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Champion CP, Miller AD, Parry S, Demeter EA. Immunohistochemical and histomorphologic characterization of canine neoplasms of the disseminated neuroendocrine system. Vet Pathol 2025:3009858251324652. [PMID: 40116004 DOI: 10.1177/03009858251324652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2025]
Abstract
Canine neoplasms of the diffuse neuroendocrine system are an enigmatic and heterogeneous group of neoplasms with a wide spectrum of immunohistochemical properties and morphologic features. Through the utilization of tissue microarrays, 82 canine neoplasms of the disseminated neuroendocrine system from 16 different anatomic locations were evaluated. The prototypical canine neoplasm of the disseminated neuroendocrine system was composed of rounded polygonal neoplastic cells arranged in packets supported by delicate fibrovascular stroma. Neoplastic cells typically had moderate quantities of pale eosinophilic cytoplasm stippled by numerous fine argyrophilic granules, round nuclei with finely stippled chromatin, and inconspicuous nucleoli. Immunohistochemical assays utilized in this study included chromogranin A, neuron-specific enolase (NSE), microtubule-associated protein 2 (MAP2), pan-cytokeratin, oligodendrocyte transcription factor 2 (OLIG2), protein gene product 9.5 (PGP9.5), vimentin, synaptophysin, neuronal nuclei (NeuN), S100, SRY-related HMG-box 10 (SOX10), glial fibrillary acidic protein (GFAP), insulinoma-associated protein 1 (INSM1), CD56, and antigen Kiel 67 (Ki67). The 4 immunohistochemical assays that were positive in over 50% of cases included PGP9.5 (77/82, 94%), NSE (68/82, 83%), synaptophysin (59/82, 72%), and chromogranin A (56/82, 69%). In 81/82 (99%) cases, neoplastic cells immunolabeled with at least 1 of these 4 assays, and thus, these 4 immunohistochemical assays are deemed most useful when attempting to substantiate that a neoplasm is of neuroendocrine origin.
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Acher AW, Hallet J. Advances in Management of Nonfunctional Pancreas Neuroendocrine Tumors. Surg Clin North Am 2024; 104:1095-1111. [PMID: 39237166 DOI: 10.1016/j.suc.2024.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/07/2024]
Abstract
This article presents updates in the surgical management of non-functional sporadic pancreas neuroendocrine tumors NET, including considerations for assessment of biologic behavior to support decision-making, indications for surgery, and surgical approaches tailored to the unique nature of neuroendocrine tumors.
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Affiliation(s)
- Alexandra W Acher
- Department of Surgery, University of Toronto, 2075 Bayview Avenue, Toronto, ON, Canada, M4N 3M5
| | - Julie Hallet
- Department of Surgery, University of Toronto, 2075 Bayview Avenue, Toronto, ON, Canada, M4N 3M5; Susan Leslie Clinic for Neuroendocrine Tumors, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
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Kelly N, Wu YT, Johnston AN. Gallbladder Neuroendocrine Neoplasms in Dogs and Humans. Vet Sci 2024; 11:371. [PMID: 39195825 PMCID: PMC11360110 DOI: 10.3390/vetsci11080371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 07/28/2024] [Accepted: 08/09/2024] [Indexed: 08/29/2024] Open
Abstract
Gallbladder neuroendocrine neoplasms (GB NENs) are among the rarest cancers reported in humans and dogs. This review provides a detailed review of the canine GB NEN literature and an interspecies comparison of demographics, clinical pathophysiology, pathobiology, and therapeutic response of GB NENs. The aim of this work is to explore the relevance of dogs as a spontaneous model for human GB NENs.
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Affiliation(s)
- Nadia Kelly
- Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA; (N.K.); (Y.-T.W.)
| | - Yen-Tse Wu
- Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA; (N.K.); (Y.-T.W.)
- Emergency & Critical Care, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA
| | - Andrea N. Johnston
- Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA; (N.K.); (Y.-T.W.)
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Ancil S, Gupta K, S S, Das L, Ahuja CK, Chhabra R, Dhandapani S, Dutta P. Clinico-radio-pathological predictors of outcomes in patients with acromegaly undergoing endoscopic transsphenoidal surgery. Surg Neurol Int 2024; 15:268. [PMID: 39246769 PMCID: PMC11380812 DOI: 10.25259/sni_1001_2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 07/07/2024] [Indexed: 09/10/2024] Open
Abstract
Background Acromegaly is a rare chronic endocrine disorder with variable biochemical remission rates from 40% to 85%. Hence, understanding the factors predicting biochemical cures helps in planning targeted and personalized treatment. We aimed to study the various clinico-radio-pathological predictors of outcomes in patients with pituitary neuroendocrine tumor (PitNET) who underwent transsphenoidal surgery (TSS) at 3 months follow-up. Methods Our cohort included 61 consecutive patients with acromegaly treated at an institute in northwest India between January 2019 and June 2021. The outcomes of TSS were assessed at the end of 3 months postoperatively as defined by Endocrine Society Guidelines 2014. Results The mean age at diagnosis was 38 ± 12 years, with the majority being females (67.2%). The median tumor volume was 2376 mm3 with high insulin-like growth factor-1 levels (3.12 ± 1.76 times the upper reference limit). Forty-two patients (68.8%) had radiological evidence of cavernous sinus invasion. Overall, the biochemical remission rate at 3 months was 34.4%. Unlike preoperative Knosp grading, T2-hypointensity was not predictive of biochemical remission. The granularity of PitNET, as well as immunohistochemical (IHC) markers such as Ki-67 index somatostatin receptor subtype (SSTR2/5) and low-molecular-weight cytokeratin (CAM5.2) expression, failed to show any significant correlation with remission. Conclusion Overall, bulky tumors, higher hormone burden, and advanced Knosp grades translated to lower rates of biochemical remission in the present study cohort. Contrary to earlier studies, conventional IHC markers such as Ki-67, SSTR2/5, and CAM5.2 were not useful for predicting biochemical remission at 3 months.
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Affiliation(s)
- Sanish Ancil
- Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Kirti Gupta
- Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Subin S
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Liza Das
- Department of Endocrinology and Telemedicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Chirag Kamal Ahuja
- Department of Radiology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Rajesh Chhabra
- Department of Neurosurgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Sivashanmugam Dhandapani
- Department of Neurosurgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Pinaki Dutta
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
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Gerber TS, Ridder DA, Goeppert B, Brobeil A, Stenzel P, Zimmer S, Jäkel J, Metzig MO, Schwab R, Martin SZ, Kiss A, Bergmann F, Schirmacher P, Galle PR, Lang H, Roth W, Straub BK. N-cadherin: A diagnostic marker to help discriminate primary liver carcinomas from extrahepatic carcinomas. Int J Cancer 2024; 154:1857-1868. [PMID: 38212892 DOI: 10.1002/ijc.34836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 11/20/2023] [Accepted: 11/24/2023] [Indexed: 01/13/2024]
Abstract
Distinguishing primary liver cancer (PLC), namely hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), from liver metastases is of crucial clinical importance. Histopathology remains the gold standard, but differential diagnosis may be challenging. While absent in most epithelial, the expression of the adherens junction glycoprotein N-cadherin is commonly restricted to neural and mesenchymal cells, or carcinoma cells that undergo the phenomenon of epithelial-to-mesenchymal transition (EMT). However, we recently established N- and E-cadherin expression as hallmarks of normal hepatocytes and cholangiocytes, which are also preserved in HCC and iCCA. Therefore, we hypothesized that E- and/or N-cadherin may distinguish between carcinoma derived from the liver vs carcinoma of other origins. We comprehensively evaluated E- and N-cadherin in 3359 different tumors in a multicenter study using immunohistochemistry and compared our results with previously published 882 cases of PLC, including 570 HCC and 312 iCCA. Most carcinomas showed strong positivity for E-cadherin. Strong N-cadherin positivity was present in HCC and iCCA. However, except for clear cell renal cell carcinoma (23.6% of cases) and thyroid cancer (29.2%), N-cadherin was only in some instances faintly expressed in adenocarcinomas of the gastrointestinal tract (0%-0.5%), lung (7.1%), pancreas (3.9%), gynecological organs (0%-7.4%), breast (2.2%) as well as in urothelial (9.4%) and squamous cell carcinoma (0%-5.6%). As expected, N-cadherin was detected in neuroendocrine tumors (25%-75%), malignant melanoma (46.2%) and malignant mesothelioma (41%). In conclusion, N-cadherin is a useful marker for the distinction of PLC vs liver metastases of extrahepatic carcinomas (P < .01).
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Affiliation(s)
- Tiemo S Gerber
- Institute of Pathology, University Medicine, Johannes Gutenberg-University, Mainz, Germany
| | - Dirk A Ridder
- Institute of Pathology, University Medicine, Johannes Gutenberg-University, Mainz, Germany
| | - Benjamin Goeppert
- Institute of Pathology and Neuropathology, RKH Klinikum Ludwigsburg, Ludwigsburg, Germany
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - Alexander Brobeil
- Institute of Pathology, University of Heidelberg, Heidelberg, Germany
| | - Philipp Stenzel
- Institute of Pathology, University Medicine, Johannes Gutenberg-University, Mainz, Germany
| | - Stefanie Zimmer
- Institute of Pathology, University Medicine, Johannes Gutenberg-University, Mainz, Germany
| | - Jörg Jäkel
- Institute of Pathology, University Medicine, Johannes Gutenberg-University, Mainz, Germany
| | - Marie Oliver Metzig
- Institute of Pathology, University Medicine, Johannes Gutenberg-University, Mainz, Germany
| | - Roxana Schwab
- Department of Gynecology and Obstetrics, University Medicine, Johannes Gutenberg-University, Mainz, Germany
| | - Steve Z Martin
- Institute of Pathology, Charité-University Medicine, Berlin, Germany
| | - András Kiss
- 2nd Institute of Pathology, Semmelweis University, Budapest, Hungary
| | - Frank Bergmann
- Institute of Pathology, University of Heidelberg, Heidelberg, Germany
| | - Peter Schirmacher
- Institute of Pathology, University of Heidelberg, Heidelberg, Germany
| | - Peter R Galle
- 1st Department of Internal Medicine, Gastroenterology and Hepatology, University Medicine, Johannes Gutenberg-University, Mainz, Germany
| | - Hauke Lang
- Department of General, Visceral and Transplant Surgery, University Medicine, Johannes Gutenberg-University, Mainz, Germany
| | - Wilfried Roth
- Institute of Pathology, University Medicine, Johannes Gutenberg-University, Mainz, Germany
| | - Beate K Straub
- Institute of Pathology, University Medicine, Johannes Gutenberg-University, Mainz, Germany
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Murphy R, Chander G, Martinez M, Ward C, Khan SR, Naik M, Barwick T, Aboagye E, Sharma R. Study protocol of LANTana: a phase Ib study to investigate epigenetic modification of somatostatin receptor-2 with ASTX727 to improve therapeutic outcome with [177Lu]Lu-DOTA-TATE in patients with metastatic neuroendocrine tumours, UK. BMJ Open 2023; 13:e075221. [PMID: 37879695 PMCID: PMC10603539 DOI: 10.1136/bmjopen-2023-075221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Accepted: 09/25/2023] [Indexed: 10/27/2023] Open
Abstract
INTRODUCTION Suitability for peptide receptor radionuclide therapy (PRRT) for neuroendocrine neoplasia (NENs) depends on presence of somatostatin receptor-2 (SSTR2) determined by [68Ga]Ga-DOTA-peptide-positron emission tomography (PET). Some patients have low or no uptake on [68Ga]Ga-DOTA-peptide-PET, precluding PRRT. The upstream promoter region of SSRT2 is methylated, with percentage of methylation correlating with SSTR2 expression. Demethylating agents increase uptake on PET imaging in vivo such that tumours previously negative on PET become positive, correlating with a dose dependent increase in tumorous SSTR2 expression. LANTana will determine whether treatment with the demethylating agent, ASTX727, results in re-expression of SSTR2 using [68Ga]Ga-DOTA-peptide-PET to image epigenetic modification of the SSTR2 locus, allowing subsequent PRRT. METHODS AND ANALYSIS 27 participants with a histological diagnosis of NEN (Ki67<55%) with no or low uptake on baseline [68Ga]Ga-DOTA-TATE-PET/CT will be recruited. Patients will receive 5 days of ASTX727 (fixed dose 35 mg decitabine+100 mg cedazuridine). [68Ga]Ga-DOTA-peptide-PET/CT will be repeated day 8±2; where there is significant uptake greater than liver in most lesions, PRRT will be administered. Primary objective is to determine re-expression of SSTR2 on PET imaging. Tolerability, progression-free survival, overall response and quality of life will be assessed. Methylation in peripheral blood mononuclear cells and tumorous methylation will be evaluated. ETHICS AND DISSEMINATION LANTana has ethical approval from Leeds West Research Ethics Committee (REC Reference: 21/YH/0247).Sponsored by Imperial College London and funded by Advanced Accelerator Applications pharmaceuticals. Results will be presented at conferences and submitted to peer-reviewed journals for publication and will be available on ClinicalTrials.gov. TRIAL REGISTRATION NUMBERS EUDRACT number: 2020-003800-15, NCT05178693.
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Affiliation(s)
- Ravindhi Murphy
- Department of Surgery and Cancer, Hammersmith Hospital, London, UK
| | - Gurvin Chander
- Department of Surgery and Cancer, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK
| | - Maria Martinez
- Department of Surgery and Cancer, Hammersmith Hospital, London, UK
| | - Caroline Ward
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Sairah R Khan
- Department of Nuclear Medicine, Hammersmith Hospital, London, UK
| | - Mitesh Naik
- Department of Nuclear Medicine, Hammersmith Hospital, London, UK
| | - Tara Barwick
- Department of Cancer and Surgery, Imperial College London, London, UK
- Department of Radiology, Imperial College Healthcare NHS Trust, London, UK
| | - Eric Aboagye
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Rohini Sharma
- Department of Surgery and Cancer, Hammersmith Hospital, London, UK
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Andriolo LG, Cammisotto V, Spagnoli A, Alunni Fegatelli D, Chicone M, Di Rienzo G, Dell’Anna V, Lobreglio G, Serio G, Pignatelli P. Overview of angiogenesis and oxidative stress in cancer. World J Meta-Anal 2023; 11:253-265. [DOI: 10.13105/wjma.v11.i6.253] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 03/07/2023] [Accepted: 07/10/2023] [Indexed: 09/13/2023] Open
Abstract
Neoplasms can be considered as a group of aberrant cells that need more vascular supply to fulfill all their functions. Therefore, they promote angiogenesis through the same neovascularization pathway used physiologically. Angiogenesis is a process characterized by a heterogeneous distribution of oxygen caused by the tumor and oxidative stress; the latter being one of the most powerful stimuli of angiogenesis. As a result of altered tumor metabolism due to hypoxia, acidosis occurs. The angiogenic process and oxidative stress can be detected by measuring serum and tissue biomarkers. The study of the mechanisms underlying angiogenesis and oxidative stress could lead to the identification of new biomarkers, ameliorating the selection of patients with neoplasms and the prediction of their response to possible anti-tumor therapies. In particular, in the treatment of patients with similar clinical tumor phenotypes but different prognoses, the new biomarkers could be useful. Moreover, they may lead to a better understanding of the mechanisms underlying drug resistance. Experimental studies show that blocking the vascular supply results in antiproliferative activity in vivo in neuroendocrine tumor cells, which require a high vascular supply.
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Affiliation(s)
- Luigi Gaetano Andriolo
- Department of General and Specialistic Surgery Paride Stefanini, Policlinico Umberto I, University of Rome Sapienza, Rome 06100, Italy
- Unità Operativa Complessa Chirurgia Toracica, Ospedale Vito Fazzi, Lecce 73100, Italy
| | - Vittoria Cammisotto
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, University of Rome Sapienza, Rome 06100, Italy
| | - Alessandra Spagnoli
- Department of Public Health and Infectious Diseases, University of Rome Sapienza, Rome 06100, Italy
| | - Danilo Alunni Fegatelli
- Department of Public Health and Infectious Diseases, University of Rome Sapienza, Rome 06100, Italy
| | - Michele Chicone
- Department of Clinical Pathology and Microbiology, Ospedale Vito Fazzi, Lecce 73100, Italy
| | - Gaetano Di Rienzo
- Unità Operativa Complessa Chirurgia Toracica, Ospedale Vito Fazzi, Lecce 73100, Italy
| | | | - Giambattista Lobreglio
- Department of Clinical Pathology and Microbiology, Ospedale Vito Fazzi, Lecce 73100, Italy
| | - Giovanni Serio
- Pathological Anatomy Unit, Ospedale Vito Fazzi, Lecce 73100, Italy
| | - Pasquale Pignatelli
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, University of Rome Sapienza, Rome 06100, Italy
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Helderman NC, Suerink M, Kilinç G, van den Berg JG, Nielsen M, Tesselaar ME. Relation between WHO Classification and Location- and Functionality-Based Classifications of Neuroendocrine Neoplasms of the Digestive Tract. Neuroendocrinology 2023; 114:120-133. [PMID: 37690447 PMCID: PMC10836754 DOI: 10.1159/000534035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 08/21/2023] [Indexed: 09/12/2023]
Abstract
Practice of neuroendocrine neoplasms (NENs) of the digestive tract, which comprise of a highly diverse group of tumors with a rising incidence, faces multiple biological, diagnostic, and therapeutic issues. Part of these issues is due to misuse and misinterpretation of the classification and terminology of NENs of the digestive tract, which make it increasingly challenging to evaluate and compare the literature. For instance, grade 3 neuroendocrine tumors (NETs) are frequently referred to as neuroendocrine carcinomas (NECs) and vice versa, while NECs are, by definition, high grade and therefore constitute a separate entity from NETs. Moreover, the term NET is regularly misused to describe NENs in general, and NETs are frequently referred to as benign, while they should always be considered malignancies as they do have metastatic potential. To prevent misconceptions in future NEN-related research, we reviewed the most recent terminology used to classify NENs of the digestive tract and created an overview that combines the classification of these NENs according to the World Health Organization (WHO) with location- and functionality-based classifications. This overview may help clinicians and researchers in understanding the current literature and could serve as a guide in the clinic as well as for writing future studies on NENs of the digestive tract. In this way, we aim for the universal use of terminology, thereby providing an efficient foundation for future NEN-related research.
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Affiliation(s)
- Noah C. Helderman
- Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
| | - Manon Suerink
- Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
| | - Gül Kilinç
- Department of Infectious Diseases, Leiden University Medical Centre, Leiden, The Netherlands
| | - José G. van den Berg
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Maartje Nielsen
- Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
| | - Margot E.T. Tesselaar
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
- Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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Chronic Treatment with Somatostatin Analogues in Recurrent Type 1 Gastric Neuroendocrine Tumors. Biomedicines 2023; 11:biomedicines11030872. [PMID: 36979851 PMCID: PMC10045480 DOI: 10.3390/biomedicines11030872] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 03/09/2023] [Accepted: 03/10/2023] [Indexed: 03/14/2023] Open
Abstract
Background: Type 1 gastric neuroendocrine tumors (GC-1) represent an uncommon subtype of neoplasms. Endoscopic resection has been proposed as the treatment of choice; active surveillance may be performed in those smaller than 1 cm, while gastric surgery may be performed for those with frequent recurrences. The antiproliferative effect of somatostatin analogues (SSA) is well known, and their action on GC-1s has been postulated as a chronic treatment to reduce recurrence. Methods: A two-centered, retrospective, observational study that included nine patients (55.6% women) diagnosed with GC-1, receiving long-term treatment with SSA, with a median follow-up from baseline of 22 months, was undertaken. Endoscopic follow-up, extension study, and analytical values of chromogranin A (Cg A) and gastrin were collected. Results: In total, 88.9% of patients presented partial or complete response. Treatment with SSA was the only independent factor with a trend to prevent tumor recurrence (Odds Ratio 0.054; p = 0.005). A nonsignificant tendency toward a decrease in CgA and gastrin was observed; lack of significance was probably related to concomitant treatment with proton pump inhibitors in some patients. Conclusions: Chronic treatment with SSA is a feasible option for recurrent GC-1s that are difficult to manage using endoscopy or gastrectomy. Randomized clinical trials to provide more scientific evidence are still needed.
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Epigenetic potentiation of somatostatin-2 by guadecitabine in neuroendocrine neoplasias as a novel method to allow delivery of peptide receptor radiotherapy. Eur J Cancer 2022; 176:110-120. [PMID: 36208569 DOI: 10.1016/j.ejca.2022.09.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 09/08/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND Somatostatin receptor-2 (SSTR2) is expressed on cell surface of neuroendocrine neoplasias; its presence is exploited for the delivery of peptide receptor radionuclide therapy (PRRT). Patients with no or low expression of SSTR2 are not candidates for PRRT. SSTR2 promotor undergoes epigenetic modification, known to regulate gene expression. We investigated whether the demethylation agent, guadecitabine, could enhance the expression of SSTR2 in NET models, using radioligand uptake/PET imaging as a biomarker of epigenetic modification. METHODS The effects of guadecitabine on the transcriptional, translational, and functional regulation of SSTR2 both in vitro and in vivo using low (QGP-1) and high (BON-1) methylated neuroendocrine neoplasia models was characterised. Promotor region methylation profiling of clinical samples (n = 61) was undertaken. Safety of combination guadecitabine and PRRT was assessed in vivo. RESULTS Pyrosequencing of cell lines illustrated differential methylation indices - BON: 1 94%, QGP: 1 21%. Following guadecitabine treatment, a dose-dependent increase in SSTR2 in BON-1 at a transcriptional, translational, and functional levels using the SSTR2-directed radioligand, 18F-FET-βAG-TOCA ([18F]-FETO) (150% increase [18F]-FETO uptake, p < 0.05) was observed. In vivo, guadecitabine treatment resulted in a 70% increase in [18F]-FETO uptake in BON-1 tumour models compared models with low baseline percentage methylation (p < 0.05). No additive toxicity was observed with the combination treatment of PRRT and guadecitabine in vivo. Methylation index in clinical samples was 10.5% compared to 5.2% in controls (p = 0.03) and correlated with SSTR2 expression (Wilcoxon rank sign -3.75,p < 0.01). CONCLUSION Guadecitabine increases SSTR2 expression both in vitro and in vivo. The combination of demethylation agents with PRRT warrants further investigation.
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El Bakouri A, El wassi A, Eddaoudi Y, Bouali M, EL Hattabi K, Bensardi F, Fadil A. Fortuitous discovery of an early neuroendocrine tumor during appendicular peritonitis. Ann Med Surg (Lond) 2022; 82:104735. [PMID: 36268349 PMCID: PMC9577830 DOI: 10.1016/j.amsu.2022.104735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/18/2022] [Accepted: 09/18/2022] [Indexed: 11/27/2022] Open
Abstract
Introduction Neuroendocrine tumors of the small bowel are rare but represent the most frequent histological type at this level; their incidence is increasing thanks to the evolution of diagnostic means.Intestinal NETs, developed at the expense of enterochromaffin cells of the embryological midgut, are frequently associated with mesenteric lymph node dissemination and distant metastasis (liver, peritoneum). Materials and methods We report a case of Incidental discovery of a small bowel neuroendocrinetumor during appendicular peritonitis in the department of Emergency visceral surgery P35 of the ibn rochd hospital in casablanca. Results Our patient Our patient was admitted to the emergency room for generalized abdominal pain with an appendicular symptomatology evolving five days before days the consultation with clinical examination: conscious patient stable on the hemodynamic and respiratory plan The examination noted generalized abdominal defense the hernial orifices were free The biological work-up revealed a hb 13 g/dL; hyperleukocytosis with predominantly PNN at 18,300 elements/mm3,CRP was elevated to 190, renal function was normal urea 5 mmol/L creatinemia 9 mg/l an abdominal ultrasound showed a 9 mm appenndix perforated at its tip with moderate peritoneal effusion.the patient were operated in the emergency room, approached by laparotomy with the exploration we found a swollen and inflamed appenndix perforated at the level of its tip with moderate peritoneal effusion with false membranes in all the peritoneal cavity with the presence of a polyp localized at 2 m from the duodenojejunal flexur .the patient benefited from a retrograde appendectomy with peritoneal cleansing and a resection of the polyp with 1cm on each side with a Grele-grele anastomosis with the examination of the anapathomopathologist: aspect compatible with a well differentiated neuroendocrine tumor of grade 2. Conclusion Digestive NETs are rare tumors, but their incidence has increased significantly in recent years. This is due to a better knowledge of these tumors, whose diagnosis is becoming easier with the advent of new morphological and biological techniques.The intestinal location is the most frequent. The digestive surgeon must therefore be familiar with its management. An update of knowledge and collaboration between surgeons, anatomopathologists, radiologists and oncologists are necessary, Whatever their location, these tumors are on the one hand capable of producing and secreting amines and on the other hand they are characterized by a common phenotype, expression of general endocrine markers (specific neuron enolase, chromogranin) or specific endocrine markers and expression of peptide receptors such as somastotatin receptors.These tumors are most often diagnosed incidentally during the workup of aspecific digestive disorders or during hormonal hypersecretion syndrome or rarely by a complication.
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Affiliation(s)
- Abdelilah El Bakouri
- Visceral Surgery Emergency Department P35, University Hospital Center Ibn Rochd, Casablanca, Morocco
| | - anas El wassi
- Visceral Surgery Emergency Department P35, University Hospital Center Ibn Rochd, Casablanca, Morocco
- Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Yassine Eddaoudi
- Visceral Surgery Emergency Department P35, University Hospital Center Ibn Rochd, Casablanca, Morocco
- Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Mounir Bouali
- Visceral Surgery Emergency Department P35, University Hospital Center Ibn Rochd, Casablanca, Morocco
- Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Khalid EL Hattabi
- Visceral Surgery Emergency Department P35, University Hospital Center Ibn Rochd, Casablanca, Morocco
- Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Fatimazahra Bensardi
- Visceral Surgery Emergency Department P35, University Hospital Center Ibn Rochd, Casablanca, Morocco
- Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Abdelaziz Fadil
- Visceral Surgery Emergency Department P35, University Hospital Center Ibn Rochd, Casablanca, Morocco
- Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
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12
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Wang Y, Huang B, Fu Q, Wang J, Ye M, Hu M, Qu K, Liu K, Hu X, Wei S, Sun K, Xiao W, Zhang B, Li H, Li J, Zhang Q, Liang T. Comprehensive Clinical Analysis of Gallbladder Neuroendocrine Neoplasms: A Large-Volume Multicenter Study During One Decade. Ann Surg Oncol 2022; 29:7619-7630. [PMID: 35849293 DOI: 10.1245/s10434-022-12107-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 06/05/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND This study aimed to comprehensively investigate the clinicopathologic characteristics and therapeutic situations of gallbladder neuroendocrine neoplasms (GB-NENs) in the real world via a multicenter, large-scale cohort study. METHODS The study searched for patients in 143 hospitals in China and enrolled 154 patients with GB-NENs diagnosed in 40 hospitals between 2004 and 2021. Clinicopathologic characteristics and therapeutic approaches were analyzed retrospectively. RESULTS The median age at the initial diagnosis of the patients with GB-NENs was 63 years (range 33-83 years), and 61.7% of the patients were women. Tumor-node-metastasis staging classified 92 patients as stage 3 or above. Based on the 2019 World Health Organization classification, 96 cases (62.3%) were confirmed pathologically as poorly differentiated neuroendocrine carcinomas, 13 cases (8.4%) as well-differentiated neuroendocrine tumors, and 45 cases as mixed neuroendocrine-non-neuroendocrine neoplasms. The liver was the most frequent metastatic site. Immunohistochemistry showed that synaptophysin was most frequently positive (80.4%), followed by chromogranin A (61.7%), and CD56 (58.4%). Computed tomography and magnetic resonance imaging showed more common clear boundaries (25/39 cases) and invasive growth features (27 cases). None of these cases had an accurate diagnosis before surgery, with a misdiagnosis rate of 100%. Surgical resection is the main treatment, and platinum-based chemotherapeutic regimens were preferred as adjuvant therapies for patients with GB-NENs. The available survival data for 74 patients showed an overall survival rate of 59% at 1 year, 33% at 3 years, and 29% at 5 years. No significant difference was found between the patients treated with and those treated without adjuvant chemotherapy. CONCLUSIONS Gallbladder neuroendocrine neoplasms have high malignancy and a poor prognosis. Importantly, this large-scale cohort study significantly improves our understanding of GB-NENs and will benefit the exploration of its mechanism and treatment modes. Further investigation is necessary to explore the management of this disease.
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Affiliation(s)
- Yangyang Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Bingfeng Huang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qihan Fu
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China.,Zhejiang University Cancer Center, Hangzhou, China.,Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianing Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Mao Ye
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Manyi Hu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Kai Qu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Kai Liu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Xiao Hu
- Department of Hepatobiliary Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shumei Wei
- Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ke Sun
- Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wenbo Xiao
- Department of Radiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Bo Zhang
- Department of General Surgery, Shenzhen University Luohu People's Hospital, Shenzhen, China
| | - Haijun Li
- Department of General Surgery, Shenzhen University Luohu People's Hospital, Shenzhen, China
| | - Jingsong Li
- The Engineering Research Center of EMR and Intelligent Expert System, Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, China.,Research Center for Healthcare Data Science, Zhejiang Lab, Hangzhou, China
| | - Qi Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. .,Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. .,Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China. .,Zhejiang University Cancer Center, Hangzhou, China.
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. .,Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. .,Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China. .,Zhejiang University Cancer Center, Hangzhou, China.
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13
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Wyld D, Moore J, Tran N, Youl P. Incidence, survival and stage at diagnosis of small intestinal neuroendocrine tumours in Queensland, Australia, 2001-2015. Asia Pac J Clin Oncol 2021; 17:350-358. [PMID: 33567164 DOI: 10.1111/ajco.13503] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 09/10/2020] [Indexed: 12/13/2022]
Abstract
AIM Multiple studies have observed increasing incidence of small intestinal (SI) neuroendocrine tumours (NETs). The aim of this study was to describe incidence, mortality and survival of SI NETs by sub-site and stage at diagnosis. METHODS Data on patients diagnosed with SI NETs between 2001 and 2015 were sourced from the Queensland Oncology Repository. Staging algorithms utilising several data sources were used to calculate stage at diagnosis (localised, regional or metastatic disease). RESULTS We identified 778 SI NETs and of those 716 (92%) had either a documented or derived stage. Incidence doubled from 0.68 per 100 000 to 1.42 per 100 000 over the 15-year period. Most common site was ileum (49.1%) and 84.2% were of carcinoid morphology type. Stage at diagnosis was calculated for 91.7% of patients with 28.3% presenting with regional involvement and 23.9% with distant metastasis. Risk factors associated with metastatic disease were jejunal and SI site not otherwise specified, neuroendocrine carcinoma histology and residing in a rural area. Increasing incidence of localised disease and a corresponding reduction in metastatic disease was observed over time. Five-year cause-specific survival for patients diagnosed between 2001 and 2005 was 82.5%, increasing to 93.8% from 2011 to 2015. Survival was lowest for those with metastatic disease (74.2%). Survival increased between 2001 to 2005 and 2011 to 2015 for each disease stage. CONCLUSIONS SI NET incidence in Queensland doubled between 2001 and 2015. Survival was high and improved over time.
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Affiliation(s)
- David Wyld
- Department of Medical Oncology, The Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Cancer Alliance Queensland, Metro South Hospital and Health Service, Brisbane, Queensland, Australia
| | - Julie Moore
- Cancer Alliance Queensland, Metro South Hospital and Health Service, Brisbane, Queensland, Australia
| | - Nancy Tran
- Cancer Alliance Queensland, Metro South Hospital and Health Service, Brisbane, Queensland, Australia
| | - Philippa Youl
- Cancer Alliance Queensland, Metro South Hospital and Health Service, Brisbane, Queensland, Australia
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14
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Wyld D, Wan MH, Moore J, Dunn N, Youl P. Epidemiological trends of neuroendocrine tumours over three decades in Queensland, Australia. Cancer Epidemiol 2019; 63:101598. [DOI: 10.1016/j.canep.2019.101598] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 08/19/2019] [Accepted: 09/05/2019] [Indexed: 01/23/2023]
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15
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Alekberzade AV, Krylov NN, Garmanova TN, Shahbazov R, Azari F, Zuykova KS, Litovchenko ED. [Duodenal neuroendocrine tumors]. Khirurgiia (Mosk) 2019:87-95. [PMID: 31355821 DOI: 10.17116/hirurgia201907187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Significant augmentation of the incidence of duodenal neuroendocrine tumors duodenum has been observed in recent decades. There are 5 histological types of these tumors: gastrinoma (50-60%), somatostatin-producing tumor (15%), inactive serotonin-containing tumors (20%), poorly differentiated neuroendocrine carcinoma (<3%) and gangliocytic paraganglioma (<2%). The majority of tumors are localized within the bulb and postbulbar part of duodenum, 20% are found in periampular area. Treatment strategy depends on dimensions, localization, histological class, stage and type of tumor. It is believed that endoscopic resection is permissible for small inactive tumors (G1) located above major duodenal papilla. The majority of other neoplasms requires surgical resection. Personal experience of various surgeons is limited by small group of patients. Therefore, it is necessary to summarize results for selection of optimal treatment.
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Affiliation(s)
- A V Alekberzade
- Sechenov First Moscow State Medical University of Ministry of Health of Russia, Moscow, Russia
| | - N N Krylov
- Sechenov First Moscow State Medical University of Ministry of Health of Russia, Moscow, Russia
| | - T N Garmanova
- Sechenov First Moscow State Medical University of Ministry of Health of Russia, Moscow, Russia
| | - R Shahbazov
- Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, USA
| | - F Azari
- Department of Surgery, University of Pennsylvania, Philadelphia PA, USA
| | - K S Zuykova
- Sechenov First Moscow State Medical University of Ministry of Health of Russia, Moscow, Russia
| | - E D Litovchenko
- Sechenov First Moscow State Medical University of Ministry of Health of Russia, Moscow, Russia
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16
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Genc CG, Klümpen HJ, van Oijen MGH, van Eijck CHJ, Nieveen van Dijkum EJM. A Nationwide Population-Based Study on the Survival of Patients with Pancreatic Neuroendocrine Tumors in The Netherlands. World J Surg 2018; 42:490-497. [PMID: 29018912 PMCID: PMC5762791 DOI: 10.1007/s00268-017-4278-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Background Large population-based studies give insight into the prognosis and treatment outcomes of patients with pancreatic neuroendocrine tumors (pNETs). Therefore, we provide an overview of the treatment and related survival of pNET in the Netherlands. Methods Patients diagnosed with pNET between 2008 and 2013 from the Netherlands Cancer Registry were included. Patient, tumors and treatment characteristics were reported. Survival analyses with log-rank testing were performed to compare survival. Results In total, 611 patients were included. Median follow-up was 25.7 months, and all-cause mortality was 42%. Higher tumor grade and TNM stage were significantly associated with worse survival in both the overall and metastasized population. The effect of distant metastases on survival was more significant in lower tumor stages (T1–3 p < 0.05, T4 p = 0.074). Resection of the primary tumor was performed in 255 (42%) patients. Patients who underwent surgery had the highest 5-year survival (86%) compared to PRRT (33%), chemotherapy (21%), targeted therapy and somatostatin analogs (24%) (all p < 0.001). Patients with T1M0 tumors (n = 115) showed favorable survival after surgical resection (N = 95) compared to no therapy (N = 20, p = 0.008). Resection also improved survival significantly in patients with metastases compared to other treatments (all p > 0.05). Without surgery, PRRT showed the best survival curves in patients with distant metastases. Grade 3 tumors and surgical resection were independently associated with survival (HR 7.23 and 0.12, respectively). Conclusion Surgical resection shows favorable outcome for all pNET tumors, including indolent tumors and tumors with distant metastases. Prospective trials should be initiated to confirm these results.
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Affiliation(s)
- C G Genc
- Department of Surgery, Academic Medical Center, Meibergdreef 9, PO Box 22660, 1105 AZ, Amsterdam, The Netherlands
| | - H J Klümpen
- Department of Medical Oncology, Academic Medical Center, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - M G H van Oijen
- Department of Medical Oncology, Academic Medical Center, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam, The Netherlands
- Department of Research, Comprehensive Cancer Centers Netherlands (IKNL), Utrecht, The Netherlands
| | - C H J van Eijck
- Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands
| | - E J M Nieveen van Dijkum
- Department of Surgery, Academic Medical Center, Meibergdreef 9, PO Box 22660, 1105 AZ, Amsterdam, The Netherlands.
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17
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Rohit M, Bhatt A, Cruise M, Wearsch PA, Goldblum JR, Sturgis CD. Endoscopic ultrasound FNA: An illustrated review of spindle cell neoplasms of the upper gastrointestinal tract including a novel case of gastric plexiform fibromyxoma. Diagn Cytopathol 2018; 46:730-738. [PMID: 30043412 DOI: 10.1002/dc.24040] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 06/27/2018] [Accepted: 07/05/2018] [Indexed: 02/06/2023]
Abstract
Plexiform fibromyxoma (PF) is a recently-described and rare mesenchymal neoplasm of the gastric wall. A few small case series reports of this spindle cell entity exist in the surgical pathology literature, but to our knowledge no prior endoscopic ultrasound guided fine needle aspiration cytology examples have been reported. In clinical practice, mural gastrointestinal (GI) lesions are often initially evaluated by endoscopic ultrasound guided (EUS) fine needle aspiration (FNA). In addition, newer EUS fine needle biopsy techniques also allow for reliable retrieval of core tissue samples with intact cellular architecture, making EUS histopathologic analyses possible. We report a combined EUS FNA and core biopsy case of PF and correlate the findings with imaging results. The cytomorphology of PF is described and illustrated, and important entities in the differential diagnosis of upper GI spindle cell lesions (including GI stromal tumor, leiomyoma, schwannoma, carcinoid tumor, desmoid-type fibromatosis, and inflammatory fibroid polyp) are reviewed. Illustrated examples of relevant cytomorphologic, cell block histomorphologic and immunohistochemical characteristics are emphasized.
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Affiliation(s)
- Maitreyi Rohit
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio
| | - Amit Bhatt
- Department of Gastrointestinal Medicine, Cleveland Clinic, Cleveland, Ohio
| | - Michael Cruise
- Department of Pathology, Cleveland Clinic, Cleveland, Ohio
| | - Pamela A Wearsch
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio
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18
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Miao DL, Song W, Qian J, Zhu ZG, Wu Q, Lv CG, Chen L. Development and Validation of a Nomogram for Predicting Overall Survival in Pancreatic NeuroendocrineTumors. Transl Oncol 2018; 11:1097-1103. [PMID: 30015262 PMCID: PMC6070700 DOI: 10.1016/j.tranon.2018.06.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 06/28/2018] [Accepted: 06/28/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND: The objective of current study was to develop and validate a nomogram to predict overall survival in pancreatic neuroendocrine tumors (PNETs). METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was queried for patients with PNETs between 2004 and 2015. Patients were randomly separated into the training set and the validation set. Cox regression model was used in training set to obtain independent prognostic factors to develop a nomogram for predicting overall survival (OS). The discrimination and calibration plots were used to evaluate the predictive accuracy of the nomogram. RESULTS: A total of 3142 patients with PNETs were collected from the SEER database. Sex, age, marital status, primary site, TNM stage, tumor grade, and therapy were associated with OS in the multivariate models. A nomogram was constructed based on these variables. The nomogram for predicting OS displayed better discrimination power than the Tumor-Node-Metastasis (TNM) stage systems 7th edition in the training set and validation set. The calibration curve indicated that the nomogram was able to accurately predict 3- and 5-year OS. CONCLUSIONS: The nomogram which could predict 3- and 5-year OS were established in this study. Our nomogram showed a good performance, suggesting that it could be served as an effective tool for prognostic evaluation of patients with PNETs.
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Affiliation(s)
- Dong-Liu Miao
- Department of Intervention and Vascular Surgery, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou Cancer Medical Center, Suzhou, Jiangsu, 215001, China
| | - Wei Song
- Department of Intervention and Vascular Surgery, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou Cancer Medical Center, Suzhou, Jiangsu, 215001, China
| | - Jun Qian
- Department of Oncology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou Cancer Medical Center, Suzhou, Jiangsu, 215001, China
| | - Zhi-Gang Zhu
- Department of Intervention and Vascular Surgery, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou Cancer Medical Center, Suzhou, Jiangsu, 215001, China
| | - Qiong Wu
- Department of Intervention and Vascular Surgery, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou Cancer Medical Center, Suzhou, Jiangsu, 215001, China
| | - Chang-Guang Lv
- Department of Intervention and Vascular Surgery, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou Cancer Medical Center, Suzhou, Jiangsu, 215001, China
| | - Lei Chen
- Department of Intervention and Vascular Surgery, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou Cancer Medical Center, Suzhou, Jiangsu, 215001, China.
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19
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Zhu L, Dai MH, Wang ST, Jin ZY, Wang Q, Denecke T, Hamm B, Xue HD. Multiple solid pancreatic lesions: Prevalence and features of non-malignancies on dynamic enhanced CT. Eur J Radiol 2018; 105:8-14. [PMID: 30017302 DOI: 10.1016/j.ejrad.2018.05.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Revised: 04/02/2018] [Accepted: 05/15/2018] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To determine the prevalence of multiple solid pancreatic lesions on dynamic enhanced CT performed for suspected pancreatic diseases, and to identify CT features of non-malignancies. METHODS We investigated 8096 consecutive patients who underwent dynamic enhanced CT pancreas protocol at a tertiary center over 40 months. The final clinical /pathological diagnosis served as reference standard. The diagnostic accuracy of dynamic enhanced CT for non-malignancies was calculated. A univariate and multivariate analysis was conducted to identify features that predict non-malignancies. RESULTS Multiple solid pancreatic lesions were identified in 121 patients. The prevalence of non-malignancies was 19.8% (24/121). The most common non-malignancy was autoimmune pancreatitis (n = 21; 17.4%). Common lesions with malignant potential included neuroendocrine neoplasia (n = 62; 51.2%), ductal adenocarcinoma (n = 15; 12.4%), metastasis (n = 9; 7.4%), and lymphoma (n = 7; 5.8%). Dynamic enhanced CT had a sensitivity of 79.2% and a specificity of 92.8% for diagnosing non-malignancies. Elevated serum IgG4 level (p < 0.001), hypo-enhancement in arterial phase (p = 0.001), hyper-enhancement in equilibrium phase (p = 0.009) and location in both proximal and distal pancreas (p = 0.036) were predictors of non-malignancies, whereas pancreatic duct morphology and vascular invasion status were not. CONCLUSION Multiple solid pancreatic lesions were rare, with a wide spectrum. Dynamic enhanced CT provides clues for identifying non-malignancies.
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Affiliation(s)
- Liang Zhu
- Peking Union Medical College Hospital, Department of Radiology, Shuaifuyuan No.1, Dongcheng District, Beijing, 100730, China
| | - Meng-Hua Dai
- Department of General Surgery, Peking Union Medical College Hospital, Shuaifuyuan No.1, Dongcheng District, Beijing, China
| | - Shi-Tian Wang
- Peking Union Medical College Hospital, Department of Radiology, Shuaifuyuan No.1, Dongcheng District, Beijing, 100730, China
| | - Zheng-Yu Jin
- Peking Union Medical College Hospital, Department of Radiology, Shuaifuyuan No.1, Dongcheng District, Beijing, 100730, China.
| | - Qiang Wang
- Department of Gastroenterology, Peking Union Medical College Hospital, Shuaifuyuan No.1, Dongcheng District, Beijing, China
| | - Timm Denecke
- Department of Radiology, Charité- Universitätsmedizin Berlin, Charitéplatz 1, Berlin, Germany
| | - Bernd Hamm
- Department of Radiology, Charité- Universitätsmedizin Berlin, Charitéplatz 1, Berlin, Germany
| | - Hua-Dan Xue
- Peking Union Medical College Hospital, Department of Radiology, Shuaifuyuan No.1, Dongcheng District, Beijing, 100730, China
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20
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Mendieta I, Nuñez-Anita RE, Pérez-Sánchez G, Pavón L, Rodríguez-Cruz A, García-Alcocer G, Berumen LC. Effect of A549 neuroendocrine differentiation on cytotoxic immune response. Endocr Connect 2018; 7:791-802. [PMID: 29700099 PMCID: PMC5987362 DOI: 10.1530/ec-18-0145] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Accepted: 04/26/2018] [Indexed: 12/29/2022]
Abstract
The present study was designed to determine the effects of factors secreted by the lung adenocarcinoma cell line with the neuroendocrine phenotype, A549NED, on cytotoxic T lymphocytes (CTLs) activity in vitro A perspective that integrates the nervous, endocrine and immune system in cancer research is essential to understand the complexity of dynamic interactions in tumours. Extensive clinical research suggests that neuroendocrine differentiation (NED) is correlated with worse patient outcomes; however, little is known regarding the effects of neuroendocrine factors on the communication between the immune system and neoplastic cells. The human lung cancer cell line A549 was induced to NED (A549NED) using cAMP-elevating agents. The A549NED cells showed changes in cell morphology, an inhibition of proliferation, an overexpression of chromogranin and a differential pattern of biogenic amine production (decreased dopamine and increased serotonin [5-HT] levels). Using co-cultures to determine the cytolytic CTLs activity on target cells, we showed that the acquisition of NED inhibits the decrease in the viability of the target cells and release of fluorescence. Additionally, the conditioned medium of A549NED and 5-HT considerably decreased the viability and proliferation of the Jurkat cells after 24 h. Thus, our study successfully generated a neuroendocrine phenotype from the A549 cell line. In co-cultures with CTLs, the pattern of secretion by A549NED impaired the proliferation and cytotoxic activity of CTLs, which might be partly explained by the increased release of 5-HT.
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Affiliation(s)
- Irasema Mendieta
- Facultad de QuímicaUniversidad Autónoma de Querétaro, Querétaro, Mexico
| | - Rosa Elvira Nuñez-Anita
- Facultad de Medicina Veterinaria y ZootecniaUniversidad Michoacana de San Nicolás Hidalgo, Morelia, Michoacán, Mexico
| | - Gilberto Pérez-Sánchez
- Departmento de PsicoimunologíaInstituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México, Mexico
| | - Lenin Pavón
- Departmento de PsicoimunologíaInstituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México, Mexico
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21
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Niazi MKK, Tavolara TE, Arole V, Hartman DJ, Pantanowitz L, Gurcan MN. Identifying tumor in pancreatic neuroendocrine neoplasms from Ki67 images using transfer learning. PLoS One 2018; 13:e0195621. [PMID: 29649302 PMCID: PMC5896941 DOI: 10.1371/journal.pone.0195621] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 03/26/2018] [Indexed: 12/17/2022] Open
Abstract
The World Health Organization (WHO) has clear guidelines regarding the use of Ki67 index in defining the proliferative rate and assigning grade for pancreatic neuroendocrine tumor (NET). WHO mandates the quantification of Ki67 index by counting at least 500 positive tumor cells in a hotspot. Unfortunately, Ki67 antibody may stain both tumor and non-tumor cells as positive depending on the phase of the cell cycle. Likewise, the counter stain labels both tumor and non-tumor as negative. This non-specific nature of Ki67 stain and counter stain therefore hinders the exact quantification of Ki67 index. To address this problem, we present a deep learning method to automatically differentiate between NET and non-tumor regions based on images of Ki67 stained biopsies. Transfer learning was employed to recognize and apply relevant knowledge from previous learning experiences to differentiate between tumor and non-tumor regions. Transfer learning exploits a rich set of features previously used to successfully categorize non-pathology data into 1,000 classes. The method was trained and validated on a set of whole-slide images including 33 NETs subject to Ki67 immunohistochemical staining using a leave-one-out cross-validation. When applied to 30 high power fields (HPF) and assessed against a gold standard (evaluation by two expert pathologists), the method resulted in a high sensitivity of 97.8% and specificity of 88.8%. The deep learning method developed has the potential to reduce pathologists’ workload by directly identifying tumor boundaries on images of Ki67 stained slides. Moreover, it has the potential to replace sophisticated and expensive imaging methods which are recently developed for identification of tumor boundaries in images of Ki67-stained NETs.
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Affiliation(s)
- Muhammad Khalid Khan Niazi
- Center for Biomedical Informatics, Wake Forest School of Medicine, Winston Salem, NC, United States of America
- * E-mail:
| | - Thomas Erol Tavolara
- Center for Biomedical Informatics, Wake Forest School of Medicine, Winston Salem, NC, United States of America
| | - Vidya Arole
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH, United States of America
| | - Douglas J. Hartman
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Liron Pantanowitz
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Metin N. Gurcan
- Center for Biomedical Informatics, Wake Forest School of Medicine, Winston Salem, NC, United States of America
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22
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Savva C, Kaye P, Soomro I, Parsons SL, James E, Madhusudan S. Primary Esophagogastric Neuroendocrine Carcinoma: a Retrospective Study from the Nottingham Upper Gastrointestinal Cancer Center. J Gastrointest Cancer 2017; 49:85-92. [PMID: 29230683 DOI: 10.1007/s12029-017-0039-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Constantinos Savva
- Department of Oncology, Nottingham University Hospitals, Nottingham, NG5 1PB, UK
| | - Philip Kaye
- Department of Pathology, Nottingham University Hospitals, Nottingham, NG5 1PB, UK
| | - Irshad Soomro
- Department of Pathology, Nottingham University Hospitals, Nottingham, NG5 1PB, UK
| | - Simon L Parsons
- Department of Surgery, Nottingham University Hospitals, Nottingham, NG5 1PB, UK
| | - Eleanor James
- Department of Oncology, Nottingham University Hospitals, Nottingham, NG5 1PB, UK
| | - Srinivasan Madhusudan
- Department of Oncology, Nottingham University Hospitals, Nottingham, NG5 1PB, UK. .,Translational Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, NG5 1PB, UK.
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Cao J, Xu W, Du Z, Sun B, Li F, Liu Y. Pathologic Progression, Possible Origin, and Management of Multiple Primary Intracranial Neuroendocrine Carcinomas. World Neurosurg 2017; 106:1054.e13-1054.e17. [PMID: 28736348 DOI: 10.1016/j.wneu.2017.07.053] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2017] [Revised: 07/08/2017] [Accepted: 07/11/2017] [Indexed: 10/19/2022]
Abstract
BACKGROUND Primary intracranial neuroendocrine carcinomas (NECs) are extremely rare malignant tumors with no previous reports of multiple ones in the literatures. CASE DESCRIPTION The clinical presentation, preoperative and reexamined magnetic resonance imaging findings, as well as histopathologic studies of a 56-year-old female subject with multiple intracranial NECs mimicking multiple intracranial meningiomas, who underwent 3 operations with left parietal craniotomy, right occipital parietal craniotomy, and left frontal craniotomy, separately and chronologically, are presented in this article. Noteworthy, the first and second tumors were confirmed as NECs exhibiting histologic characteristics of typical anaplastic meningiomas with features of whorl formation, while the third tumor was a typical NEC with features of organoid cancer nests. In other words, the first 2 lesions were diagnosed as meningioma as opposed to NEC. It was only after the third surgery that the pathology for the first 2 cases was reviewed and had a revised diagnosis. After the third surgical resection, the patient further received whole brain radiotherapy and systemic chemotherapy (temozolomide combined with YH-16). At her 10-month follow-up, the patient achieved a good outcome. CONCLUSIONS Multiple primary intracranial NECs are extremely rare. The tumor might be of arachnoidal or leptomeningeal origin, with histologic patterns that might lead to transformation and/or progression. Maximal surgical resection is warranted for symptomatic mass effect. Postoperative adjuvant treatments including radiotherapy and chemotherapy should be a recommended therapeutic modality.
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Affiliation(s)
- Jingwei Cao
- Department of Neurosurgery, Qilu Hospital and Brain Science Research Institute of Shandong University, Shandong, People's Republic of China; Department of Neurosurgery, Qilu Children's Hospital of Shandong University, Shandong, People's Republic of China
| | - Wenzhe Xu
- Department of Neurosurgery, Qilu Hospital and Brain Science Research Institute of Shandong University, Shandong, People's Republic of China
| | - Zhenhui Du
- Department of Neurosurgery, Qilu Hospital and Brain Science Research Institute of Shandong University, Shandong, People's Republic of China
| | - Bin Sun
- Department of Neurosurgery, Qilu Hospital and Brain Science Research Institute of Shandong University, Shandong, People's Republic of China
| | - Feng Li
- Department of Neurosurgery, Qilu Hospital and Brain Science Research Institute of Shandong University, Shandong, People's Republic of China.
| | - Yuguang Liu
- Department of Neurosurgery, Qilu Hospital and Brain Science Research Institute of Shandong University, Shandong, People's Republic of China.
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Lee KJ, Cho JH, Lee SH, Lee KH, Park BK, Lee JK, Woo SM, Ryu JK, Lee JK, Kim YS, Kim JW, Lee WJ. Clinicopathological characteristics of biliary neuroendocrine neoplasms: a multicenter study. Scand J Gastroenterol 2017; 52:437-441. [PMID: 27924650 DOI: 10.1080/00365521.2016.1261938] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVES This study assessed the clinicopathological features, therapeutic approaches, and prognosis of patients with biliary neuroendocrine neoplasm (NENs). MATERIALS AND METHODS Multicenter retrospective study of patients with biliary tract NENs in the gallbladder, the extrahepatic bile duct, or the ampulla of Vater between 2005 and 2014. RESULTS Total of 43 patients were included in the study. The median age was 62 years (range: 29-84 years) and 58.1% of the patients were male. The tumors occurred in the gallbladder (n = 11), the extrahepatic bile duct (n = 5) or the ampulla of Vater (n = 27). The liver was the most common metastatic site. Based on the 2010 World Health Organization classification, more patients with gallbladder NENs (11/11 (100%)) had neuroendocrine carcinoma G3 than those with NENs in the ampulla of Vater (10/27 (37.1%)). The median progression free survival time (39.3 vs 5.1 months, p = 0.001) and median overall survival time (46.9 vs 7.9 months, p < 0.001) were significantly longer in patients with ampulla of Vater NENs than gallbladder NENs. A 2010 World Health Organization classification of neuroendocrine carcinoma G3 was independently related to poor overall survival (hazard ratio (HR), 27.1; 95% confidence intervals (CI), 2.81-260.68; p = 0.004). CONCLUSION The 2010 World Health Organization classification of neuroendocrine carcinoma G3 was the only factor related to poor prognosis in patients with biliary neuroendocrine neoplasms.
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Affiliation(s)
- Kyong Joo Lee
- a Department of Internal Medicine , Yonsei University Wonju College of Medicine , Wonju , South Korea
| | - Jae Hee Cho
- b Department of Internal Medicine , Gachon university, Gil Medical Center , Incheon , South Korea
| | - Sang Hyub Lee
- c Department of Internal Medicine and Liver Research Institute , Seoul National University College of Medicine , Seoul , South Korea
| | - Kwang Hyuk Lee
- d Department of Internal Medicine , Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul , South Korea
| | - Byung Kyu Park
- e National Health Insurance Corporation Ilsan Hospital , Goyang , South Korea
| | - Jun Kyu Lee
- f Department of Internal Medicine , Dongguk University Ilsan Hospital, Dongguk University , Goyang , South Korea
| | - Sang Myung Woo
- g Center for Liver Cancer, National Cancer Center , Goyang , South Korea
| | - Ji Kon Ryu
- c Department of Internal Medicine and Liver Research Institute , Seoul National University College of Medicine , Seoul , South Korea
| | - Jong Kyun Lee
- d Department of Internal Medicine , Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul , South Korea
| | - Yeon Suk Kim
- b Department of Internal Medicine , Gachon university, Gil Medical Center , Incheon , South Korea
| | - Jae Woo Kim
- a Department of Internal Medicine , Yonsei University Wonju College of Medicine , Wonju , South Korea
| | - Woo Jin Lee
- g Center for Liver Cancer, National Cancer Center , Goyang , South Korea
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Intra-arterial radiopeptide therapy of hepatic metastases of neuroendocrine tumors: a systematic review. Clin Transl Imaging 2017. [DOI: 10.1007/s40336-016-0220-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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A novel injectable formulation of 6-fluoro-l-DOPA imaging agent for diagnosis of neuroendocrine tumors and Parkinson's disease. Int J Pharm 2017; 519:304-313. [PMID: 28119123 DOI: 10.1016/j.ijpharm.2017.01.038] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Revised: 01/16/2017] [Accepted: 01/18/2017] [Indexed: 12/25/2022]
Abstract
Two [19F]F-l-DOPA (F-DOPA) new β-cyclodextrin (CD)-based dosage forms (FA and FB, respectively) have been studied and their physico-chemical and pharmacological features determined to overcome the administration site reactions showed by the currently used [18F]F-l-DOPA formulation (IASOdopa®) to perform PET-CT diagnosis in oncology (neuroendocrine tumors) and neurological (Parkinson's disease) field. Chemical stability of FA and FB was found to be longer than IASOdopa® by adding the thiol-antioxidant agent, L-Cysteine. 1H and 19F NMR investigations suggest the formation of an inclusion complex of F-DOPA with β-CD. In vitro experiments on the effects of FA and FB on mouse skeletal muscle fibers and on the human neuroblastoma SH-SY5Y and embryonal kidney tsA201 cell lines viability showed that FA was the most performant formulation compared to F-DOPA solutions. In vivo tolerability tests of FA on adult male rat showed no significant effects on body weight and no change in their dried organs weight. In addition, their metabolic and physiological parameters were not affected. In conclusion, [18F]F-l-DOPA, formulated as FA, constitutes a promising dosage form for PET-CT diagnosis of both neuroendocrine tumors and Parkinson's disease.
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Trama A, Marcos-Gragera R, Sánchez Pérez MJ, van der Zwan JM, Ardanaz E, Bouchardy C, Melchor JM, Martinez C, Capocaccia R, Vicentini M, Siesling S, Gatta G. Data quality in rare cancers registration: the report of the RARECARE data quality study. TUMORI JOURNAL 2017; 103:22-32. [PMID: 27716878 DOI: 10.5301/tj.5000559] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/10/2016] [Indexed: 12/23/2022]
Abstract
PURPOSE Rare cancers represent 22% of all tumors in Europe; however, the quality of the data of rare cancers may not be as good as the quality of data for common cancer. The project surveillance of rare cancers in Europe (RARECARE) had, among others, the objective of assessing rare cancer data quality in population-based cancer registries (CRs). Eight rare cancers were considered: mesothelioma, liver angiosarcoma, sarcomas, tumors of oral cavity, CNS tumors, germ cell tumors, leukemia, and malignant digestive endocrine tumors. METHODS We selected data on 18,000 diagnoses and revised, on the basis of the pathologic and clinical reports (but not on pathologic specimens), unspecified morphology and topography codes originally attributed by CR officers and checked the quality of follow-up of long-term survivors of poor prognosis cancers. RESULTS A total of 38 CRs contributed from 13 European countries. The majority of unspecified morphology and topography cases were confirmed as unspecified. The few unspecified cases that, after the review, changed to a more specific diagnosis increased the incidence of the common cancer histotypes. For example, 11% of the oral cavity epithelial cancers were reclassified from unspecified to more specific diagnoses: 8% were reclassified as squamous cell carcinoma (commoner) and only 1% as adenocarcinoma (rarer). The revision confirmed the majority of long-term survivors revealing a relative high proportion of mesothelioma long-term survivors. The majority of appendix carcinoids changed behavior from malignant to borderline lesions. CONCLUSIONS Our study suggests that the problem of poorly specified morphology and topography cases is mainly one of difficulty in reaching a precise diagnosis. The awareness of the importance of data quality for rare cancers should increase among registrars, pathologists, and clinicians.
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Affiliation(s)
- Annalisa Trama
- Evaluative Epidemiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy
| | - Rafael Marcos-Gragera
- Epidemiology Unit and Girona Cancer Registry, Oncology Coordination Plan, Department of Health, Girona Biomedical Research Institute, Girona - Spain
| | - Maria Josè Sánchez Pérez
- Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria ibs.GRANADA. Hospitales Universitarios de Granada/Universidad de Granada, Granada - Spain
- CIBER de Epidemiología y Salud Pública (CIBERESP) - Spain
| | | | - Eva Ardanaz
- CIBER de Epidemiología y Salud Pública (CIBERESP) - Spain
- Instituto de Salud Pública de Navarra, Pamplona - Spain
| | - Christine Bouchardy
- Geneva Cancer Registry, Institute of Global Health, Faculty of Medicine, University of Geneva, Geneva - Switzerland
| | - Juan Manuel Melchor
- Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria ibs.GRANADA. Hospitales Universitarios de Granada/Universidad de Granada, Granada - Spain
| | - Carmen Martinez
- Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria ibs.GRANADA. Hospitales Universitarios de Granada/Universidad de Granada, Granada - Spain
| | - Riccardo Capocaccia
- Centro Nazionale di Epidemiologia, Sorveglianza e Promozione della Salute (CNESPS), Istituto Superiore di Sanità, Rome - Italy
| | - Massimo Vicentini
- Servizio Interaziendale di Epidemiologia, Azienda Unità Sanitaria Locale and IRCCS, Arcispedale Santa Maria Nuova, Reggio Emilia - Italy
| | - Sabine Siesling
- Department of Research, Comprehensive Cancer Centre The Netherlands, Utrecht - The Netherlands
- Department of Health Technology and services research, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede - The Netherlands
| | - Gemma Gatta
- Evaluative Epidemiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy
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Boyar Cetinkaya R, Aagnes B, Thiis-Evensen E, Tretli S, Bergestuen DS, Hansen S. Trends in Incidence of Neuroendocrine Neoplasms in Norway: A Report of 16,075 Cases from 1993 through 2010. Neuroendocrinology 2017; 104:1-10. [PMID: 26562558 DOI: 10.1159/000442207] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Accepted: 11/05/2015] [Indexed: 12/16/2022]
Abstract
BACKGROUND Epidemiological studies show an increasing trend in the incidence of neuroendocrine neoplasms (NENs). A significant number of NENs occur in less common primary sites, but they are often excluded from the population-based studies. We studied the incidence trends of all NENs in Norway according to different primary sites. MATERIALS AND METHODS Our analyses were based on cancer cases diagnosed between 1993 and 2010 and reported to the national population-based Cancer Registry of Norway. A total of 65 morphological codes were identified as neuroendocrine and stratified into 3 different groups of aggressiveness: low, intermediate and high. RESULTS We identified 16,075 NENs of which 49.5% were in women. The median age at diagnosis was 65 years. The most common primary sites were the lung (48.1%) and the gastroenteropancreatic system (18.0%). Stage at diagnosis was local in 40.4% of the cases, regional in 17.5% and distant in 42.1%. The stage distribution was stable throughout the study period. The age-standardized (European) incidence rate (per 100,000 person-years) increased from 13.3 in 1993 to 21.3 in 2010 with an estimated annual increase of 5.1% in women and 2.1% in men. The increase was most pronounced for tumors of intermediate aggressiveness from 3.3 in 1993 to 7.3 in 2010. The largest annual increases were estimated for the adrenal gland (8.8%), the pancreas (6.9%) and the lungs (6.1%). CONCLUSION The incidence of NENs increased. Most primary tumors were found in the lungs or in the gastroenteropancreatic system. The increase in the incidence differed according to the primary site, gender and tumor aggressiveness.
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Affiliation(s)
- Raziye Boyar Cetinkaya
- Neuroendocrine Tumor Center of Excellence, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
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Gantenbein N, Haybaeck J. Neuroendocrine Tumorigenesis. MECHANISMS OF MOLECULAR CARCINOGENESIS – VOLUME 2 2017:141-146. [DOI: 10.1007/978-3-319-53661-3_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Sato Y, Hashimoto S, Mizuno KI, Takeuchi M, Terai S. Management of gastric and duodenal neuroendocrine tumors. World J Gastroenterol 2016; 22:6817-6828. [PMID: 27570419 PMCID: PMC4974581 DOI: 10.3748/wjg.v22.i30.6817] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 06/16/2016] [Accepted: 07/06/2016] [Indexed: 02/06/2023] Open
Abstract
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.
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Chan DT, Luk AOY, So WY, Kong APS, Chow FCC, Ma RCW, Lo AWI. Natural history and outcome in Chinese patients with gastroenteropancreatic neuroendocrine tumours: - a 17-year retrospective analysis. BMC Endocr Disord 2016; 16:12. [PMID: 26911576 PMCID: PMC4766724 DOI: 10.1186/s12902-016-0087-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 01/20/2016] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND There is rising incidence of gastroenteropancreatic neuroendocrine tumours (GEP- NETs) in many parts of the world, but epidemiological data from Asian populations is rare. METHODS We conducted a retrospective study in a tertiary medical centre in Hong Kong, using updated diagnostic criteria. The presentation, clinical features, and disease outcome were reviewed for all patients with GEP-NETs confirmed histopathologically at the Prince of Wales Hospital, the Chinese University of Hong Kong, between 1996 and 2013, according to the latest 2010 World Health Organization Classification. RESULTS Among 126 patients, GEP- NETs were found in pancreas (34.9 %), rectum (33.3 %), and stomach (8.7 %), and most of them were non- functional GEP- NETs (91.3 %), mostly of grade 1 (G1) (87.3 %), and about 20 % had metastases on presentation. Age under 55 years, G1 tumours and absence of metastases were significant favourable predictors for survival in univariate analysis; whereas G2/3 tumours, size ≥2 cm, and metastases were significant predictors for disease progression (p < 0.05). In multivariate analysis, age and metastases on presentation were significant predictors of mortality (respective hazard ratios [HR] 1.05 [95 % confidence interval {CI} 1.02-1.08] and 6.52 [95 % CI 3.22-13.2]) and disease progression (respective HRs 1.05 [95 % CI 1.02-1.07] and 4.12 [95 % CI 1.96-8.68]), while higher tumour grade also independently predicted disease progression (HR 5.17 [95 % CI 2.05-13.05]) (all p < 0.05). CONCLUSION Non-functional tumours with non-specific symptoms account for the vast majority of GEP-NETs in this Chinese series. Multidisciplinary approach in the management of patients with GEP-NETs may help improve the treatment efficacy and outcome.
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Affiliation(s)
- Doris T Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
| | - Andrea O Y Luk
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
| | - W Y So
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
| | - Alice P S Kong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
| | - Francis C C Chow
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
| | - Ronald C W Ma
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
| | - Anthony W I Lo
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
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Radulova-Mauersberger O, Stelzner S, Witzigmannn H. [Rectal neuroendocrine tumors: surgical therapy]. Chirurg 2016; 87:292-7. [PMID: 26888707 DOI: 10.1007/s00104-016-0153-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
The incidence of rectal neuroendocrine tumors (NET) has increased in recent years. Most of these neoplasms are asymptomatic and are diagnosed by colonoscopy screening, which could be one of the reasons for the increasing occurrence. As less than 1 % of rectal NET produce serotonin they are practically never discovered due to a carcinoid syndrome. The current guidelines of the European (ENETS) and North American (NANETS) Neuroendocrine Tumor Societies support clinicians with useful diagnostic and treatment algorithms. The most important criteria for therapy are tumor size and histopathological risk factors for metastases. For well-differentiated rectal neuroendocrine neoplasms < 1 cm, local endoscopic or surgical excision is recommended. Due to the lack of evidence tumors sized 1-2 cm represent a grey area for prognosis and treatment. All NET > 1.5 cm must be excised by radical surgery as low anterior rectal resection or abdominoperineal extirpation with total mesorectal excision (TME). Resectable liver and lung metastases of well-differentiated NETs should be surgically treated with curative intent.
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Affiliation(s)
- O Radulova-Mauersberger
- Klinik für Allgemein-, Viszeral- und Thoraxchirurgie, Städtisches Klinikum Dresden-Friedrichstadt, Friedrichstrasse 41, 01067, Dresden, Deutschland
| | - S Stelzner
- Klinik für Allgemein-, Viszeral- und Thoraxchirurgie, Städtisches Klinikum Dresden-Friedrichstadt, Friedrichstrasse 41, 01067, Dresden, Deutschland
| | - H Witzigmannn
- Klinik für Allgemein-, Viszeral- und Thoraxchirurgie, Städtisches Klinikum Dresden-Friedrichstadt, Friedrichstrasse 41, 01067, Dresden, Deutschland.
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Li J, Lin JP, Shi LH, Wang WJ, Li AQ, Si JM, Chen SJ. How reliable is the Ki-67 cytological index in grading pancreatic neuroendocrine tumors? A meta-analysis. J Dig Dis 2016; 17:95-103. [PMID: 26713749 DOI: 10.1111/1751-2980.12310] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2015] [Revised: 12/11/2015] [Accepted: 12/20/2015] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To investigate the accuracy of the cytological Ki-67 index in distinguishing intermediate and high-grade (G2 + G3) from low-grade (G1) pancreatic neuroendocrine tumors (PNETs). METHODS Two investigators independently searched databases to identify eligible studies using the following term: ('Ki-67') AND ('pancreatic endocrine tumor' OR 'pancreatic neuroendocrine tumor' OR 'pancreatic endocrine tumour' OR 'pancreatic neuroendocrine tumour' OR 'pancreatic endocrine tumors' OR 'pancreatic neuroendocrine tumors' OR 'pancreatic endocrine tumours' OR 'pancreatic neuroendocrine tumours'), and meta-analysis was performed to calculate the pooled sensitivity, specificity, positive (PLR) and negative likelihood ratio (NLR), and diagnostic odds ratio (DOR). RESULTS A total of 263 lesions from 13 studies were included in the study. The pooled sensitivity and specificity of Ki-67 (cut-off value: 2%) in the differential diagnosis of G2 + G3 from G1 PNETs were 64% and 87%, respectively. The pooled PLR, NLR and DOR were 3.96, 0.42 and 11.21, respectively. The area under the summary receiver operating characteristic curve (AUROC) was 0.8397. While the cut-off value of Ki-67 index was set as 5%, the sensitivity and specificity were increased up to 69% and 93%, respectively, and the AUROC was increased to 0.955. CONCLUSION The cytological Ki-67 index is very useful in distinguishing intermediate and high-grade from low-grade PNETs, and a cut-off value of 5% had a better predictive value compared with that of 2%.
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Affiliation(s)
- Jun Li
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University.,Institute of Gastroenterology, Zhejiang University
| | - Jin Ping Lin
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University.,Institute of Gastroenterology, Zhejiang University
| | - Liu Hong Shi
- Department of Ultrasound, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Wei Jia Wang
- Department of Internal Medicine, Tufts Medical Center, Boston, Massachusetts, USA
| | - Ai Qing Li
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University.,Institute of Gastroenterology, Zhejiang University
| | - Jian Min Si
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University.,Institute of Gastroenterology, Zhejiang University
| | - Shu Jie Chen
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University.,Institute of Gastroenterology, Zhejiang University
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Crona J, Norlén O, Antonodimitrakis P, Welin S, Stålberg P, Eriksson B. Multiple and Secondary Hormone Secretion in Patients With Metastatic Pancreatic Neuroendocrine Tumours. J Clin Endocrinol Metab 2016; 101:445-52. [PMID: 26672633 DOI: 10.1210/jc.2015-2436] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
CONTEXT As a group, neuroendocrine tumors (NETs) secrete many different peptide hormones, yet heretofore each NET patient is typically thought to produce at most one hormone that causes a distinct hormonal syndrome. A minority of patients have multiple hormones at diagnosis and may also develop secondary hormone secretion at a later stage. OBJECTIVES The objectives of the study were to determine the frequency and to describe the impact of multiple and secondary hormone secretion in sporadic gasteroenteropancreatic NET patients. DESIGN, SETTING, AND PARTICIPANTS This was a retrospective analysis of patients (n = 972) with gasteroenteropancreatic NET treated at Uppsala University Hospital, Uppsala, Sweden. Patients with the secretion of multiple hormones at diagnosis and/or those developing secondary hormone secretion during the disease course were identified and studied in further detail. RESULTS In pancreatic NETs (PNETs), a total of 19 of 323 patients (6%) had secretion of multiple hormones at diagnosis, and 14 of 323 (4%) had secondary changes during the disease course. These phenomena occurred exclusively in patients with an advanced disease stage, and secondary hormones were detected in a close time span with progressive disease. Patients with secondary insulin hypersecretion had increased morbidity as well as reduced survival (P < .002). In contrast, multiple and secondary hormone secretion was rarely seen in NETs of the small intestine with 0 and 1 of 603 cases, respectively. CONCLUSION Diversity of PNET hormone secretion either at diagnosis or during the disease course occurred in a minority of patients (9.3%). These phenomena had a major impact on patient outcome both through increased morbidity and mortality. Our results support that patients with metastatic PNETs should be monitored for clinical symptoms of secondary hormone secretion during the disease course.
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Affiliation(s)
- Joakim Crona
- Departments of Medical Sciences (J.C., P.A., S.W., B.E.) and Surgical Sciences (O.N., P.S.), Uppsala University, 75185 Uppsala, Sweden
| | - Olov Norlén
- Departments of Medical Sciences (J.C., P.A., S.W., B.E.) and Surgical Sciences (O.N., P.S.), Uppsala University, 75185 Uppsala, Sweden
| | - Pantelis Antonodimitrakis
- Departments of Medical Sciences (J.C., P.A., S.W., B.E.) and Surgical Sciences (O.N., P.S.), Uppsala University, 75185 Uppsala, Sweden
| | - Staffan Welin
- Departments of Medical Sciences (J.C., P.A., S.W., B.E.) and Surgical Sciences (O.N., P.S.), Uppsala University, 75185 Uppsala, Sweden
| | - Peter Stålberg
- Departments of Medical Sciences (J.C., P.A., S.W., B.E.) and Surgical Sciences (O.N., P.S.), Uppsala University, 75185 Uppsala, Sweden
| | - Barbro Eriksson
- Departments of Medical Sciences (J.C., P.A., S.W., B.E.) and Surgical Sciences (O.N., P.S.), Uppsala University, 75185 Uppsala, Sweden
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Balachandran A, Bhosale PR, Charnsangavej C, Tamm EP. Imaging of pancreatic neoplasms. Surg Oncol Clin N Am 2015; 23:751-88. [PMID: 25246049 DOI: 10.1016/j.soc.2014.07.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Ductal adenocarcinoma accounts for 85% to 90% of all solid pancreatic neoplasms, is increasing in incidence, and is the fourth leading cause of cancer-related deaths. There are currently no screening tests available for the detection of ductal adenocarcinoma. The only chance for cure in pancreatic adenocarcinoma is surgery. Imaging has a crucial role in the identification of the primary tumor, vascular variants, identification of metastases, disease response assessment to treatment, and prediction of respectability. Pancreatic neuroendocrine neoplasms can have a distinctive appearance and pattern of spread, which should be recognized on imaging for appropriate management of these patients.
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Affiliation(s)
- Aparna Balachandran
- Abdominal Imaging, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1473, Houston, TX 77030, USA.
| | - Priya R Bhosale
- Abdominal Imaging, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1473, Houston, TX 77030, USA
| | - Chuslip Charnsangavej
- Abdominal Imaging, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Eric P Tamm
- Abdominal Imaging, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1473, Houston, TX 77030, USA
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Wolin EM, Jarzab B, Eriksson B, Walter T, Toumpanakis C, Morse MA, Tomassetti P, Weber MM, Fogelman DR, Ramage J, Poon D, Gadbaw B, Li J, Pasieka JL, Mahamat A, Swahn F, Newell-Price J, Mansoor W, Öberg K. Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues. DRUG DESIGN DEVELOPMENT AND THERAPY 2015; 9:5075-86. [PMID: 26366058 PMCID: PMC4562767 DOI: 10.2147/dddt.s84177] [Citation(s) in RCA: 144] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In a randomized, double-blind, Phase III study, we compared pasireotide long-acting release (pasireotide LAR) with octreotide long-acting repeatable (octreotide LAR) in managing carcinoid symptoms refractory to first-generation somatostatin analogues. Adults with carcinoid tumors of the digestive tract were randomly assigned (1:1) to receive pasireotide LAR (60 mg) or octreotide LAR (40 mg) every 28 days. Primary outcome was symptom control based on frequency of bowel movements and flushing episodes. Objective tumor response was a secondary outcome. Progression-free survival (PFS) was calculated in a post hoc analysis. Adverse events were recorded. At the time of a planned interim analysis, the data monitoring committee recommended halting the study because of a low predictive probability of showing superiority of pasireotide over octreotide for symptom control (n=43 pasireotide LAR, 20.9%; n=45 octreotide LAR, 26.7%; odds ratio, 0.73; 95% confidence interval [CI], 0.27–1.97; P=0.53). Tumor control rate at month 6 was 62.7% with pasireotide and 46.2% with octreotide (odds ratio, 1.96; 95% CI, 0.89–4.32; P=0.09). Median (95% CI) PFS was 11.8 months (11.0 – not reached) with pasireotide versus 6.8 months (5.6 – not reached) with octreotide (hazard ratio, 0.46; 95% CI, 0.20–0.98; P=0.045). The most frequent drug-related adverse events (pasireotide vs octreotide) included hyperglycemia (28.3% vs 5.3%), fatigue (11.3% vs 3.5%), and nausea (9.4% vs 0%). We conclude that, among patients with carcinoid symptoms refractory to available somatostatin analogues, similar proportions of patients receiving pasireotide LAR or octreotide LAR achieved symptom control at month 6. Pasireotide LAR showed a trend toward higher tumor control rate at month 6, although it was statistically not significant, and was associated with a longer PFS than octreotide LAR.
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Affiliation(s)
- Edward M Wolin
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA
| | - Barbara Jarzab
- Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Barbro Eriksson
- Department of Medical Sciences, Endocrine Oncology Unit, University Hospital, Uppsala, Sweden
| | - Thomas Walter
- Department of Medical Oncology, Edouard Herriot Hospital, Lyon, France
| | | | - Michael A Morse
- Department of Medical Oncology, Duke University Medical Center, Durham, NC, USA
| | - Paola Tomassetti
- Department of Medical and Surgical Sciences, University Hospital St Orsola, Bologna, Italy
| | - Matthias M Weber
- Medizinische Klinik und Poliklinik, Johannes Gutenberg-Universität Mainz, Mainz, Germany
| | - David R Fogelman
- Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | - John Ramage
- Gastroenterology Unit, North Hampshire Hospital, Basingstoke, UK
| | - Donald Poon
- Department of Medical Oncology, Raffles Hospital and Duke-NUS Graduate Medical School, Singapore
| | - Brian Gadbaw
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
| | - Jiang Li
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
| | - Janice L Pasieka
- Surgery and Oncology Faculty of Medicine, Foothills Hospital, Calgary, AB, Canada
| | - Abakar Mahamat
- Department of Gastrointestinal Oncology, CHU de Nice Hôpital de l'Archet 1, Nice, France
| | - Fredrik Swahn
- Department of Clinical Science, Intervention and Technology, Karolinska Universitatssjukhuset, Huddinge, Stockholm, Sweden
| | - John Newell-Price
- Department of Human Metabolism, School of Medicine and Biomedical Science, The University of Sheffield, and Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Wasat Mansoor
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - Kjell Öberg
- Department of Medical Sciences, Endocrine Oncology Unit, University Hospital, Uppsala, Sweden
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Zhu X, Yong H, Zhang L, Huang Y, Zheng J, Liu C, Xiu D, Zhang P. Pure alpha-fetoprotein-producing neuroendocrine carcinoma of the pancreas: a case report. BMC Gastroenterol 2015; 15:16. [PMID: 25886790 PMCID: PMC4337100 DOI: 10.1186/s12876-015-0246-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 02/02/2015] [Indexed: 11/18/2022] Open
Abstract
Background Alpha-fetoprotein (AFP)-producing pancreatic neuroendocrine tumors (pNETs) are rare, and the few reported cases usually coexisted with other malignant components such as adenocarcinoma or hepatoid carcinoma. We present here the first case of pure AFP-producing pNET. Case presentation A 56-year-old male patient underwent resection of the pancreatic tail and body because of elevated serum AFP levels and pancreatic mass. Microscopy showed that the tumor tissue consisted of large and small solid nests of polygonal cells. The tumor cells were positive for chromogranin A, synaptophysin, CD99, cytokeratin 19, pan-cytokeratin and β-catenin, and also showed diffuse immunoreactivity for AFP and human chorionic gonadotrophin. The mitotic rate was nearly 30 per 10 high-power fields and the Ki-67 index was nearly 25%. The histopathologic findings supported the diagnosis of an AFP-producing pNET. Other malignant components were not found. Serum AFP levels decreased to near-normal after operation and gradually increased to >1000 ng/ml at 5 months post-surgery. Recurrence and hepatic metastases were revealed by computed tomography. The patient died 21 months after surgery. Conclusion This was the first case of pure AFP-producing pNET to be reported in the English literature. Serum AFP levels may provide useful information for monitoring the therapeutic effectiveness, early recurrence or metastases.
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Affiliation(s)
- Xiang Zhu
- Department of Pathology, Peking University Third Hospital, Beijing, 100191, China. .,Department of Pathology, Peking University Health Science Center, Beijing, 100191, China.
| | - Huijuan Yong
- Department of Gastroenterology, Peking University Third Hospital, Beijing, 100191, China.
| | - Li Zhang
- Department of Gastroenterology, Peking University Third Hospital, Beijing, 100191, China.
| | - Yonghui Huang
- Department of Gastroenterology, Peking University Third Hospital, Beijing, 100191, China.
| | - Jie Zheng
- Department of Pathology, Peking University Third Hospital, Beijing, 100191, China. .,Department of Pathology, Peking University Health Science Center, Beijing, 100191, China.
| | - Cuiling Liu
- Department of Pathology, Peking University Third Hospital, Beijing, 100191, China. .,Department of Pathology, Peking University Health Science Center, Beijing, 100191, China.
| | - Dianrong Xiu
- Department of Surgery, Peking University Third Hospital, Beijing, 100191, China.
| | - Pan Zhang
- Department of Gastroenterology, Peking University Third Hospital, Beijing, 100191, China.
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Abstract
OBJECTIVE The purpose of this article is to present our experience in treating patients with hepatic metastases from a neuroendocrine primary malignancy. CONCLUSION The tumor and patient characteristics, vascular access, and features of treatment all play a role in the long-term management of patients with metatastic neuroendocrine tumors. Routine prophylactic measures are recommended to reduce the frequency and severity of crisis events related to hormone release in patients with neuroendocrine tumors.
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MIĘKUS NATALIA, OLĘDZKA ILONA, PLENIS ALINA, WOŹNIAK ZOFIA, LEWCZUK ANNA, KOSZAŁKA PATRYCJA, SEROCZYŃSKA BARBARA, BĄCZEK TOMASZ. Gel electrophoretic separation of proteins from cultured neuroendocrine tumor cell lines. Mol Med Rep 2014; 11:1407-15. [DOI: 10.3892/mmr.2014.2864] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Accepted: 06/05/2014] [Indexed: 11/05/2022] Open
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ACTH-secreting neuroendocrine pancreatic tumor: A case report. Int J Surg 2014; 12 Suppl 1:S222-4. [DOI: 10.1016/j.ijsu.2014.05.035] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2014] [Accepted: 05/03/2014] [Indexed: 01/17/2023]
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Pulkkinen V, Ezer S, Sundman L, Hagström J, Remes S, Söderhäll C, Greco D, Dario G, Haglund C, Kere J, Arola J. Neuropeptide S receptor 1 (NPSR1) activates cancer-related pathways and is widely expressed in neuroendocrine tumors. Virchows Arch 2014; 465:173-83. [PMID: 24915894 PMCID: PMC4116602 DOI: 10.1007/s00428-014-1602-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Revised: 04/28/2014] [Accepted: 05/22/2014] [Indexed: 02/06/2023]
Abstract
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.
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Affiliation(s)
- V Pulkkinen
- Pulmonary Division, Department of Medicine, University of Helsinki, Helsinki, Finland
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Venkitaraman B, Karunanithi S, Kumar A, Khilnani GC, Kumar R. Role of 68Ga-DOTATOC PET/CT in initial evaluation of patients with suspected bronchopulmonary carcinoid. Eur J Nucl Med Mol Imaging 2014; 41:856-64. [PMID: 24435773 DOI: 10.1007/s00259-013-2659-5] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Accepted: 11/28/2013] [Indexed: 11/28/2022]
Abstract
PURPOSE The objective of this study was to evaluate the role of (68)Ga-DOTATOC positron emission tomography (PET)/CT scan in patients with suspected pulmonary carcinoid tumour and to compare its results with (18)F-fluorodeoxyglucose (FDG) PET/CT scan. METHODS In this prospective study, 32 patients (age 34.22 ± 12.03 years; 53.1 % female) with clinical suspicion of bronchopulmonary carcinoid were evaluated with (68)Ga-DOTATOC PET/CT and (18)F-FDG PET/CT. The two imaging modalities were compared, considering the tissue diagnosis as the reference standard. RESULTS Based on the reference standard 26 cases were carcinoid tumours [21 typical carcinoids (TC) and 5 atypical carcinoids (AC)] and 6 cases were non-carcinoid tumours. The sensitivity, specificity and accuracy of (68)Ga-DOTATOC PET/CT in the diagnosis of pulmonary carcinoid tumour were 96.15, 100 and 96.87 % respectively, whereas those of (18)F-FDG PET/CT were 78.26, 11.1 and 59.37 % respectively. The maximum standardised uptake value (SUV max) of TC on (68)Ga-DOTATOC PET/CT scan ranged from 3.58 to 55, while that of AC ranged from 1.1 to 32.5. (18)F-FDG PET/CT was true-positive in all cases of AC and false-negative in eight cases of TC (sensitivity for TC 61.9 % and for AC 100 %). CONCLUSION (68)Ga-DOTATOC PET/CT is a useful imaging investigation for the evaluation of pulmonary carcinoids. (18)F-FDG PET/CT scan suffers from low sensitivity and specificity in differentiating the pulmonary carcinoids from other tumours.
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Schillaci O. 18F-DOPA and Other Radiopharmaceuticals for Imaging Unknown Primary Neuroendocrine Tumors. J Nucl Med 2014; 55:357-9. [DOI: 10.2967/jnumed.113.133116] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
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Jedrych J, Busam K, Klimstra DS, Pulitzer M. Cutaneous metastases as an initial manifestation of visceral well-differentiated neuroendocrine tumor: a report of four cases and a review of literature. J Cutan Pathol 2013; 41:113-22. [PMID: 24218988 DOI: 10.1111/cup.12263] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2013] [Revised: 10/21/2013] [Accepted: 11/03/2013] [Indexed: 12/28/2022]
Abstract
Well-differentiated neuroendocrine tumors metastasize to the skin uncommonly, and only 35 cases are reported in the literature. In only five of these patients, cutaneous metastases were the presenting symptom of malignancy; herein, we report four such cases. Two patients were female and two male, aged 50-74 years (mean: 64.5 years), each with a solitary painless, slowly enlarging, non-ulcerated cutaneous nodule of 3-12 months duration (mean: 9 months). The lesions were on the scalp (n = 3) and trunk (n = 1), and ranged in greatest dimension from 0.5 to 2.5 cm. The distinction from other microscopically similar entities, and the interpretation of origination from gastrointestinal, pancreatic or respiratory system primaries, was made clinically, or was based on the morphological features and the immunohistochemical profile. One patient died of the disease progression after 36 months whereas two patients are alive with significant disease progression after 24 and 60 months. Metastatic neuroendocrine tumor should be considered in the differential diagnosis of cutaneous tumors with neuroendocrine morphology even in patients with no known history of visceral malignancy.
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Affiliation(s)
- Jaroslaw Jedrych
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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46
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Primary large cell neuroendocrine carcinoma of the renal pelvis: a case report. Urologia 2013; 81:57-9. [PMID: 24474544 DOI: 10.5301/urologia.5000033] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/29/2013] [Indexed: 11/20/2022]
Abstract
We report a case of primary large cell neuroendocrine carcinoma of the renal pelvis, diagnosed in a 79-year-old man. The abdominal computed tomography showed a solid, vegetant lesion in the left renal pelvis, conditioning marked hydronephrosis. The patient underwent radical nephroureterectomy. The histological examination showed a large cell neuroendocrine carcinoma associated with a high-grade urothelial carcinoma, with local invasion (pT3). Large cell renal neuroendocrine carcinomas are rare tumors with an aggressive course and a bad prognosis. At present, only five cases were reported in literature.
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Chemometric evaluation of urinary steroid hormone levels as potential biomarkers of neuroendocrine tumors. Molecules 2013; 18:12857-76. [PMID: 24135941 PMCID: PMC6269673 DOI: 10.3390/molecules181012857] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 09/25/2013] [Accepted: 10/10/2013] [Indexed: 01/08/2023] Open
Abstract
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.
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Herbach N, Nagel L, Zwick T, Hermanns W. Multiple Glucagon-Producing Pancreatic Neuroendocrine Tumors in a Horse (Equus caballus). Vet Pathol 2013; 51:607-11. [DOI: 10.1177/0300985813492803] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Pancreatic neuroendocrine tumors of glucagon-producing cells are extremely rare in domestic animals. In this report, we describe for the first time, to our knowledge, the incidental finding of multiple glucagon-producing neuroendocrine tumors of the pancreas of a horse. The animal was euthanized due to severe local infection after tooth extraction. On postmortem examination, multiple white nodules of up to 4 cm in diameter were observed in the pancreas. Histologically, pancreatic nodules had the appearance of neuroendocrine neoplasms with positive immunoreactivity for glucagon, synaptophysin, chromogranin A, and neuron-specific enolase. Electron microscopy revealed numerous electron-dense granules, similar to those observed in normal pancreatic alpha cells, in the neoplastic cells. In addition, the left adrenal gland showed multiple hyperplastic foci and adenomas in the medulla that were identified as pheochromocytomas. Based on the morphologic appearance and immunohistochemical staining pattern of pancreatic nodules, a diagnosis of multiple glucagon-producing neuroendocrine tumors was made.
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Affiliation(s)
- N. Herbach
- Institute of Veterinary Pathology, Center for Clinical Veterinary Medicine, Ludwig-Maximilians-University, Munich, Germany
| | - L. Nagel
- Institute of Veterinary Pathology, Center for Clinical Veterinary Medicine, Ludwig-Maximilians-University, Munich, Germany
| | - T. Zwick
- Veterinary Clinic Gessertshausen, Gessertshausen, Germany
| | - W. Hermanns
- Institute of Veterinary Pathology, Center for Clinical Veterinary Medicine, Ludwig-Maximilians-University, Munich, Germany
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Pancreatic neuroendocrine tumor with cystlike changes: evaluation with MDCT. AJR Am J Roentgenol 2013; 200:W283-90. [PMID: 23436873 DOI: 10.2214/ajr.12.8941] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE The objective of our study was to determine the prevalence and CT appearance of cystlike changes of pancreatic neuroendocrine tumor (NET), particularly of small (≤ 3 cm) tumors. MATERIALS AND METHODS The clinical records, images, and pathologic reports of 74 consecutive patients (average age, 55.5 years) with surgically resected pancreatic NETs who underwent preoperative CT were retrospectively reviewed. The size and location of the pancreatic NETs were recorded. The tumors were classified on the basis of CT appearance as small (≤ 3 cm) or large (> 3 cm) and as solid, partially (≤ 50% or > 50%) cystic, or purely (≈ 100%) cystic. Peripheral contrast enhancement on CT was characterized, and lymph node and liver metastases found by pathologic examination were recorded. RESULTS A total of 78 pancreatic NETs were reviewed. Five were not visualized on CT, leaving 73 pancreatic NETs in 69 patients (multiple tumors were visualized on CT of three patients) for analysis. The mean size of the 73 tumors was 3.0 ± 2.6 (SD) cm (range, 0.7-13.1 cm); 52 tumors were 3 cm or smaller and 21 tumors were larger than 3 cm. Gross pathologic results confirmed that 13 of the 73 (17.8%) tumors were predominantly (> 50% or ≈ 100%) cystic: 10 of the 52 (19.2%) tumors 3 cm or smaller and three of the 21 (14.3%) tumors larger than 3 cm. Peripheral contrast enhancement was seen in 11 of the 13 (85%) predominantly cystic pancreatic NETs. Compared with solid pancreatic NETs, predominantly cystic pancreatic NETs were less commonly associated with lymph node and liver metastases. CONCLUSION Cystic pancreatic NETs are not rare and should be included in the differential diagnosis of a cystic pancreatic mass, particularly if the cystic mass is associated with peripheral contrast enhancement. A minority of cystic pancreatic NETs can present with no peripheral enhancement.
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Incidental neuroendocrine tumors of the pancreas: MDCT findings and features of malignancy. AJR Am J Roentgenol 2013; 200:355-62. [PMID: 23345357 DOI: 10.2214/ajr.11.8037] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE The objective of our study was to evaluate the MDCT features of incidentally detected neuroendocrine tumors (NETs) of the pancreas, identify features that can predict tumor biology or aggressiveness and long-term outcome, and determine the incidence of "nonbenign" behavior. MATERIALS AND METHODS In this retrospective study, 60 histologically verified pancreatic NETs incidentally detected with contrast-enhanced MDCT were included. Various MDCT features such as size, morphology, enhancement, and presence of calcifications were evaluated and were correlated with tumor biology on histopathology. The sensitivity, specificity, predictive values, and accuracy were calculated for MDCT features in predicting nonbenign biology and risk of recurrence. RESULTS A total of 32 of 60 (53%) NETs were nonbenign: most were large (mean, 29.1 mm) with a solid or complex pattern. NET size of 3 cm or larger yielded a positive predictive value of 61% for nonbenign tumors and 100% when calcification was present. In 12 patients with recurrence, 92% of NETs were nonbenign. The presence of calcification, local invasion, main pancreatic duct dilatation, vascular invasion, and lymph node enlargement along with angioinvasion and a Ki-67 index greater than 2% on histology were associated with a nonbenign diagnosis and a higher risk of recurrence. CONCLUSION Approximately 50% of incidental NETs show uncertain or malignant behavior. Solid tumors 3 cm or larger are commonly nonbenign; however, about 30% of tumors smaller than that size cutoff can be malignant. Nonbenign tumors and those with invasive features on MDCT have a higher incidence of recurrence.
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