1
|
Clement DSVM, van Leerdam ME, Tesselaar MET, Srinivasan P, Menon K, Kuhlmann K, den Hartog A, Giovos G, Weickert MO, Srirajaskanthan R. High Prevalence of Sarcopenia in Patients with Newly Diagnosed Gastroenteropancreatic Neuroendocrine Tumours (GEP-NETs), but No Association with the Risk of Surgical Complications. Nutrients 2024; 16:3790. [PMID: 39599579 PMCID: PMC11597585 DOI: 10.3390/nu16223790] [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] [Received: 09/25/2024] [Revised: 10/22/2024] [Accepted: 10/29/2024] [Indexed: 11/29/2024] Open
Abstract
Background: Sarcopenia is a muscle disease that occur across a lifetime. It is commonly described in the aging population but can occur earlier in life in patients with cancer. Previous studies demonstrated sarcopenia is highly prevalent in patients with gastroenteropancreatic neuroendocrine tumours (GEP-NETs). In solid organ cancers, such as colorectal or pancreatic cancer, the presence of sarcopenia is associated with surgical complications. It is unknown if sarcopenia in patients with GEP-NETs is a risk factor for surgical complications. Methods: A multicentre retrospective study was performed in patients with a recently diagnosed GEP-NET and surgery to the primary tumour. CT scans were analysed for body composition analyses to assess for the presence of sarcopenia. Data regarding surgical procedures and complications were collected. Any major surgical complication was considered as Clavien-Dindo score ≥ 3. Results: This study included 180 patients, with 83 being male (46%) with a median age of 62 years (IQR 54-69). Most patients (n = 138, 77%) had a small intestinal NET, while 36 patients (20%) had pancreatic NETs. Sarcopenia was present in 109 patients (61%). In 43 patients (24%), surgical complications were recorded, and 21 complications (49%) were considered as major. Any type of surgical complication was not statistically different between patients without sarcopenia (n = 17, 24%) and with sarcopenia (n = 26, 24%)-a p-value of 0.36. This was the same for major complications; between patients without sarcopenia (n = 5, 24%) and with sarcopenia (n = 16, 76%)-a p-value of 0.18. Conclusions: Sarcopenia is highly prevalent in patients with a recently diagnosed GEP-NET, but this is not associated with major surgical complications. Future studies should include pathophysiological mechanisms that could be used to identify the causes of sarcopenia, its effect on quality of life and other oncological outcomes.
Collapse
Affiliation(s)
- Dominique S. V. M. Clement
- Kings Health Partners, ENETS Centre of Excellence, Institute of Liver Studies, King’s College Hospital, London SE5 9RS, UK
- Department of Gastroenterology, King’s College Hospital, London SE5 9RS, UK
| | - Monique E. van Leerdam
- Department of Gastrointestinal Oncology, Netherlands Cancer Institute, ENETS Centre of Excellence, 1066 CX Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Margot E. T. Tesselaar
- Department of Gastrointestinal Oncology, Netherlands Cancer Institute, ENETS Centre of Excellence, 1066 CX Amsterdam, The Netherlands
| | - Parthi Srinivasan
- Kings Health Partners, ENETS Centre of Excellence, Institute of Liver Studies, King’s College Hospital, London SE5 9RS, UK
- Department of Hepatopancreaticobiliairy Surgery, King’s College Hospital, London SE5 9RS, UK
| | - Krishna Menon
- Kings Health Partners, ENETS Centre of Excellence, Institute of Liver Studies, King’s College Hospital, London SE5 9RS, UK
- Department of Hepatopancreaticobiliairy Surgery, King’s College Hospital, London SE5 9RS, UK
| | - Koert Kuhlmann
- Department of Gastrointestinal Surgery, Netherlands Cancer Institute, ENETS Centre of Excellence, 1066 CX Amsterdam, The Netherlands
| | - Anne den Hartog
- Department of Gastrointestinal Surgery, Netherlands Cancer Institute, ENETS Centre of Excellence, 1066 CX Amsterdam, The Netherlands
| | - George Giovos
- The ARDEN NET Centre, ENETS Centre of Excellence, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK; (G.G.)
| | - Martin O. Weickert
- The ARDEN NET Centre, ENETS Centre of Excellence, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK; (G.G.)
| | - Rajaventhan Srirajaskanthan
- Kings Health Partners, ENETS Centre of Excellence, Institute of Liver Studies, King’s College Hospital, London SE5 9RS, UK
| |
Collapse
|
2
|
Stefàno E, De Castro F, Ciccarese A, Muscella A, Marsigliante S, Benedetti M, Fanizzi FP. An Overview of Altered Pathways Associated with Sensitivity to Platinum-Based Chemotherapy in Neuroendocrine Tumors: Strengths and Prospects. Int J Mol Sci 2024; 25:8568. [PMID: 39201255 PMCID: PMC11354135 DOI: 10.3390/ijms25168568] [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] [Received: 05/30/2024] [Revised: 07/26/2024] [Accepted: 08/02/2024] [Indexed: 09/02/2024] Open
Abstract
Neuroendocrine neoplasms (NENs) are a diverse group of malignancies with a shared phenotype but varying prognosis and response to current treatments. Based on their morphological features and rate of proliferation, NENs can be classified into two main groups with a distinct clinical behavior and response to treatment: (i) well-differentiated neuroendocrine tumors (NETs) or carcinoids (with a low proliferation rate), and (ii) poorly differentiated small- or large-cell neuroendocrine carcinomas (NECs) (with a high proliferation rate). For certain NENs (such as pancreatic tumors, higher-grade tumors, and those with DNA damage repair defects), chemotherapy is the main therapeutic approach. Among the different chemotherapic agents, cisplatin and carboplatin, in combination with etoposide, have shown the greatest efficacy in treating NECs compared to NETs. The cytotoxic effects of cisplatin and carboplatin are primarily due to their binding to DNA, which interferes with normal DNA transcription and/or replication. Consistent with this, NECs, which often have mutations in pathways involved in DNA repair (such as Rb, MDM2, BRCA, and PTEN), have a high response to platinum-based chemotherapy. Identifying mutations that affect molecular pathways involved in the initiation and progression of NENs can be crucial in predicting the response to platinum chemotherapy. This review aims to highlight targetable mutations that could serve as predictors of therapeutic response to platinum-based chemotherapy in NENs.
Collapse
Affiliation(s)
| | | | | | | | | | - Michele Benedetti
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Via Monteroni, I-73100 Lecce, Italy; (E.S.); (F.D.C.); (A.C.); (A.M.); (S.M.); (F.P.F.)
| | | |
Collapse
|
3
|
Komiyama S, Okusaka T, Maruki Y, Ohba A, Nagashio Y, Kondo S, Hijioka S, Morizane C, Ueno H, Sukeda A, Mizui T, Takamoto T, Nara S, Ban D, Esaki M, Hiraoka N, Shimada K. Clinicopathological Findings and Treatment Outcomes of Patients with Primary Hepatobiliary Neuroendocrine Neoplasms: A Retrospective Single-institution Analysis. Intern Med 2024; 63:891-901. [PMID: 37612088 PMCID: PMC11045373 DOI: 10.2169/internalmedicine.2016-23] [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: 03/31/2023] [Accepted: 07/11/2023] [Indexed: 08/25/2023] Open
Abstract
Objective Primary hepatobiliary neuroendocrine neoplasms (NENs) are rare tumors exhibiting several morphological and behavioral characteristics. Considering the lack of relevant data on this topic, we evaluated the clinicopathological features and treatment outcomes of patients with primary hepatobiliary NENs. Methods/Patients We examined 43 consecutive patients treated at the National Cancer Center Hospital with pathological diagnoses of primary hepatobiliary NEN between 1980 and 2016. Results Nine patients were diagnosed with neuroendocrine tumor (NET) G1, 9 with NET G2, and 25 with neuroendocrine carcinoma (NEC) based on the World Health Organization 2019 classification. Patients with NEC had primary sites across the hepatobiliary organs, although sites in patients with NET G1 and NET G2 only included the liver and ampulla of Vater. Patients with primary extrahepatic bile duct or ampulla of Vater NENs tended to be diagnosed earlier than patients with primary gallbladder NENs. The median survival times in the NET G1, NET G2, and NEC groups were 167.9, 97.4, and 11.1 months, respectively. A good performance status, absence of distant metastases, and low tumor grade were identified as independent predictors of a favorable prognosis. Conclusion The NET-to-NEC ratio and tumor stage distribution at the diagnosis differed depending on the primary site. Patients with G1 and G2 NETs who underwent surgical resection had good prognoses, whereas those with NEC exhibited more advanced disease and poorer prognoses. The performance status, staging classification, and tumor grade are important factors to consider when devising an appropriate treatment strategy and predicting the prognoses of patients with primary hepatobiliary NEN.
Collapse
Affiliation(s)
- Satoshi Komiyama
- Chemotherapy Department, Yokohama City University Medical Center, Japan
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Yuta Maruki
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Akihiro Ohba
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Yoshikuni Nagashio
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Shunsuke Kondo
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Susumu Hijioka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Chigusa Morizane
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Hideki Ueno
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Aoi Sukeda
- Pathology and Clinical Laboratories, National Cancer Center Hospital, Japan
- Department of Anatomic Pathology, Tokyo Medical University, Japan
| | - Takahiro Mizui
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
| | - Takeshi Takamoto
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
| | - Satoshi Nara
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
| | - Daisuke Ban
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
| | - Minoru Esaki
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
| | - Nobuyoshi Hiraoka
- Pathology and Clinical Laboratories, National Cancer Center Hospital, Japan
| | - Kazuaki Shimada
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
| |
Collapse
|
4
|
Clement DSVM, van Leerdam ME, Tesselaar MET, Cananea E, Martin W, Weickert MO, Sarker D, Ramage JK, Srirajaskanthan R. The global leadership into malnutrition criteria reveals a high percentage of malnutrition which influences overall survival in patients with gastroenteropancreatic neuroendocrine tumours. J Neuroendocrinol 2024; 36:e13376. [PMID: 38389192 DOI: 10.1111/jne.13376] [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: 02/07/2023] [Revised: 01/23/2024] [Accepted: 02/07/2024] [Indexed: 02/24/2024]
Abstract
Patients with neuroendocrine tumours located in the gastroenteropancreatic tract (GEP-NETs) and treatment with somatostatin analogues (SSA's) are at risk of malnutrition which has been reported previously evaluating weight loss or body mass index (BMI) only. The global leadership into malnutrition (GLIM) criteria include weight loss, BMI, and sarcopenia, for diagnosing malnutrition. These GLIM criteria have not been assessed in patients with GEP-NETs on SSA. The effect of malnutrition on overall survival has not been explored before. The aim of this study is to describe the presence of malnutrition in patients with GEP-NET on SSA based on the GLIM criteria and associate this with overall survival. Cross-sectional study screening all patients with GEP-NETs on SSA's for malnutrition using the GLIM criteria. Body composition analysis for sarcopenia diagnosis were performed. Bloods including vitamins, minerals, and lipid profile were collected. Overall survival since the date of nutrition screening was calculated. Uni- and multivariate Cox regression analysis were performed to identify malnutrition as risk factor for overall survival. A total of 118 patients, 47% male, with median age 67 years (IQR 56.8-75.0) were included. Overall, malnutrition was present in 88 patients (75%); based on low BMI in 26 (22%) patients, based on weight loss in 35 (30%) patients, and based on sarcopenia in 83 (70%) patients. Vitamin deficiencies were present for vitamin D in 64 patients (54%), and vitamin A in 29 patients (25%). The presence of malnutrition demonstrated a significantly worse overall survival (p-value = .01). In multivariate analysis meeting 2 or 3 GLIM criteria was significantly associated with worse overall survival (HR 2.16 95% CI 1.34-3.48, p-value = .002). Weight loss was the most important risk factor out of the 3 GLIM criteria (HR 3.5 95% CI 1.14-10.85, p-value = .03) for worse overall survival. A high percentage (75%) of patients with GEP-NETs using a SSA meet the GLIM criteria for malnutrition. Meeting more than 1 GLIM criterium, especially if there is weight loss these are risk factors for worse overall survival.
Collapse
Affiliation(s)
- Dominique S V M Clement
- Kings Health Partners, ENETS Centre of Excellence, Institute of Liver Studies, King's College Hospital London, London, UK
- Department of Gastroenterology, King's College Hospital, London, UK
| | - Monique E van Leerdam
- Department of Gastrointestinal Oncology, Netherlands Cancer Institute, ENETS Centre of Excellence, Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Margot E T Tesselaar
- Department of Gastrointestinal Oncology, Netherlands Cancer Institute, ENETS Centre of Excellence, Amsterdam, The Netherlands
| | - Elmie Cananea
- Kings Health Partners, ENETS Centre of Excellence, Institute of Liver Studies, King's College Hospital London, London, UK
| | - Wendy Martin
- Kings Health Partners, ENETS Centre of Excellence, Institute of Liver Studies, King's College Hospital London, London, UK
| | - Martin O Weickert
- The ARDEN NET Centre, ENETS Centre of Excellence, University Hospitals Coventry & Warwickshire NHS Trust, Coventry, UK
| | - Debashis Sarker
- Department Medical Oncology, Guy's and St. Thomas Hospital, London, UK
| | - John K Ramage
- Kings Health Partners, ENETS Centre of Excellence, Institute of Liver Studies, King's College Hospital London, London, UK
| | - Rajaventhan Srirajaskanthan
- Kings Health Partners, ENETS Centre of Excellence, Institute of Liver Studies, King's College Hospital London, London, UK
- Department of Gastroenterology, King's College Hospital, London, UK
| |
Collapse
|
5
|
Bulj N, Tomasic V, Cigrovski Berkovic M. Managing end-stage carcinoid heart disease: A case report and literature review. World J Gastrointest Oncol 2024; 16:1076-1083. [PMID: 38577438 PMCID: PMC10989396 DOI: 10.4251/wjgo.v16.i3.1076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 12/26/2023] [Accepted: 01/24/2024] [Indexed: 03/12/2024] Open
Abstract
BACKGROUND Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare tumors, often diagnosed in an advanced stage when curative treatment is impossible and grueling symptoms related to vasoactive substance release by tumor cells affect patients' quality of life. Cardiovascular complications of GEP-NENs, primarily tricuspid and pulmonary valve disease, and right-sided heart failure, are the leading cause of death, even compared to metastatic disease. CASE SUMMARY We present a case of a 35-year-old patient with progressive dyspnea, back pain, polyneuropathic leg pain, and nocturnal diarrhea lasting for a decade before the diagnosis of neuroendocrine carcinoma of unknown primary with extensive liver metastases. During the initial presentation, serum biomarkers were not evaluated, and the patient received five cycles of doxorubicin, which he did not tolerate well, so he refused further therapy and was lost to follow-up. After 10 years, he presented to the emergency room with signs and symptoms of right-sided heart failure. Panneuroendocrine markers, serum chromogranin A, and urinary 5-hydroxyindoleacetic acid were extremely elevated (900 ng/mL and 2178 µmol/L), and transabdominal ultrasound confirmed hepatic metastases. Computed tomography (CT) showed liver metastases up to 6 cm in diameter and metastases in mesenteric lymph nodes and pelvis. Furthermore, an Octreoscan showed lesions in the heart, thoracic spine, duodenum, and ascendent colon. A standard transthoracic echocardiogram confirmed findings of carcinoid heart disease. The patient was not a candidate for valve replacement. He started octreotide acetate treatment, and the dose escalated to 80 mg IM monthly. Although biochemical response and symptomatic improvement were noted, the patient died. CONCLUSION Carcinoid heart disease occurs with carcinoid syndrome related to advanced neuroendocrine tumors, usually with liver metastases, which manifests as right-sided heart valve dysfunction leading to right-sided heart failure. Carcinoid heart disease and tumor burden are major prognostic factors of poor survival. Therefore, they must be actively sought by available biochemical markers and imaging techniques. Moreover, imaging techniques aiding tumor detection and staging, somatostatin receptor positron emission tomography/CT, and CT or magnetic resonance imaging, should be performed at the time of diagnosis and in 3- to 6-mo intervals to determine tumor growth rate and assess the possibility of locoregional therapy and/or palliative surgery. Valve replacement at the onset of symptoms or right ventricular dysfunction may be considered, while any delay can worsen right-sided ventricular failure.
Collapse
Affiliation(s)
- Nikola Bulj
- Department of Cardiology, University Hospital Centre “Sestre Milosrdnice,“ Zagreb 10000, Croatia
| | - Vedran Tomasic
- Division of Gastroenterology, Department of Internal Medicine, University Hospital Centre “Sestre Milosrdnice,” Zagreb 10000, Croatia
| | - Maja Cigrovski Berkovic
- Department for Sport and Exercise Medicine, University of Zagreb Faculty of Kinesiology, Zagreb 10000, Croatia
| |
Collapse
|
6
|
Alfagih A, AlJassim A, Alqahtani N, Vickers M, Goodwin R, Asmis T. Small Bowel Neuroendocrine Tumors-10-Year Experience of the Ottawa Hospital (TOH). Curr Oncol 2023; 30:7508-7519. [PMID: 37623025 PMCID: PMC10453717 DOI: 10.3390/curroncol30080544] [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] [Received: 06/16/2023] [Revised: 08/04/2023] [Accepted: 08/07/2023] [Indexed: 08/26/2023] Open
Abstract
(1) Aim: The prevalence and incidence of small bowel NETs have increased significantly over the past two decades. This study aims to report the 10-year experience of SB-NET management at a regional cancer center in Canada. (2) Materials and methods: We conducted a retrospective study of the clinical and pathological data of patients diagnosed with biopsy-proven SB-NET at The Ottawa Hospital (TOH), Ottawa, Canada between 2011 and 2021. We report the clinicopathological characteristics of these patients, as well as their outcomes data, including survival rates. (3) Results: Between 2011 and 2021, a total of 177 SB-NET cases were identified with 51% (n = 91) of cases being males. The most common sites of the tumors were the ileum 53% (n = 94), followed by the duodenum 9% (n = 16) and jejunum 7% (n = 12). Approximately 24% (n = 42) of the patients had symptoms for over six months prior to diagnosis and 18% (n = 32) had functioning SB-NET during the course of the disease. The majority of patients had locally advanced or metastatic disease at the time of presentation with stage III, and stage IV representing 42% (n = 75), and 41% (n = 73) respectively. The majority of patients 84% (n = 148) had well-differentiated histology. One hundred twenty patients underwent surgical resection of the primary tumor including 28 patients (16%) with limited metastatic disease. A total of 21 patients (18%) had recurrence after curative surgery. A total of 62 patients (35%) received first-line somatostatin analog (SSA) therapy for unresectable disease and seven patients had PRRT after progression on SSA. Five years OS was 100%, 91%, 97%, and 73% for stages I, II, III, and IV respectively. In univariate analysis, carcinoid symptoms, T stage, and differentiation were significant predictors for worse overall survival, but not RFS. (4) Conclusions: Compared to published historical controls, our study suggests improvement in the 5-year survival rate of SB-NETs over the last 10 years.
Collapse
Affiliation(s)
- Abdulhameed Alfagih
- Division of Medical Oncology, Department of Medicine, The Ottawa Hospital, The University of Ottawa, Ottawa, ON K1N 6N5, Canada; (A.A.); (A.A.); (N.A.); (M.V.); (R.G.)
- Medical Oncology Department, Comprehensive Cancer Center, King Fahad Medical City, Riyadh 11525, Saudi Arabia
| | - Abdulaziz AlJassim
- Division of Medical Oncology, Department of Medicine, The Ottawa Hospital, The University of Ottawa, Ottawa, ON K1N 6N5, Canada; (A.A.); (A.A.); (N.A.); (M.V.); (R.G.)
- Kuwait Cancer Control Center, Kuwait City 42262, Kuwait
| | - Nasser Alqahtani
- Division of Medical Oncology, Department of Medicine, The Ottawa Hospital, The University of Ottawa, Ottawa, ON K1N 6N5, Canada; (A.A.); (A.A.); (N.A.); (M.V.); (R.G.)
- King Abdulaziz Hospital, Ministry of National Guard Health Affairs, Al Ahsa 11426, Saudi Arabia
| | - Michael Vickers
- Division of Medical Oncology, Department of Medicine, The Ottawa Hospital, The University of Ottawa, Ottawa, ON K1N 6N5, Canada; (A.A.); (A.A.); (N.A.); (M.V.); (R.G.)
| | - Rachel Goodwin
- Division of Medical Oncology, Department of Medicine, The Ottawa Hospital, The University of Ottawa, Ottawa, ON K1N 6N5, Canada; (A.A.); (A.A.); (N.A.); (M.V.); (R.G.)
| | - Timothy Asmis
- Division of Medical Oncology, Department of Medicine, The Ottawa Hospital, The University of Ottawa, Ottawa, ON K1N 6N5, Canada; (A.A.); (A.A.); (N.A.); (M.V.); (R.G.)
| |
Collapse
|
7
|
Grundmann E, Curioni-Fontecedro A, Christ E, Siebenhüner AR. Outcome of carcinoid heart syndrome in patients enrolled in the SwissNet cohort. BMC Cancer 2023; 23:338. [PMID: 37055717 PMCID: PMC10099832 DOI: 10.1186/s12885-023-10739-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 03/14/2023] [Indexed: 04/15/2023] Open
Abstract
BACKGROUND Carcinoid heart disease is a rare disease which develops in patients with functional neuroendocrine tumors in an advanced tumor state. Patients diagnosed with carcinoid heart disease have a poor longtime prognosis with respect to morbidity and mortality and long-term data on patient outcomes are lacking. METHODS AND RESULTS In this retrospective study, we analyzed outcomes of 23 patients with carcinoid heart disease enrolled into the SwissNet database. We observed that early diagnosis with echocardiographic surveillance of carcinoid heart disease during the course of the neuroendocrine tumor disease was beneficial to overall survival of patients. CONCLUSION Through nationwide patient enrollment, the SwissNet registry is a powerful data tool to identify, follow-up and evaluate long-term patient outcomes in patients with rare neuroendocrine tumor driven pathologies including carcinoid heart syndrome with observational methods enabling better therapy optimization to improve patient`s long-term perspectives and survival. In line with the current ESMO recommendations, our data proposes that heart echocardiography should be included as part of the general physical assessment in patients with newly diagnosed NET.
Collapse
Affiliation(s)
- Eva Grundmann
- Department of Medical Oncology and Hematology, University Hospital Zurich and University Zurich, Rämistrasse 100, Zurich, CH-8091, Switzerland
| | - Alessandra Curioni-Fontecedro
- Department of Medical Oncology and Hematology, University Hospital Zurich and University Zurich, Rämistrasse 100, Zurich, CH-8091, Switzerland
| | - Emanuel Christ
- Department of Endocrinology, Diabetes, and Metabolism, Basel University Hospital, University of Basel, Basel, Switzerland
| | - Alexander R Siebenhüner
- Department of Medical Oncology and Hematology, University Hospital Zurich and University Zurich, Rämistrasse 100, Zurich, CH-8091, Switzerland.
- Clinic of Medical Oncology and Hematology, Hirslanden Zurich AG, Witellikerstrasse 40, Zurich, CH-8032, Switzerland.
| |
Collapse
|
8
|
Prevalence of Sarcopenia and Impact on Survival in Patients with Metastatic Gastroenteropancreatic Neuroendocrine Tumours. Cancers (Basel) 2023; 15:cancers15030782. [PMID: 36765740 PMCID: PMC9913815 DOI: 10.3390/cancers15030782] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/17/2023] [Accepted: 01/23/2023] [Indexed: 01/31/2023] Open
Abstract
Sarcopenia in patients with cancer is associated with adverse outcomes such as shorter survival. However, there exists little evidence regarding the prevalence of sarcopenia in patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP-NETs). Patients with a histologically confirmed newly diagnosed metastatic GEP-NET between 2006 and 2018, CT scan, and anthropometric data at diagnosis were included in this study. CT scans were analysed for the presence of sarcopenia and correlated with overall survival (OS). In total, 183 patients, 87 male (48%), with a median age of 62 years (IQR 52-68 years), were included. In 44 patients (24%), there was a pancreas NET, and in 136 patients, there was a small bowel NET (74%). Sarcopenia was present in 128 patients (69%) and unrelated to BMI (median 25.1). There were significant survival differences between patients with pancreatic and small bowel NETs at 86 vs. 141 months, respectively (p = 0.04). For patients with pancreatic NETs, the presence of sarcopenia was independently associated with shorter OS (HR 3.79 95% CI 1.1-13.03, p-value 0.035). A high prevalence of sarcopenia at the time of diagnosis of a metastatic GEP-NET was seen and associated with worse OS in patients with pancreatic NETs. Further research should focus on how to reverse sarcopenia and its impact on OS and/or quality of life.
Collapse
|
9
|
Fayyaz F, Reardon MF, Byrne L. Insulinoma as a cause of seizure-like activity and spontaneous hypoglycaemia. BMJ Case Rep 2023; 16:e250799. [PMID: 36627134 PMCID: PMC9835887 DOI: 10.1136/bcr-2022-250799] [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] [Accepted: 12/16/2022] [Indexed: 01/11/2023] Open
Abstract
A woman in her 60s presented to our hospital with recurrent episodes of confusion and double vision with spontaneous recovery to baseline within 10 min. Her initial workup was unremarkable, and she was diagnosed with complex partial seizures and commenced on levetiracetam. The following week, she re-presented with a recurrence of her symptoms, associated with spontaneous hypoglycaemia, with blood glucose levels of 1.9 mmol/L. She was found to have endogenously elevated serum insulin and C peptide levels, which were concomitantly associated with hypoglycaemia. An initial diagnosis of insulinoma was made and she was commenced on diazoxide. MRI and endoscopic ultrasound revealed 16 mm insulinoma in her uncinate process. She underwent surgical resection and remained symptom free at follow-up. This case highlights the importance of blood glucose measurements in patients presenting with neuroglycopenic symptoms and outlines the workup and management of insulinoma.
Collapse
Affiliation(s)
- Fahd Fayyaz
- Medicine, Wexford General Hospital, Wexford, Ireland
| | | | - Luke Byrne
- Cardiology, Tallaght University Hospital, Dublin, Ireland
| |
Collapse
|
10
|
Jayasekera M, Sartin S, Bhargava P. Ga-68 DOTATATE PET/CT in a patient with Zollinger-Ellison syndrome. Radiol Case Rep 2023; 18:1046-1048. [PMID: 36684643 PMCID: PMC9849991 DOI: 10.1016/j.radcr.2022.12.038] [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: 09/26/2022] [Revised: 12/12/2022] [Accepted: 12/14/2022] [Indexed: 01/09/2023] Open
Abstract
This case report follows a 70-year-old male patient with Zollinger-Ellison syndrome undergoing computed tomography (CT) for weight loss and surveillance of bilateral adrenal nodules. Incidentally, diffuse gastric and duodenal wall thickening was noted on CT. The patient underwent esophagogastroduodenoscopy with biopsy results showing well-differentiated neuroendocrine tumors (NET) in the stomach and duodenum. Subsequent imaging with gallium-68 DOTATATE PET/CT showed intense tracer uptake in the stomach and proximal duodenum with liver and regional nodal metastases around the superior mesenteric artery. This case outlines the utility of Ga-68 DOTATATE PET/CT in diagnosing, localizing, and staging NET such as gastrinomas.
Collapse
|
11
|
177Lu-DOTATATE Efficacy and Safety in Functioning Neuroendocrine Tumors: A Joint Analysis of Phase II Prospective Clinical Trials. Cancers (Basel) 2022; 14:cancers14246022. [PMID: 36551507 PMCID: PMC9776442 DOI: 10.3390/cancers14246022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/31/2022] [Accepted: 11/25/2022] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Neuroendocrine tumors (NETs) are rare malignancies with different prognoses. At least 25% of metastatic patients have functioning neuroendocrine tumors (F-NETs) that secrete bioactive peptides, causing specific debilitating and occasionally life-threatening symptoms such as diarrhea and flushing. Somatostatin analogs (SSAs) are usually effective but beyond them few treatment options are available. We evaluated the clinical efficacy of 177 Lu-DOTATATE in patients with progressive metastatic F-NETs and SSA-refractory syndrome. PATIENTS AND METHODS A non-pre-planned joint analysis was conducted in patients enrolled in phase II clinical trials on metastatic NETs. We extrapolated data from F-NET patients with ≥1 refractory sign/symptom to octreotide, and ≥1 measurable lesion. Syndrome response (SR), overall survival (OS), progression-free survival (PFS), tolerance and disease response were analyzed. RESULTS Sixty-eight patients were enrolled, the majority (88.1%) with a SR. According to RECIST criteria, 1 (1.5%) patient showed a CR, 21 (32.3%) had a PR and 40 (61.5%) SD. At a median follow-up of 28.9 months (range 2.2-63.2) median PFS was 33.0 months (95%CI: 27.1-48.2). Median OS (mOS) had not been reached at the time of the analysis; the 2-year OS was 87.8% (95%CI: 76.1-94.1). Syndromic responders showed better survival than non-responders, with a 2-year OS of 93.9% (95%CI: 92.2-98.0) vs. 40.0% (95%CI: 6.6-73.4), respectively. A total of 233 adverse events were recorded. Grade 1-2 hematological toxicity was the most frequent. CONCLUSION The 177 Lu-DOTATATE improved symptoms and disease control in patients with F-NETs. Treatment was well tolerated. The syndrome had an impact on both quality of life and OS.
Collapse
|
12
|
Ehlken H, Younis F, Wolter S, Schrader J. Spannungsfeld endoskopische Resektionsverfahren bei GEP-NET // Endoscopic resection for GEP-NET. Zentralbl Chir 2022; 147:256-263. [PMID: 35705087 DOI: 10.1055/a-1829-7370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
ZusammenfassungNeuroendokrine Tumoren des Verdauungstraktes (GEP-NET) sind eine seltene Tumorentität, die häufig als Zufallsbefund diagnostiziert werden. Ein großer Teil dieser Zufallsdiagnosen wird im
Rahmen einer endoskopischen Untersuchung gestellt. Während die vollständige Entfernung des Tumors im Sinne einer kurativen chirurgischen Resektion nach onkologischen Kriterien das
Standardvorgehen für lokalisierte Tumorerkrankungen ist, kann bei kleinen Tumoren ohne Hinweis und Risiko für eine lymphogene Metastasierung eine endoskopische Abtragung in gleicher
Intention erfolgen. Während dies für Magen-, Duodenum- und Rektum-NET der Standard ist, sollten NET des Jejunums und Ileums aufgrund der hohen Metastasierungsrate trotz geringer Tumorgröße
regelhaft nicht endoskopisch angegangen werden. Die Grenze für eine endoskopische Resektion ergibt sich sowohl durch die technische Machbarkeit im Sinne des Erreichens einer R0-Resektion,
der erwarteten Komplikationen im Sinne von Blutung und Perforationen als auch durch das vermutete Risiko für eine lymphogene Metastasierung. Generell wird eine endoskopische Resektion bei
Befunden < 1 cm regelhaft empfohlen, da sowohl die gute technische Machbarkeit als auch das geringe Metastasierungsrisiko für eine endoskopische Resektion sprechen. Bei allen Befunden
über 2 cm Größe sind sowohl die technischen Erfolgsaussichten so niedrig als auch das Metastasierungsrisiko so hoch, dass in dieser Situation regelhaft ein chirurgisches Vorgehen erfolgen
sollte. Es bleibt somit ein Graubereich bei der Tumorgröße zwischen 1 und 2 cm, wo sowohl endoskopische, aber auch chirurgische Resektionsverfahren sinnvoll eingesetzt werden können.
Zunehmend kommen auch gemeinsame Eingriffe im Sinne eines endoskopisch-laparoskopischen Rendezvous-Verfahrens zum Einsatz – insbesondere im Duodenum bieten sich diese Eingriffe an, um eine
minimale Resektion mit größtmöglicher R0-Erfolgsrate und niedriger Perforationsrate zu erreichen.
Collapse
Affiliation(s)
- Hanno Ehlken
- Klinik und Poliklinik für interdisziplinäre Endoskopie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland
| | - Fadi Younis
- Klinik und Poliklinik für interdisziplinäre Endoskopie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland
| | - Stefan Wolter
- Klinik für Allgemein-, Viszeral und Thoraxchirurgie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland
| | - Jörg Schrader
- I. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland
| |
Collapse
|
13
|
Dai M, Mullins CS, Lu L, Alsfasser G, Linnebacher M. Recent advances in diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms. World J Gastrointest Surg 2022; 14:383-396. [PMID: 35734622 PMCID: PMC9160679 DOI: 10.4240/wjgs.v14.i5.383] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 01/17/2022] [Accepted: 04/28/2022] [Indexed: 02/06/2023] Open
Abstract
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a rare group of tumors originating from neuroendocrine cells of the digestive system. Their incidence has increased over the last decades. The specific pathogenetic mechanisms underlying GEP-NEN development have not been completely revealed. Unfunctional GEP-NENs are usually asymptomatic; some grow slowly and thus impede early diagnosis, which ultimately results in a high rate of misdiagnosis. Therefore, many GEP-NEN patients present with later staged tumors. Motivated hereby, research attention for diagnosis and treatment for GEP-NENs increased in recent years. The result of which is great progress in clinical diagnosis and treatment. According to the most recent clinical guidelines, improved grading standards can accurately define poorly differentiated grade 3 neuroendocrine tumors and neuroendocrine carcinomas (NECs), which are subclassified into large and small cell NECs. Combining different functional imaging methods facilitates precise diagnosis. The expression of somatostatin receptors helps to predict prognosis. Genetic analyses of mutations affecting death domain associated protein (DAXX), multiple endocrine neoplasia type 1 (MEN 1), alpha thalassemia/intellectual disability syndrome X-linked (ATRX), retinoblastoma transcriptional corepressor 1 (RB 1), and mothers against decapentaplegic homolog 4 (SMAD 4) help distinguishing grade 3 NENs from poorly differentiated NECs. The aim of this review is to summarize the latest research progress on diagnosis and treatment of GEP-NENs.
Collapse
Affiliation(s)
- Meng Dai
- Clinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany
| | - Christina S Mullins
- Clinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany
| | - Lili Lu
- Clinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany
| | - Guido Alsfasser
- Clinic of General Surgery, Rostock University Medical Center, 18057 Rostock, Germany
| | - Michael Linnebacher
- Clinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany
| |
Collapse
|
14
|
[Surgery of pancreatic neuroendocrine neoplasms: state of the art]. Chirurg 2022; 93:745-750. [PMID: 35499762 DOI: 10.1007/s00104-022-01641-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/04/2022] [Indexed: 10/18/2022]
Abstract
Pancreatic neuroendocrine neoplasms (pNEN) have a rising incidence and are increasingly diagnosed at early and thus potentially resectable stages. Due to the rarity of these neoplasms the recommendations of currently available guidelines are mainly based on retrospective data. Surgical and oncological treatment of these rare diseases should only be performed at specialized centers. In cases of resectability without indications of diffuse metastases, complete resection with curative intent should be the treatment of choice. For small nonfunctional pNENs < 2 cm watch and wait strategies are recommended as an alternative to surgical treatment. Recent data, however, also showed an increased survival even of small (1-2 cm) pNENs after resection. For benign insulinomas and small nonfunctional well-differentiated pNENs parenchyma-sparing procedures, such as enucleation and segmental resection are available. The question of the influence of lymph node metastases on long-term disease-free survival and overall survival and consequently the role of systematic lymphadenectomy is still a matter of debate. In pNENs > 2 cm formal resection with lymphadenectomy is considered the gold standard. Minimally invasive and robotic-assisted procedures are of increasing importance also for formal pancreatic resection.
Collapse
|
15
|
Zhou J, Zhao R, Pan Y, Ju H, Huang X, Jiang Y, Jin J, Zhang Y. The Diagnostic and Grading Accuracy of 68Ga-DOTATATE and 18F-FDG PET/MR for Pancreatic Neuroendocrine Neoplasms. Front Oncol 2022; 12:796391. [PMID: 35273910 PMCID: PMC8901996 DOI: 10.3389/fonc.2022.796391] [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: 10/16/2021] [Accepted: 01/25/2022] [Indexed: 11/13/2022] Open
Abstract
Accurate diagnosis and grading are critical for pancreatic neuroendocrine neoplasm (pNEN) management. This study compares the diagnostic and grading value of 68Ga-DOTATATE PET/MR and 18F-FDG PET/MR for pNENs separately as well as in combination. A total of 36 patients with histologically confirmed pNENs, who underwent both 68Ga-DOTATATE PET/MR and 18F-FDG PET/MR within 2 weeks from 2020 to 2021, were retrospectively collected and analyzed. The maximum standardized uptake values of 68Ga-DOTATATE (G-SUVmax) and 18F-FDG (F-SUVmax) on PET and the minimum values of apparent diffusion coefficient (ADCmin) on MR were measured on the lesions with known histological grading (25 by surgery, 11 by biopsy). Receiver-operating characteristic analysis was applied to determine the cutoffs of these parameters or their combinations for differentiation between G1 and G2, as well as between low-grade and high-grade pNENs. The Spearman rank correlation coefficient was used to assess the correlation between the imaging parameters and the maximum tumor diameters. The detection rate of 68Ga-DOTATATE PET imaging alone was 95%, 87.5%, and 37.5% for G1, G2, and G3, respectively. Adding 18F-FDG PET or MR sequences of PET/MR increased the detection rate to 100% in all grades. Among the three parameters, G-SUVmax had the highest diagnostic rate in predicting tumor grade. It presented a sensitivity of 87.5% and a specificity of 80.0% with a cutoff value of 42.75 for differentiating G2 from G1 pNETs and a sensitivity and specificity of 100% and 71.4% with a cutoff value of 32.75 in predicting high-grade pNENs. The ratio of G-SUVmax to F-SUVmax (G-SUVmax/F-SUVmax) showed slight improvement in the diagnostic rate, while the product of G-SUVmax and ADCmin (G-SUVmax*ADCmin) did not improve the diagnostic rate. 68Ga-DOTATATE PET/MR alone is sufficient for the diagnosis of pNENs and the prediction of various grades.
Collapse
Affiliation(s)
- Jinxin Zhou
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Runze Zhao
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu Pan
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huijun Ju
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinyun Huang
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu Jiang
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiabin Jin
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yifan Zhang
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
16
|
Mettler E, Fottner C, Bakhshandeh N, Trenkler A, Kuchen R, Weber MM. Quantitative Analysis of Plasma Cell-Free DNA and Its DNA Integrity and Hypomethylation Status as Biomarkers for Tumor Burden and Disease Progression in Patients with Metastatic Neuroendocrine Neoplasias. Cancers (Basel) 2022; 14:cancers14041025. [PMID: 35205773 PMCID: PMC8870292 DOI: 10.3390/cancers14041025] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/11/2022] [Accepted: 02/15/2022] [Indexed: 01/05/2023] Open
Abstract
Simple Summary Neuroendocrine neoplasias (NEN) are a heterogeneous group of frequent slow-progressing malignant tumors for which a reliable marker for tumor relapse and progression is still lacking. Previously, circulating cell-free DNA and its global methylation status and fragmentation rate have been proposed to be valuable prognostic tumor markers in a variety of malignancies. In the current study, we compared plasma cell-free DNA (cfDNA) properties of NEN patients with a healthy control group and a group of surgically cured patients. Our results revealed significantly higher plasma cfDNA concentrations with increased fragmentation and hypomethylation in patients with advanced metastatic NEN, which was strongly associated with tumor load and could help to differentiate between metastasized disease and presumably cured patients. This suggests that the combined analysis of plasma cfDNA characteristics is a potent and sensitive prognostic and therapeutic biomarker for tumor burden and disease progression in patients with neuroendocrine neoplasias. Abstract Background: Neuroendocrine neoplasia (NEN) encompasses a diverse group of malignancies marked by histological heterogeneity and highly variable clinical outcomes. Apart from Chromogranin A, specific biomarkers predicting residual tumor disease, tumor burden, and disease progression in NEN are scant. Thus, there is a strong clinical need for new and minimally invasive biomarkers that allow for an evaluation of the prognosis, clinical course, and response to treatment of NEN patients, thereby helping implement individualized treatment decisions in this heterogeneous group of patients. In the current prospective study, we evaluated the role of plasma cell-free DNA concentration and its global hypomethylation and fragmentation as possible diagnostic and prognostic biomarkers in patients with neuroendocrine neoplasias. Methods: The plasma cfDNA concentration, cfDNA Alu hypomethylation, and LINE-1 cfDNA integrity were evaluated prospectively in 63 NEN patients with presumably cured or advanced metastatic disease. The cfDNA characteristics in NEN patients were compared to the results of a group of 29 healthy controls and correlated with clinical and histopathological data of the patients. Results: Patients with advanced NEN showed a significantly higher cfDNA concentration and percentage of Alu hypomethylation and a reduced LINE-1 cfDNA integrity as compared to the surgically cured NET patients and the healthy control group. The increased hypomethylation and concentration of cfDNA and the reduced cfDNA integrity in NEN patients were strongly associated with tumor burden and poor prognosis, while no correlation with tumor grading, differentiation, localization, or hormonal activity could be found. Multiparametric ROC analysis of plasma cfDNA characteristics was able to distinguish NEN patients with metastatic disease from the control group and the cured NEN patients with AUC values of 0.694 and 0.908, respectively. This was significant even for the group with only a low tumor burden. Conclusions: The present study, for the first time, demonstrates that the combination of plasma cfDNA concentration, global hypomethylation, and fragment length pattern has the potential to serve as a potent and sensitive prognostic and therapeutic “liquid biopsy” biomarker for tumor burden and disease progression in patients with neuroendocrine neoplasias.
Collapse
Affiliation(s)
- Esther Mettler
- Department of Endocrinology and Metabolism, I Medical Clinic, University Hospital, Johannes Gutenberg University of Mainz, 55131 Mainz, Germany; (C.F.); (N.B.); (A.T.); (M.M.W.)
- Correspondence:
| | - Christian Fottner
- Department of Endocrinology and Metabolism, I Medical Clinic, University Hospital, Johannes Gutenberg University of Mainz, 55131 Mainz, Germany; (C.F.); (N.B.); (A.T.); (M.M.W.)
| | - Neda Bakhshandeh
- Department of Endocrinology and Metabolism, I Medical Clinic, University Hospital, Johannes Gutenberg University of Mainz, 55131 Mainz, Germany; (C.F.); (N.B.); (A.T.); (M.M.W.)
| | - Anja Trenkler
- Department of Endocrinology and Metabolism, I Medical Clinic, University Hospital, Johannes Gutenberg University of Mainz, 55131 Mainz, Germany; (C.F.); (N.B.); (A.T.); (M.M.W.)
| | - Robert Kuchen
- Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany;
| | - Matthias M. Weber
- Department of Endocrinology and Metabolism, I Medical Clinic, University Hospital, Johannes Gutenberg University of Mainz, 55131 Mainz, Germany; (C.F.); (N.B.); (A.T.); (M.M.W.)
| |
Collapse
|
17
|
Hashimoto S, Nakaoka K, Tanaka H, Kuzuya T, Kawabe N, Nagasaka M, Nakagawa Y, Miyahara R, Shibata T, Hirooka Y. Transabdominal ultrasonographic diagnosis of relatively rare pancreatic neoplasms. J Med Ultrason (2001) 2022; 49:187-197. [PMID: 35149959 DOI: 10.1007/s10396-022-01192-9] [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] [Received: 11/22/2021] [Accepted: 01/12/2022] [Indexed: 11/28/2022]
Abstract
There are various types of pancreatic neoplasms, and their prognosis and treatment methods are different. Therefore, accurate diagnosis is important to determine the best treatment strategy. Transabdominal ultrasonography is frequently used as a screening examination for diagnostic imaging of pancreatic neoplasms. In this review, we have focused on the characteristics of ultrasonic findings for relatively rare pancreatic neoplasms.
Collapse
Affiliation(s)
- Senju Hashimoto
- Department of Gastroenterology and Hepatology, Fujita Health University School of Medicine, 1‑98 Dengakugakubo, Kutukake‑cho, Toyoake, Aichi, 470‑1192, Japan
| | - Kazunori Nakaoka
- Department of Gastroenterology and Hepatology, Fujita Health University School of Medicine, 1‑98 Dengakugakubo, Kutukake‑cho, Toyoake, Aichi, 470‑1192, Japan
| | - Hiroyuki Tanaka
- Department of Gastroenterology and Hepatology, Fujita Health University School of Medicine, 1‑98 Dengakugakubo, Kutukake‑cho, Toyoake, Aichi, 470‑1192, Japan
| | - Teiji Kuzuya
- Department of Gastroenterology and Hepatology, Fujita Health University School of Medicine, 1‑98 Dengakugakubo, Kutukake‑cho, Toyoake, Aichi, 470‑1192, Japan
| | - Naoto Kawabe
- Department of Gastroenterology and Hepatology, Fujita Health University School of Medicine, 1‑98 Dengakugakubo, Kutukake‑cho, Toyoake, Aichi, 470‑1192, Japan
| | - Mitsuo Nagasaka
- Department of Gastroenterology and Hepatology, Fujita Health University School of Medicine, 1‑98 Dengakugakubo, Kutukake‑cho, Toyoake, Aichi, 470‑1192, Japan
| | - Yoshihito Nakagawa
- Department of Gastroenterology and Hepatology, Fujita Health University School of Medicine, 1‑98 Dengakugakubo, Kutukake‑cho, Toyoake, Aichi, 470‑1192, Japan
| | - Ryoji Miyahara
- Department of Gastroenterology and Hepatology, Fujita Health University School of Medicine, 1‑98 Dengakugakubo, Kutukake‑cho, Toyoake, Aichi, 470‑1192, Japan
| | - Tomoyuki Shibata
- Department of Gastroenterology and Hepatology, Fujita Health University School of Medicine, 1‑98 Dengakugakubo, Kutukake‑cho, Toyoake, Aichi, 470‑1192, Japan
| | - Yoshiki Hirooka
- Department of Gastroenterology and Hepatology, Fujita Health University School of Medicine, 1‑98 Dengakugakubo, Kutukake‑cho, Toyoake, Aichi, 470‑1192, Japan.
| |
Collapse
|
18
|
Allaw MB, Switchenko JM, Khalil L, Wu C, Alese OB, Akce M, Draper A, Jones AT, El-Rayes B, Shaib W. Comparing Somatostatin Analogs in the Treatment of Advanced Gastroenteropancreatic Neuroendocrine Tumors. Oncology 2022; 100:131-139. [PMID: 35078191 PMCID: PMC9052205 DOI: 10.1159/000519605] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 08/24/2021] [Indexed: 11/19/2022]
Abstract
BACKGROUND The 2 approved somatostatin analogs (SSAs) in the first-line treatment of advanced, well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are octreotide long-acting release (Sandostatin LAR) and somatuline depot (Lanreotide). The study's objective was to compare progression-free survival (PFS) and overall survival (OS) of patients (pts) with GEP-NETs treated with somatuline or octreotide LAR. Pts and Methods: Pts with advanced well-differentiated GEP-NET who received either SSA at Emory University between 1995 and 2019 were included after institutional review board approval. The primary end point was PFS, defined as time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.1, or clinical progression) or death. The secondary end point was OS. Kaplan-Meier curves were generated, and log-rank tests were conducted to compare the survival outcomes. RESULTS A total of 105 pts were identified. The mean age was 62.1 years (SD ± 11.8). The male-to-female ratio was 51:54. The majority (N = 69, 65.7%) were white. Most pts had grade 2 (G2) disease (N = 44, 41.9%). Primary location was small bowel in 58 (55.2%), pancreas in 27 (25.7%), and other in 20 (19.0%). Functional tumors were defined in 32 pts distributed equally between the 2 groups. Distribution of treatment was similar in the 2 groups, with 54 receiving octreotide LAR and 51 receiving somatuline depot. The median PFS for the octreotide LAR and somatuline depot groups was 12 months (95% CI, 6-18 months) and 10.8 months (95% CI, 6-15.6 months), respectively, and the difference was not statistically significant (p = 0.2665). For pts with G1 disease, the median PFS for the octreotide LAR and somatuline depot was 8.4 versus 32.4 months, respectively, and the difference was not statistically significant (p = 0.159). For G2 disease, the difference in median PFS between octreotide LAR and somutaline depot groups was statistically significant (12 vs. 7.2 months, respectively; p = 0.0372). The mean follow-up time for octreotide LAR was 21.6 months versus 11.3 months for somatuline depot. CONCLUSIONS Overall, there was no difference in PFS between octreotide LAR and somatuline depot for pts with well-differentiated, metastatic GEP-NETs. A prospective study is worth designing selecting for G.
Collapse
Affiliation(s)
- Mohammed B. Allaw
- Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Jeffrey M. Switchenko
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Lana Khalil
- Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Christina Wu
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Olatunji B. Alese
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Mehmet Akce
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Amber Draper
- Clinical Pharmacy, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Aaron T. Jones
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Bassel El-Rayes
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Walid Shaib
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| |
Collapse
|
19
|
Fijalkowski R, Reher D, Rinke A, Gress TM, Schrader J, Baum RP, Kaemmerer D, Hörsch D. Clinical Features and Prognosis of Patients with Carcinoid Syndrome and Carcinoid Heart Disease: A Retrospective Multicentric Study of 276 Patients. Neuroendocrinology 2022; 112:547-554. [PMID: 34348326 DOI: 10.1159/000518651] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 07/22/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Carcinoid syndrome is the most frequent functional syndrome of neuroendocrine neoplasia. It is characterized by flushing, diarrhea, wheezing, hypotension, and exanthema and may cause carcinoid heart disease. METHODS We assessed clinical characteristics and prognosis of patients with carcinoid syndrome and carcinoid heart disease in 276 patients from 3 referral centers. RESULTS Carcinoid syndrome patients had a mean age of 57 years (range 21-84) and a normal BMI of 24.9 (SD 4.5; range 13.8-39.6). Most primaries were of small bowel or unknown primaries with distant metastasis in 94.6%. Flushing was the most frequent symptom in 74.3% of patients, followed by diarrhea in 68.8%, and wheezing in 40.9%. Pain was described by 45.3%, weakness by 23.5%, and weight loss of >10% in 6 months by 30.1% of patients. Carcinoid heart disease was diagnosed in 37.3% of patients (n = 104) by echocardiography and involved predominantly in the tricuspid valve. Combinations with other valve defects were common. Somatostatin analogs were taken by 80.4% of patients and 17% needed additional loperamide/opium tincture. Surgery and peptide receptor radiotherapy were most frequent treatments. The median survival of patients with carcinoid syndrome after diagnosis was 9 years. Prognosis was significantly impaired by male sex and diagnosis of carcinoid heart disease but surprisingly significantly increased by the presence of symptoms flushing and weakness. DISCUSSION/CONCLUSION Carcinoid syndrome is associated with extensive disease and primaries in small bowels or of unknown primary. Weight loss, weakness, and pain are frequent, and carcinoid heart disease is diagnosed in more than one-third of patients.
Collapse
Affiliation(s)
- Robert Fijalkowski
- ENETS Center of Excellence Bad Berka, Internal Medicine/Gastroenterology and Endocrinology, Bad Berka, Germany
| | - Dominik Reher
- I. Department of Medicine, ENETS Center of Excellence, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anja Rinke
- ENETS Center of Excellence, Internal Medicine, Philipps-University Marburg, Marburg, Germany
| | - Thomas M Gress
- ENETS Center of Excellence, Internal Medicine, Philipps-University Marburg, Marburg, Germany
| | - Jörg Schrader
- I. Department of Medicine, ENETS Center of Excellence, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Richard P Baum
- ENETS Center of Excellence Bad Berka, Molecular Radiotherapy, Bad Berka, Germany
- CURANOSTICUM Wiesbaden-Frankfurt, DKD Helios Clinic, Wiesbaden, Germany
| | - Daniel Kaemmerer
- ENETS Center of Excellence Bad Berka, General and Visceral Surgery, Bad Berka, Germany
| | - Dieter Hörsch
- ENETS Center of Excellence Bad Berka, Internal Medicine/Gastroenterology and Endocrinology, Bad Berka, Germany
| |
Collapse
|
20
|
Sotiropoulou M, Mulita F, Verras GI, Schizas D, Papalampros A, Tchabashvili L, Kaplanis C, Liolis E, Perdikaris I, Maroulis I, Vailas M. A novel tool for visualization and detection of pancreatic neuroendocrine tumours. A 'fluorescent' world is calling for exploration? PRZEGLAD MENOPAUZALNY = MENOPAUSE REVIEW 2021; 20:207-210. [PMID: 35069073 PMCID: PMC8764961 DOI: 10.5114/pm.2021.110834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 09/10/2021] [Indexed: 02/07/2023]
Abstract
AIM OF THE STUDY Pancreatic neuroendocrine tumours (pNETs) are rare tumours with a propensity to metastasize. Physicians frequently face a huge clinical challenge during the localization of these lesions. The aim of this study is to investigate whether fluorescence-guided localization techniques with indocyanine green (ICG) can be utilized as a detection tool in pNETs, along with any other clinical implications of this technique. MATERIAL AND METHODS A thorough literature search in PubMed and Google Scholar, under the terms 'ICG OR Indocyanine OR Fluorescence AND Neuroendocrine' until 31 June 2021, regarding the utilization of indocyanine-fluorescence in localization of pancreatic neuroendocrine, was conducted by the authors, and the associated results are presented. RESULTS Indocyanine fluorescence imaging may facilitate the efforts of surgeons to identify occult pancreatic neuroendocrine lesions, assisting them in the identification of resection margins and delineation of the surgical anatomy when it is difficult to clarify. CONCLUSIONS Indocyanine-fluorescence imaging might play a pivotal role in pancreatic surgery in terms of localization for neuroendocrine tumours. However, further large-scale clinical studies are needed to assess the absolute indications and optimal use of this technique.
Collapse
Affiliation(s)
- Maria Sotiropoulou
- Department of Surgery, National and Kapodistrian University of Athens, Athens, Greece
| | - Francesk Mulita
- Department of Surgery, General University Hospital of Patras, Greece
- Corresponding author: Francesk Mulita, MD, General University Hospital of Patras, Greece, e-mail:
| | | | - Dimitrios Schizas
- Department of Surgery, National and Kapodistrian University of Athens, Athens, Greece
| | | | | | | | - Elias Liolis
- Department of Internal Medicine, Division of Oncology, General University Hospital of Patras, Greece
| | | | - Ioannis Maroulis
- Department of Surgery, General University Hospital of Patras, Greece
| | - Michail Vailas
- Department of Surgery, General University Hospital of Patras, Greece
| |
Collapse
|
21
|
Zhang Q, Huang J, He Y, Cao R, Shu J. Insulinoma-associated protein 1(INSM1) is a superior marker for the diagnosis of gastroenteropancreatic neuroendoerine neoplasms: a meta-analysis. Endocrine 2021; 74:61-71. [PMID: 34021851 DOI: 10.1007/s12020-021-02754-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 05/05/2021] [Indexed: 12/15/2022]
Abstract
PURPOSE An increasing number of studies have shown that insulinoma-associated protein 1 (INSM1) is a robust marker for the diagnosis of gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN). The overall diagnostic accuracy of INSM1 for GEP-NEN remains unclear. The purpose of this study is to estimate the diagnostic value of INSM1 for GEP-NEN through a meta-analysis. METHODS We searched relevant studies addressing the accuracy of INSM1 in the diagnosis of GEP-NEN from PubMed, Web of Science, Embase, Cochrane Library and China National Knowledge Infrastructure (CNKI) as well as from reference lists since the establishment of the database to January 12, 2021. Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC) curves were used to comprehensively evaluate the diagnostic value of INSM1 for GEP-NEN. Statistical analysis was performed by Stata 15.0 and RevMan 5.4. RESULTS Nine studies with a total of 393 patients were included in the meta-analysis. The meta-analysis results showed that the pooled sensitivity and specificity of INSM1 for the diagnosis of GEP-NEN were 0.99 (95% CI: 0.87-1.00) and 0.96 (95% CI: 0.93-0.98), respectively. The PLR and NLR were 23.3 (95% CI: 13.3-40.8) and 0.01 (95% CI: 0.00-0.14), respectively. The DOR was 380.31 (95% CI: 164.14-881.21), and the area under the curve (AUC) of SROC curve was 0.98 (95% CI: 0.96-0.99). CONCLUSIONS The results show that INSM1 is an effective marker for the diagnosis of GEP-NEN with high sensitivity and specificity. INSM1 is recommended for clinical application to improve the diagnostic accuracy of GEP-NEN. However, more high-quality studies are needed to confirm these findings.
Collapse
Affiliation(s)
- Qinghui Zhang
- Department of Gastroenterology, Guangzhou Red Cross Hospital Affiliated to Jinan University, Guangzhou, 510220, Guangdong, China
| | - Jiahuang Huang
- Department of Gastroenterology, Guangzhou Red Cross Hospital Affiliated to Jinan University, Guangzhou, 510220, Guangdong, China
| | - Yajun He
- Department of Clinical Laboratory, Guangzhou Red Cross Hospital Affiliated to Jinan University, Guangzhou, 510220, Guangdong, China
| | - Runze Cao
- Department of Emergency, Xiangyang No. 1 People's Hospital Affiliated to Hubei University of Medicine, Xiangyang, 441000, Hubei, China
| | - Jianchang Shu
- Department of Gastroenterology, Guangzhou Red Cross Hospital Affiliated to Jinan University, Guangzhou, 510220, Guangdong, China.
| |
Collapse
|
22
|
Rinke A, Auernhammer CJ, Bodei L, Kidd M, Krug S, Lawlor R, Marinoni I, Perren A, Scarpa A, Sorbye H, Pavel ME, Weber MM, Modlin I, Gress TM. Treatment of advanced gastroenteropancreatic neuroendocrine neoplasia, are we on the way to personalised medicine? Gut 2021; 70:1768-1781. [PMID: 33692095 DOI: 10.1136/gutjnl-2020-321300] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 02/03/2021] [Accepted: 02/08/2021] [Indexed: 12/14/2022]
Abstract
Gastroenteropancreatic neuroendocrine neoplasia (GEPNEN) comprises clinically as well as prognostically diverse tumour entities often diagnosed at late stage. Current classification provides a uniform terminology and a Ki67-based grading system, thereby facilitating management. Advances in the study of genomic and epigenetic landscapes have amplified knowledge of tumour biology and enhanced identification of prognostic and potentially predictive treatment subgroups. Translation of this genomic and mechanistic biology into advanced GEPNEN management is limited. 'Targeted' treatments such as somatostatin analogues, peptide receptor radiotherapy, tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors are treatment options but predictive tools are lacking. The inability to identify clonal heterogeneity and define critical oncoregulatory pathways prior to therapy, restrict therapeutic efficacy as does the inability to monitor disease status in real time. Chemotherapy in the poor prognosis NEN G3 group, though associated with acceptable response rates, only leads to short-term tumour control and their molecular biology requires delineation to provide new and more specific treatment options.The future requires an exploration of the NEN tumour genome, its microenvironment and an identification of critical oncologic checkpoints for precise drug targeting. In the advance to personalised medical treatment of patients with GEPNEN, clinical trials need to be based on mechanistic and multidimensional characterisation of each tumour in order to identify the therapeutic agent effective for the individual tumour.This review surveys advances in NEN research and delineates the current status of translation with a view to laying the basis for a genome-based personalised medicine management of advanced GEPNEN.
Collapse
Affiliation(s)
- Anja Rinke
- Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, University Hospital Marburg and Philipps University, Marburg, Germany
| | - Christoph J Auernhammer
- Department of Internal Medicine IV and Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Ludwig Maximilian University, LMU Klinikum, Munich, Germany
| | - Lisa Bodei
- Department of Radiology, Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Mark Kidd
- Wren Laboratories, Branford, Connecticut, USA
| | - Sebastian Krug
- Clinic for Internal Medicine I, Martin Luther University, Halle, Germany
| | - Rita Lawlor
- Applied Research on Cancer Centre, Department of Pathology and Diagnostics, University of Verona, Verona, Italy
| | - Ilaria Marinoni
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Aurel Perren
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Aldo Scarpa
- Applied Research on Cancer Centre, Department of Pathology and Diagnostics, University of Verona, Verona, Italy
| | - Halfdan Sorbye
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Marianne Ellen Pavel
- Department of Internal Medicine I, Endocrinology, University of Erlangen, Erlangen, Germany
| | - Matthias M Weber
- Department of Internal Medicine I, Endocrinology, Johannes Gutenberg University Hospital Mainz, Mainz, Germany
| | - Irvin Modlin
- Gastroenterological and Endoscopic Surgery, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Thomas M Gress
- Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, University Hospital Marburg and Philipps University, Marburg, Germany
| |
Collapse
|
23
|
Spada F, Rossi RE, Kara E, Laffi A, Massironi S, Rubino M, Grimaldi F, Bhoori S, Fazio N. Carcinoid Syndrome and Hyperinsulinemic Hypoglycemia Associated with Neuroendocrine Neoplasms: A Critical Review on Clinical and Pharmacological Management. Pharmaceuticals (Basel) 2021; 14:ph14060539. [PMID: 34199977 PMCID: PMC8228616 DOI: 10.3390/ph14060539] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 05/31/2021] [Accepted: 06/01/2021] [Indexed: 02/05/2023] Open
Abstract
The carcinoid syndrome (CS) and hyperinsulinemic hypoglycemia (HH) represent two of the most common clinical syndromes associated with neuroendocrine neoplasms (NENs). The former is mainly related to the serotonin secretion by a small bowel NEN, whereas the latter depends on an insulin hypersecretion by a pancreatic insulinoma. Both syndromes/conditions can affect prognosis and quality of life of patients with NENs. They are often diagnosed late when patients become strongly symptomatic. Therefore, their early detection and management are a critical step in the clinical management of NEN patients. A dedicated and experienced multidisciplinary team with appropriate therapeutic strategies is needed and should be encouraged to optimize clinical outcomes. This review aims to critically analyze clinical features, evidence and treatment options of CS and HH and therefore to improve their management.
Collapse
Affiliation(s)
- Francesca Spada
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO) IRCCS, via G. Ripamonti 435, 20141 Milano, Italy; (F.S.); (A.L.); (M.R.)
| | - Roberta E. Rossi
- Hepatology and Hepato-Pancreatic-Biliary Surgery and Liver Transplantation, Fondazione IRCCS, Istituto Nazionale Tumori (INT), via G. Venezian 1, 20133 Milano, Italy; (R.E.R.); (S.B.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, via Festa del Perdono 7, 20122 Milano, Italy
| | - Elda Kara
- Endocrinology and Metabolism Unit, University Hospital S. Maria della Misericordia, Piazzale Santa Maria della Misericordia, 15, 33100 Udine, Italy; (E.K.); (F.G.)
| | - Alice Laffi
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO) IRCCS, via G. Ripamonti 435, 20141 Milano, Italy; (F.S.); (A.L.); (M.R.)
| | - Sara Massironi
- Division of Gastroenterology, San Gerardo Hospital, Bicocca School of Medicine, University of Milano Bicocca, 20126 Milano, Italy;
| | - Manila Rubino
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO) IRCCS, via G. Ripamonti 435, 20141 Milano, Italy; (F.S.); (A.L.); (M.R.)
| | - Franco Grimaldi
- Endocrinology and Metabolism Unit, University Hospital S. Maria della Misericordia, Piazzale Santa Maria della Misericordia, 15, 33100 Udine, Italy; (E.K.); (F.G.)
| | - Sherrie Bhoori
- Hepatology and Hepato-Pancreatic-Biliary Surgery and Liver Transplantation, Fondazione IRCCS, Istituto Nazionale Tumori (INT), via G. Venezian 1, 20133 Milano, Italy; (R.E.R.); (S.B.)
| | - Nicola Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO) IRCCS, via G. Ripamonti 435, 20141 Milano, Italy; (F.S.); (A.L.); (M.R.)
- Correspondence: ; Tel.: +39-025-748-9258
| |
Collapse
|
24
|
Wu Y, Xiong G, Zhang H, Wang M, Zhu F, Qin R. Adrenocorticotropic Hormone-Producing Pancreatic Neuroendocrine Neoplasms: A Systematic Review. Endocr Pract 2021; 27:152-157. [PMID: 33616046 DOI: 10.1016/j.eprac.2020.10.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 09/22/2020] [Accepted: 10/12/2020] [Indexed: 01/08/2023]
Abstract
OBJECTIVE Adrenocorticotropic hormone-producing pancreatic neuroendocrine neoplasm (ACTHoma) is an exceedingly rare type of pancreatic neuroendocrine neoplasm (pNEN) that often causes ectopic adrenocorticotropic hormone syndrome. These neoplasms have been found to be very aggressive and challenging to treat. The current systematic review aimed to analyze the clinical features, immunohistochemical characteristics, diagnosis, therapy, and prognosis of ACTHoma. METHODS A systematic review of the English- and Chinese-language literature was performed. PubMed, EMBASE, and Wanfang databases were searched to identify articles about ACTHoma in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. RESULTS A total of 210 studies encompassing 336 patients diagnosed with ACTHoma were selected for the systematic review, including 16 Chinese patients. CONCLUSION ACTHoma was more common in women (66.4%), and the mean age was 44.7 years. Tumors were generally large, and the mean tumor size was 4.43 cm. The incidence of clinical manifestations was: hypokalemia, 69.3%; diabetes, 63.2%; weakness, 60.1%, hypertension, 56.4%; moon face 41.1%; and edema, 37.4%. These tumors are more commonly found in the tail of pancreas, and the most frequent site of metastasis was the liver. The pNENs or other functioning pNENs could evolve into ACTHoma. ACTHoma is a very rare disease, and the mean follow-up time was 28.3 months.
Collapse
Affiliation(s)
- Yi Wu
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guangbing Xiong
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hang Zhang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Min Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Zhu
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Renyi Qin
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| |
Collapse
|
25
|
Eads JR, Reidy-Lagunes D, Soares HP, Chan JA, Anthony LB, Halfdanarson TR, Naraev BG, Wolin EM, Halperin DM, Li D, Pommier RF, Zacks JS, Morse MA, Metz DC. Differential Diagnosis of Diarrhea in Patients With Neuroendocrine Tumors. Pancreas 2020; 49:1123-1130. [PMID: 32991344 DOI: 10.1097/mpa.0000000000001658] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience diarrhea that can have a debilitating effect on quality of life. Diarrhea also may develop in response to other hormonal syndromes associated with NETs, surgical complications, medical comorbidities, medications, or food sensitivities. Limited guidance on the practical approach to the differential diagnosis of diarrhea in these patients can lead to delays in appropriate treatment. This clinical review and commentary underscore the complexity in identifying the etiology of diarrhea in patients with NETs. Based on our collective experience and expertise, we offer a practical algorithm to guide medical oncologists and other care providers to expedite effective management of diarrhea and related symptoms in patients with NETs.
Collapse
Affiliation(s)
- Jennifer R Eads
- From the Department of Medicine, Division of Hematology and Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
| | - Diane Reidy-Lagunes
- Department of Medicine, Division of Solid Tumor, Gastrointestinal Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Heloisa P Soares
- Division of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
| | - Jennifer A Chan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - Lowell B Anthony
- Division of Medical Oncology, University of Kentucky Medical Center, Markey Cancer Center, Lexington, KY
| | | | - Boris G Naraev
- Division of Cancer Medicine, Banner MD Anderson Cancer Center, The University of Texas MD Anderson Cancer Center, Gilbert, AZ
| | - Edward M Wolin
- Department of Medicine, Division of Hematology/Oncology, Icahn School of Medicine, Center for Carcinoid and Neuroendocrine Tumors, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY
| | - Daniel M Halperin
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Daneng Li
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center and Beckman Research Institute, Duarte, CA
| | - Rodney F Pommier
- Division of Surgical Oncology, Oregon Health & Science University, Portland, OR
| | - Jerome S Zacks
- Department of Medicine (Cardiology), The Mount Sinai School of Medicine, The Carcinoid Heart Center, New York, NY
| | - Michael A Morse
- Department of Medical Oncology, Duke University Medical Center, Durham, NC
| | - David C Metz
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | | |
Collapse
|
26
|
Pobłocki J, Jasińska A, Syrenicz A, Andrysiak-Mamos E, Szczuko M. The Neuroendocrine Neoplasms of the Digestive Tract: Diagnosis, Treatment and Nutrition. Nutrients 2020; 12:E1437. [PMID: 32429294 PMCID: PMC7284837 DOI: 10.3390/nu12051437] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 05/04/2020] [Accepted: 05/13/2020] [Indexed: 12/18/2022] Open
Abstract
Nuroendocrine neoplasms (NENs) are a group of rare neoplasms originating from dispersed neuroendocrine cells, mainly of the digestive and respiratory tract, showing characteristic histology and immunoprofile contributing to classification of NENs. Some NENs have the ability to produce biogenic amines and peptide hormones, which may be associated with clinical syndromes like, e.g., the carcinoid syndrome caused by unmetabolized overproduced serotonin, hypoglycemic syndrome in case of insulinoma, or Zollinger-Ellison syndrome accompanying gastrinoma. Diagnostics for these include ultrasound with endoscopic ultrasound (EUS), computed tomography (CT), magnetic resonance imaging (MRI), and positron-emission tomography/computed tomography (PET/CT). Different nuclear medicine procedures can also be used, like somatostatin analogues scintigraphy (SRS) and 68Ga-Dota-Peptide PET/CT, as well as biochemical methods to determine the level of general neuroendocrine markers, such as chromogranin A (CgA), 5-hydroxyindolacetic acid (5-HIAA), synaptopfysin and cell type-specific peptide hormones, and neurotransmitters like gastrin, insulin, serotonin, and histamine. NENs influence the whole organism by modulating metabolism. The treatment options for neuroendocrine neoplasms include surgery, somatostatin analogue therapy, radionuclide therapy, chemotherapy, molecular targeted therapies, alpha-interferon therapy, and inhibitors of serotonin production. In the case of hypersensitivity to biogenic amines, a diet that limits the main sources of amines should be used. The symptoms are usually connected with histamine, tyramine and putrescine. Exogenic sources of histamine are products that take a long time to mature and ferment. Patients with a genetic insufficiency of the diamine oxidase enzyme (DAO), and those that take medicine belonging to the group of monoamine oxidases (MAO), are particularly susceptible to the negative effects of amines. Diet plays an important role in the initiation, promotion, and progression of cancers. As a result of the illness, the consumption of some nutrients can be reduced, leading to nutritional deficiencies and resulting in malnutrition. Changes in metabolism may lead to cachexia in some patients suffering from NENs. The aim of this narrative review was to advance the knowledge in this area, and to determine possibilities related to dietary support. The authors also paid attention to role of biogenic amines in the treatment of patients with NENs. We can use this information to better understand nutritional issues faced by patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), and to help inform the development of screening tools and clinical practice guidelines.
Collapse
Affiliation(s)
- Jakub Pobłocki
- Department of Endocrinology, Metabolic Diseases and Internal Diseases, Pomeranian Medical University in Szczecin, Unii Lubelskiej 1str, 70-252 Szczecin, Poland; (J.P.); (A.S.); (E.A.-M.)
| | - Anna Jasińska
- Department of Human Nutrition and Metabolomic, Pomeranian Medical University in Szczecin, Broniewskiego 24 str, 71-460 Szczecin, Poland;
| | - Anhelli Syrenicz
- Department of Endocrinology, Metabolic Diseases and Internal Diseases, Pomeranian Medical University in Szczecin, Unii Lubelskiej 1str, 70-252 Szczecin, Poland; (J.P.); (A.S.); (E.A.-M.)
| | - Elżbieta Andrysiak-Mamos
- Department of Endocrinology, Metabolic Diseases and Internal Diseases, Pomeranian Medical University in Szczecin, Unii Lubelskiej 1str, 70-252 Szczecin, Poland; (J.P.); (A.S.); (E.A.-M.)
| | - Małgorzata Szczuko
- Department of Human Nutrition and Metabolomic, Pomeranian Medical University in Szczecin, Broniewskiego 24 str, 71-460 Szczecin, Poland;
| |
Collapse
|
27
|
Update on Pathophysiology, Treatment, and Complications of Carcinoid Syndrome. JOURNAL OF ONCOLOGY 2020; 2020:8341426. [PMID: 32322270 PMCID: PMC7160731 DOI: 10.1155/2020/8341426] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 12/07/2019] [Accepted: 12/26/2019] [Indexed: 12/23/2022]
Abstract
Carcinoid syndrome (CS) develops in patients with hormone-producing neuroendocrine neoplasms (NENs) when hormones reach a significant level in the systemic circulation. The classical symptoms of carcinoid syndrome are flushing, diarrhoea, abdominal pain, and wheezing. Neuroendocrine neoplasms can produce multiple hormones: 5-hydroxytryptamine (serotonin) is the most well-known one, but histamine, catecholamines, and brady/tachykinins are also released. Serotonin overproduction can lead to symptoms and also stimulates fibrosis formation which can result in development of carcinoid syndrome-associated complications such as carcinoid heart disease (CaHD) and mesenteric fibrosis. Transforming growth factor beta (TGF-β) is one of the main factors in developing fibrosis, but platelet-derived growth factor (PDGF), basic fibroblast growth factor (FGF2), and connective tissue growth factor (CTGF or CCN2) are also related to fibrosis development. Treatment of CS focuses on reducing serotonin levels with somatostatin analogues (SSA's). Telotristat ethyl and peptide receptor radionuclide therapy (PRRT) have recently become available for patients with symptoms despite being established on SSA's. Screening for CaHD is advised, and early intervention prolongs survival. Mesenteric fibrosis is often present and associated with poorer survival, but the role for prophylactic surgery of this is unclear. Depression, anxiety, and cognitive impairment are frequently present symptoms in patients with CS but not always part of their care plan. The role of antidepressants, mainly SSRIs, is debatable, but recent retrospective studies show evidence for safe use in patients with CS. Carcinoid crisis is a life-threatening complication of CS which can appear spontaneously but mostly described during surgery, anaesthesia, chemotherapy, PRRT, and radiological procedures and may be prevented by octreotide administration.
Collapse
|
28
|
Li MX, Li QY, Xiao M, Wan DL, Chen XH, Zhou L, Xie HY, Zheng SS. Survival comparison between primary hepatic neuroendocrine neoplasms and primary pancreatic neuroendocrine neoplasms and the analysis on prognosis-related factors. Hepatobiliary Pancreat Dis Int 2019; 18:538-545. [PMID: 30981633 DOI: 10.1016/j.hbpd.2019.03.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 03/29/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Primary hepatic neuroendocrine neoplasms (PHNENs) are extremely rare and few articles have compared the prognosis of PHNENs with other neuroendocrine neoplasms (NENs). This study aimed to investigate the different prognosis between PHNENs and pancreatic NEN (PanNENs) and evaluate the relevant prognosis-related factors. METHODS From January 2012 to October 2016, a total of 44 NENs patients were enrolled and divided into two groups according to the primary tumor location which were named group PHNENs (liver; n = 12) and group PanNENs (pancreas; n = 32). Demographic, clinical characteristics and survival data were compared between the two groups with Kaplan-Meier method and log-rank tests. Prognostic factors were analyzed using the Cox regression model. RESULTS The overall survival of group PHNENs and group PanNENs were 25.4 ± 6.7 months and 39.8 ± 3.7 months, respectively (P = 0.037). The cumulative survival of group PanNENs was significantly higher than that of group PHNENs (P = 0.029). Univariate analysis revealed that sex, albumin, total bilirubin, total bile acid, aspartate aminotransferase, alkaline phosphatase, α-fetoprotein and carbohydrate antigen 19-9, histological types, treatments and primary tumor site were the prognostic factors. Further multivariate analysis indicated that albumin (P = 0.008), histological types NEC (P = 0.035) and treatments (P = 0.005) were the independent prognostic factors. Based on the histological types, the cumulative survival of patients with well-differentiated neuroendocrine tumor was significant higher than that of patients with poorly differentiated neuroendocrine carcinoma in group PHNENs (P = 0.022), but not in group PanNENs (P > 0.05). According to the different treatments, patients who received surgery had significantly higher cumulative survival than those with conservative treatment in both groups (P < 0.05). CONCLUSIONS PHNENs have lower survival compared to PanNENs. Histological types and treatments affect the prognosis. Surgical resection still remains the first line of treatment for resectable lesions and can significantly improve the survival.
Collapse
Affiliation(s)
- Meng-Xia Li
- Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qi-Yong Li
- Division of Hepatobiliary Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou 310004, China
| | - Min Xiao
- Division of Hepatobiliary Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou 310004, China
| | - Da-Long Wan
- Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Xin-Hua Chen
- Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Lin Zhou
- Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Hai-Yang Xie
- Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Shu-Sen Zheng
- Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
| |
Collapse
|
29
|
Boons G, Vandamme T, Peeters M, Van Camp G, Op de Beeck K. Clinical applications of (epi)genetics in gastroenteropancreatic neuroendocrine neoplasms: Moving towards liquid biopsies. Rev Endocr Metab Disord 2019; 20:333-351. [PMID: 31368038 DOI: 10.1007/s11154-019-09508-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
High-throughput analysis, including next-generation sequencing and microarrays, have strongly improved our understanding of cancer biology. However, genomic data on rare cancer types, such as neuroendocrine neoplasms, has been lagging behind. Neuroendocrine neoplasms (NENs) develop from endocrine cells spread throughout the body and are highly heterogeneous in biological behavior. In this challenging disease, there is an urgent need for new therapies and new diagnostic, prognostic, follow-up and predictive biomarkers to aid patient management. The last decade, molecular data on neuroendocrine neoplasms of the gastrointestinal tract and pancreas, termed gastroenteropancreatic NENs (GEP-NENs), has strongly expanded. The aim of this review is to give an overview of the recent advances on (epi)genetic level and highlight their clinical applications to address the current needs in GEP-NENs. We illustrate how molecular alterations can be and are being used as therapeutic targets, how mutations in DAXX/ATRX and copy number variations could be used as prognostic biomarkers, how far we are in identifying predictive biomarkers and how genetics can contribute to GEP-NEN classification. Finally, we discuss recent studies on liquid biopsies in the field of GEP-NENs and illustrate how liquid biopsies can play a role in patient management. In conclusion, molecular studies have suggested multiple potential biomarkers, but further validation is ongoing.
Collapse
Affiliation(s)
- Gitta Boons
- Center for Oncological Research (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium
| | - Timon Vandamme
- Center for Oncological Research (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium
- Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, Dr. Molewaterplein 50, 3015GE, Rotterdam, The Netherlands
| | - Marc Peeters
- Center for Oncological Research (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium
| | - Guy Van Camp
- Center for Oncological Research (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium.
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium.
| | - Ken Op de Beeck
- Center for Oncological Research (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium
| |
Collapse
|
30
|
Sekulic M, Waikar S, Motwani SS, Weins A, Rennke HG. Chromogranin A Tubulopathy: Differing Histopathologic Patterns of Acute Tubular Injury in the Setting of Neuroendocrine Neoplasms. Kidney Int Rep 2019; 4:1085-1093. [PMID: 31440699 PMCID: PMC6698283 DOI: 10.1016/j.ekir.2019.04.025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Accepted: 04/29/2019] [Indexed: 02/01/2023] Open
Abstract
Introduction Neoplasms of neuroendocrine derivation or differentiation may express specific peptides, some of which are capable of producing clinical symptomatology and others used as biomarkers: one such peptide being chromogranin A (CGA). Herein, we describe histopathologic changes present in kidney specimens from patients with such neoplasms, and illustrate 2 patterns of acute tubular injury (ATI) attributable to CGA. Methods Eleven patients with a history of a neoplasm of neuroendocrine derivation or differentiation and having histopathologic sampling of the kidney were retrospectively identified, 3 of whom had ATI with either engorgement of the proximal tubular epithelium by resorbed material or tubular cast formation. Results Two patterns of ATI were observed. One characterized by acutely injured proximal tubular cells engorged with resorption granules that expressed CGA via immunoperoxidase staining. Another pattern was characterized by intraluminal tubular cast material associated with ATI that did not exhibit restriction of immunoglobulin light chains (LCs), but immunoperoxidase staining for CGA revealed that the cast material was composed of the neuroendocrine-associated peptide. The level of serum CGA does not appear to necessarily equate to developing either of these 2 patterns of ATI. Conclusions Patients with a neoplasm of neuroendocrine derivation or differentiation may develop ATI, and in certain cases may be secondary to CGA renal tubular deposition.
Collapse
Affiliation(s)
- Miroslav Sekulic
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Sushrut Waikar
- Division of Nephrology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Shveta S Motwani
- Division of Nephrology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Astrid Weins
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Helmut G Rennke
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| |
Collapse
|
31
|
Zhang WH, Wang WQ, Gao HL, Yu XJ, Liu L. The tumor immune microenvironment in gastroenteropancreatic neuroendocrine neoplasms. Biochim Biophys Acta Rev Cancer 2019; 1872:188311. [PMID: 31442475 DOI: 10.1016/j.bbcan.2019.188311] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 08/15/2019] [Accepted: 08/15/2019] [Indexed: 02/07/2023]
Abstract
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a group of rare tumors that are increasing in prevalence. The complex tumor immune microenvironment (TIME) plays an important role in tumor development and the response to immunotherapy but is poorly understood. In this review, the components of the TIME are described in detail, including discussion about infiltrating immune cells, the immune checkpoint system, the cytokine and chemokine milieu, and immunomodulatory factors. Moreover, a comparison between TIMEs among different types of GEP-NENs and the interplay among the TIME, tumor cells, and the stromal microenvironment is described. Novel treatment options for GEP-NENs and potential biomarkers for the immune response are also characterized. We provide a comprehensive generalized review of the TIME that can inform GEP-NEN treatment strategies.
Collapse
Affiliation(s)
- Wu-Hu Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wen-Quan Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China.
| | - He-Li Gao
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xian-Jun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China.
| | - Liang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China.
| |
Collapse
|
32
|
Abstract
Pancreatic neuroendocrine tumors are a diverse group of neoplasms with a generally favorable prognosis. Although they exhibit indolent growth, metastases are seen in roughly 60% of patients. Pancreatic neuroendocrine tumors may produce a wide variety of hormones, which are associated with dramatic symptoms, but the majority are nonfunctional. The diagnosis and treatment of these tumors is a multidisciplinary effort, and management guidelines continue to evolve. This review provides a concise summary of the presentation, diagnosis, surgical management, and systemic treatment of pancreatic neuroendocrine tumors.
Collapse
Affiliation(s)
- Aaron T. Scott
- Department of Surgery, University of Iowa Carver College of Medicine
| | - James R. Howe
- Department of Surgery, University of Iowa Carver College of Medicine
- Division of Surgical Oncology and Endocrine Surgery
| |
Collapse
|
33
|
Clement DSVM, Tesselaar MET, van Leerdam ME, Srirajaskanthan R, Ramage JK. Nutritional and vitamin status in patients with neuroendocrine neoplasms. World J Gastroenterol 2019; 25:1171-1184. [PMID: 30886501 PMCID: PMC6421241 DOI: 10.3748/wjg.v25.i10.1171] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 02/13/2019] [Accepted: 02/22/2019] [Indexed: 02/06/2023] Open
Abstract
Symptoms of gastroenteropancreatic located neuroendocrine neoplasms (GEP-NENs) are often related to food intake and manifest as abdominal pain or diarrhoea which can influence patients nutritional status. Malnutrition is common in cancer patients and influences quality of life, treatment options and survival but is also present in up to 40% of patients with GEP-NENs. As part of malnutrition there are often deficiencies in fat-soluble vitamins, mainly vitamin D. Little knowledge exists on trace elements. Several factors influence the development of malnutrition such as size and localisation of the primary tumour as well as metastases, side effects from treatment but also hormone production of the tumour itself. One of the main influencing factors leading to malnutrition is diarrhoea which leads to dehydration and electrolyte disturbances. Treatment of diarrhoea should be guided by its cause. Screening for malnutrition should be part of routine care in every GEP-NEN patient. Multidisciplinary treatment including dietician support is necessary for all malnourished patients with GEP-NENs.
Collapse
Affiliation(s)
- Dominique SVM Clement
- Neuroendocrine Tumour Unit, King’s College Hospital ENETS Centre of Excellence, London SE5 9RS, United Kingdom
| | - Margot ET Tesselaar
- Department of Medical Oncology, Netherlands Cancer Institute ENETS Centre of Excellence, Amsterdam 1066 CX, Netherlands
| | - Monique E van Leerdam
- Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam 1066 CX, Netherlands
| | - Rajaventhan Srirajaskanthan
- Neuroendocrine Tumour Unit, King’s College Hospital ENETS Centre of Excellence, London SE5 9RS, United Kingdom
- Department of Gastroenterology, King’s College Hospital, London SE5 9RS, United Kingdom
| | - John K Ramage
- Neuroendocrine Tumour Unit, King’s College Hospital ENETS Centre of Excellence, London SE5 9RS, United Kingdom
| |
Collapse
|
34
|
Jin XF, Spampatti MP, Spitzweg C, Auernhammer CJ. Supportive therapy in gastroenteropancreatic neuroendocrine tumors: Often forgotten but important. Rev Endocr Metab Disord 2018; 19:145-158. [PMID: 29464446 DOI: 10.1007/s11154-018-9443-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Neuroendocrine tumors (NETs) are a group of rare and heterogeneous malignancies that can develop in various organs. A significant number of gastroenteropancreatic neuroendocrine tumours (GEP-NETs) is functionally active and presents with symptoms related to the secretion of biologically active substances, leading to the development of distinct clinical syndromes. There are various therapeutic approaches for GEP-NETs, including curative surgery, palliative surgery, local-ablative and loco-regional therapies as well as systemic therapeutic options including peptide receptor radionuclide therapy, cytotoxic therapy, and molecularly targeted therapies. Specific supportive therapy of patients with NETs includes management or prevention of hormone-related clinical syndromes and paraneoplastic states. Supportive therapy plays a key role in NET treatment. Supportive therapy includes debulking surgery and interventional radiologic techniques to reduce tumour bulk or load, as well as systemic medical treatment options to manage or prevent hypersecretion syndromes and treatment-related side effects. Supportive therapies are a type of of comprehensive treatment addressing the patient as a whole person throughout the process of NET treatment. Therefore, supportive therapy also encompasses psychosocial support, expert nursing, nutritional support and management of cancer related pain.
Collapse
Affiliation(s)
- Xi-Feng Jin
- Department of Internal Medicine IV, University-Hospital Campus Grosshadern, Ludwig-Maximilian University of Munich, Munich, Germany
| | - Matilde P Spampatti
- Department of Internal Medicine II, University-Hospital Campus Grosshadern, Ludwig-Maximilian University of Munich, Munich, Germany
- Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universitaet Muenchen, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Marchioninistr, 15, 81377, Munich, Germany
| | - Christine Spitzweg
- Department of Internal Medicine IV, University-Hospital Campus Grosshadern, Ludwig-Maximilian University of Munich, Munich, Germany
- Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universitaet Muenchen, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Marchioninistr, 15, 81377, Munich, Germany
| | - Christoph J Auernhammer
- Department of Internal Medicine IV, University-Hospital Campus Grosshadern, Ludwig-Maximilian University of Munich, Munich, Germany.
- Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universitaet Muenchen, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Marchioninistr, 15, 81377, Munich, Germany.
| |
Collapse
|
35
|
Abstract
Neuroendocrine neoplasms (NEN) are rare and heterogeneous. Therefore, they often remain unrecognized for many years, causing significant disease burden. We here report on four unusual NEN presentations including a metastatic NEN of the kidney, hypoglycemia caused by an insulin-like growth factor-2-oma (previously called non-islet-cell tumor hypoglycemia), multifocal pheochromocytoma in von Hippel Lindau syndrome, and ileal NEN metastatic to the heart. One could say that each one of these tumors were "black swans" and learning about them will increase further awareness of the spectrum of NEN.
Collapse
Affiliation(s)
- Christian A Koch
- Medicover GmbH, Berlin / Hannover, Germany.
- Carl von Ossietzky University of Oldenburg, Oldenburg, Germany.
- Technical University of Dresden, Dresden, Germany.
- University of Louisville, Louisville, KY, USA.
| | - S Petersenn
- ENDOC Center for Endocrine Tumors, Hamburg, Germany
| |
Collapse
|
36
|
Ariotti R, Partelli S, Muffatti F, Andreasi V, Della Sala F, Falconi M. How should incidental NEN of the pancreas and gastrointestinal tract be followed? Rev Endocr Metab Disord 2018. [PMID: 29527619 DOI: 10.1007/s11154-018-9445-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Neuroendocrine gastro-entero-pancreatic neoplasms (GEP-NENs) constitute a heterogeneous group of tumors, whose incidence has increased over the years. The most frequent site for primary disease is the stomach followed by small and large intestine, and pancreas. In the last decade, a dramatic growing in the incidence of small, incidental GEP-NENs has been recorded. In parallel, an increasing attitude toward more conservative approaches instead of surgical management has being widely spreading. This is particularly true for small, asymptomatic, pancreatic NEN as for these tumor forms an active surveillance has proven to be safe and feasible. Primary site and biological features of the neoplasms lead to different strategies and indications for surveillance and follow-up. This review focuses on the current evidence on modality and timing of surveillance and conservative treatment of incidentally discovered lesions.
Collapse
Affiliation(s)
- Riccardo Ariotti
- Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" University, Via Olgettina 60, 20132, Milan, Italy
| | - Stefano Partelli
- Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" University, Via Olgettina 60, 20132, Milan, Italy
| | - Francesca Muffatti
- Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" University, Via Olgettina 60, 20132, Milan, Italy
| | - Valentina Andreasi
- Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" University, Via Olgettina 60, 20132, Milan, Italy
| | - Francesca Della Sala
- Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" University, Via Olgettina 60, 20132, Milan, Italy
| | - Massimo Falconi
- Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" University, Via Olgettina 60, 20132, Milan, Italy.
| |
Collapse
|
37
|
Petersenn S, Koch CA. Neuroendocrine neoplasms - still a challenge despite major advances in clinical care with the development of specialized guidelines. Rev Endocr Metab Disord 2017; 18:373-378. [PMID: 29480376 DOI: 10.1007/s11154-018-9442-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Stephan Petersenn
- ENDOC Center for Endocrine Tumors, Erik-Blumenfeld-Platz 27a, 22587, Hamburg, Germany.
| | - Christian A Koch
- Medicover Oldenburg MVZ, Oldenburg, Germany
- Department of Medicine III, Technical University of Dresden, Dresden, Germany
- University of Louisville, Louisville, KY, USA
| |
Collapse
|