF) sample was collected at surgery, and melatonin levels determined. In all patients, serum and CSF beta subunit of human chorionic gonadotrophin (betaHCG), carcino embryonic antigen (CEA), and alpha-fetoprotein (AFP) levels were measured. Histology revealed four pineocytomas, one pineoblastoma, four germinomas, one immature teratoma, one pilocytic astrocytoma, one lymphoma, and one meningioma. Serum and CSF levels of serological biomarkers were normal, except for one of the germinoma cases. In most patients, alteration either in the circadian rhythm or in the melatonin concentration was observed before surgery. In benign neoplasms the circadian rhythm was conserved. In pineoblastoma, lymphoma, and three out of four germinomas, melatonin concentrations were undetectable. In one case of germinoma, melatonin levels were high, with the circadian rhythm being abolished. According to conventional histology, all germinomas were similar. Therefore, in a rare case of pineal germinoma with high melatonin levels, the tissue was subjected to an in depth investigation (immunohistochemical and ultrastructural) in order to determine the pathology and the possible differences from the other typical germinomas. Results were compared to those provided from other pineal neoplasms. Electron microscopy examination detected the presence of clusters of intermediate filaments and numerous electrondense granules only in the case of a germinoma producing melatonin. PMID:9745983

  12. Pancreatic neuroendocrine tumors with transformation to insulinoma: an unusual presentation of a rare disease

    PubMed Central

    Grozinsky-Glasberg, Simona; Salmon, Asher; Gross, David J

    2015-01-01

    Summary Approximately 35% of the pancreatic neuroendocrine tumors (pNETs) are functional, the most common of which is an insulinoma. Rarely can initially nonfunctioning tumor undergo biological transformation to a hormone-secreting tumor with subsequent changes in the clinical picture. We present here three unique patients with long-standing pNETs who developed life-threatening hyperinsulinemic hypoglycemia along with tumor progression. In two of the patients, everolimus (Afinitor) was administered in an attempt to control both tumor growth and hypoglycemia. In two cases everolimus therapy resulted in the abolishment of hypoglycemia and induced significant tumor regression; however these beneficial responses were transient. These cases highlight the exceptional ability of pNETs to change biological behavior in parallel with disease progression. Our experience concurs with recently published studies demonstrating the utility of everolimus for the control of both hypoglycemia and tumor progression. Learning points Nonfunctional pNET can gain new features such as insulin secretion with related morbidity.Gain of function in a previously nonfunctional pNET signifies tumor progression and is usually associated with poor prognosis.Everolimus proved to be a viable treatment for hypoglycemia in insulinoma patients and was also proven highly effective in the patients presented here.As disease progresses, the effect of everolimus on hypoglycemia wanes. We report for the first time the development of hypoglycemia during everolimus treatment. PMID:26113980

  13. Phospholipid Ether Analogs for the Detection of Colorectal Tumors

    PubMed Central

    Deming, Dustin A.; Maher, Molly E.; Leystra, Alyssa A.; Grudzinski, Joseph P.; Clipson, Linda; Albrecht, Dawn M.; Washington, Mary Kay; Matkowskyj, Kristina A.; Hall, Lance T.; Lubner, Sam J.; Weichert, Jamey P.; Halberg, Richard B.

    2014-01-01

    The treatment of localized colorectal cancer (CRC) depends on resection of the primary tumor with adequate margins and sufficient lymph node sampling. A novel imaging agent that accumulates in CRCs and the associated lymph nodes is needed. Cellectar Biosciences has developed a phospholipid ether analog platform that is both diagnostic and therapeutic. CLR1502 is a near-infrared fluorescent molecule, whereas 124/131I-CLR1404 is under clinical investigation as a PET tracer/therapeutic agent imaged by SPECT. We investigated the use of CLR1502 for the detection of intestinal cancers in a murine model and 131I-CLR1404 in a patient with metastatic CRC. Mice that develop multiple intestinal tumors ranging from adenomas to locally advanced adenocarcinomas were utilized. After 96 hours post CLR1502 injection, the intestinal tumors were analyzed using a Spectrum IVIS (Perkin Elmer) and a Fluobeam (Fluoptics). The intensity of the fluorescent signal was correlated with the histological characteristics for each tumor. Colon adenocarcinomas demonstrated increased accumulation of CLR1502 compared to non-invasive lesions (total radiant efficiency: 1.76×1010 vs 3.27×109 respectively, p = 0.006). Metastatic mesenteric tumors and uninvolved lymph nodes were detected with CLR1502. In addition, SPECT imaging with 131I-CLR1404 was performed as part of a clinical trial in patients with advanced solid tumors. 131I-CLR1404 was shown to accumulate in metastatic tumors in a patient with colorectal adenocarcinoma. Together, these compounds might enhance our ability to properly resect CRCs through better localization of the primary tumor and improved lymph node identification as well as detect distant disease. PMID:25286226

  14. Phospholipid ether analogs for the detection of colorectal tumors.

    PubMed

    Deming, Dustin A; Maher, Molly E; Leystra, Alyssa A; Grudzinski, Joseph P; Clipson, Linda; Albrecht, Dawn M; Washington, Mary Kay; Matkowskyj, Kristina A; Hall, Lance T; Lubner, Sam J; Weichert, Jamey P; Halberg, Richard B

    2014-01-01

    The treatment of localized colorectal cancer (CRC) depends on resection of the primary tumor with adequate margins and sufficient lymph node sampling. A novel imaging agent that accumulates in CRCs and the associated lymph nodes is needed. Cellectar Biosciences has developed a phospholipid ether analog platform that is both diagnostic and therapeutic. CLR1502 is a near-infrared fluorescent molecule, whereas 124/131I-CLR1404 is under clinical investigation as a PET tracer/therapeutic agent imaged by SPECT. We investigated the use of CLR1502 for the detection of intestinal cancers in a murine model and 131I-CLR1404 in a patient with metastatic CRC. Mice that develop multiple intestinal tumors ranging from adenomas to locally advanced adenocarcinomas were utilized. After 96 hours post CLR1502 injection, the intestinal tumors were analyzed using a Spectrum IVIS (Perkin Elmer) and a Fluobeam (Fluoptics). The intensity of the fluorescent signal was correlated with the histological characteristics for each tumor. Colon adenocarcinomas demonstrated increased accumulation of CLR1502 compared to non-invasive lesions (total radiant efficiency: 1.76×10(10) vs 3.27×10(9) respectively, p = 0.006). Metastatic mesenteric tumors and uninvolved lymph nodes were detected with CLR1502. In addition, SPECT imaging with 131I-CLR1404 was performed as part of a clinical trial in patients with advanced solid tumors. 131I-CLR1404 was shown to accumulate in metastatic tumors in a patient with colorectal adenocarcinoma. Together, these compounds might enhance our ability to properly resect CRCs through better localization of the primary tumor and improved lymph node identification as well as detect distant disease. PMID:25286226

  15. Radioembolization with yttrium-90 resin microspheres for neuroendocrine tumor liver metastases

    PubMed Central

    Peker, Ahmet; Çiçek, Okan; Soydal, Çiğdem; Küçük, Nuriye Özlem; Bilgiç, Sadık

    2015-01-01

    PURPOSE We aimed to evaluate the effectiveness and safety of radioembolization with yttrium-90 (90Y) microspheres in cases with unresectable neuroendocrine tumor liver metastases (NETLMs). METHODS Thirty patients (mean age, 55 years) underwent resin-based 90Y radioembolization for unresectable NETLM at a single institution between April 2008 and June 2013. Post-treatment tumor response was assessed by cross-sectional imaging using the Response Evaluation Criteria in Solid Tumors (RECIST). Prognostic variables that affected survival were determined. RESULTS The mean follow-up was 23.0±19.4 months and the median overall survival was 39 months (95% CI, 12.6–65.4 months), with one- and two-year survival rates of 71% and 45%, respectively. Imaging follow-up using RECIST at three-month intervals demonstrated partial response in 43%, complete remission in 3%, stable disease in 37%, and progressive disease in 17% of patients. Extent of tumor involvement was found to have a statistically significant influence on overall survival (P = 0.03). The existence of extrahepatic disease at the time of radioembolization, radiographic response, age, and primary neuroendocrine tumor site were not significant prognostic factors. CONCLUSION The current study demonstrates the effectiveness and safety of radioembolization for the treatment of unresectable NETLMs. We identified that the extent of tumor involvement has a significant effect on overall survival. The use of imaging methods reflecting metabolic activity or cellularity such as scintigraphy or diffusion-weighted MRI would be more appropriate, for the response evaluation of liver metastases after radioembolization. PMID:25430526

  16. Clinicopathological Analysis of Factors Related to Colorectal Tumor Perforation

    PubMed Central

    Medina-Arana, Vicente; Martínez-Riera, Antonio; Delgado-Plasencia, Luciano; Rodríguez-González, Diana; Bravo-Gutiérrez, Alberto; Álvarez-Argüelles, Hugo; Alarcó-Hernández, Antonio; Salido-Ruiz, Eduardo; Fernández-Peralta, Antonia M.; González-Aguilera, Juan J.

    2015-01-01

    Abstract Colorectal tumor perforation is a life-threatening complication of this disease. However, little is known about the anatomopathological factors or pathophysiologic mechanisms involved. Pathological and immunohistochemical analysis of factors related with tumoral neo-angiogenesis, which could influence tumor perforation are assessed in this study. A retrospective study of patients with perforated colon tumors (Group P) and T4a nonperforated (controls) was conducted between 2001 and 2010. Histological variables (differentiation, vascular invasion, and location) and immunohistochemical (CD31, Growth Endothelial Vascular Factor (VEGF) and p53) related with tumor angiogenesis were analyzed. Of 2189 patients, 100 (4.56%) met the inclusion criteria. Of these, 49 patients had nonperforated (2.23%) and 51 had perforated tumors (2.32%). The P group had lower number of right-sided tumors (7/51, 13.7%) compared with controls (13/49, 36.7%) (P = .01). The high-grade tumors (undifferentiated) represented only 3.9% of the perforated tumors; the remaining 96.1% were well differentiated (P = .01). No differences between groups in the frequency of TP53 mutation or VEGF and CD31 expression were found. In the P group, only 2 (3.9%) had vascular invasion (P = .01). Of the 12 tumors with vascular invasion, only 2 were perforated (16.6%). The median number of metastatic lymph-nodes in P Group was 0 versus 3 in controls (Z = −4.2; P < .01). Pathological analysis of variables that indirectly measure the presence of tumor angiogenesis (differentiation, vascular invasion, and the number of metastatic lymph nodes) shows a relationship between this and the perforation, location, and tumor differentiation. We could not directly validate our hypothesis, by immunohistochemistry of TP53, VEGF, and CD31, that perforated tumors exhibit less angiogenesis. PMID:25881846

  17. p27 Loss Is Associated with Poor Prognosis in Gastroenteropancreatic Neuroendocrine Tumors

    PubMed Central

    Kim, Hee Sung; Lee, Hye Seung; Nam, Kyung Han; Choi, Jiwoon; Kim, Woo Ho

    2014-01-01

    Purpose Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) represent a heterogeneous disease group originating from the neuroendocrine cells. Identification of prognostic markers, related to neuroendocrine tissue-selective tumorigenesis, is necessary to find therapeutic targets. Materials and Methods A total of 327 patients with GEP-NETs were included in this study; there were 49 gastric, 29 duodenal, 49 pancreatic, 12 hepatobiliary, 33 appendiceal, 5 proximal colon, and 150 distal colon cases. We performed immunostaining with the tissue microarray method for menin, p27, and p18. Results We observed negative staining for menin, p27, and p18 in 34%, 21%, and 56% of GEP-NETs, respectively. The loss of p27, but not menin, was positively correlated with the grade of Ki-67. Menin–/p27–, menin–/p27+, menin+/p27–, and menin+/p27+ phenotype groups included 13%, 22%, 8%, and 57% of patients, respectively. A dichotomized comparison showed that menin– or p27– tumors were significantly associated with foregut and midgut localizations, high World Health Organization (WHO) grade, lymph node metastasis, and more advanced stage as compared to menin+/p27+ patients. Kaplan-Meier analysis for the overall survival showed that p27 loss was significantly associated with decreased survival. Multivariate analysis showed that p27 loss is an independent factor for poor overall survival. Conclusion Our results revealed that the loss of p27 is associated with poor prognosis and the menin-p27 pathway is important in the tumorigenesis of GEP-NETs. PMID:25036575

  18. Complete Resolution of Neuroendocrine Tumor Soft Tissue Metastases After 177Lu DOTATATE PRRT Induction and Maintenance Therapy.

    PubMed

    Makis, William; McCann, Karey; Buteau, Francois A; McEwan, Alexander J B

    2015-08-01

    A 60-year-old woman diagnosed with a well-differentiated neuroendocrine tumor metastatic to the liver and lymph nodes was treated with 4 induction cycles and 2 maintenance cycles of (177)Lu [DOTA,(0)Tyr(3)]octreotate (DOTATATE) peptide receptor radionuclide therapy. Her posttreatment imaging showed partial response after 4 induction cycles and complete response after 2 additional maintenance cycles. This case highlights the need for further research into maintenance (177)Lu DOTATATE therapy to improve outcomes in neuroendocrine tumor patients. PMID:25546219

  19. Overexpression of Membrane Proteins in Primary and Metastatic Gastrointestinal Neuroendocrine Tumors

    PubMed Central

    Wang, Donghong; Dahdaleh, Fadi S.; Bellizzi, Andrew M.; O’Dorisio, M. Sue; O’Dorisio, Thomas M.; Howe, James R.

    2014-01-01

    Background Small bowel and pancreatic neuroendocrine tumors (SBNETs and PNETs) are rare tumors whose incidence is increasing. Drugs targeting the somatostatin receptor are beneficial in these tumors. To identify additional cell-surface targets, we recently found receptors and membrane proteins with gene expression significantly different from adjacent normal tissues in a small number of primary SBNETs and PNETs. We set out to validate these expression differences in a large group of primary neuroendocrine tumors and to determine whether they are present in corresponding liver and lymph node metastases. Methods Primary SBNETs and PNETs, normal tissue, nodal, and liver metastases were collected and mRNA expression of six target genes was determined by quantitative PCR. Expression was normalized to GAPDH and POLR2A internal controls, and differences as compared to normal tissue were assessed by Welch’s t test. Results Gene expression was determined in 45 primary PNETs with 20 nodal and 17 liver metastases, and 51 SBNETs with 50 nodal and 29 liver metastases. Compared to normal tissue, the oxytocin receptor (OXTR) showed significant overexpression in both primary and metastatic SBNETs and PNETs. Significant overexpression was observed for MUC13 and MEP1B in PNET primary tumors, and for GPR113 in primary SBNETs and their metastases. SCTR and ADORA1 were significantly underexpressed in PNETs and their metastases. OXTR protein expression was confirmed by immunohistochemistry. Conclusions OXTR is significantly overexpressed relative to normal tissue in primary SBNETs and PNETs, and this overexpression is present in their liver and lymph node metastases, making OXTR a promising target for imaging and therapeutic interventions. PMID:24114056

  20. Detection of neuroendocrine tumors using promoter-specific secreted Gaussia luciferase.

    PubMed

    Tseng, Alan Wei-Shun; Akerstrom, Victoria; Chen, Chiachen; Breslin, Mary B; Lan, Michael S

    2016-01-01

    Accurate detection of neuroendocrine (NE) tumors is critically important for better prognosis and treatment outcomes in patients. To demonstrate the efficacy of using an adenoviral vector for the detection of NE tumors, we have constructed a pair of adenoviral vectors which, in combination, can conditionally replicate and release Gaussia luciferase into the circulation after infecting the NE tumors. The expression of these two vectors is regulated upstream by an INSM1-promoter (insulinoma-associated-1) that is specifically active in NE tumors and developing NE tissues, but silenced in normal adult tissues. In order to retain the tumor-specificity of the INSM1 promoter, we have modified the promoter using the core insulator sequence from the chicken β-globin HS4 insulator and the neuronal restrictive silencing element (NRSE). This modified INSM1-promoter can retain NE tumor specificity in an adenoviral construct while driving a mutated adenovirus E1A gene (∆24E1A), the Metridia, or Gaussia luciferase gene. The in vitro cell line and mouse xenograft human tumor studies revealed the NE specificity of the INSM1-promoter in NE lung cancer, neuroblastoma, medulloblastoma, retinoblastoma, and insulinoma. When we combined the INSM1-promoter driven Gaussia luciferase with ∆24E1A, the co-infected NE tumor secreted higher levels of Gaussia luciferase as compared to the INSM1p-Gaussia virus alone. In a mouse subcutaneous xenograft tumor model, the combination viruses secreted detectable level of Gaussia luciferase after infecting an INSM1-positive NE lung tumor for ≥12 days. Therefore, the INSM1-promoter specific conditional replicating adenovirus represents a sensitive diagnostic tool to aid clinicians in the detection of NE tumors. PMID:26530405

  1. Diagnosis and management of gastrointestinal neuroendocrine tumors: An evidence-based Canadian consensus.

    PubMed

    Singh, Simron; Asa, Sylvia L; Dey, Chris; Kennecke, Hagen; Laidley, David; Law, Calvin; Asmis, Timothy; Chan, David; Ezzat, Shereen; Goodwin, Rachel; Mete, Ozgur; Pasieka, Janice; Rivera, Juan; Wong, Ralph; Segelov, Eva; Rayson, Daniel

    2016-06-01

    The majority of neuroendocrine tumors originate in the digestive system and incidence is increasing within Canada and globally. Due to rapidly evolving evidence related to diagnosis and clinical management, updated guidance on the diagnosis and treatment of gastrointestinal neuroendocrine tumors (GI-NETs) are of clinical importance. Well-differentiated GI-NETs may exhibit indolent clinical behavior and are often metastatic at diagnosis. Some NET patients will develop secretory disease requiring symptom control to optimize quality of life and clinical outcomes. Optimal management of GI-NETs is in a multidisciplinary environment and is multimodal, requiring collaboration between medical, surgical, imaging and pathology specialties. Clinical application of advances in pathological classification and diagnostic technologies, along with evolving surgical, radiotherapeutic and medical therapies are critical to the advancement of patient care. We performed a systematic literature search to update our last set of published guidelines (2010) and identified new level 1 evidence for novel therapies, including telotristat etiprate (TELESTAR), lanreotide (CLARINET), everolimus (RADIANT-2; RADIANT-4) and peptide receptor radionuclide therapy (PRRT; NETTER-1). Integrating these data with the clinical knowledge of 16 multi-disciplinary experts, we devised consensus recommendations to guide state of the art clinical management of GI-NETs. PMID:27236421

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

    PubMed Central

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

    2013-01-01

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

  3. Gastrointestinal stromal tumors regularly express synaptic vesicle proteins: evidence of a neuroendocrine phenotype.

    PubMed

    Bümming, Per; Nilsson, Ola; Ahlman, Håkan; Welbencer, Anna; Andersson, Mattias K; Sjölund, Katarina; Nilsson, Bengt

    2007-09-01

    Gastrointestinal stromal tumors (GISTs) are thought to originate from the interstitial cells of Cajal, which share many properties with neurons of the gastrointestinal tract. Recently, we demonstrated expression of the hormone ghrelin in GIST. The aim of the present study was therefore to evaluate a possible neuroendocrine phenotype of GIST. Specimens from 41 GISTs were examined for the expression of 12 different synaptic vesicle proteins. Expression of synaptic-like microvesicle proteins, e.g., Synaptic vesicle protein 2 (SV2), synaptobrevin, synapsin 1, and amphiphysin was demonstrated in a majority of GISTs by immunohistochemistry, western blotting, and quantitative reversetranscriptase PCR. One-third of the tumors also expressed the large dense core vesicle protein vesicular monoamine transporter 1. Presence of microvesicles and dense core vesicles in GIST was confirmed by electron microscopy. The expression of synaptic-like microvesicle proteins in GIST was not related to risk profile or to KIT/platelet derived growth factor alpha (PDGFRA) mutational status. Thus, GISTs regularly express a subset of synaptic-like microvesicle proteins necessary for the regulated secretion of neurotransmitters and hormones. Expression of synaptic-like micro-vesicle proteins, ghrelin and peptide hormone receptors in GIST indicate a neuroendocrine phenotype and suggest novel possibilities to treat therapy-resistant GIST. PMID:17914114

  4. 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

  5. APC mutations in colorectal tumors with mismatch repair deficiency.

    PubMed Central

    Huang, J; Papadopoulos, N; McKinley, A J; Farrington, S M; Curtis, L J; Wyllie, A H; Zheng, S; Willson, J K; Markowitz, S D; Morin, P; Kinzler, K W; Vogelstein, B; Dunlop, M G

    1996-01-01

    We have investigated the influence of genetic instability [replication error (RER) phenotype] on APC (adenomatous polyposis coli), a gene thought to initiate colorectal tumorigenesis. The prevalence of APC mutations was similar in RER and non-RER tumors, indicating that both tumor types share this step in neoplastic transformation. However, in a total of 101 sequenced mutations, we noted a substantial excess of APC frameshift mutations in the RER cases (70% in RER tumors versus 47% in non-RER tumors, P < 0.04). These frameshifts were characteristic of mutations arising in cells deficient in DNA mismatch repair, with a predilection for mononucleotide repeats in the RER tumors (P < 0.0002), particularly (A)n tracts (P < 0.00007). These findings suggest that the genetic instability that is reflected by the RER phenotype precedes, and is responsible for, APC mutation in RER large bowel tumors and have important implications for understanding the very earliest stages of neoplasia in patients with tumors deficient in mismatch repair. Images Fig. 2 PMID:8799152

  6. The expanding role of somatostatin analogs in gastroenteropancreatic and lung neuroendocrine tumors.

    PubMed

    Cives, Mauro; Strosberg, Jonathan

    2015-05-01

    Somatostatin analogs (SSAs) were initially developed as antisecretory agents used for the control of hormonal syndromes associated with neuroendocrine tumors (NETs). In recent years, accumulating evidence has also supported their role as antiproliferative agents in well or moderately differentiated NETs. The phase III PROMID trial demonstrated that octreotide long-acting repeatable (LAR) can significantly prolong time to progression among patients with metastatic midgut NETs. More recently, the randomized CLARINET trial reported a significant improvement in progression-free survival in a heterogeneous population of patients with gastroenteropancreatic (GEP)-NETs treated with depot lanreotide. Octreotide and lanreotide target somatostatin receptor subtypes in a similar fashion, and appear to be clinically interchangeable; however, comparative noninferiority trials have not been performed. Further studies are needed to evaluate the efficacy of novel SSAs such as pasireotide in the refractory setting, and the role of high-dose SSAs for symptom and tumor control. PMID:25911185

  7. 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. PMID:27295530

  8. Polymorphic genetic control of tumor invasion in a mouse model of pancreatic neuroendocrine carcinogenesis.

    PubMed

    Chun, Matthew G H; Mao, Jian-Hua; Chiu, Christopher W; Balmain, Allan; Hanahan, Douglas

    2010-10-01

    Cancer is a disease subject to both genetic and environmental influences. In this study, we used the RIP1-Tag2 (RT2) mouse model of islet cell carcinogenesis to identify a genetic locus that influences tumor progression to an invasive growth state. RT2 mice inbred into the C57BL/6 (B6) background develop both noninvasive pancreatic neuroendocrine tumors (PNET) and invasive carcinomas with varying degrees of aggressiveness. In contrast, RT2 mice inbred into the C3HeB/Fe (C3H) background are comparatively resistant to the development of invasive tumors, as are RT2 C3HB6(F1) hybrid mice. Using linkage analysis, we identified a 13-Mb locus on mouse chromosome 17 with significant linkage to the development of highly invasive PNETs. A gene residing in this locus, the anaplastic lymphoma kinase (Alk), was expressed at significantly lower levels in PNETs from invasion-resistant C3H mice compared with invasion-susceptible B6 mice, and pharmacological inhibition of Alk led to reduced tumor invasiveness in RT2 B6 mice. Collectively, our results demonstrate that tumor invasion is subject to polymorphic genetic control and identify Alk as a genetic modifier of invasive tumor growth. PMID:20855625

  9. Development of neuroendocrine tumors in the gastrointestinal tract of transgenic mice. Heterogeneity of hormone expression.

    PubMed Central

    Rindi, G.; Grant, S. G.; Yiangou, Y.; Ghatei, M. A.; Bloom, S. R.; Bautch, V. L.; Solcia, E.; Polak, J. M.

    1990-01-01

    Expression of hormones in endocrine tumors and derived cell lines of transgenic mice carrying insulin-promoted oncogenes has been investigated by histochemical, immunohistochemical, ultrastructural, and radioimmunologic means. Tumors of the pancreas, small intestine, mesentery, and liver were examined. Insulin-immunoreactive cells were prevalent in pancreatic tumors, with a significant subpopulation of pancreatic polypeptide-immunoreactive elements. Conventional ultrastructural and immunogold analysis identified insulin-storing beta granules in pancreatic tumor cells. In contrast, the largest immunoreactive subpopulation of intestinal tumors expressed secretin (53% of total cells), followed by proglucagon-related peptides (15%), glucose-dependent insulinotropic polypeptide (7%), gastrin (7%), pancreatic polypeptide (2%), neurotensin (2%), and somatostatin (1%). No detectable immunoreactivity for either insulin or serotonin was observed. Electron microscopy and immunogold labeling showed that intestinal tumor cells contained secretin-storing S-type granules. Lymph node and liver tumors contained secretin-immunoreactive cells with ultrastructural features similar to those of intestinal tumors. In addition, high levels of circulating insulinlike and secretinlike immunoreactants were detectable. Analogous hormone profiles were identified in tumor cell lines and culture media. Large T-antigen immunoreactivity was detected in all the nuclei of neoplastic cells, as well as in insulin-immunoreactive elements of non-neoplastic islets and pancreatic ducts and in some secretin-immunoreactive cells of small intestinal mucosa. These data indicate that neuroendocrine tumors arise both in beta cell and S-cell subpopulations of transgenic mice. Images Figure 5 Figure 1 Figure 2 Figure 3 Figure 4 Figure 6 PMID:2162628

  10. Metanephrine neuroendocrine tumor marker detection by SERS using Au nanoparticle/Au film sandwich architecture.

    PubMed

    Boca, Sanda; Farcau, Cosmin; Baia, Monica; Astilean, Simion

    2016-02-01

    Neuroendocrine tumors, such as pheochromocytoma or paraganglioma, are dangerous tumors that constitute a potential threat for a large number of patients. Currently, the biochemical diagnosis of neuroendocrine tumors is based on measurement of the direct secretory products of the adrenomedullary-sympathetic system or of their metabolites, such as catecholamines or their metanephrine derivatives, from plasma or urine. The techniques used for analysis of plasma free metanephrines, i.e. high-performance liquid chromatography or high-performance liquid chromatography coupled with mass-spectrometry are technically-demanding and time consuming, which limit their availability. Here we demonstrate a simple, fast and low-cost method for detecting metanephrine by Surface Enhanced Raman Scattering (SERS). The protocol consists in using evaporation-induced self-assembly of gold (Au) nanoparticles incubated with the analyte, on planar gold films. The assembly process produces regions with a dense distribution of both inter-particle gaps and particle-film gaps. Finite-difference time-domain simulations confirm that both kinds of gaps are locations of enhanced electromagnetic fields resulting from inter-particle and particle-film plasmonic coupling, useful for SERS amplification. Metanephrine vibrational bands assignment was performed according to density functional theory calculations. Metanephrine metabolite was detected in liquid at concentration levels lower than previously reported for other similar metabolites. The obtained results demonstrate that the Au nanoparticle/Au film exhibits noticeable SERS amplification of the adsorbed metabolite and can be used in the design of efficient, stable SERS-active substrates for the detection and identification of specific tumor markers. PMID:26820563

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

    PubMed Central

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

    2016-01-01

    Patients with inoperable or unresectable pancreatic neuroendocrine tumors (NETs) have limited treatment options. These rare human tumors often express somatostatin receptors (SSTRs) and thus are clinically responsive to certain relatively stable somatostatin analogs, such as octreotide. Unfortunately, however, this tumor response is generally short-lived. Here we designed a hybrid adeno-associated virus and phage (AAVP) vector displaying biologically active octreotide on the viral surface for ligand-directed delivery, cell internalization, and transduction of an apoptosis-promoting tumor necrosis factor (TNF) transgene specifically to NETs. These functional attributes of AAVP-TNF particles displaying the octreotide peptide motif (termed Oct-AAVP-TNF) were confirmed in vitro, in SSTR type 2-expressing NET cells, and in vivo using cohorts of pancreatic NET-bearing Men1 tumor-suppressor gene KO mice, a transgenic model of functioning (i.e., insulin-secreting) tumors that genetically and clinically recapitulates the human disease. Finally, preclinical imaging and therapeutic experiments with pancreatic NET-bearing mice demonstrated that Oct-AAVP-TNF lowered tumor metabolism and insulin secretion, reduced tumor size, and improved mouse survival. Taken together, these proof-of-concept results establish Oct-AAVP-TNF as a strong therapeutic candidate for patients with NETs of the pancreas. More broadly, the demonstration that a known, short, biologically active motif can direct tumor targeting and receptor-mediated internalization of AAVP particles may streamline the potential utility of myriad other short peptide motifs and provide a blueprint for therapeutic applications in a variety of cancers and perhaps many nonmalignant diseases as well. PMID:26884209

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

    PubMed

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

    2016-03-01

    Patients with inoperable or unresectable pancreatic neuroendocrine tumors (NETs) have limited treatment options. These rare human tumors often express somatostatin receptors (SSTRs) and thus are clinically responsive to certain relatively stable somatostatin analogs, such as octreotide. Unfortunately, however, this tumor response is generally short-lived. Here we designed a hybrid adeno-associated virus and phage (AAVP) vector displaying biologically active octreotide on the viral surface for ligand-directed delivery, cell internalization, and transduction of an apoptosis-promoting tumor necrosis factor (TNF) transgene specifically to NETs. These functional attributes of AAVP-TNF particles displaying the octreotide peptide motif (termed Oct-AAVP-TNF) were confirmed in vitro, in SSTR type 2-expressing NET cells, and in vivo using cohorts of pancreatic NET-bearing Men1 tumor-suppressor gene KO mice, a transgenic model of functioning (i.e., insulin-secreting) tumors that genetically and clinically recapitulates the human disease. Finally, preclinical imaging and therapeutic experiments with pancreatic NET-bearing mice demonstrated that Oct-AAVP-TNF lowered tumor metabolism and insulin secretion, reduced tumor size, and improved mouse survival. Taken together, these proof-of-concept results establish Oct-AAVP-TNF as a strong therapeutic candidate for patients with NETs of the pancreas. More broadly, the demonstration that a known, short, biologically active motif can direct tumor targeting and receptor-mediated internalization of AAVP particles may streamline the potential utility of myriad other short peptide motifs and provide a blueprint for therapeutic applications in a variety of cancers and perhaps many nonmalignant diseases as well. PMID:26884209

  13. A Big Bang model of human colorectal tumor growth

    PubMed Central

    Sottoriva, Andrea; Kang, Haeyoun; Ma, Zhicheng; Graham, Trevor A.; Salomon, Matthew P.; Zhao, Junsong; Marjoram, Paul; Siegmund, Kimberly; Press, Michael F.; Shibata, Darryl; Curtis, Christina

    2015-01-01

    What happens in the early, still undetectable human malignancy is unknown because direct observations are impractical. Here we present and validate a “Big Bang” model, whereby tumors grow predominantly as a single expansion producing numerous intermixed sub-clones that are not subject to stringent selection, and where both public (clonal) and most detectable private (subclonal) alterations arise early during growth. Genomic profiling of 349 individual glands from 15 colorectal tumors revealed the absence of selective sweeps, uniformly high intra-tumor heterogeneity (ITH), and sub-clone mixing in distant regions, as postulated by our model. We also verified the prediction that most detectable ITH originates from early private alterations, and not from later clonal expansions, thus exposing the profile of the primordial tumor. Moreover, some tumors appear born-to-be-bad, with sub-clone mixing indicative of early malignant potential. This new model provides a quantitative framework to interpret tumor growth dynamics and the origins of ITH with significant clinical implications. PMID:25665006

  14. Gastrointestinal neuroendocrine tumors: Searching the optimal treatment strategy--A literature review.

    PubMed

    Berardi, Rossana; Rinaldi, Silvia; Torniai, Mariangela; Morgese, Francesca; Partelli, Stefano; Caramanti, Miriam; Onofri, Azzurra; Polenta, Vanessa; Pagliaretta, Silvia; Falconi, Massimo; Cascinu, Stefano

    2016-02-01

    Neuroendocrine tumors of the gastro-entero-pancreatic system (GEP-NETs) are a heterogeneous group of neoplasms, with different malignant potential and behavior. Many treatment options are available. Surgery should be considered for localized tumors and in some selected cases of metastatic disease. Somatostatin analogs, useful for symptoms control in functioning tumors, are also effective to inhibit tumor progression in specific settings. The multi-TKI sunitinib and of the mTOR-inhibitor everolimus are efficacy for metastatic pancreatic NET (P-NET) treatment. Chemotherapy is generally used in symptomatic and progressive NETs. Peptide receptor radionuclide therapy (PRRT) should be recommended after failure of medical therapy. For tumors confined to the liver ablative techniques should be considered. Nevertheless a shared therapeutic sequence for GEP-NET treatment still does not exist. In this review, we analyzed available data trying to identify the better treatment strategy and to suggest potential therapeutic algorithms distinguishing P-NETs from gastrointestinal NETs (GI-NETs). PMID:26643525

  15. 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). PMID:26994644

  16. Gastrointestinal hormones stimulate growth of Foregut Neuroendocrine Tumors by transactivating the EGF receptor

    PubMed Central

    Di Florio, Alessia; Sancho, Veronica; Moreno, Paola; Fave, Gianfranco Delle; Jensen, Robert T.

    2012-01-01

    Foregut Neuroendocrine Tumors[NETs] usually pursuit a benign course, but some show aggressive behavior. The treatment of patients with advanced NETs is marginally effective and new approaches are needed. In other tumors, transactivation of the EGF receptor(EGFR) by growth factors, gastrointestinal(GI) hormones and lipids can stimulate growth, which has led to new treatments. Recent studies show a direct correlation between NET malignancy and EGFR expression, EGFR inhibition decreases basal NET growth and an autocrine growth effect exerted by GI hormones, for some NETs. To determine if GI hormones can stimulate NET growth by inducing transactivation of EGFR, we examined the ability of EGF, TGFα and various GI hormones to stimulate growth of the human foregut carcinoid, BON, the somatostatinoma QGP-1 and the rat islet tumor, Rin-14B-cell lines. The EGFR tyrosine-kinase inhibitor, AG1478 strongly inhibited EGF and the GI hormones stimulated cell growth, both in BON and QGP-1 cells. In all the three neuroendocrine cell lines studied, we found EGF, TGFα and the other growth-stimulating GI hormones increased Tyr1068 EGFR phosphorylation. In BON cells, both the GI hormones neurotensin and a bombesin analogue caused a time- and dose-dependent increase in EGFR phosphorylation, which was strongly inhibited by AG1478. Moreover, we found this stimulated phosphorylation was dependent on Src kinases, PKCs, matrix metalloproteinase activation and the generation of reactive oxygen species. These results raise the possibility that disruption of this signaling cascade by either EGFR inhibition alone or combined with receptor antagonists may be a novel therapeutic approach for treatment of foregut NETs/PETs. PMID:23220008

  17. 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

  18. 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

  19. Neuropeptide S receptor 1 (NPSR1) activates cancer-related pathways and is widely expressed in neuroendocrine tumors.

    PubMed

    Pulkkinen, V; Ezer, S; Sundman, L; Hagström, J; Remes, S; Söderhäll, C; Greco, D; Dario, G; Haglund, C; Kere, J; Arola, J

    2014-08-01

    Neuroendocrine tumors (NETs) arise from disseminated neuroendocrine cells and express general and specific neuroendocrine markers. Neuropeptide S receptor 1 (NPSR1) is expressed in neuroendocrine cells and its ligand neuropeptide S (NPS) affects cell proliferation. Our aim was to study whether NPS/NPSR1 could be used as a biomarker for neuroendocrine neoplasms and to identify the gene pathways affected by NPS/NPSR1. We collected a cohort of NETs comprised of 91 samples from endocrine glands, digestive tract, skin, and lung. Tumor type was validated by immunostaining of chromogranin-A and synaptophysin expression and tumor grade was analyzed by Ki-67 proliferation index. NPS and NPSR1 expression was quantified by immunohistochemistry using polyclonal antibodies against NPS and monoclonal antibodies against the amino-terminus and carboxy-terminus of NPSR1 isoform A (NPSR1-A). The effects of NPS on downstream signaling were studied in a human SH-SY5Y neuroblastoma cell line which overexpresses NPSR1-A and is of neuroendocrine origin. NPSR1 and NPS were expressed in most NET tissues, with the exception of adrenal pheochromocytomas in which NPS/NPSR1 immunoreactivity was very low. Transcriptome analysis of NPSR1-A overexpressing cells revealed that mitogen-activated protein kinase (MAPK) pathways, circadian activity, focal adhesion, transforming growth factor beta, and cytokine-cytokine interactions were the most altered gene pathways after NPS stimulation. Our results show that NETs are a source of NPS and NPSR1, and that NPS affects cancer-related pathways. PMID:24915894

  20. Liver and bone metastases from small bowel neuroendocrine tumor respond to 177Lu-DOTATATE induction and maintenance therapies.

    PubMed

    Makis, William; McCann, Karey; Buteau, Francois A; McEwan, Alexander J B

    2015-02-01

    A 73-year-old man diagnosed with small bowel neuroendocrine tumor (NET) with liver and bone metastases was treated with 4 induction cycles and 2 maintenance cycles of Lu-DOTATATE peptide receptor radionuclide therapy (PRRT). His symptoms and mobility improved significantly following induction as well as maintenance treatments, and posttherapy imaging studies showed significant improvement in metastatic liver and bone disease. Current protocols consisting of 4 induction cycles of Lu-DOTATATE only may not be sufficient to optimally treat neuroendocrine liver and bone metastases, and further research into maintenance Lu-DOTATATE therapy is warranted. PMID:25243941

  1. Unexpected endoscopic full-thickness resection of a duodenal neuroendocrine tumor.

    PubMed

    Hatogai, Ken; Oono, Yasuhiro; Fu, Kuang-I; Odagaki, Tomoyuki; Ikematsu, Hiroaki; Kojima, Takashi; Yano, Tomonori; Kaneko, Kazuhiro

    2013-07-14

    A 57-year-old man underwent endoscopy for investigation of a duodenal polyp. Endoscopy revealed a hemispheric submucosal tumor, about 5 mm in diameter, in the anterior wall of the duodenal bulb. Endoscopic biopsy disclosed a neuroendocrine tumor histologically, therefore endoscopic mucosal resection was conducted. The tumor was effectively and evenly elevated after injection of a mixture of 0.2% hyaluronic acid and glycerol at a ratio of 1:1 into the submucosal layer. A small amount of indigo-carmine dye was also added for coloration of injection fluid. The lesion was completely resected en bloc with a snare after submucosal fluid injection. Immediately, muscle-fiber-like tissues were identified in the marginal area of the resected defect above the blue-colored layer, which suggested perforation. The defect was completely closed with a total of 9 endoclips, and no symptoms associated with peritonitis appeared thereafter. Histologically, the horizontal and vertical margins of the resected specimen were free of tumor and muscularis propria was also seen in the resected specimen. Generally, endoscopic mucosal resection is considered to be theoretically successful if the mucosal defect is colored blue. The blue layer in this case, however, had been created by unplanned injection into the subserosal rather than the submucosal layer. PMID:23864794

  2. Questions and answers: what can be said by diagnostic imaging in neuroendocrine tumors?

    PubMed

    Cuccurullo, V; Faggiano, A; Scialpi, M; Cascini, G L; Piunno, A; Catalano, O; Colao, A; Mansi, L

    2012-12-01

    The neuroendocrine tumors (NET) of the gastro-entero-pancreatic area (GEP) represent a heterogeneous group of malignancies from the histologic, clinico-laboratoristic (functioning and non-functioning variants), and therapeutic point of view. It is an issue becoming more frequent for the diagnostic imager, being radiologist as well as nuclear physician. Imaging (together with biopsy) plays a key role in the diagnostic assessment and staging (including grading and prognostic definition), in evaluating response to treatment, and in follow-up of GEP-NET. Multislice computed tomography (MSCT), octreoscan and PET-CT are the most widely diffuse and accurate imaging modalities employed in this setting. Other methods, such as Magnetic Resonance and Endoscopic Ultrasound, may also play a significant role. PMID:23235192

  3. Role of surgery and transplantation in the treatment of hepatic metastases from neuroendocrine tumor

    PubMed Central

    Alagusundaramoorthy, Sayee Sundar; Gedaly, Roberto

    2014-01-01

    Neuroendocrine tumors (NET) are a heterogeneous group of cancers, with indolent behavior. The most common primary origin is the gastro-intestinal tract but can also appear in the lungs, kidneys, adrenals, ovaries and other organs. In general, NET is usually discovered in the metastatic phase (40%-80%). The liver is the most common organ involved when metastases occur (40%-93%), followed by bone (12%-20%) and lung (8%-10%).A number of different therapeutic options are available for the treatment of hepatic metastases including surgical resection, transplantation, ablation, trans-arterial chemoembolization, chemotherapy and somatostatin analogues. Recently, molecular targeted therapies have been used, usually in combination with other treatment options, to improve outcomes in patients with metastases. This article emphasizes on the role of surgery in the treatment of liver metastases from NET. PMID:25339822

  4. Ampullary neuroendocrine tumor diagnosed by endoscopic papillectomy in previously confirmed ampullary adenoma.

    PubMed

    Lee, Seoung Ho; Lee, Tae Hoon; Jang, Si-Hyong; Choi, Chi Young; Lee, Won Myung; Min, Ji Hey; Cho, Hyun Deuk; Park, Sang-Heum

    2016-04-01

    Ampullary adenoma is a common indication for endoscopic papillectomy. Ampullary neuroendocrine tumor (NET) is a rare disease for which complete surgical resection is the treatment of choice. However, because of the morbidity and mortality associated with surgical resection, endoscopic papillectomy is increasingly used in selected cases of low grade, with no metastasis and no invasion of the pancreatic or bile duct. Also, confirmed and complete endoscopic resection of ampullary NET accompanied by adenoma has not been reported to date. We report herein a rare case of an ampullary NET accompanied with adenoma, which was successfully and completely resected via endoscopic papillectomy. Prior to papillectomy, this case was diagnosed as an ampullary adenoma. PMID:27053861

  5. 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. PMID:23524618

  6. Twenty years of gastroenteropancreatic neuroendocrine tumors: is reclassification worthwhile and feasible?

    PubMed

    Grillo, Federica; Albertelli, Manuela; Annunziata, Francesca; Boschetti, Mara; Caff, Andrea; Pigozzi, Simona; Ferone, Diego; Mastracci, Luca

    2016-07-01

    Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are rare neoplasms with heterogeneous clinical behavior and potential long-term survival. In 2006/2007, the European Neuroendocrine Tumors Society introduced an important parameter, grade (based on mitoses and Ki-67 proliferation rate), which became part of the latest 2010-WHO classification. Since this is an important tool in the choice of therapeutic algorithm of patients with NETs, our aim was to audit whether retrospective reclassification is possible and feasible and correlate pathological findings with survival. From the histopathology archive, 338 GEP-NETs (1994-2014) were identified, of which 250 were diagnosed pre-2010 and 80 of these have needed, up till now, classification (morphology and grade-mitotic count/Ki-67). Morphology was well differentiated (WD) in 74 cases while only 6 cases were poorly differentiated (PD). Grade was reclassified: G1-45 cases (56 %); G2-28 cases (35 %); G3-7 cases (9 %). Overall survival (OS) in WD NETs was strikingly better compared to PD neoplasms. Differences in OS between grade were statistically significant (p < 0.0001) and, in particular, grade identified a subgroup of patients with WD lesions but with less favorable clinical behavior (OS at 5 years: G1-89 %; G2-48 %; G3-0 %; G1 vs G2 p = 0.03). Feasibility analysis quantified time for reclassification to be between 45 and 64 min/case. Our series confirms the importance of grade in prognostic stratification and underlines that reclassification is feasible, and may prove worthwhile in patient management, especially in view of the potential long survival of patients with NETs and risk of use of inappropriate therapies. PMID:26362059

  7. [Liver trasplantation for the treatment of non-resectable metastases of neuroendocrine tumors: first report in Argentina].

    PubMed

    Quiñonez, Emilio; Capitanich, Pablo; Anders, Margarita; Fernández, José Luis; Serafini, Víctor; Viola, Luis; Mastai, Ricardo; McCormack, Lucas

    2011-09-01

    Neuroendocrine tumors are uncommon cancers characterized by a slow grow rate. Unresectable liver metastases are the main cause of death in patients with these tumors. This is the first Argentine report of a liver transplantation as an indication for the treatment of unresectable liver metastases from a pancreatic neuroendocrine tumor. We present a 48-year-old woman with diagnosis of a pancreatic neuroendocrine tumor with multiple bilobar unresectable liver metastases. A splenopancreatectomy was performed after a complete staging revealed absence of extrahepatic disease. Six months later, a follow-up performed with thoracoabdominal CT scan and octreo-scan was consistent with no tumor recurrence or extrahepatic disease. As the huge hepatomegaly caused a notorius deterioration in the patient's quality of life, we decided to include her in the waiting list for liver transplantation. Priority points were requested to the MELD (model for end stage liver disease) Exceptions Experts Committee with a positive response. Twelve months after the primary surgery, with a MELD score of 23 points, a deceased donor liver transplantation was performed without evidence at that moment of residual disease. Eighteen months after liver transplantation, the patient required the surgical repair of a stenosis in the biliary anastomosis. At the surgery peritoneal tumor recurrence was diagnosed. Now, 24 months after liver transplantation the patient has an excellent quality of life and a well functioning graft. We report this case of a liver transplantation as an indication for the treatment of liver metastases from a neuroendocrine tumor and we review the literature on this controversial issue. PMID:22233004

  8. [Treatment Strategy for Non-Functional Pancreatic Neuroendocrine Tumors (P-NETs) at Kurume University Hospital].

    PubMed

    Kawashima, Yusuke; Ishikawa, Hiroto; Hisaka, Toru; Okuda, Kouji; Akagi, Yoshito

    2016-01-01

    Pancreatic neuroendocrine tumors (P-NETs) are relatively rare. Approximately 50-90% of non-functioning P-NETs are malignant, and the only curative treatment is surgical resection. Liver and lymph node metastases often occur. In Japan, the mTOR inhibitor everolimus is now covered by the national health insurance for treatment of P-NETs, including advanced and unresectable tumors. We present a case of P-NETs with liver metastases seen at our hospital and discuss our treatment strategy for this disease. Patients with tumors≤1 cm receive follow-up observation. For G1 and G2 (other than G3) tumors, if their size is >1 cm when first discovered, resection of the primary lesion along with lymph node dissection (as for pancreatic cancer) is performed. In G1 and G2 tumors with synchronous distant metastases, the primary lesion is first resected, and depending on the pathological findings, chemotherapy (LAR plus everolimus) may be administered. After 4 courses of chemotherapy, the response is assessed, and if further resection is possible, resection is performed. When there are synchronous liver metastases, if partial resection and local treatment (such as RFA) are possible, the primary lesion and synchronous lesions are resected. If a major hepatic resection procedure such as a segmentectomy or lobectomy is possible, the primary lesion is resected, followed by chemotherapy. After 4 courses of chemotherapy, the response is assessed, and if further resection is possible, hepatic resection is performed. G3 tumors are usually highly malignant, advanced, and often associated with metastases at the time of diagnosis. Chemotherapy may be an option for treating patients with G3 tumors. PMID:26809536

  9. Impact and Clinical Predictors of Lymph Node Metastases in Nonfunctional Pancreatic Neuroendocrine Tumors

    PubMed Central

    Jiang, Yu; Jin, Jia-Bin; Zhan, Qian; Deng, Xia-Xing; Shen, Bai-Yong

    2015-01-01

    Background: The optimal surgical management of nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) is still controversial. Here, we evaluated the impact of lymph node status on postoperative recurrence in patients with NF-PNET and the potential of preoperative variables for predicting lymph node metastasis (LNM). Methods: In this mono-institutional retrospective cohort study conducted in 100 consecutive patients who underwent NF-PNET resection between January 2004 and December 2014, we evaluated risk factors for survival using the Kaplan–Meier method and the Cox regression model. Predictors of LNM were evaluated using the logistic regression model, and the power of predictive models was evaluated using receiver operating characteristic curve analysis. Results: Five-year disease-free survival of resected NF-PNET was 64.1%. LNM was independently associated with postoperative recurrence (hazard ratio = 3.995, P = 0.003). Multivariate analysis revealed tumor grade as an independent factor associated with LNM (G2 vs. G1: odds ratio [OR] =6.287, P = 0.008; G3 vs. G1: OR = 12.407, P = 0.001). When tumor grade was excluded, radiological tumor diameter >2.5 cm (OR = 5.430, P = 0.013) and presence of symptoms (OR = 3.366, P = 0.039) were significantly associated with LNM. Compared to neoplasms with radiological diameter >2.5 cm (32.1%), tumors ≤2.5 cm had an obviously lower risk of LNM (7.7%), indicating the reliability of this parameter in predicting LNM (area under the curve, 0.693). Incidentally discovered NF-PNETs ≤2.5 cm were associated with a low-risk of LNM and excellent survival. Conclusions: LNM is significantly associated with postoperative recurrence. Radiological tumor diameter is a reliable predictor of LNM in NF-PNETs. Our results indicate that lymphadenectomy in small (≤2.5 cm) NF-PNETs is not routinely necessary. PMID:26668149

  10. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo

    PubMed Central

    Saunders, Laura R.; Bankovich, Alexander J.; Anderson, Wade C.; Aujay, Monette A.; Bheddah, Sheila; Black, KristenAnn; Desai, Radhika; Escarpe, Paul A.; Hampl, Johannes; Laysang, Amy; Liu, David; Lopez-Molina, Javier; Milton, Milly; Park, Albert; Pysz, Marybeth A.; Shao, Hui; Slingerland, Brian; Torgov, Michael; Williams, Samuel A.; Foord, Orit; Howard, Philip; Jassem, Jacek; Badzio, Andrzej; Czapiewski, Piotr; Harpole, David H.; Dowlati, Afshin; Massion, Pierre P.; Travis, William D.; Pietanza, M. Catherine; Poirier, J. T.; Rudin, Charles M.; Stull, Robert A.; Dylla, Scott J.

    2016-01-01

    The high-grade pulmonary neuroendocrine tumors, small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), remain among the most deadly malignancies. Therapies that effectively target and kill tumor-initiating cells (TICs) in these cancers should translate to improved patient survival. Patient-derived xenograft (PDX) tumors serve as excellent models to study tumor biology and characterize TICs. Increased expression of delta-like 3 (DLL3) was discovered in SCLC and LCNEC PDX tumors and confirmed in primary SCLC and LCNEC tumors. DLL3 protein is expressed on the surface of tumor cells but not in normal adult tissues. A DLL3-targeted antibody-drug conjugate (ADC), SC16LD6.5, comprised of a humanized anti-DLL3 monoclonal antibody conjugated to a DNA-damaging pyrrolobenzodiazepine (PBD) dimer toxin, induced durable tumor regression in vivo across multiple PDX models. Serial transplantation experiments executed with limiting dilutions of cells provided functional evidence confirming that the lack of tumor recurrence after SC16LD6.5 exposure resulted from effective targeting of DLL3-expressing TICs. In vivo efficacy correlated with DLL3 expression, and responses were observed in PDX models initiated from patients with both limited and extensive-stage disease and were independent of their sensitivity to standard-of-care chemotherapy regimens. SC16LD6.5 effectively targets and eradicates DLL3-expressing TICs in SCLC and LCNEC PDX tumors and is a promising first-in-class ADC for the treatment of high-grade pulmonary neuroendocrine tumors. PMID:26311731

  11. Non-functional neuroendocrine tumors of the pancreas: Advances in diagnosis and management

    PubMed Central

    Cloyd, Jordan M; Poultsides, George A

    2015-01-01

    Nonfunctional neuroendocrine tumors of the pancreas (NF-PNETs) are a heterogeneous group of neoplasms. Although rare, the incidence of NF-PNETs is increasing significantly. The classification of PNETs has evolved over the past decades and is now based on a proliferation grading system. While most NF-PNETs are slow growing, tumors with more aggressive biology may become incurable once they progress to unresectable metastatic disease. Tumors of higher grade can be suspected preoperatively based on the presence of calcifications, hypoenhancement on arterial phase computed tomography, positron emission technology avidity and lack of octreotide scan uptake. Surgery is the only curative treatment and is recommended for most patients for whom complete resection is possible. Liver-directed therapies (thermal ablation, transarterial embolization) can be useful in controlling unresectable hepatic metastatic disease. In the presence of unresectable progressive disease, somatostatin analogues, everolimus and sunitinib can prolong progression-free survival. This article provides a comprehensive review of NF-PNETs with special emphasis on recent advances in diagnosis and management. PMID:26327759

  12. Gastrointestinal neuroendocrine tumor with unresectable liver metastases: an example of multimodal therapeutic approach.

    PubMed

    Martínez, Jorge; Besa, Santiago; Arab, Juan P; Quintana, Juan C; Regonesi, Carlos; Huete, Alvaro; Jarufe, Nicolás; Guerra, Juan F; Benítez, Carlos; Arrese, Marco

    2015-01-01

    Gastrointestinal neuroendocrine tumors (NET) frequently present with unresectable hepatic metastases, which poses a barrier for curative treatment. Resection of the primary tumor and subsequent orthotopic liver transplantation (OLT) has been proposed as a treatment approach but available data in this regard is limited. We present a clinical case of an otherwise asymptomatic 44-yo man complaining of abdominal pain and dyspepsia that was diagnosed of a 10 cm duodenal tumor with multiple hepatic metastases. A CT-guided biopsy confirmed a NET. He underwent first a Whipple's procedure, and then was listed for liver transplantation. During the waiting time a multimodal therapeutic approach was used including the use of radioactive 177lutetium-labeled somatostatin analogues, long-acting somastostatin analogues and antiangiogenic antibodies (bevacizumab) in order to keep neoplastic disease under control. Two years after Whipple's procedure and given disease stability he underwent OLT with an uneventful postoperative evolution. Patient condition and graft function are optimal after a 4-year follow-up period with no evidence of recurrence. This case report underscores how a multimodal approach involving careful patient selection, resective surgery as well as use of somatostatin analogues and antiangiogenic biological therapy followed by liver transplantation can achieve excellent long-term results in this difficult patient population. PMID:26256906

  13. FAM172A is a tumor suppressor in colorectal carcinoma.

    PubMed

    Cui, Chunhui; Ye, Lili; Huang, Zonghai; Huang, Shuxin; Liu, Hao; Yu, Jinlong

    2016-05-01

    The present study was designed to elucidate the regulatory role of a novel protein FAM172A in carcinogenesis of colorectal carcinoma (CRC). Investigation of clinical samples using Western blotting showed that expression of FAM172A is significantly lower in cancerous tissues than in adjacent tissues. Furthermore, we constructed in vitro model for continuous overexpression and silencing of FAM172A with a retroviral vector system. FAM172A suppressed the proliferative and invasive potentials of LOVO cells as shown in MTT test, transwell migration assay, wound healing assay, 3D-culture morphologic study, and xenograft experiment. RT-PCR and Western blotting showed that FAM172A overexpression inhibited expressions of Cyclin D1, CDK2, MMP-2, MMP-9, PERK, elF2α, ATF6, XBP1, and GRP78, while FAM172A silencing induced their expressions. FAM172A might regulate ERS through PERK-elF2α, ATF6-XBP1-GRP78 signal pathway. The results implicated that FAM172A functioned as a tumor suppressor in colorectal carcinoma. PMID:26637224

  14. Appropriateness of systemic treatments in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors

    PubMed Central

    Strosberg, Jonathan R; Fisher, George A; Benson, Al B; Anthony, Lowell B; Arslan, Bulent; Gibbs, John F; Greeno, Edward; Iyer, Renuka V; Kim, Michelle K; Maples, William J; Philip, Philip A; Wolin, Edward M; Cherepanov, Dasha; Broder, Michael S

    2015-01-01

    AIM: To evaluate systemic treatment choices in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors (PNETs) and provide consensus treatment recommendations. METHODS: Systemic treatment options for pancreatic neuroendocrine tumors have expanded in recent years to include somatostatin analogs, angiogenesis inhibitors, inhibitors of mammalian target of rapamycin and cytotoxic agents. At this time, there is little data to guide treatment selection and sequence. We therefore assembled a panel of expert physicians to evaluate systemic treatment choices and provide consensus treatment recommendations. Treatment appropriateness ratings were collected using the RAND/UCLA modified Delphi process. After studying the literature, a multidisciplinary panel of 10 physicians assessed the appropriateness of various medical treatment scenarios on a 1-9 scale. Ratings were done both before and after an extended discussion of the evidence. Quantitative measurements of agreement were made and consensus statements developed from the second round ratings. RESULTS: Specialties represented were medical and surgical oncology, interventional radiology, and gastroenterology. Panelists had practiced for a mean of 15.5 years (range: 6-33). Among 202 rated scenarios, disagreement decreased from 13.2% (26 scenarios) before the face-to-face discussion of evidence to 1% (2) after. In the final ratings, 46.5% (94 scenarios) were rated inappropriate, 21.8% (44) were uncertain, and 30.7% (62) were appropriate. Consensus statements from the scenarios included: (1) it is appropriate to use somatostatin analogs as first line therapy in patients with hormonally functional tumors and may be appropriate in patients who are asymptomatic; (2) it is appropriate to use everolimus, sunitinib, or cytotoxic chemotherapy therapy as first line therapy in patients with symptomatic or progressive tumors; and (3) beyond first line, these same agents can be used. In patients with uncontrolled

  15. Phase II clinical trial of pasireotide long-acting repeatable in patients with metastatic neuroendocrine tumors

    PubMed Central

    Cives, M; Kunz, P L; Morse, B; Coppola, D; Schell, M J; Campos, T; Nguyen, P T; Nandoskar, P; Khandelwal, V; Strosberg, J R

    2015-01-01

    Pasireotide long-acting repeatable (LAR) is a novel somatostatin analog (SSA) with avid binding affinity to somatostatin receptor subtypes 1, 2, 3 (SSTR1,2,3) and 5 (SSTR5). Results from preclinical studies indicate that pasireotide can inhibit neuroendocrine tumor (NET) growth more robustly than octreotide in vitro. This open-label, phase II study assessed the clinical activity of pasireotide in treatment-naïve patients with metastatic grade 1 or 2 NETs. Patients with metastatic pancreatic and extra-pancreatic NETs were treated with pasireotide LAR (60 mg every 4 weeks). Previous systemic therapy, including octreotide and lanreotide, was not permitted. Tumor assessments were performed every 3 months using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), overall radiographic response rate (ORR), and safety. Twenty-nine patients were treated with pasireotide LAR (60 mg every 4 weeks) and 28 were evaluable for response. The median PFS was 11 months. The most favorable effect was observed in patients with low hepatic tumor burden, normal baseline chromogranin A, and high tumoral SSTR5 expression. Median OS has not been reached; the 30-month OS rate was 70%. The best radiographic response was partial response in one patient (4%), stable disease in 17 patients (60%), and progressive disease in ten patients (36%). Although grade 3/4 toxicities were rare, pasireotide LAR treatment was associated with a 79% rate of hyperglycemia including 14% grade 3 hyperglycemia. Although pasireotide appears to be an effective antiproliferative agent in the treatment of advanced NETs, the high incidence of hyperglycemia raises concerns regarding its suitability as a first-line systemic agent in unselected patients. SSTR5 expression is a potentially predictive biomarker for response. PMID:25376618

  16. Colorectal cancer-derived tumor spheroids retain the characteristics of original tumors.

    PubMed

    Lee, Sun-Hwa; Hong, Jun Hwa; Park, Hwan Ki; Park, Jun Seok; Kim, Bo-Kyung; Lee, Jung-Yi; Jeong, Ji Yun; Yoon, Ghil Suk; Inoue, Masahiro; Choi, Gyu-Seog; Lee, In-Kyu

    2015-10-10

    Primary cultures of cancer cells are useful for developing personalized medicine. In this study, we characterized three lines of three-dimensional (3D) tumor spheroids established directly from tumor tissues of patients with colorectal cancers (CRCs). Each line mainly included EpCAM-positive cells and cells expressing putative cancer stem cell markers such as CD133, CD44, CD24, ALDH1, and LGR5. These characteristic stem cell markers remained identically for months in vitro. Short tandem repeat genotyping suggested that genetic fingerprints of these tumor spheroids were similar to those of the original tumor tissues from which they were derived. Mutational analysis showed that each line had the same mutation profile for APC, KRAS, MLH1, serine-threonine kinase 11, and TP53 as its parental tumor tissue. One line harboring an activating KRAS mutation was resistant to cetuximab while the remaining two lines harboring wild-type KRAS showed different responses to cetuximab. Immunohistochemical analysis showed that xenograft tumors derived from these lines retained the histopathological and mutational patterns of their parental tumors. Collectively, these results clearly showed that 3D tumor spheroids directly generated from tumor tissues of patients with CRCs preserved the characteristics of their parental tumor tissues and could be used for developing personalized medicines for CRCs. PMID:26185002

  17. Circulating Chromogranin A as A Marker for Monitoring Clinical Response in Advanced Gastroenteropancreatic Neuroendocrine Tumors

    PubMed Central

    Li, Na; Li, Yanyan; Lu, Ming; Li, Zhongwu; Lu, Zhihao; Li, Jie; Shen, Lin

    2016-01-01

    Chromogranin A (CgA), present in the chromaffin granules of neuroendocrine cells, is a useful biomarker for the diagnosis of patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This study was conducted to investigate the potential role of circulating CgA in monitoring clinical response in Chinese patients with advanced GEP-NETs. Eighty patients with advanced GEP-NETs treated in Peking University Cancer Hospital from September 2011 to May 2014 and 65 healthy individuals were included in this study. Serum CgA levels were analyzed for relationship with patient’s baseline characteristics and clinical outcome. Median CgA levels were significantly higher in patients with advanced GEP-NETs than in healthy individuals (93.8 ng/mL vs. 37.1 ng/mL; P<0.01), as well as significantly higher in patients with carcinoid syndrome or liver metastasis than in those without carcinoid syndrome (298.8 ng/mL vs. 82.9 ng/mL; P = 0.011) or liver metastasis (137.0 ng/mL vs. 64.4 ng/mL; P = 0.023). A CgA cutoff value of 46.2 ng/mL was used in this study with a sensitivity of 78.8% and specificity of 73.8%. Patients with CgA levels higher than 46.2 ng/mL had a worse prognosis than patients with CgA levels lower than 46.2 ng/mL (P = 0.045). Notably, a weak correlation was observed between changes in serum CgA levels and clinical response to the IP regimen as well as SSAs. Our data also indicate that serum CgA could be a useful indicator of patient prognosis though there is more research required in order to validate such claims. PMID:27159453

  18. Liver Metastases of Neuroendocrine Tumors Rarely Show Overlapping Immunoprofile with Hepatocellular Carcinomas.

    PubMed

    Jin, Ming; Zhou, Xiaoping; Yearsley, Martha; Frankel, Wendy L

    2016-09-01

    The distinction of hepatocellular carcinoma (HCC), neuroendocrine tumor (NET) metastatic to the liver, and cholangiocarcinoma (CC) can sometimes be challenging on small biopsies. Tissue microarrays were constructed from HCCs, NETs, and CCs. The immunoprofile was evaluated using HepPar1, glypican-3 (GPC3), synaptophysin (SYN), chromogranin A (CHR), CD56, MOC-31, and pCEA. One hundred thirteen HCCs, 48 NETs, and 44 CCs were included. Of HCCs, 107 (95 %) expressed HepPar1 and/or GPC3, 52 (46 %) both, and 97 (88 %) marked with pCEA (canalicular pattern). Seven (6 %) expressed CD56, of which 3 (3 %) expressed SYN. All 7 HCCs that expressed CD56 and/or SYN also expressed HepPar1 and/or GPC3, and none of the HCCs expressed CHR. Fourteen (13 %) expressed MOC-31. All 48 NETs expressed at least one neuroendocrine marker: 47 (98 %) positive for SYN, 40 (83 %) for CHR, 39 (81 %) for CD56, and 34 (71 %) for all three markers. None expressed HepPar1 or GPC3. All 44 CCs showed at least focal reactivity with MOC-31 and pCEA (membranous/cytoplasmic). One (2 %) was positive for HepPar1, 4 (9 %) for GPC3, 1 (2 %) for SYN and CHR, and 7 (16 %) for CD56. HCCs rarely express CD56 and SYN, while all express either HepPar1 or GPC3. NETs do not express HepPar1 or GPC3 and almost always express SYN, while CHR and CD56 are seen in most cases. Rare CCs focally express HepPar1 and GPC3. Utilizing a limited staining panel can efficiently distinguish HCCs, NETs, and CCs and help avoid diagnostic pitfalls on small biopsies. PMID:27300354

  19. Primary Neuroendocrine Tumor of the Parotid Gland: A Case Report and a Comprehensive Review of a Rare Entity

    PubMed Central

    Molina-Cerrillo, Javier; Moreno García del Real, Carmen; Díez, Juan J.; Alonso-Gordoa, Teresa; Pulido, Enrique Grande

    2016-01-01

    Neuroendocrine tumors (NETs) comprise a heterogeneous group of malignancies from cells derived from the neural crest with neuroendocrine differentiation. Despite the differences in the site of origin, nomenclature, biological behavior, and functional status, NETs share certain ultrastructural and immunohistochemical features. NETs are relative rare tumors with an annual incidence of 5.76 new cases per 100.000 inhabitants and they usually appear in the gastrointestinal tract or in the pulmonary system. Head and neck NETs are uncommon with limited information regarding frequency, most of them showing small cell carcinoma features. NETs that arise from the salivary glands are exceedingly rare. Regardless of their low frequency, it is imperative to accurately differentiate these tumors from the much more common squamous cell carcinomas and from metastasis from another primary tumor due to the completely different therapeutic approaches and prognosis. The diagnosis is based on the recognition of the typical neuroendocrine architecture and immunohistochemical staining and on an exhaustive work-up. Hereby, we report a case of a moderately differentiated NET of the parotid gland that was treated with a complete parotidectomy. We summarize the clues that led to the final diagnosis and major strategies that were employed to manage the patient. We also perform a comprehensive review of the scarce available literature on this topic. PMID:27610258

  20. Primary Neuroendocrine Tumor of the Parotid Gland: A Case Report and a Comprehensive Review of a Rare Entity.

    PubMed

    Martínez-Sáez, Olga; Molina-Cerrillo, Javier; Moreno García Del Real, Carmen; Barberá Durban, Rafael; Díez, Juan J; Alonso-Gordoa, Teresa; Pulido, Enrique Grande

    2016-01-01

    Neuroendocrine tumors (NETs) comprise a heterogeneous group of malignancies from cells derived from the neural crest with neuroendocrine differentiation. Despite the differences in the site of origin, nomenclature, biological behavior, and functional status, NETs share certain ultrastructural and immunohistochemical features. NETs are relative rare tumors with an annual incidence of 5.76 new cases per 100.000 inhabitants and they usually appear in the gastrointestinal tract or in the pulmonary system. Head and neck NETs are uncommon with limited information regarding frequency, most of them showing small cell carcinoma features. NETs that arise from the salivary glands are exceedingly rare. Regardless of their low frequency, it is imperative to accurately differentiate these tumors from the much more common squamous cell carcinomas and from metastasis from another primary tumor due to the completely different therapeutic approaches and prognosis. The diagnosis is based on the recognition of the typical neuroendocrine architecture and immunohistochemical staining and on an exhaustive work-up. Hereby, we report a case of a moderately differentiated NET of the parotid gland that was treated with a complete parotidectomy. We summarize the clues that led to the final diagnosis and major strategies that were employed to manage the patient. We also perform a comprehensive review of the scarce available literature on this topic. PMID:27610258

  1. New concepts in the treatment strategy of neuroendocrine tumors: the role of biotherapy.

    PubMed

    Papaxoinis, George; Syrigos, Kostas; Saif, Muhammad Wasif

    2016-05-01

    Neuroendocrine tumors (NETs) comprise a wide range of neoplasms with diverse biological behaviors, often secreting excessive amounts of endocrine-active substances causing hormone syndromes. They are classified according to the location of the primary site and the level of histological differentiation, which has prognostic as well as therapeutic implications. Biotherapy had traditionally a significant role in the treatment of these tumors, when not amenable to surgery or local treatments. Control of carcinoid syndrome with somatostatin analogs (SSAs) significantly contributed to the improvement of the quality of life. Also, interferon has long been administered, but data were based on small studies. In contrast, PROMID and CLARINET randomized phase III trials provided the first strong evidence of significant improvement in progression-free survival in patients with gastroenteropancreatic (GEP)-NETs with octreotide and lanreotide, respectively, validating somatostatin receptors as important targets. Clinical trials testing the role of these SSAs in other primaries, e.g., lung carcinoids, as well as the efficacy of newer analogs are underway. PMID:27355334

  2. Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors.

    PubMed

    Cives, M; Ghayouri, M; Morse, B; Brelsford, M; Black, M; Rizzo, A; Meeker, A; Strosberg, J

    2016-09-01

    The capecitabine and temozolomide (CAPTEM) regimen is active in the treatment of metastatic pancreatic neuroendocrine tumors (pNETs), with response rates ranging from 30 to 70%. Small retrospective studies suggest that O(6)-methylguanine DNA methyltransferase (MGMT) deficiency predicts response to temozolomide. High tumor proliferative activity is also commonly perceived as a significant predictor of response to cytotoxic chemotherapy. It is unclear whether chromosomal instability (CIN), which correlates with alternative lengthening of telomeres (ALT), is a predictive factor. In this study, we evaluated 143 patients with advanced pNET who underwent treatment with CAPTEM for radiographic and biochemical response. MGMT expression (n=52), grade (n=128) and ALT activation (n=46) were investigated as potential predictive biomarkers. Treatment with CAPTEM was associated with an overall response rate (ORR) of 54% by RECIST 1.1. Response to CAPTEM was not influenced by MGMT expression, proliferative activity or ALT pathway activation. Based on these results, no biomarker-driven selection criteria for use of the CAPTEM regimen can be recommended at this time. PMID:27552969

  3. Sentinel node navigation surgery for gastroduodenal neuroendocrine tumors: Two case reports.

    PubMed

    Arigami, Takaaki; Uenosono, Yoshikazu; Yanagita, Shigehiro; Okubo, Keishi; Kijima, Takashi; Matsushita, Daisuke; Amatatsu, Masahiko; Hagihara, Takahiko; Haraguchi, Naoto; Mataki, Yuko; Ehi, Katsuhiko; Ishigami, Sumiya; Natsugoe, Shoji

    2016-06-01

    The percentage of gastroduodenal neuroendocrine tumors (NETs) among all gastroenteropancreatic (GEP) NETs has gradually increased worldwide. Sentinel node navigation surgery (SNNS) has been developed as a personalized approach in the surgical strategy for early gastrointestinal tract cancers. We herein report 2 cases of gastroduodenal NETs treated with SNNS. Technetium-tin colloid including indocyanine green was endoscopically injected into the submucosa around a tumor the day before surgery. Basin dissection including the sentinel nodes (SNs), which were identified by Navigator GPS and near-infrared fluorescence imaging, was performed during laparoscopic surgery. SNs were intraoperatively examined using hematoxylin-eosin (HE) staining.SNs were detected in 2 patients. Lymph node metastasis was intraoperatively identified in 1 of the 2 patients. Consequently, 1 patient with metastatic SNs underwent laparoscopic gastrectomy with lymphadenectomy. Pathological findings identified submucosal NET measuring 6.0 mm × 5.0 mm.Our results suggest that SNNS is a promising surgical tool for detecting subclinical lymph node metastasis in patients with gastroduodenal NETs. PMID:27368046

  4. Case Report of Contrast-Enhanced Ultrasound Features of Primary Hepatic Neuroendocrine Tumor

    PubMed Central

    Li, Wei; Zhuang, Bo-wen; Wang, Zhu; Liao, Bing; Hong, Ling-yao; Xu, Ming; Lin, Xiao-na; Xie, Xiao-yan; Lu, Ming-de; Chen, Li-da; Wang, Wei

    2016-01-01

    Abstract Primary hepatic neuroendocrine tumors (PHNETs) are very rare and their clinical features and treatment outcomes are not well understood. It is difficult to reach a proper diagnosis before biopsy or resection. The aim of this study was to analyze the imaging features of PHNETs on contrast-enhanced ultrasound (CEUS). The clinical characteristics, CEUS findings, pathological features, treatment and prognosis of 6 patients with PHNET treated in our hospital were retrospectively analyzed. Most PHNETs occurred in middle-aged patients, and the most common clinical manifestation was right upper quadrant palpable mass and abdominal pain. Multiple small anechoic intralesional cavities occurred frequently in PHNET. Multilocular cystic with internal septation or monolocular with wall nodule could also be detected. On contrast-enhanced ultrasonography (CEUS), heterogeneous hyperenhancement in the arterial phase and wash-out hypoenhancement were observed in most patients, while computed tomography scanning yielded similar results. Diagnosis of PHNET was confirmed by immunohistochemical result and follow-up with the absence of extrahepatic primary sites. Five patients received surgical resection and 2 cases exhibited recurrence. Transcatheter arterial chemoembolization was performed in 1 patient with recurrence. Only 1 patient received conservative care. The median overall survival in 5 patients who underwent surgical treatment was 27 months (18–36 months). PHNET is a rare tumor, and its diagnosis is difficult. The CEUS features reported in this series may enrich the knowledge base for characterization of PHNET. PMID:27227910

  5. Telomere length abnormalities and telomerase RNA component expression in gastroenteropancreatic neuroendocrine tumors.

    PubMed

    Kim, Hee Sung; Lee, Hye Seung; Nam, Kyung Han; Choi, Jiwoon; Kim, Woo Ho

    2015-06-01

    Telomere lengths in normal human cells are tightly regulated within a narrow range. Telomere length abnormalities are prevalent genetic alterations in malignant transformation. We studied telomere length abnormalities, telomerase RNA component (TERC) expression, alpha-thalassemia X-linked mental retardation (ATRX) expression, and death domain-associated protein (DAXX) expression in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We used tissue microarrays to perform telomere fluorescent in situ hybridization (FISH) and TERC in situ hybridization in 327 formalin-fixed paraffin-embedded tissues of GEP-NETs. Telomere length abnormalities were detected in 35% of 253 informative cases by using telomere FISH. Ten cases had altered lengthening of telomeres (ALT), an ALT-positive phenotype (4%), and 79 cases had telomere shortening (31%). The ALT-positive phenotype was significantly associated with tumors of pancreatic origin (7/10) and loss of ATRX or DAXX protein (8/10). Telomere shortening was significantly associated with low TERC expression. In the survival analysis, loss of ATRX or DAXX protein was associated with a decreased overall survival. Multivariate regression analysis showed that lymph node metastasis and high TERC expression were independent prognostic factors of reduced overall survival (OS) for patients with GEP-NETs. Our results showed that telomere lengthening (the ALT-positive phenotype) and telomere shortening accompanied by low TERC levels are two types of clinically significant telomere abnormalities in GEP-NETs. PMID:26026117

  6. An Infection-enhanced Oncolytic Adenovirus Secreting H. pylori Neutrophil-activating Protein with Therapeutic Effects on Neuroendocrine Tumors

    PubMed Central

    Ramachandran, Mohanraj; Yu, Di; Wanders, Alkwin; Essand, Magnus; Eriksson, Fredrik

    2013-01-01

    Helicobacter pylori neutrophil-activating protein (HP-NAP) is a major virulence factor involved in H. pylori infection. HP-NAP can mediate antitumor effects by recruiting neutrophils and inducing Th1-type differentiation in the tumor microenvironment. It therefore holds strong potential as a therapeutic gene. Here, we armed a replication-selective, infection-enhanced adenovirus with secretory HP-NAP, Ad5PTDf35-[Δ24-sNAP], and evaluated its therapeutic efficacy against neuroendocrine tumors. We observed that it could specifically infect and eradicate a wide range of tumor cells lines from different origin in vitro. Insertion of secretory HP-NAP did not affect the stability or replicative capacity of the virus and infected tumor cells could efficiently secrete HP-NAP. Intratumoral administration of the virus in nude mice xenografted with neuroendocrine tumors improved median survival. Evidence of biological HP-NAP activity was observed 24 hours after treatment with neutrophil infiltration in tumors and an increase of proinflammatory cytokines such as tumor necrosis factor (TNF)-α and MIP2-α in the systemic circulation. Furthermore, evidence of Th1-type immune polarization was observed as a result of increase in IL-12/23 p40 cytokine concentrations 72 hours postvirus administration. Our observations suggest that HP-NAP can serve as a potent immunomodulator in promoting antitumor immune response in the tumor microenvironment and enhance the therapeutic effect of oncolytic adenovirus. PMID:23817216

  7. Chemometric evaluation of urinary steroid hormone levels as potential biomarkers of neuroendocrine tumors.

    PubMed

    Plenis, Alina; Miękus, Natalia; Olędzka, Ilona; Bączek, Tomasz; Lewczuk, Anna; Woźniak, Zofia; Koszałka, Patrycja; Seroczyńska, Barbara; Skokowski, Jarosław

    2013-01-01

    Neuroendocrine tumors (NETs) are uncommon tumors which can secrete specific hormone products such as peptides, biogenic amines and hormones. So far, the diagnosis of NETs has been difficult because most NET markers are not specific for a given tumor and none of the NET markers can be used to fulfil the criteria of high specificity and high sensitivity for the screening procedure. However, by combining the measurements of different NET markers, they become highly sensitive and specific diagnostic tests. The aim of the work was to identify whether urinary steroid hormones can be identified as potential new biomarkers of NETs, which could be used as prognostic and clinical course monitoring factors. Thus, a rapid and sensitive reversed-phase high-performance liquid chromatographic method (RP-HPLC) with UV detection has been developed for the determination of cortisol, cortisone, corticosterone, testosterone, epitestosterone and progesterone in human urine. The method has been validated for accuracy, precision, selectivity, linearity, recovery and stability. The limits of detection and quantification were 0.5 and 1 ng mL-1 for each steroid hormone, respectively. Linearity was confirmed within a range of 1-300 ng mL-1 with a correlation coefficient greater than 0.9995 for all analytes. The described method was successfully applied for the quantification of six endogenous steroid levels in human urine. Studies were performed on 20 healthy volunteers and 19 patients with NETs. Next, for better understanding of tumor biology in NETs and for checking whether steroid hormones can be used as potential biomarkers of NETs, a chemometric analysis of urinary steroid hormone levels in both data sets was performed. PMID:24135941

  8. Chromogranin A as Serum Marker for Gastroenteropancreatic Neuroendocrine Tumors: A Single Center Experience and Literature Review

    PubMed Central

    Nölting, Svenja; Kuttner, Axel; Lauseker, Michael; Vogeser, Michael; Haug, Alexander; Herrmann, Karin A.; Hoffmann, Johannes N.; Spitzweg, Christine; Göke, Burkhard; Auernhammer, Christoph J.

    2012-01-01

    The aim of this study was to assess the clinical sensitivities of the tumor markers chromogranin A (CgA), urinary 5-hydroxyindoleacetic acid (5-HIAA) and alkaline phosphatase (AP) in neuroendocrine tumors (NETs) of the GastroEnteroPancreatic-(GEP-) system depending on tumor primary location and metastatic spread. In a retrospective single-center series, sensitivities were evaluated in serum samples from 110 patients with midgut (n = 62) and pancreatic (n = 48) NETs. CgA levels were analyzed by a commercially-available immunoradiometric assay (CIS-bio) during routine follow-up in the years 2000–2009. CgA showed a higher sensitivity for midgut (68%) than pancreatic (54%) NETs. A higher CgA sensitivity and significantly higher median CgA values were found in patients with liver metastases than in those without, and in patients with hepatic and additionally extra-hepatic metastases than in those with hepatic and nodal metastases alone, respectively. We found an overall sensitivity for elevated 5HIAA excretion of 69% for midgut NETs and a significant correlation between median CgA and 5-HIAA values. The sensitivity of AP and the correlations of AP/CgA-data-pairs were low in both midgut and pancreatic NETs, although highest for metastatic pancreatic NETs. The sensitivity of CgA measurement depends on the NET primary location and spread of disease. 5-HIAA and CgA showed comparable sensitivity in midgut NETs, while AP does not seem to be useful as a tumor marker in GEP-NETs. PMID:24213232

  9. Prospective Study of Bevacizumab Plus Temozolomide in Patients With Advanced Neuroendocrine Tumors

    PubMed Central

    Chan, Jennifer A.; Stuart, Keith; Earle, Craig C.; Clark, Jeffrey W.; Bhargava, Pankaj; Miksad, Rebecca; Blaszkowsky, Lawrence; Enzinger, Peter C.; Meyerhardt, Jeffrey A.; Zheng, Hui; Fuchs, Charles S.; Kulke, Matthew H.

    2012-01-01

    Purpose Both tyrosine kinase inhibitors targeting the vascular endothelial growth factor (VEGF) receptor and bevacizumab, a monoclonal antibody targeting VEGF, have antitumor activity in neuroendocrine tumors (NETs). Temozolomide, an oral analog of dacarbazine, also has activity against NETs when administered alone or in combination with other agents. We performed a phase II study to evaluate the efficacy of temozolomide in combination with bevacizumab in patients with locally advanced or metastatic NETs. Patients and Methods Thirty-four patients (56% with carcinoid, 44% with pancreatic NETs) were treated with temozolomide 150 mg/m2 orally per day on days 1 through 7 and days 15 through 21, together with bevacizumab at a dose of 5 mg/kg per day intravenously on days 1 and 15 of each 28-day cycle. All patients received prophylaxis against Pneumocystis carinii and varicella zoster. Patients were followed for toxicity, biochemical and radiologic response, and survival. Results The combination of temozolomide and bevacizumab was associated with anticipated grade 3 to 4 toxicities, including lymphopenia (53%) and thrombocytopenia (18%). Although the overall radiographic response rate was 15% (five of 34), response rates differed between patients with pancreatic NETs (33%; five of 15) and those with carcinoid tumors (zero of 19). The median progression-free survival was 11.0 months (14.3 months for pancreatic NETs v 7.3 months for carcinoid tumors). The median overall survival was 33.3 months (41.7 months for pancreatic NETs v 18.8 months for carcinoid tumors). Conclusion Temozolomide and bevacizumab can be safely administered together in patients with advanced NETs, and the combination regimen appears promising for patients with pancreatic NETs. Studies evaluating the relative contributions of these two agents to the observed antitumor activity are warranted. PMID:22778320

  10. 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. PMID:25012983

  11. Deregulation of Wnt/β-catenin signaling through genetic or epigenetic alterations in human neuroendocrine tumors.

    PubMed

    Kim, Ji Tae; Li, Jing; Jang, Eun Ryoung; Gulhati, Pat; Rychahou, Piotr G; Napier, Dana L; Wang, Chi; Weiss, Heidi L; Lee, Eun Y; Anthony, Lowell; Townsend, Courtney M; Liu, Chunming; Evers, B Mark

    2013-05-01

    Carcinoid tumors are rare neuroendocrine tumors (NETs) that are increasing in incidence. Mutation and altered expression of Wnt/β-catenin signaling components have been described in many tumors but have not been well-studied in NETs. Here, we observed accumulation of β-catenin in the cytoplasm and/or nucleus in 25% of clinical NET tissues. By mutational analysis, the mutations of β-catenin (I35S) and APC (E1317Q, T1493T) were identified in NET cells and the tissues. Expression of representative Wnt inhibitors was absent or markedly decreased in BON, a human pancreatic carcinoid cell line; treatment with 5-aza-2'-deoxycytidine (5-aza-CdR) increased expression levels of the Wnt inhibitors. Methylation analyses demonstrated that CpG islands of SFRP-1 and Axin-2 were methylated, whereas the promoters of DKK-1, DKK-3 and WIF-1 were unmethylated in four NET cells. Aberrant methylation of SFRP-1 was particularly observed in most of clinical NET tissues. In addition, the repression of these unmethylated genes was associated with histone H3 lysine 9 dimethylation (H3K9me2) in BON cells. Together, 5-aza-CdR treatment inhibited cell proliferation and decreased the protein levels of H3K9me2 and G9a. Moreover, a novel G9a inhibitor, UNC0638, suppressed BON cell proliferation through inhibition of Wnt/β-catenin pathway. Overexpression of the inhibitory genes, particularly SFRP-1 and WIF-1 in BON cells, resulted in suppression of anchorage-independent growth and inhibition of tumor growth in mice. Our findings suggest that aberrant Wnt/β-catenin signaling, through either mutations or epigenetic silencing of Wnt antagonists, contributes to the pathogenesis and growth of NETs and have important clinical implications for the prognosis and treatment of NETs. PMID:23354304

  12. 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

  13. Uterus neuroendocrine tumor - a severe prognostic factor in a female patient with alcoholic cirrhosis undergoing chronic hemodialysis.

    PubMed

    Sinescu, Ruxandra Diana; Niculae, Andrei; Peride, Ileana; Vasilescu, Florina; Bratu, Ovidiu Gabriel; Mischianu, Dan Liviu Dorel; Jinga, Mariana; Checheriţă, Ionel Alexandru

    2015-01-01

    There is increased evidence that end-stage renal disease patients, especially the hemodialyzed population, may present various unexpected forms of complications, contributing to a poor prognosis. Furthermore, neuroendocrine tumors, rarely encountered in daily practice, present in dialyzed individuals can significantly exacerbate the inflammatory condition with negative impact on patients' quality of life. We present an unusual case of uterus neuroendocrine tumor with multiple metastases in a 49-year-old female hemodialyzed patient with a history of alcoholic liver cirrhosis and uterus fibromatous. Multiple endoscopic techniques (e.g., upper endoscopy, colonoscopy, upper and lower echoendoscopy), histological evaluation of biopsy samples from involved areas (the operatory piece) were performed in order to complete and refine the diagnosis. PMID:26193237

  14. Consensus Recommendations for the Diagnosis and Management of Pancreatic Neuroendocrine Tumors: Guidelines from a Canadian National Expert Group.

    PubMed

    Singh, Simron; Dey, Chris; Kennecke, Hagen; Kocha, Walter; Maroun, Jean; Metrakos, Peter; Mukhtar, Tariq; Pasieka, Janice; Rayson, Daniel; Rowsell, Corwyn; Sideris, Lucas; Wong, Ralph; Law, Calvin

    2015-08-01

    Pancreatic neuroendocrine tumors (pNETs) are rare heterogeneous tumors that have been steadily increasing in both incidence and prevalence during the past few decades. Pancreatic NETs are categorized as functional (F) or nonfunctional (NF) based on their ability to secrete hormones that elicit clinically relevant symptoms. Specialized diagnostic tests are required for diagnosis. Treatment options are diverse and include surgical resection, intraarterial hepatic therapy, and peptide receptor radionuclide therapy (PRRT). Systemic therapy options include targeted agents as well as chemotherapy when indicated. Diagnosis and management should occur through a collaborative team of health care practitioners well-experienced in managing pNETs. Recent advances in pNET treatment options have led to the development of the Canadian consensus document described in this report. The discussion includes the epidemiology, classification, pathology, clinical presentation and prognosis, imaging and laboratory testing, medical and surgical management, and recommended treatment algorithms for pancreatic neuroendocrine cancers. PMID:25366583

  15. Definition of the role of somatostatin receptor scintigraphy in gastrointestinal neuroendocrine tumor localization.

    PubMed Central

    Jensen, R. T.; Gibril, F.; Termanini, B.

    1997-01-01

    There are six major steps in the management of patients with neuroendocrine tumors (NETs) (carcinoids and pancreatic endocrine tumors). One of the steps that is increasing in its importance is the need to assess primary tumor location and tumor extent in these patients. Without such information, it is not possible to adequately manage these patients. Conventional imaging studies (CT scan, MRI, ultrasound, angiography), functional localization studies measuring hormonal gradients, endoscopic ultrasound, and most recently, somatostatin receptor scintigraphy (SRS) with [125I-DTPA-DPhe1]-octreotide have all been advocated to localize NETs in different studies. Whereas it is now established that for all NETs, except insulinomas, SRS has the greatest sensitivity, it remains unclear whether this increased sensitivity translates into increased clinical usefulness. It, therefore, remains unclear based on fiscal and clinical considerations what should be the recommended algorithm for the use of the different localization methods. To address this issue, we have recently performed two prospective studies on patients with gastrinomas. In this paper, the methods and results of each are summarized and based on these results, an algorithm for localization studies in NETs is proposed. One study assessed the role of SRS in management in 122 patients and shows that the use of SRS changed management in 47 percent of patients according to six different criteria when the patients were stratified according to their principal management problem. Determining whether liver metastases were present is one of the major goals of tumor localization studies and is frequently a source of confusion because of the difficulty in distinguishing small NETs liver metastases from hemangiomas. In the second study, the ability of SRS and other tumor localization methods to distinguish these two possibilities was assessed in 15 patients with small hemangiomas and 15 patients with small hepatic metastases

  16. Clinicopathologic significance of immunostaining of α-thalassemia/mental retardation syndrome X-linked protein and death domain-associated protein in neuroendocrine tumors.

    PubMed

    Chen, Shi-Fan; Kasajima, Atsuko; Yazdani, Samaneh; Chan, Monica S M; Wang, Lin; He, Yang-Yang; Gao, Hong-Wen; Sasano, Hironobu

    2013-10-01

    α-Thalassemia/mental retardation syndrome X-linked protein (ATRX) and death domain-associated protein (DAXX) genes are tumor suppressors whose mutations have been identified in sporadic pancreatic neuroendocrine tumors as well as in patients with MEN1. However, it is unknown whether ATRX and DAXX alterations are specific for pancreatic neuroendocrine tumor. In addition, the association of ATRX/DAXX protein loss with tumor cell proliferation has not been examined. We, therefore, immunostained ATRX and DAXX in 10 gastric, 15 duodenal, 20 rectal, 70 pancreatic, and 22 pulmonary neuroendocrine tumors with 15 nonneoplastic pancreases and 27 pancreatic adenocarcinomas to elucidate the site-specific roles of ATRX/DAXX abnormalities. At least 1 loss of ATRX and DAXX immunoreactivity was detected in all neuroendocrine tumor cases but not in any of nonneoplastic pancreatic tissues or pancreatic adenocarcinomas. The loss of DAXX protein was correlated with the Ki-67 index (ATRX, P = .904; DAXX, P = .044). The status of DAXX immunoreactivity correlated positively with World Health Organization histologic grade (P = .026). These results suggest that the status of ATRX or DAXX protein loss in neuroendocrine tumor differed among the organs in which these tumors arose, and these proteins may play site-specific roles in the development of these tumors. PMID:23954140

  17. Treatment Outcomes, Growth Height, and Neuroendocrine Functions in Patients With Intracranial Germ Cell Tumors Treated With Chemoradiation Therapy

    SciTech Connect

    Odagiri, Kazumasa; Omura, Motoko; Hata, Masaharu; Aida, Noriko; Niwa, Tetsu; Ogino, Ichiro; Kigasawa, Hisato; Adachi, Masataka; Inoue, Tomio

    2012-11-01

    Purpose: We carried out a retrospective review of patients receiving chemoradiation therapy (CRT) for intracranial germ cell tumor (GCT) using a lower dose than those previously reported. To identify an optimal GCT treatment strategy, we evaluated treatment outcomes, growth height, and neuroendocrine functions. Methods and Materials: Twenty-two patients with GCT, including 4 patients with nongerminomatous GCT (NGGCT) were treated with CRT. The median age at initial diagnosis was 11.5 years (range, 6-19 years). Seventeen patients initially received whole brain irradiation (median dose, 19.8 Gy), and 5 patients, including 4 with NGGCT, received craniospinal irradiation (median dose, 30.6 Gy). The median radiation doses delivered to the primary site were 36 Gy for pure germinoma and 45 Gy for NGGCT. Seventeen patients had tumors adjacent to the hypothalamic-pituitary axis (HPA), and 5 had tumors away from the HPA. Results: The median follow-up time was 72 months (range, 18-203 months). The rates of both disease-free survival and overall survival were 100%. The standard deviation scores (SDSs) of final heights recorded at the last assessment tended to be lower than those at initial diagnosis. Even in all 5 patients with tumors located away from the HPA, final height SDSs decreased (p = 0.018). In 16 patients with tumors adjacent to the HPA, 8 showed metabolic changes suggestive of hypothalamic obesity and/or growth hormone deficiency, and 13 had other pituitary hormone deficiencies. In contrast, 4 of 5 patients with tumors away from the HPA did not show any neuroendocrine dysfunctions except for a tendency to short stature. Conclusions: CRT for GCT using limited radiation doses resulted in excellent treatment outcomes. Even after limited radiation doses, insufficient growth height was often observed that was independent of tumor location. Our study suggests that close follow-up of neuroendocrine functions, including growth hormone, is essential for all patients with

  18. Use of radioactive substances in diagnosis and treatment of neuroendocrine tumors

    PubMed Central

    Kjaer, Andreas; Knigge, Ulrich

    2015-01-01

    Abstract Radionuclides are needed both for nuclear medicine imaging as well as for peptide-receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NET). Imaging is important in the initial diagnostic work-up and for staging NETs. In therapy planning, somatostatin receptor imaging (SRI) is used when treatment is targeted at the somatostatin receptors as with the use of somatostatin analogues or PRRT. SRI with gamma camera technique using the tracer 111In-DTPA-octreotide has for many years been the backbone of nuclear imaging of NETs. However, increasingly PET tracers for SRI are now used. 68Ga-DOTATATE, 68Ga-DOTATOC and 68Ga-DOTANOC are the three most often used PET tracers. They perform better than SPECT tracers and should be preferred. FDG-PET is well suited for visualization of most of the somatostatin receptor-negative tumors prognostic in NET patients. Also 11C-5-HTP, 18F-DOPA and 123I-MIBG may be used in NET. However, with FDG-PET and somatostatin receptor PET at hand we see limited necessity of other tracers. PRRT is an important tool in the treatment of advanced NETs causing complete or partial response in 20% and minor response or tumor stabilization in 60% with response duration of up to 3 years. Grade 3–4 kidney or bone marrow toxicity is seen in 1.5% and 9.5%, respectively, but are completely or partly reversible in most patients. 177Lu-DOTATATE seems to have less toxicity than 90Y-DOTATOC. However, until now only retrospective, non-randomized studies have been performed and the role of PRRT in treatment of NETs remains to be established. PMID:25959100

  19. Plasma acylated and plasma unacylated ghrelin: useful new biomarkers in patients with neuroendocrine tumors?

    PubMed

    van Adrichem, Roxanne C S; van der Lely, Aart Jan; Huisman, Martin; Kramer, Piet; Feelders, Richard A; Delhanty, Patric J D; de Herder, Wouter W

    2016-07-01

    To date, the value of fasting plasma acylated ghrelin (AG) and unacylated ghrelin (UAG) as potential novel biomarkers in patients with neuroendocrine tumors (NETs) is unknown. The aims of this study are to (i) compare fasting AG and UAG levels between nonobese, nondiabetic NET patients (N=28) and age- (±3 years) and sex-matched nonobese, nondiabetic controls (N=28); and (ii) study the relationship between AG, UAG, and AG/UAG ratios and biochemical (chromogranin-A (CgA) and neuron-specific enolase (NSE) levels) and clinical parameters (age at diagnosis, sex, primary tumor location, carcinoid syndrome, ENETS TNM classification, Ki-67 proliferation index, grading, prior incomplete surgery) in NET patients. Fasting venous blood samples (N=56) were collected and directly stabilized with 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride after withdrawal. Plasma AG and UAG levels were determined by ELISA. Expression of ghrelin was examined in tumor tissue by immunohistochemistry. There were no significant differences between NET patients and controls in AG (median: 62.5 pg/mL, IQR: 33.1-112.8 vs median: 57.2pg/mL, IQR: 26.7-128.3, P=0.66) and UAG in levels (median: 76.6pg/mL, IQR: 35.23-121.7 vs median: 64.9, IQR: 27.5-93.1, P=0.44). No significant correlations were found between AG, UAG, and AG/UAG ratios versus biochemical and clinical parameters in NET patients with the exception of age at diagnosis (AG: ρ= -0.47, P=0.012; AG/UAG ratio: ρ= -0.50, P=0.007) and baseline chromogranin-A levels (AG/UAG ratio: ρ= -0.44, P=0.019). In our view, fasting plasma acylated and unacylated ghrelin appear to have no value as diagnostic biomarkers in the clinical follow-up of patients with NETs. PMID:27215920

  20. Molecular Imaging Radiotherapy: Theranostics for Personalized Patient Management of Neuroendocrine Tumors (NETs)

    PubMed Central

    Öberg, Kjell

    2012-01-01

    Neuroendocrine tumors (NETs) possess unique features including expression of peptide hormone receptors as well as the capacity to concentrate and take up precursor forms of amines and peptides making hormones that are stored in secretory granules within the tumor cells (APUD). The expression of somatostatin receptors on tumor cells have been widely explored during the last two decades starting with 111In-DTPA-Octreotide as an imaging agent followed by 68Ga-DOTATOC/TATE positron emission tomography scanning. The new generation of treatment includes 90Yttrium-DOTATOC/DOTATATE as well as 177Lutetium-DOTATOC/DOTATATE/DOTANOC treatment of various subtypes of NETs. The objective response rate by these types of PRRT is in the range of 30-45% objective responses with 5-10% grade 3/4 toxicity mainly hematologic and renal toxicity. The APUD mechanism is another unique feature of NETs which have generated an interest over the last two decades to develop specific tracers including 11C-5HTP, 18F-DOPA and 11C-hydroxyefedrin. These radioactive tracers have been developed in centres with specific interest in NETs and are not available everywhere. 111In-DTPA-Octreotide is still the working horse in diagnosis and staging of metastatic NETs, but will in the future be replaced by 68Ga-DOTATOC/DOTATATE PET/CT scanning which provide higher sensitivity and specificity and is also more convenient for the patient because it is a one-stop-procedure. Both 90Yttrium-DOTATOC/DOTATATE as well as 177Lutetium-DOTATOC/DOTATATE are important new therapies for malignant metastatic NETs. However, the precise role in the treatment algorithm has to be determined in forthcoming randomized trials. PMID:22768025

  1. Molecular Imaging Radiotherapy: Theranostics for Personalized Patient Management of Neuroendocrine Tumors (NETs).

    PubMed

    Oberg, Kjell

    2012-01-01

    Neuroendocrine tumors (NETs) possess unique features including expression of peptide hormone receptors as well as the capacity to concentrate and take up precursor forms of amines and peptides making hormones that are stored in secretory granules within the tumor cells (APUD). The expression of somatostatin receptors on tumor cells have been widely explored during the last two decades starting with (111)In-DTPA-Octreotide as an imaging agent followed by (68)Ga-DOTATOC/TATE positron emission tomography scanning. The new generation of treatment includes (90)Yttrium-DOTATOC/DOTATATE as well as (177)Lutetium-DOTATOC/DOTATATE/DOTANOC treatment of various subtypes of NETs. The objective response rate by these types of PRRT is in the range of 30-45% objective responses with 5-10% grade 3/4 toxicity mainly hematologic and renal toxicity. The APUD mechanism is another unique feature of NETs which have generated an interest over the last two decades to develop specific tracers including (11)C-5HTP, (18)F-DOPA and (11)C-hydroxyefedrin. These radioactive tracers have been developed in centres with specific interest in NETs and are not available everywhere. (111)In-DTPA-Octreotide is still the working horse in diagnosis and staging of metastatic NETs, but will in the future be replaced by (68)Ga-DOTATOC/DOTATATE PET/CT scanning which provide higher sensitivity and specificity and is also more convenient for the patient because it is a one-stop-procedure. Both (90)Yttrium-DOTATOC/DOTATATE as well as (177)Lutetium-DOTATOC/DOTATATE are important new therapies for malignant metastatic NETs. However, the precise role in the treatment algorithm has to be determined in forthcoming randomized trials. PMID:22768025

  2. Metastatic pancreatic neuroendocrine tumor to the central nervous system in a patient with von Hippel-Lindau disease: A case report and literature review.

    PubMed

    Reynolds, Matthew R; Crilly, Shane M; Sweeney, Kieron J; Farrell, Michael; Rawluk, Daniel

    2015-04-01

    Pancreatic neuroendocrine tumor (NET) is frequently encountered in patients with von Hippel-Lindau disease (VHL) and uncommonly metastasizes to the central nervous system. Here, we present the case of a VHL patient with symptomatic pancreatic NET metastases to both the cervical spinal cord and a preexisting brainstem hemangioblastoma (e.g., tumor- to-tumor metastasis). PMID:25232806

  3. Sporadic Gastric Well-Differentiated Neuroendocrine Tumors Have a Higher Ki-67 Proliferative Index.

    PubMed

    Lee, Hee Eun; Mounajjed, Taofic; Erickson, Lori A; Wu, Tsung-Teh

    2016-09-01

    Well-differentiated neuroendocrine tumor (WDNET) of the stomach can arise in three distinct clinical settings: (1) in association with autoimmune atrophic gastritis, (2) in association with multiple neuroendocrine neoplasia type I (MEN I) or Zollinger-Ellison syndrome (ZES), or (3) sporadic. The Ki-67 proliferative index (PI) in gastric WDNETs in these three distinct clinical settings has not been evaluated in detail. Forty-five gastric WNETs underwent polypectomy (n = 4), endoscopic mucosal resection (n = 12), and surgical resection (n = 29) between 1994 and 2015 were included. H&E slides from each case were reviewed, and Ki-67 immunostain was performed on one representative tumor block. Ki-67 PI was determined by quantitative Aperio image analysis software in areas of strongest nuclear labeling ("hot spots"), and correlated with underlying clinical and pathological features. Twenty-one patients were male and 24 female with a median age of 57 years (range, 30-80 years). Tumors were classified as type I (n = 17), type II (n = 6), and type III (n = 22) WDNETs. Types II and III showed more advanced TNM stage compared to type I (p = 0.02, overall). WHO grade based on Ki-67 PI was higher in type III WDNETs [grade 1 (G1), n = 3; grade 2 (G2), n = 15; and grade 3 (G3), n = 4] than in type I WDNETs [G1, n = 5; G2, n = 12] and in type II WDNETs [G1, n = 2; G2, n = 4] (p = 0.050, overall). Ki-67 PI was significantly higher in type III WDNETs (mean ± SD = 13.0 ± 13.3 %) than in non-sporadic (type I and II) WDNETs (mean ± SD = 5.3 ± 3.3 %; p = 0.015). There was no difference in Ki-67 PI between type I WDNETs (mean ± SD = 5.2 ± 3.5 %) and type II WDNETs (mean ± SD = 5.6 ± 3.1%; p = 0.817). Higher Ki-67 PI was associated with higher tumor T stage (p = 0.003) and also tended to be associated with lymph node metastasis (p = 0.071). In the Kaplan-Meier survival analysis, type I was associated with a

  4. Induction of colorectal cancer in mice and histomorphometric evaluation of tumors.

    PubMed

    Crncec, Ilija; Pathria, Paulina; Svinka, Jasmin; Eferl, Robert

    2015-01-01

    Colorectal cancer (CRC) originates from the epithelial cells lining the colon or rectum of the gastrointestinal tract and represents the third most common form of cancer worldwide. CRC is frequently associated with Colitis Ulcerosa or Crohn's Disease demonstrating the tumor-promoting role of inflammation. Colorectal tumor cells establish heterotypic interactions with inflammatory cells and cancer-associated fibroblasts in the tumor stroma that support tumor angiogenesis and are essential for tumor progression. Therefore, establishment of suitable mouse models mimicking the inflammatory etiology of CRC is important. Here we describe methods to induce CRC in mice, to quantify tumor parameters (multiplicity, tumor load, mean tumor size), and to analyze the cellular composition of the CRC tumor stroma. PMID:25636468

  5. Regulative Effect of Nampt on Tumor Progression and Cell Viability in Human Colorectal Cancer

    PubMed Central

    Lv, Xiaoqun; Zhang, Lingyun; Zhu, Yanyan; Said, Harun M.; Shi, Jimin; Xu, Guoxiong

    2015-01-01

    Colorectal cancer (CRC) is the third most common cancer disease. Here we examined Nampt expression in patients with CRC and the effect of Nampt on cell viability in CRC cells. Nampt protein was overexpressed in colorectal adenoma as well as colorectal carcinoma. The immunoreactive staining of Nampt was negative in the adjacent normal colorectal tissue, weak in colorectal adenoma, and strong in colorectal carcinoma, which may represent tumor progression. Further evaluation of clinical data showed that Nampt expression was not correlated with the clinicopathological characteristics of CRC. Additionally, our in vitro studies demonstrated that Nampt promotes CRC cell viability, whereas the Nampt inhibitor FK866 suppressed CRC cell viability, which was in concordance with the previous studies in other cancer cells. Treatment with Nampt-siRNA reduced the Nampt protein expression resulting in the inhibition of the cell viability of HCT116 and Caco2. Thus, the involvement of Nampt in cell growth indicates that Nampt may play an important role in colorectal tumorigenesis. As a consequence, our results suggest that Nampt may be considered as a progression marker of colorectal tumor and a potentially therapeutic target for the treatment of CRC. PMID:26284136

  6. A Phase II Trial of a Histone Deacetylase Inhibitor Panobinostat in Patients With Low-Grade Neuroendocrine Tumors

    PubMed Central

    Lubner, Sam J.; Mulkerin, Daniel L.; Rajguru, Saurabh; Carmichael, Lakeesha; Chen, Herb; Holen, Kyle D.; LoConte, Noelle K.

    2016-01-01

    Lessons Learned Pancreatic neuroendocrine tumors versus carcinoid tumors should be examined separately in clinical trials. Progression-free survival is more clinically relevant as the primary endpoint (rather than response rate) in phase II trials for low-grade neuroendocrine tumors. Background. The most common subtypes of neuroendocrine tumors (NETs) are pancreatic islet cell tumors and carcinoids, which represent only 2% of all gastrointestinal malignancies. Histone deacetylase (HDAC) inhibitors have already been shown to suppress tumor growth and induce apoptosis in various malignancies. In NET cells, HDAC inhibitors have resulted in increased Notch1 expression and subsequent inhibition of growth. We present here a phase II study of the novel HDAC inhibitor panobinostat in patients with low-grade NET. Methods. Adult patients with histologically confirmed, metastatic, low-grade NETs and an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 were treated with oral panobinostat 20 mg once daily three times per week. Treatment was continued until patients experienced unacceptable toxicities or disease progression. The study was stopped at planned interim analysis based on a Simon two-stage design. Results. Fifteen patients were accrued, and 13 were evaluable for response. No responses were seen, but the stable disease rate was 100%. The median progression-free survival (PFS) was 9.9 months, and the median overall survival was 47.3 months. Fatigue (27%), thrombocytopenia (20%), diarrhea (13%), and nausea (13%) were the most common related grade 3 toxicities. There was one grade 4 thrombocytopenia (7%). These results did not meet the prespecified criteria to open the study to full accrual. Conclusion. The HDAC inhibitor panobinostat has a high stable disease rate and reasonable PFS in low-grade NET, but has a low response rate. PMID:27261467

  7. Treatment of neuroendocrine tumors: new recommendations based on the CLARINET study

    PubMed Central

    2015-01-01

    Somatostatin analogs (SSAs), including lanreotide, play a fundamental role in treatment of neuroendocrine tumors (NETs) of the gastrointestinal tract. SSAs control the clinical symptoms and are the treatment of choice in functioning NETs. Data indicating that SSAs have anti-proliferative activity has mainly come from prospective or retrospective observational studies. A recently published CLARINET study confirmed the anti-proliferative effect of lanreotide in a much broader range of NET patients than previously reported. As a result, it is now possible for clinicians to use lanreotide to treat patients with well-differentiated metastatic grade 1 and grade 2 GEP NETs (i.e., with a Ki-67 proliferative index < 10%) located in the pancreas, small intestine, or of unknown primary location, regardless of the degree of liver involvement. The results of the CLARINET study also challenge the current “wait and watch” strategy for NET treatment. Instead, it is proposed that SSAs are considered at an early stage of NET management, as already suggested by many organizations and scientific societies. PMID:26793016

  8. Treatment of neuroendocrine tumors: new recommendations based on the CLARINET study.

    PubMed

    Kos-Kudła, Beata

    2015-01-01

    Somatostatin analogs (SSAs), including lanreotide, play a fundamental role in treatment of neuroendocrine tumors (NETs) of the gastrointestinal tract. SSAs control the clinical symptoms and are the treatment of choice in functioning NETs. Data indicating that SSAs have anti-proliferative activity has mainly come from prospective or retrospective observational studies. A recently published CLARINET study confirmed the anti-proliferative effect of lanreotide in a much broader range of NET patients than previously reported. As a result, it is now possible for clinicians to use lanreotide to treat patients with well-differentiated metastatic grade 1 and grade 2 GEP NETs (i.e., with a Ki-67 proliferative index < 10%) located in the pancreas, small intestine, or of unknown primary location, regardless of the degree of liver involvement. The results of the CLARINET study also challenge the current "wait and watch" strategy for NET treatment. Instead, it is proposed that SSAs are considered at an early stage of NET management, as already suggested by many organizations and scientific societies. PMID:26793016

  9. Genetic polymorphisms of interleukin 1β gene and sporadic pancreatic neuroendocrine tumors susceptibility

    PubMed Central

    Karakaxas, Dimitrios; Sioziou, Anna; Aravantinos, Gerasimos; Coker, Ahmet; Papanikolaou, Ioannis S; Liakakos, Theodoros; Dervenis, Christos; Gazouli, Maria

    2016-01-01

    AIM: To evaluate the association between the interleukin 1β (IL-1β) polymorphisms and the pancreatic neuroendocrine tumor (pNET) development. METHODS: A case-control study was conducted analyzing IL-1β polymorphisms using germline DNA collected in a population-based case-control study of pancreatic cancer (51 pNET cases, 85 pancreatic ductal adenocarcinoma cases, 19 intraductal papillary mucinous neoplasm and 98 healthy controls). RESULTS: The distribution of genotypes for the -511 C/T polymorphism in the pNET patient groups showed significant difference compared to the control group. It is known that the carriers of the IL-1β -511T allele have increased concentrations of IL-1β. The -511 CT and TT high-expression genotypes were over-represented in pNET patients. CONCLUSION: The findings of this study suggested a possible role of IL-1β -511 C/T genotypes in the pathogenesis of pNETs since the presence of the IL-1β -511 CT and TT genotypes and the T allele was associated with an increased risk of pNET only. PMID:27326321

  10. 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. PMID:24075930