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Manoharan J, Albers M, Khizanishvili N, Krasser-Gercke N, Schmitt M, Mintziras I, Wächter S, Rinke A, Gao Y, Bartsch JW, Jesinghaus M, Di Fazio P, Bartsch DK. Prognostic value of clinical parameters and exosomal lncRNA NEAT1_1 in MEN1-related non-functioning pancreatic neuroendocrine tumors. J Neuroendocrinol 2025:e70024. [PMID: 40170567 DOI: 10.1111/jne.70024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 02/20/2025] [Accepted: 03/08/2025] [Indexed: 04/03/2025]
Abstract
Non-functioning pancreatic neuroendocrine tumors (NF-pNETs) significantly contribute to the premature death of multiple endocrine neoplasia type 1 (MEN1) patients. Reliable prognostic markers are not yet available. MicroRNAs (miRNA) and long-non-coding (lnc) RNAs, transported by extracellular vesicles, are emerging as new prognostic tools. This study aimed to analyze the clinical characteristics, the exosomal-miRNA 451 (exo-miR451) and the lnc-RNA nuclear paraspeckle assembly transcript 1 (NEAT1_1, 3.7 kB) in the mild and aggressive courses of MEN1-NFpNET disease. Patient characteristics were assessed regarding an aggressive course of disease. In addition, exo-miR451 and exo-lnc-NEAT1_1 expression levels were quantified in serum by RT-qPCR and correlated with clinical data. Immunohistochemistry results of STAT3 (signal transducer and activator of transcription 3), regulated by NEAT1, were performed in NF-pNET tissue and correlated with exo-lnc-NEAT1_1 expression. Among 66 MEN1 patients with NF-pNETs, 13 (20%) had an aggressive disease course. No significant differences in patient characteristics were observed between those with aggressive (n = 13) and mild (n = 53) disease (all p > .5). Exosomal miRNA-451 was dysregulated in 55% (n = 23) of cases, showing a trend toward higher upregulation in the aggressive group (36% vs. 19%), although this difference was not statistically significant (p = .215). Exo-NEAT1_1 was overexpressed in 42% (16/38) of patients, without significant differences between groups (p = .0523). However, exo-NEAT1_1 expression strongly correlated with STAT3 immunohistochemical staining (p = .001). Although no prognostic marker could be identified, we show for the first time that the STAT3-NEAT1 pathway plays a role in MEN1-associated NF-pNET tumorigenesis.
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Affiliation(s)
- Jerena Manoharan
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Max Albers
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Natalia Khizanishvili
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Norman Krasser-Gercke
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Maxime Schmitt
- Department of Pathology, Philipps University Marburg, Marburg, Germany
| | - Ioannis Mintziras
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Sabine Wächter
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Anja Rinke
- Department of Internal Medicine, Division of Gastroenterology and Endocrinology, University Hospital Marburg, Philipps University Marburg, Marburg, Germany
| | - Yutong Gao
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany
| | - Jörg W Bartsch
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany
| | - Moritz Jesinghaus
- Department of Pathology, Philipps University Marburg, Marburg, Germany
| | - Pietro Di Fazio
- Department of Nuclear Medicine, Philipps University Marburg, Marburg, Germany
- Center for Tumor and Immune Biology, Molecular Imaging, Philipps University Marburg, Marburg, Germany
| | - Detlef K Bartsch
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
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Mohsin M, Dube R, Hamza D, Ali M, Garg H. Primary ovarian neuroendocrine neoplasia with concurrent large epithelial borderline ovarian tumor, coexistent with non-malignant pleural effusion and multiple uterine fibroids: a case report and review of the literature. J Med Case Rep 2025; 19:125. [PMID: 40108706 PMCID: PMC11921653 DOI: 10.1186/s13256-025-05170-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 03/05/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Neuroendocrine neoplasms are a group of neoplasms often originating from the neuroendocrine cells in the gastrointestinal tract, pancreas, and respiratory tract. Neuroendocrine neoplasms rarely occur in female reproductive organs and less than a hundred cases of ovarian high-grade lesions have been reported in the literature so far. Fewer still are cases reported in the literature associated with a borderline epithelial tumor in the same ovary. Owing to the rarity of the condition, there is a lack of specific guidelines for staging, and optimal management of these tumors. CASE PRESENTATION We are reporting a case of primary ovarian neuroendocrine neoplasm in association with an epithelial borderline tumor. She is a 50-year-old Filipino woman who presented with nonspecific symptoms. Initial imaging revealed a large mass with suspicion of widespread metastasis. However, further imaging and laparotomy revealed early-stage neuroendocrine neoplasm, a large borderline epithelial tumor, with no evidence of pulmonary metastasis, despite having pleural effusion. She was lost to follow-up, presented again after a year with evidence of residual disease/metastasis, and was treated with chemotherapy. DISCUSSION AND CONCLUSION The case posed significant difficulty owing to a lack of typical symptoms at presentation, nonmalignant changes in lungs in imaging, and therapeutic challenges due to the noncompliance of the patient. This report highlights the importance of considering the combination of borderline tumors of the ovary with neuroendocrine carcinoma as a possible differential diagnosis in ovarian tumors, the use of imaging and specific bio-markers for early identification, timely treatment, and follow-ups.
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Affiliation(s)
- Mariam Mohsin
- Department of Obstetrics and Gynecology, Dubai Health Authority, Dubai, United Arab Emirates
| | - Rajani Dube
- Department of Obstetrics and Gynecology, RAK Medical and Health Sciences University, RAK Medical & Health Science University, Ras Al Khaimah, United Arab Emirates.
| | - Dina Hamza
- Department of Obstetrics and Gynecology, Dubai Health Authority, Dubai, United Arab Emirates
| | - Mavra Ali
- Department of Obstetrics and Gynecology, RAK Medical and Health Sciences University, RAK Medical & Health Science University, Ras Al Khaimah, United Arab Emirates
| | - Heena Garg
- Department of Obstetrics and Gynecology, Al Zahrawi Hospital, Ras Al Khaimah, United Arab Emirates
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Tang X, Liu Z, Song L, Zhu H, Su S, Wang D. Prognostic value of circulating Chromogranin A in prostate cancer: a systematic review and meta-analysis. Front Oncol 2025; 15:1521558. [PMID: 39975592 PMCID: PMC11835686 DOI: 10.3389/fonc.2025.1521558] [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: 11/02/2024] [Accepted: 01/20/2025] [Indexed: 02/21/2025] Open
Abstract
Background There are discrepancies between the results of different studies regarding the prognostic role of circulating Chromogranin A (CgA) in prostate cancer. Therefore, we conducted a meta-analysis of the available findings to explore the value of circulating Chromogranin A in the prognosis of prostate cancer. Methods We systematically searched the PubMed, Embase, Web of Science, Cochrane Library, and Clinical Trials databases for studies on the relationship between CgA and survival outcomes in prostate cancer from inception until December 2024, and we focused on articles detecting circulating CgA, with the primary endpoints of the studies being overall survival (OS), and progression-free survival (PFS). Results Of the 2049 articles retrieved, 10 articles met our inclusion criteria, involving a total of 1445 patients. Elevated circulating CgA was associated with poorer OS (HR=1.82, 95% CI: 1.38-2.41; p<0.001) and PFS (HR=2.04, 95% CI: 1.42-2.94; p<0.001). However, no correlation was found between post-treatment circulating CgA changes and OS (HR=0.95, 95% CI: 0.66-1.37; p=0.767). Conclusion Circulating CgA is a predictive marker of poor survival outcomes in prostate cancer However, the sample size of the current study is small and larger studies are needed to further validate this in the future.
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Affiliation(s)
| | | | | | | | - Shuai Su
- Department of Urology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Delin Wang
- Department of Urology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Fatima A, Chandra S, Fatima S, Izhar MY, Bokhari SFH, Iqbal A. Role of advanced imaging in primary hepatic neuroendocrine tumor with borderline raised AFP and negative chromogranin staining: A case report. Int J Surg Case Rep 2024; 125:110647. [PMID: 39602931 PMCID: PMC11638599 DOI: 10.1016/j.ijscr.2024.110647] [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: 10/26/2024] [Revised: 11/22/2024] [Accepted: 11/22/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Primary hepatic neuroendocrine tumors (PHNETs) are rare, accounting for approximately 0.3 % of all neuroendocrine tumors (NETs) and are often difficult to diagnose due to their nonspecific symptoms and imaging features. Standard diagnostic and treatment protocols are lacking due to their rarity, but imaging and immunohistochemistry (IHC) remain key tools for diagnosis. CASE REPORT A 68-year-old male presented with abdominal discomfort and loss of appetite. Imaging revealed a large exophytic mass in the left lobe of the liver. After ruling out extrahepatic primary sources, a left lobe hepatectomy was performed. Histopathology confirmed the diagnosis of PHNET, with positive IHC staining for synaptophysin and CK-7. Postoperative PET-CT ruled out any distant metastases. The patient had an uneventful recovery. DISCUSSION PHNETs are believed to originate from ectopic neuroendocrine cells in the liver, though several theories exist. Imaging alone cannot conclusively diagnose PHNETs, as they mimic other hepatic tumors like hepatocellular carcinoma. Histopathological examination, along with IHC markers like chromogranin and synaptophysin, is essential for diagnosis. Surgical resection remains the treatment of choice, with good outcomes despite the risk of recurrence. Non-surgical therapies, such as chemotherapy or ablation, are under investigation but lack consensus. CONCLUSION PHNETs are rare and challenging to diagnose, requiring imaging and IHC for confirmation. Surgery offers the best prognosis, making personalized, surgery-centered treatment plans essential for management. Comprehensive follow-up, including functional imaging, is necessary to monitor recurrence or metastasis.
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Affiliation(s)
- Asma Fatima
- Department of General Surgery, Vikarabad Government Medical College, India
| | - Suresh Chandra
- Department of Surgical Gastroenterology, Deccan College of Medical Sciences, India
| | - Saubia Fatima
- Department of Radiology, Deccan College Of Medical Sciences, India
| | | | | | - Asma Iqbal
- MBBS, King Edward Medical University, Mayo Hospital, Lahore, Pakistan.
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Franchina M, Cavalcoli F, Falco O, La Milia M, Elvevi A, Massironi S. Biochemical Markers for Neuroendocrine Tumors: Traditional Circulating Markers and Recent Development-A Comprehensive Review. Diagnostics (Basel) 2024; 14:1289. [PMID: 38928704 PMCID: PMC11203125 DOI: 10.3390/diagnostics14121289] [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: 05/08/2024] [Revised: 06/13/2024] [Accepted: 06/15/2024] [Indexed: 06/28/2024] Open
Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms presenting unique challenges in diagnosis and management. Traditional markers such as chromogranin A (CgA), pancreatic polypeptide (PP), and neuron-specific enolase (NSE) have limitations in terms of specificity and sensitivity. Specific circulating markers such as serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) and various gastrointestinal hormones such as gastrin, glucagon, somatostatin, and vasoactive intestinal peptide (VIP) have a role in identifying functional NENs. Recent advances in molecular and biochemical markers, also accounting for novel genomic and proteomic markers, have significantly improved the landscape for the diagnosis and monitoring of NENs. This review discusses these developments, focusing on both traditional markers such as CgA and NSE, as well as specific hormones like gastrin, insulin, somatostatin, glucagon, and VIP. Additionally, it covers emerging genomic and proteomic markers that are shaping current research. The clinical applicability of these markers is highlighted, and their role in improving diagnostic accuracy, predicting surgical outcomes, and monitoring response to treatment is demonstrated. The review also highlights the need for further research, including validation of these markers in larger studies, development of standardized assays, and integration with imaging techniques. The evolving field of biochemical markers holds promise for improving patient outcomes in the treatment of NENs, although challenges in standardization and validation remain.
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Affiliation(s)
- Marianna Franchina
- Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
| | - Federica Cavalcoli
- Gastroenterology and Digestive Endoscopy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Olga Falco
- Department of Medicine and Surgery, University of Milano-Bicocca, 20126 Milan, Italy
| | - Marta La Milia
- Department of Medicine and Surgery, University of Milano-Bicocca, 20126 Milan, Italy
| | - Alessandra Elvevi
- Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
| | - Sara Massironi
- Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
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Xing Y, Shi H, Guo Q, Wang C, Li C, Hao C. Chromogranin A as a diagnostic marker of pheochromocytoma and paraganglioma: A systematic review and meta-analysis. Int J Urol 2024; 31:637-645. [PMID: 38380475 DOI: 10.1111/iju.15423] [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: 10/30/2023] [Accepted: 01/31/2024] [Indexed: 02/22/2024]
Abstract
OBJECTIVES This work aims to assess the diagnostic value of chromogranin A (CgA) in the laboratory diagnosis of neuroendocrine tumors classified as pheochromocytoma and paraganglioma (PPGL). METHODS A comprehensive search was performed in PubMed, Embase, the Cochrane Library, and Web of Science databases to obtain relevant studies reporting the diagnostic accuracy of CgA in patients with PPGL. The search involved studies written in English between the time of library inception and May 1, 2023. We computed the pooled sensitivity, specificity, and diagnostic odds ratio (DOR). Additionally, the receiver operating characteristic curve and area under the curve (AUC) were determined. The heterogeneity was assessed using the Chi-square test and the I2 test. The subgroup analyses were performed to investigate the origins of heterogeneity. Stata 15.1 statistical software was used in all data analyses. RESULTS This meta-analysis included 13 studies involving 1470 patients. CgA had a pooled diagnostic sensitivity of 0.86 (95% CI 0.81-0.91), a specificity of 0.90 (95% CI 0.81-0.95), and a DOR of 57 (95% CI 23-142). CgA had an AUC of 0.93. The studies did not reveal any threshold effect (r = -0.165; p > 0.05). The subgroup analyses revealed that the control group category and the detection method caused the overall heterogeneity. CONCLUSIONS Our study suggests that CgA is a helpful PPGL biomarker. However, relying solely on CgA for diagnosis is not advisable. A comprehensive approach is essential for accurate diagnosis. Future large-scale research is needed to refine CgA's clinical application.
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Affiliation(s)
- Yanbo Xing
- Department of Urology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
- Second Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Haoying Shi
- Department of Urology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
- Second Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Qiang Guo
- Department of Urology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Cong Wang
- Department of Urology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
- Second Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Chengyong Li
- Department of Urology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Chuan Hao
- Department of Urology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
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Saeed A, Abuzaid Y, Hammad M. Prevalence of, Subtypes of, and the Role of Age in Incidental Appendiceal Neoplasms in Acute Appendicitis: A Single-Institute Study from Bahrain. Cureus 2024; 16:e60150. [PMID: 38864054 PMCID: PMC11166375 DOI: 10.7759/cureus.60150] [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] [Accepted: 05/12/2024] [Indexed: 06/13/2024] Open
Abstract
INTRODUCTION Primary appendiceal neoplasms (ANs) are rare entities that can present with acute appendicitis symptoms. Accurate diagnosis of these diverse subtypes is crucial for prognosis and proper management. AIMS AND OBJECTIVES This descriptive retrospective study aims to determine the prevalence and pathological subtypes of incidental ANs in patients presenting with acute appendicitis symptoms at Salmaniya Medical Center (SMC) in Bahrain between the period of January 2020 and March 2024. Particular focus was placed on investigating whether advanced age is a significant risk factor for these neoplasms. MATERIALS AND METHODS The study included 38,643 patients (aged 15 years and above) who underwent appendectomy for suspected acute appendicitis during the study period. Demographic data, clinical diagnoses, preoperative imaging findings, histopathological reports, and management details were analyzed. Medical records of patients were retrieved from ISEHA system. Statistical analysis was done using Microsoft Excel. RESULTS The results showed that 12 patients (0.04% per year) had different subtypes of appendiceal tumors. Neuroendocrine tumors were the most common, identified in nine patients (75%), including nine cases of well-differentiated neuroendocrine carcinoma (NEC). Other histopathological subtypes included low-grade appendiceal mucinous neoplasm (LAMN), adenocarcinoma, and goblet cell adenocarcinoma, each found in one patient. Additionally, two patients had confirmed appendiceal mucocele. The mean age of patients with ANs was 30 years (range: 19-52 years), and 66.6% were younger than 38 years. Conclusion: These findings highlight the importance of considering ANs in the differential diagnosis of acute appendicitis, especially in older patients. Further research is warranted to confirm the role of age as a risk factor and guide clinical decision-making.
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Affiliation(s)
- Ahmed Saeed
- Surgery, Salmaniya Medical Complex, Manama, BHR
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Kidess E, Giesecke Y, Eichhorn I, Mohr R, Jann H, Fischer C, Wiedenmann B, Roderburg C, Tacke F, Sigal M. Osteopontin is a prognostic circulating biomarker in patients with neuroendocrine neoplasms. J Cancer Res Clin Oncol 2023; 149:10925-10933. [PMID: 37318593 PMCID: PMC10423109 DOI: 10.1007/s00432-023-04979-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Accepted: 06/07/2023] [Indexed: 06/16/2023]
Abstract
PURPOSE Osteopontin (OPN), also called secreted phosphoprotein 1 (SPP1) is a matricellular glycoprotein whose expression is elevated in various types of cancer and which has been shown to be involved in tumorigenesis and metastasis in many malignancies. Its role in neuroendocrine neoplasms (NEN) remains to be established. The aim of the study was to analyze plasma concentrations of OPN in patients with NEN and to explore its diagnostic and prognostic value as a clinical biomarker. METHODS OPN plasma concentrations were measured in a total of 38 patients with histologically proven NEN at three different time points during the course of disease and therapy (at the start of the study, after 3 and 12 months, respectively) as well as in healthy controls. Clinical and imaging data as well as concentrations of Chromogranin A (CgA) and Neuron Specific Enolase (NSE) were assessed. RESULTS OPN levels were significantly higher in patients with NEN compared to healthy controls. High-grade tumors (grade 3) showed the highest OPN levels. OPN levels were neither different between male and female patients nor between different primary tumor sites. OPN correlated significantly with corresponding NSE levels, while there was no correlation with Chromogranin A. High OPN levels above a cutoff value of 200 ng/ml at initial analysis predicted a worsened prognosis with significantly shorter progression-free survival of patients with NEN, which also held true within the subgroup of well-differentiated G1/G2 tumors. CONCLUSION Our data indicate that high baseline OPN levels in patients with NEN are predictive of an adverse outcome with shorter progression-free survival, even within the group of well differentiated G1/G2 tumors. Therefore, OPN may be used as a surrogate prognostic biomarker in patients with NEN.
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Affiliation(s)
- Evelyn Kidess
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany.
| | - Yvonne Giesecke
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany
| | - Ines Eichhorn
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany
| | - Raphael Mohr
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany
| | - Henning Jann
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany
| | - Christian Fischer
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany
| | - Bertram Wiedenmann
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany
| | - Christoph Roderburg
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany
| | - Michael Sigal
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany.
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Haruma K, Kinoshita Y, Yao T, Kushima R, Akiyama J, Aoyama N, Kanoo T, Miyata K, Kusumoto N, Uemura N. Randomised clinical trial: 3-year interim analysis results of the VISION trial to evaluate the long-term safety of vonoprazan as maintenance treatment in patients with erosive oesophagitis. BMC Gastroenterol 2023; 23:139. [PMID: 37127558 PMCID: PMC10152792 DOI: 10.1186/s12876-023-02772-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 04/18/2023] [Indexed: 05/03/2023] Open
Abstract
BACKGROUND VISION is a randomised, phase 4, open-label, parallel-group, multicentre study conducted in 33 centres in Japan. The aim of this study was to assess the long-term safety of vonoprazan for maintenance treatment of healed erosive oesophagitis versus lansoprazole. METHODS Patients with endoscopically diagnosed erosive oesophagitis were randomised 2:1 to once-daily vonoprazan 20 mg or lansoprazole 30 mg, for a 4- to 8-week healing phase. Patients with endoscopically confirmed healing entered a 260-week maintenance phase with a once-daily starting dose of vonoprazan 10 mg or lansoprazole 15 mg. Primary endpoint was change in gastric mucosal histopathology. RESULTS Of 208 patients (vonoprazan, n = 139; lansoprazole, n = 69) entering the healing phase, 202 entered the maintenance phase (vonoprazan, n = 135; lansoprazole, n = 67). At 3 years, 109 vonoprazan-treated and 58 lansoprazole-treated patients remained on treatment. Histopathological evaluation of gastric mucosa showed that hyperplasia of parietal, foveolar and G cells was more common with vonoprazan than lansoprazole at week 156 of the maintenance phase. There was no marked increase in the occurrence of parietal, foveolar and G cell hyperplasia among patients in the vonoprazan group from week 48 to week 156. Histopathological evaluation of the gastric mucosa also showed no neoplastic changes in either group. No new safety issues were identified. CONCLUSIONS In this interim analysis of VISION, no new safety concerns were identified in Japanese patients with healed erosive oesophagitis receiving vonoprazan or lansoprazole as maintenance treatment for 3 years. (CT.gov identifier: NCT02679508; JapicCTI-163153; Japan Registry of Clinical Trials: jRCTs031180040).
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Affiliation(s)
- Ken Haruma
- Department of General Internal Medicine 2, Kawasaki Medical School, General Medical Center, Okayama, Japan
| | - Yoshikazu Kinoshita
- General Internal Medicine, Hyogo Prefectural Harima-Himeji General Medical Center, Himeji, Hyogo, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ryoji Kushima
- Department of Clinical Laboratory Medicine, Shiga University of Medical Science Hospital, Otsu, Shiga, Japan
| | - Junichi Akiyama
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Nobuo Aoyama
- GI Endoscopy and IBD Center, Aoyama Medical Clinic, Kobe, Hyogo, Japan
| | | | | | | | - Naomi Uemura
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Kohnodai Hospital, Ichikawa, Chiba, Japan
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Management of Small Nonfunctioning Pancreatic Neuroendocrine Neoplasms: Current Opinion and Controversies. J Clin Med 2022; 12:jcm12010251. [PMID: 36615051 PMCID: PMC9821009 DOI: 10.3390/jcm12010251] [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: 12/07/2022] [Revised: 12/21/2022] [Accepted: 12/27/2022] [Indexed: 12/31/2022] Open
Abstract
The incidence of small and asymptomatic pancreatic neuroendocrine neoplasms (PNENs) has increased due to the widespread use of high-resolution diagnostic imaging in screening programs. Most PNENs are slow-growing indolent neoplasms. However, a local invasion or metastasis can sometimes occur with PNENs, leading to a poor prognosis. The management of small, nonfunctioning PNENs remains under debate. The National Comprehensive Cancer Network guidelines recommend observation in selected cases of small PNENs less than 2 cm. Pancreatic surgery remains a high-risk operation with a 28-30% morbidity and 1% mortality. Therefore, the decision on how to manage small PNENs is challenging. This review focuses on the management of small nonfunctioning PNENs. We also highlight the malignant potential of small PNENs according to tumor size, tumor grade, and tumor biomarker. Endoscopic-ultrasound-guided biopsy is recommended to evaluate the potential risk of malignancy. Furthermore, we discuss the current guidelines and future directions for the management of small PNENs.
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11
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Koehler K, Iams WT. Carcinoid tumors outside the abdomen. Cancer Med 2022; 12:7893-7903. [PMID: 36560885 PMCID: PMC10134339 DOI: 10.1002/cam4.5564] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 12/06/2022] [Accepted: 12/13/2022] [Indexed: 12/24/2022] Open
Abstract
Neuroendocrine tumors (NETs) are epithelial malignancies that can arise from multiple tissues. Gastrointestinal (GI) NETs are the most common; in this review of extra-abdominal carcinoid tumors, we focus our discussion on bronchial and thymic carcinoid tumors. Bronchial carcinoid tumors comprise a quarter of all NETs and less than 2% of all lung cancers. Thymic carcinoid tumors are extremely rare, accounting for 5% of thymic tumors. Both bronchial and thymic carcinoid tumors are histologically classified as either typical or atypical based on their mitotic rate (less than 2 or 2-10 mitoses per 10 high-powered fields (HPF), respectively). Both bronchial and thymic carcinoids can present with symptoms of obstruction and potentially carcinoid syndrome. The gold standard of management of bronchial and thymic carcinoid tumors is surgical resection. For patients with advanced disease, first-line systemic therapy is generally somatostatin analog monotherapy with octreotide or lanreotide. In patients with refractory disease, therapy generally involves peptide receptor radioligand therapy, everolimus, or cytotoxic chemotherapy. There are ongoing, prospective trials comparing the mainstays of systemic therapy for these patients, as well as ongoing evaluations of immune checkpoint inhibitors and multi-kinase inhibitors. Prognosis for both bronchial and thymic carcinoid tumors depends on histologic grade, local versus invasive disease, and extent of metastases. Herein we provide a summary of the pathophysiologic and clinical background, the current state of the field in diagnosis and management, and note of key ongoing prospective trials for patients with bronchial and thymic carcinoid tumors.
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Affiliation(s)
- Kenna Koehler
- Department of Medicine, Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Wade T Iams
- Department of Medicine, Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.,Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA
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12
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Lyubimova NV, Timofeev YS, Markovich AA, Lebedeva AV, Karamisheva EI, Delektorskaya VV, Kushlinskii NE. Chromogranin B in blood serum of patients with neuroendocrine tumors. Klin Lab Diagn 2022; 67:440-443. [PMID: 36095079 DOI: 10.51620/0869-2084-2022-67-8-440-443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms from cells of the diffuse neuroendocrine system. Chromogranin B (CgB) is an acidic protein of the granin family, which can be used to detect the tumours of neuroendocrine nature. Analysis of levels and evaluation of the diagnostic efficiency of CgB in the blood serum of patients with NETs of various localizations. Patients with NETs (n=121) without specific treatment were examined. In the study were presented next localizations: 74 - pancreas, 20 - stomach, 12 - large intestine, 15 - other localizations (lungs, mammary gland, prostate gland, NETs with unidentified primary). 54 practically healthy donors were examined as control group. The determination of CgB in blood serum was performed with ELISA method on BEP 2000 analyzer using a standardized test system Human Chromogranin B (USCN, China). CgB levels in common NET group (median 18.9 ng/mL) were statistically significantly higher than in the control group (8.8 ng/mL). The highest median was obtained in group of intestinal NETs (21.2 ng/ml), which exceeded the median of the control group by more than 2.4 times. According to ROC analysis in the common NET group relative to the control group, the area under the curve AUC was 0.88 (95% CI 0.83-0.929). According to cut-off level of CgB - 15.8 ng/ml, the diagnostic sensitivity was 69.4%, with a specificity of 96.3%. The highest diagnostic sensitivity was in the group of the intestinal NETs (75.0%) and pancreas (71.2%). The study showed the significance of CgB as a potential biochemical marker of NETs with various localizations, alternative to CgA.
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Affiliation(s)
| | - Yu S Timofeev
- N.N. Blokhin National Medical Research Center of Oncology
| | - A A Markovich
- N.N. Blokhin National Medical Research Center of Oncology
| | - A V Lebedeva
- N.N. Blokhin National Medical Research Center of Oncology
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13
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Neuroendocrine Neoplasms of the Gynecologic Tract. Cancers (Basel) 2022; 14:cancers14071835. [PMID: 35406607 PMCID: PMC8998008 DOI: 10.3390/cancers14071835] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 04/01/2022] [Accepted: 04/01/2022] [Indexed: 01/11/2023] Open
Abstract
Simple Summary Neuroendocrine refers to the cells that synthesize and secrete messenger chemicals such as neuropeptides and amines. Neuroendocrine neoplasms (NENs) are aggressive tumors arising from neuroendocrine cells, with an annual incidence of 6.98/100,000 and a prevalence of 170,000 in the United States. Primary gynecologic NENs constitute ≤2% of female reproductive tumors. NENs of the gynecologic tract are associated with high recurrence rates and dismal prognosis, making their treatment challenging. This article focuses on the updated staging classifications, clinicopathological characteristics, imaging, and management of NENs of the gynecological tract. Abstract Gynecological tract neuroendocrine neoplasms (NEN) are rare, aggressive tumors from endocrine cells derived from the neuroectoderm, neural crest, and endoderm. The primary gynecologic NENs constitute 2% of gynecologic malignancies, and the cervix is the most common site of NEN in the gynecologic tract. The updated WHO classification of gynecologic NEN is based on the Ki-67 index, mitotic index, and tumor characteristics such as necrosis, and brings more uniformity in the terminology of NENs like other disease sites. Imaging plays a crucial role in the staging, triaging, restaging, and surveillance of NENs. The expression of the somatostatin receptors on the surface of neuroendocrine cells forms the basis of increasing evaluation with functional imaging modalities using traditional and new tracers, including 68Ga-DOTA-Somatostatin Analog-PET/CT. Management of NENs involves a multidisciplinary approach. New targeted therapies could improve the paradigm of care for these rare malignancies. This article focuses on the updated staging classifications, clinicopathological characteristics, imaging, and management of gynecologic NENs of the cervix, ovary, endometrium, vagina, and vulva, emphasizing the relatively common cervical neuroendocrine carcinomas among these entities.
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14
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Capdevila J, Grande E, García-Carbonero R, Simó M, del Olmo-García MI, Jiménez-Fonseca P, Carmona-Bayonas A, Pubul V. Position Statement on the Diagnosis, Treatment, and Response Evaluation to Systemic Therapies of Advanced Neuroendocrine Tumors, With a Special Focus on Radioligand Therapy. Oncologist 2022; 27:e328-e339. [PMID: 35380724 PMCID: PMC8982404 DOI: 10.1093/oncolo/oyab041] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 10/08/2021] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND The aim of this study was to provide a guidance for the management of neuroendocrine tumors (NETs) in clinical practice. MATERIAL AND METHODS Nominal group and Delphi techniques were used. A steering committee of 8 experts reviewed the current management of NETs, identified controversies and gaps, critically analyzed the available evidence, and formulated several guiding statements for clinicians. Subsequently, a panel of 26 experts, was selected to test agreement with the statements through 2 Delphi rounds. Items were scored on a 4-point Likert scale from 1 = totally agree to 4 = totally disagree. The agreement was considered if ≥75% of answers pertained to Categories 1 and 2 (consensus with the agreement) or Categories 3 and 4 (consensus with the disagreement). RESULTS Overall, 132 statements were proposed, which incorporated the following areas: (1) overarching principles; (2) progression and treatment response criteria; (3) advanced gastro-enteric NETs; (4) advanced pancreatic NETs; (5) advanced NETs in other locations; (6) re-treatment with radioligand therapy (RLT); (7) neoadjuvant therapy. After 2 Delphi rounds, only 4 statements lacked a clear consensus. RLT was not only recommended in the sequencing of different NETs but also as neoadjuvant treatment, while several indications for retreatment with RLT were also established. CONCLUSION This document sought to pull together the experts' attitudes when dealing with different clinical scenarios of patients suffering from NETs, with RLT having a specific role where evidence-based data are limited.
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Affiliation(s)
- Jaume Capdevila
- Department of Medical Oncology, Vall Hebron University Hospital, Vall Hebron Institute of Oncology (VHIO), IOB-Quiron-Teknon Barcelona, Barcelona, Spain
| | - Enrique Grande
- Department of Medical Oncology, MD Anderson Cancer Center, Madrid, Spain
| | | | - Marc Simó
- Department of Nuclear Medicine and Molecular Imaging, Hospital Universitari Vall d’Hebron, Barcelona, Spain
| | - Mª Isabel del Olmo-García
- Department of Endocrinology, Hospital Universitario y Politécnico la Fe de Valencia, Valencia, Spain
| | - Paula Jiménez-Fonseca
- Department of Medical Oncology, Hospital Universitario Central de Asturias, ISPA, Madrid, Spain
| | - Alberto Carmona-Bayonas
- Department of Hematology and Medical Oncology, Hospital General Universitario Morales Meseguer, University of Murcia, IMIB, CP13/00126, PI17/0050 (ISCIII & FEDER) and Fundación Séneca (04515/GERM/06), Murcia, Spain
| | - Virginia Pubul
- Department of Nuclear Medicine Department and Molecular Imaging Research Group, University Hospital and Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
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15
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Tsai HJ, Hsiao CF, Chang JS, Chen LT, Chao YJ, Yen CJ, Shan YS. The Prognostic and Predictive Role of Chromogranin A in Gastroenteropancreatic Neuroendocrine Tumors - A Single-Center Experience. Front Oncol 2021; 11:741096. [PMID: 34868938 PMCID: PMC8632826 DOI: 10.3389/fonc.2021.741096] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 10/28/2021] [Indexed: 11/13/2022] Open
Abstract
Chromogranin A (CgA) is a non-specific biomarker excreted by neuroendocrine tumor (NET) cells. Elevation of circulating CgA level can be detected in gastroenteropancreatic (GEP)-NET patients and has been shown to correlate with tumor burden. The prognostic and predictive roles of CgA level and the change of CgA level are controversial. In this study, we retrospectively analyzed 102 grade 1/2 GEP-NET patients with available baseline or serial follow-up CgA levels from the National Cheng Kung University Hospital to evaluate the association between circulating CgA level and the tumor extent, overall survival (OS), and tumor response prediction. The baseline characteristics, baseline CgA level, and change of CgA level during follow-up and their association was analyzed. Sixty cases had baseline CgA levels available prior to any treatment and ninety-four cases had serial follow-up CgA levels available during treatment or surveillance. Baseline CgA levels were associated with stage and sex. Higher baseline CgA levels were associated with worse OS after adjusting for sex, stage, grade, primary site, and functionality (hazard ratio=13.52, 95% confidence interval (CI), 1.06-172.47, P=0.045). The cross-sectional analysis for the change of CgA level during follow-up showed that a ≥ 40% increase of CgA meant a higher probability of developing tumor progression or recurrence than those with a < 40% increase of CgA level (odds ratio=5.04, 95% CI, 1.31-19.4, P=0.019) after adjusting for sex, age, grade, stage, and functionality. Our study results suggest that CgA may be a predictive marker for tumor burden, OS, and tumor progression in GEP-NET patients.
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Affiliation(s)
- Hui-Jen Tsai
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.,Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Chin-Fu Hsiao
- Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan
| | - Jeffrey S Chang
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
| | - Li-Tzong Chen
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.,Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ying-Jui Chao
- Division of General Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Ju Yen
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yan-Shen Shan
- Division of General Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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16
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Ciobanu OA, Martin S, Fica S. Perspectives on the diagnostic, predictive and prognostic markers of neuroendocrine neoplasms (Review). Exp Ther Med 2021; 22:1479. [PMID: 34765020 PMCID: PMC8576627 DOI: 10.3892/etm.2021.10914] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 09/23/2021] [Indexed: 12/15/2022] Open
Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous group of rare tumors with different types of physiology and prognosis. Therefore, prognostic information, including morphological differentiation, grade, tumor stage and primary location, are invaluable and contribute to the formulation of treatment decisions. Biomarkers that are currently used, including chromogranin A (CgA), serotonin and neuron-specific enolase, are singular parameters that cannot be used to accurately predict variables associated with tumor growth, including proliferation, metabolic rate and metastatic potential. In addition, site-specific biomarkers, such as insulin and gastrin, cannot be applied to all types of NENs. The clinical application of broad-spectrum markers, as it is the case for CgA, remains controversial despite being widely used. Due to limitations of the currently available mono-analyte biomarkers, recent studies were conducted to explore novel parameters for NEN diagnosis, prognosis, therapy stratification and evaluation of treatment response. Identification of prognostic factors for predicting NEN outcome is a critical requirement for the planning of adequate clinical management. Advances in ‘liquid’ biopsies and genomic analysis techniques, including microRNA, circulating tumor DNA or circulating tumor cells and sophisticated biomathematical analysis techniques, such as NETest or molecular image-based biomarkers, are currently under investigation as potentially novel tools for the management of NENs in the future. Despite these recent findings yielding promising observations, further research is necessary. The present review therefore summarizes the existing knowledge and recent advancements in the exploration of biochemical markers for NENs, with focus on gastroenteropancreatic-neuroendocrine tumors.
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Affiliation(s)
- Oana Alexandra Ciobanu
- Department of Endocrinology and Diabetes, Elias Hospital, 011461 Bucharest, Romania.,Department of Endocrinology, Carol Davila University of Medicine and Pharmacy, 20021 Bucharest, Romania
| | - Sorina Martin
- Department of Endocrinology and Diabetes, Elias Hospital, 011461 Bucharest, Romania.,Department of Endocrinology, Carol Davila University of Medicine and Pharmacy, 20021 Bucharest, Romania
| | - Simona Fica
- Department of Endocrinology and Diabetes, Elias Hospital, 011461 Bucharest, Romania.,Department of Endocrinology, Carol Davila University of Medicine and Pharmacy, 20021 Bucharest, Romania
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17
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Yozgat A, Kekilli M, Altay M. Time to give up traditional methods for the management of gastrointestinal neuroendocrine tumours. World J Clin Cases 2021; 9:8627-8646. [PMID: 34734042 PMCID: PMC8546836 DOI: 10.12998/wjcc.v9.i29.8627] [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: 02/20/2021] [Revised: 05/19/2021] [Accepted: 08/24/2021] [Indexed: 02/06/2023] Open
Abstract
Neuroendocrine tumors (NETs) are a rare and heterogeneous disease group and constitute 0.5% of all malignancies. The annual incidence of NETs is increasing worldwide. The reason for the increase in the incidence of NETs is the detection of benign lesions, incidental detection due to the highest use of endoscopic and imaging procedures, and higher recognition rates of pathologists. There have been exciting developments regarding NET biology in recent years. Among these, first of all, somatostatin receptors and downstream pathways in neuroendocrine cells have been found to be important regulatory mechanisms for protein synthesis, hormone secretion, and proliferation. Subsequently, activation of the mammalian target of rapamycin pathway was found to be an important mechanism in angiogenesis and tumor survival and cell metabolism. Finally, the importance of proangiogenic factors (platelet-derived growth factor, vascular endothelial growth factor, fibroblastic growth factor, angiopoietin, and semaphorins) in the progression of NET has been determined. Using the combination of biomarkers and imaging methods allows early evaluation of the appropriateness of treatment and response to treatment.
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Affiliation(s)
- Ahmet Yozgat
- Department of Gastroenterology, Ufuk University, Ankara, 06510, Turkey
| | - Murat Kekilli
- Department of Gastroenterology, Gazi University, Ankara 06560, Turkey
| | - Mustafa Altay
- Department of Endocrinology and Metabolism, University of Health Sciences Turkey, Keçiören Health Administration and Research Center, Ankara 06190, Turkey
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18
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Do MY, Jang SI, Kang HP, Kim EJ, Lee KJ, Park GE, Lee SJ, Lee DK, Woo SM, Cho JH. Comparison of the Clinical Features and Outcomes of Gallbladder Neuroendocrine Carcinoma with Those of Adenocarcinoma: A Propensity Score-Matched Analysis. Cancers (Basel) 2021; 13:cancers13184713. [PMID: 34572940 PMCID: PMC8471353 DOI: 10.3390/cancers13184713] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/16/2021] [Accepted: 09/18/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Neuroendocrine neoplasms (NENs) of the gallbladder (GB) are extremely rare. We aimed to compare the clinical features of GB-NENs with those of adenocarcinomas (ADCs) of the GB. Among 21 patients with GB-NENs, 20 were diagnosed with poorly differentiated small-cell neuroendocrine carcinoma (NEC), and 1 patient had large-cell NEC. At initial presentation, all patients had advanced stages of cancer, with extensive local extension and/or distant metastasis. Nine patients with GB-NEC who underwent surgical resection had a significantly better progression-free survival (PFS) than those who did not undergo surgery. After a propensity score matching with a 1:1 ratio using the American Joint Committee on Cancer (AJCC) stage, age, sex, and operation status, there was no difference in the overall survival or PFS between AJCC stage-matched patients with GB-NEC or GB-ADC. In conclusion, GB-NEC is difficult to diagnose early and has a prognosis similar to that of GB-ADC. Abstract Neuroendocrine neoplasms (NENs) of the gallbladder (GB) are extremely rare. We aimed to compare the clinical features, disease progression, management, and prognosis of patients with GB-NENs with those of patients with GB-adenocarcinomas (ADCs). A total of 21 patients with GB-NENs and 206 patients with GB-ADCs, treated at three tertiary medical centers between January 2010 and December 2020, were enrolled. Of the 21 patients with GB-NENs, 20 were diagnosed with poorly differentiated small-cell neuroendocrine carcinomas (NECs), and 1 patient had large-cell NEC. All patients presented with advanced stages of cancer with extensive local extension and/or distant metastasis and non-specific symptoms. Tumor-node-metastasis stage IIIB and IV (A/B) tumors were found in 6 and 15 (1/14) patients, respectively. Nine patients with GB-NEC who underwent surgical resection had a significantly better progression-free survival (PFS) than those who did not undergo surgery. After a propensity score matching with a 1:1 ratio using the American Joint Committee on Cancer stage, age, sex, and operation status, 19 pairs of patients were included. Compared with stage-matched patients with GB-ADC, patients with GB-NEC had similar overall survival and PFS. However, as GB-NEC is rarely diagnosed early, further studies investigating methods for the early diagnosis and improvement in the survival of patients with GB-NEC are needed.
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Affiliation(s)
- Min-Young Do
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea; (M.-Y.D.); (S.-I.J.); (D.-K.L.)
| | - Sung-Ill Jang
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea; (M.-Y.D.); (S.-I.J.); (D.-K.L.)
| | - Hua-Pyong Kang
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon 21565, Korea; (H.-P.K.); (E.-J.K.)
| | - Eui-Joo Kim
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon 21565, Korea; (H.-P.K.); (E.-J.K.)
| | - Kyong-Joo Lee
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju 26426, Korea;
| | - Go-Eun Park
- Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul 06273, Korea; (G.-E.P.); (S.-J.L.)
| | - Su-Jee Lee
- Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul 06273, Korea; (G.-E.P.); (S.-J.L.)
| | - Dong-Ki Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea; (M.-Y.D.); (S.-I.J.); (D.-K.L.)
| | - Sang-Myung Woo
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang 10408, Korea
- Correspondence: (S.-M.W.); (J.-H.C.)
| | - Jae-Hee Cho
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea; (M.-Y.D.); (S.-I.J.); (D.-K.L.)
- Correspondence: (S.-M.W.); (J.-H.C.)
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Abstract
Surgical management of pancreatic neuroendocrine tumors (PNETS) is steadily evolving and is influenced by multiple factors. Sporadic PNETs are generally managed more aggressively than those occurring in the background of hereditary syndromes, and functioning PNETs are almost always resected if they are not metastatic. Localized nonfunctioning PNETs less than 2 cm can often be observed. Surgical resection for localized PNET greater than 2 cm comprises parenchymal sparing pancreas resections, such as enucleations, or formal anatomic resection, such as distal pancreatectomy or pancreaticoduodenectomy. PNETs commonly metastasize to the liver, and several systemic and liver-directed options to treat hepatic metastases are available.
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20
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Lazebnik LB, Sarsenbaeva AS, Avalueva EB, Oreshko LS, Sitkin SI, Golovanova EV, Turkina SV, Khlynova OV, Sagalova OI, Mironchev OV. Clinical guidelines “Chronic diarrhea in adults”. EXPERIMENTAL AND CLINICAL GASTROENTEROLOGY 2021:7-67. [DOI: 10.31146/1682-8658-ecg-188-4-7-67] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Affiliation(s)
- L. B. Lazebnik
- Federal State Budgetary Educational Institution of Higher Education “A. I. Yevdokimov Moscow State University of Medicine and Dentistry” of the Ministry of Healthcare of the Russion Federation
| | | | - E. B. Avalueva
- North-Western state medical University named after I. I. Mechnikov, Ministry of health of the Russian Federation
| | - L. S. Oreshko
- North-Western state medical University named after I. I. Mechnikov, Ministry of health of the Russian Federation
| | - S. I. Sitkin
- North- Western state medical University named after I. I. Mechnikov, Ministry of health of the Russian Federation;
Federal State Budgetary Institution “Almazov National Medical Research Centre” of the Ministry of Health of the Russian Federation
| | - E. V. Golovanova
- Federal State Budgetary Educational Institution of Higher Education “A. I. Yevdokimov Moscow State University of Medicine and Dentistry” of the Ministry of Healthcare of the Russion Federation
| | - S. V. Turkina
- State-funded Educational Establishment of Higher Professional Education “Volgograd State Medical University of the Ministry of Public Health of the Russian Federation”
| | - O. V. Khlynova
- Perm State Medical University named after academician E. A. Vagner Ministry of Health care of Russia
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Papantoniou D, Grönberg M, Landerholm K, Welin S, Ziolkowska B, Nordvall D, Janson ET. Assessment of hormonal levels as prognostic markers and of their optimal cut-offs in small intestinal neuroendocrine tumours grade 2. Endocrine 2021; 72:893-904. [PMID: 33244704 PMCID: PMC8159831 DOI: 10.1007/s12020-020-02534-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 10/24/2020] [Indexed: 12/11/2022]
Abstract
PURPOSE Small intestinal neuroendocrine tumours (siNETs) with a Ki-67 proliferation index between 3 and 20% belong to WHO grade 2. Response to treatment may be monitored by blood chromogranin A (CgA) and urine 5-hydroxyindoleacetic acid (5HIAA). The aim of this retrospective study was to investigate the prognostic value of baseline CgA and 5HIAA and of the early biochemical response to treatment, and to compare different cut-off values used in the literature. METHODS A retrospective cohort study of 184 patients with siNET Grade 2 treated with somatostatin analogues (SSA), interferon-alpha (IFN) or peptide receptor radionuclide therapy (PRRT). RESULTS Baseline CgA was a statistically significant prognostic marker for both cancer-specific survival (CSS) and progression-free survival (PFS). A cut-off of 5 × ULN (upper limit of normal) was best discriminative in most cases, but 2 × ULN discriminated better for SSA. Baseline 5HIAA was a prognostic marker for CSS in treatment with IFN and PRRT, but not for single SSA. Early changes of CgA and 5HIAA correlated well with CSS (HR 3.18, 95% CI 1.82-5.56 and HR 1.47, 95% CI 1.16-1.86) and PFS (HR 3.08, 95% CI 1.86-5.10 and HR 1.37, 95% CI 1.11-1.68) for SSA, but not for PRRT. CONCLUSIONS Baseline CgA and to a lesser extent 5HIAA are associated with CSS irrespective of treatment used, and with PFS after PRRT, and 5 × ULN provides best discrimination in many, but not all, cases. Early reductions of CgA and 5HIAA are prognostic for treatment with SSA, but not PRRT.
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Affiliation(s)
- Dimitrios Papantoniou
- Department of Medical Sciences, Endocrine Oncology, Uppsala University, Uppsala, Sweden.
- Department of Oncology, Ryhov County Hospital, Jönköping, Sweden.
| | - Malin Grönberg
- Department of Medical Sciences, Endocrine Oncology, Uppsala University, Uppsala, Sweden
| | | | - Staffan Welin
- Department of Medical Sciences, Endocrine Oncology, Uppsala University, Uppsala, Sweden
| | - Barbara Ziolkowska
- Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland
| | | | - Eva Tiensuu Janson
- Department of Medical Sciences, Endocrine Oncology, Uppsala University, Uppsala, Sweden
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22
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Rocca C, Grande F, Granieri MC, Colombo B, De Bartolo A, Giordano F, Rago V, Amodio N, Tota B, Cerra MC, Rizzuti B, Corti A, Angelone T, Pasqua T. The chromogranin A 1-373 fragment reveals how a single change in the protein sequence exerts strong cardioregulatory effects by engaging neuropilin-1. Acta Physiol (Oxf) 2021; 231:e13570. [PMID: 33073482 DOI: 10.1111/apha.13570] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 10/13/2020] [Accepted: 10/14/2020] [Indexed: 12/16/2022]
Abstract
AIM Chromogranin A (CgA), a 439-residue long protein, is an important cardiovascular regulator and a precursor of various bioactive fragments. Under stressful/pathological conditions, CgA cleavage generates the CgA1-373 proangiogenic fragment. The present work investigated the possibility that human CgA1-373 influences the mammalian cardiac performance, evaluating the role of its C-terminal sequence. METHODS Haemodynamic assessment was performed on an ex vivo Langendorff rat heart model, while mechanistic studies were performed using perfused hearts, H9c2 cardiomyocytes and in silico. RESULTS On the ex vivo heart, CgA1-373 elicited direct dose-dependent negative inotropism and vasodilation, while CgA1-372 , a fragment lacking the C-terminal R373 residue, was ineffective. Antibodies against the PGPQLR373 C-terminal sequence abrogated the CgA1-373 -dependent cardiac and coronary modulation. Ex vivo studies showed that CgA1-373 -dependent effects were mediated by endothelium, neuropilin-1 (NRP1) receptor, Akt/NO/Erk1,2 pathways, nitric oxide (NO) production and S-nitrosylation. In vitro experiments on H9c2 cardiomyocytes indicated that CgA1-373 also induced eNOS activation directly on the cardiomyocyte component by NRP1 targeting and NO involvement and provided beneficial action against isoproterenol-induced hypertrophy, by reducing the increase in cell surface area and brain natriuretic peptide (BNP) release. Molecular docking and all-atom molecular dynamics simulations strongly supported the hypothesis that the C-terminal R373 residue of CgA1-373 directly interacts with NRP1. CONCLUSION These results suggest that CgA1-373 is a new cardioregulatory hormone and that the removal of R373 represents a critical switch for turning "off" its cardioregulatory activity.
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Affiliation(s)
- Carmine Rocca
- Laboratory of Cellular and Molecular Cardiovascular Patho‐Physiology Department of Biology, E. and E.S. University of Calabria Rende Italy
| | - Fedora Grande
- Laboratory of Medicinal and Analytical Chemistry Department of Pharmacy, Health and Nutritional Sciences University of Calabria Rende Italy
| | - Maria Concetta Granieri
- Laboratory of Cellular and Molecular Cardiovascular Patho‐Physiology Department of Biology, E. and E.S. University of Calabria Rende Italy
| | - Barbara Colombo
- Division of Experimental Oncology Vita‐Salute San Raffaele University–Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute Milan Italy
| | - Anna De Bartolo
- Laboratory of Cellular and Molecular Cardiovascular Patho‐Physiology Department of Biology, E. and E.S. University of Calabria Rende Italy
- Department of Pharmacy, Health and Nutritional Sciences University of Calabria Rende Italy
| | - Francesca Giordano
- Department of Pharmacy, Health and Nutritional Sciences University of Calabria Rende Italy
| | - Vittoria Rago
- Department of Pharmacy, Health and Nutritional Sciences University of Calabria Rende Italy
| | - Nicola Amodio
- Department of Experimental and Clinical Medicine Magna Graecia University of Catanzaro Catanzaro Italy
| | - Bruno Tota
- Laboratory of Cellular and Molecular Cardiovascular Patho‐Physiology Department of Biology, E. and E.S. University of Calabria Rende Italy
- Laboratory of Organ and System Physiology Department of Biology, E. and E.S. University of Calabria Rende Italy
| | - Maria Carmela Cerra
- Laboratory of Organ and System Physiology Department of Biology, E. and E.S. University of Calabria Rende Italy
| | - Bruno Rizzuti
- CNR‐NANOTEC Licryl‐UOS Cosenza and CEMIF.Cal Department of Physics University of Calabria Rende Italy
| | - Angelo Corti
- Division of Experimental Oncology Vita‐Salute San Raffaele University–Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute Milan Italy
| | - Tommaso Angelone
- Laboratory of Cellular and Molecular Cardiovascular Patho‐Physiology Department of Biology, E. and E.S. University of Calabria Rende Italy
- National Institute of Cardiovascular Research (INRC) Bologna Italy
| | - Teresa Pasqua
- Laboratory of Cellular and Molecular Cardiovascular Patho‐Physiology Department of Biology, E. and E.S. University of Calabria Rende Italy
- "Fondazione Umberto Veronesi" Milan Italy
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Muniraj T, Aslanian HR. Pancreatic Neuroendocrine Tumors. GERIATRIC GASTROENTEROLOGY 2021:1933-1951. [DOI: 10.1007/978-3-030-30192-7_81] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Cavalcoli F, Rossi RE, Massironi S. Circulating Biochemical Markers of Gastro-Entero-Pancreatic (GEP) Neuroendocrine Neoplasms (NENs). NEUROENDOCRINE NEOPLASIA MANAGEMENT 2021:55-74. [DOI: 10.1007/978-3-030-72830-4_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Malczewska A, Oberg K, Kos-Kudla B. NETest is superior to chromogranin A in neuroendocrine neoplasia: a prospective ENETS CoE analysis. Endocr Connect 2021; 10:110-123. [PMID: 33289691 PMCID: PMC7923057 DOI: 10.1530/ec-20-0417] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 12/03/2020] [Indexed: 12/16/2022]
Abstract
INTRODUCTION The absence of a reliable, universal biomarker is a significant limitation in neuroendocrine neoplasia (NEN) management. We prospectively evaluated two CgA assays, (NEOLISA, EuroDiagnostica) and (CgA ELISA, Demeditec Diagnostics (DD)) and compared the results to the NETest. METHODS NEN cohort (n = 258): pancreatic, n = 67; small intestine, n = 40; appendiceal, n = 10; rectal, n = 45; duodenal, n = 9; gastric, n = 44; lung, n = 43. Image-positive disease (IPD) (n = 123), image & histology- negative (IND) (n = 106), and image-negative and histology positive (n = 29). CgA metrics: NEOLISA, ULN: 108 ng/mL, DD: ULN: 99 ng/mL. Data mean ± s.e.m. NETest: qRT-PCR - multianalyte analyses, ULN: 20. All samples de-identified and assessed blinded. Statistics: Mann-Whitney U-test, Pearson correlation and McNemar-test. RESULTS CgA positive in 53/258 (NEOLISA), 32 (DD) and NETest-positive in 157/258. In image- positive disease (IPD, n = 123), NEOLISA-positive: 33% and DD: 19%. NETest-positive: 122/123 (99%; McNemar's Chi2= 79-97, P < 0.0001). NEOLISA was more accurate than DD (P = 0.0003). In image- negative disease (IND), CgA was NEOLISA-positive (11%), DD (8%), P = NS, and NETest (33%). CgA assays could not distinguish progressive (PD) from stable disease (SD) or localized from metastatic disease (MD). NETest was significantly higher in PD (47 ± 5) than SD (29 ± 1, P = 0.0009). NETest levels in MD (35 ± 2) were elevated vs localized disease (24 ± 1.3, P = 0.008). CONCLUSIONS NETest, a multigenomic mRNA biomarker, was ~99% accurate in the identification of NEN disease. The CgA assays detected NEN disease in 19-33%. Multigenomic blood analysis using NETest is more accurate than CgA and should be considered the biomarker standard of care.
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Affiliation(s)
- Anna Malczewska
- Department of Endocrinology and Neuroendocrine Tumours, Medical University of Silesia, Katowice, Poland
| | - Kjell Oberg
- Department of Endocrine Oncology, University Hospital, Uppsala, Sweden
| | - Beata Kos-Kudla
- Department of Endocrinology and Neuroendocrine Tumours, Medical University of Silesia, Katowice, Poland
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Towards Understanding of Gastric Cancer Based upon Physiological Role of Gastrin and ECL Cells. Cancers (Basel) 2020; 12:cancers12113477. [PMID: 33266504 PMCID: PMC7700139 DOI: 10.3390/cancers12113477] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/19/2020] [Accepted: 11/21/2020] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Generally, we know that cancers represent genetic changes in tumour cells, but we most often do not know the causes of cancers or how they develop. Our knowledge of the regulation of gastric acid secretion is well known, with the gastric hormone gastrin maintaining gastric acidity by stimulation of the enterochromaffin-like (ECL) cell to release histamine, which subsequently augments acid secretion. Furthermore, it seems to be a general principle that stimulation of function (which, for the ECL cell, is release of histamine) in a parallel way stimulates the proliferation of the same cell. Long-term hyperstimulation of cell division predisposes to genetic changes and, thus, development of tumours. All conditions with reduced gastric acidity result in an increased risk of gastric tumours due to elevated gastrin in order to restore gastric acidity. It is probable that Helicobacter pylori infection (the most important cause of gastric cancer), as well as drugs inhibiting gastric acid secretion induce gastric cancer in the long-term, due to an elevation of gastrin caused by reduced gastric acidity. Gastric carcinomas have been shown to express ECL cell markers, further strengthening this relationship. Abstract The stomach is an ideal organ to study because the gastric juice kills most of the swallowed microbes and, thus, creates rather similar milieu among individuals. Combined with a rather easy access to gastric juice, gastric physiology was among the first areas to be studied. During the last century, a rather complete understanding of the regulation of gastric acidity was obtained, establishing the central role of gastrin and the histamine producing enterochromaffin-like (ECL) cell. Similarly, the close connection between regulation of function and proliferation became evident, and, furthermore, that chronic overstimulation of a cell with the ability to proliferate, results in tumour formation. The ECL cell has long been acknowledged to give rise to neuroendocrine tumours (NETs), but not to play any role in carcinogenesis of gastric adenocarcinomas. However, when examining human gastric adenocarcinomas with the best methods presently available (immunohistochemistry with increased sensitivity and in-situ hybridization), it became clear that many of these cancers expressed neuroendocrine markers, suggesting that some of these tumours were of neuroendocrine, and more specifically, ECL cell origin. Thus, the ECL cell and its main regulator, gastrin, are central in human gastric carcinogenesis, which make new possibilities in prevention, prophylaxis, and treatment of this cancer.
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Aburjania Z, Whitt JD, Jang S, Nadkarni DH, Chen H, Rose JB, Velu SE, Jaskula-Sztul R. Synthetic Makaluvamine Analogs Decrease c-Kit Expression and Are Cytotoxic to Neuroendocrine Tumor Cells. Molecules 2020; 25:molecules25214940. [PMID: 33114525 PMCID: PMC7663375 DOI: 10.3390/molecules25214940] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 10/14/2020] [Accepted: 10/22/2020] [Indexed: 12/12/2022] Open
Abstract
In an effort to discover viable systemic chemotherapeutic agents for neuroendocrine tumors (NETs), we screened a small library of 18 drug-like compounds obtained from the Velu lab against pulmonary (H727) and thyroid (MZ-CRC-1 and TT) neuroendocrine tumor-derived cell lines. Two potent lead compounds (DHN-II-84 and DHN-III-14) identified from this screening were found to be analogs of the natural product makaluvamine. We further characterized the antitumor activities of these two compounds using pulmonary (H727), thyroid (MZ-CRC-1) and pancreatic (BON) neuroendocrine tumor cell lines. Flow cytometry showed a dose-dependent increase in apoptosis in all cell lines. Induction of apoptosis with these compounds was also supported by the decrease in myeloid cell leukemia-1 (MCL-1) and X-chromosome linked inhibitor of apoptosis (XIAP) detected by Western blot. Compound treatment decreased NET markers chromogranin A (CgA) and achaete-scute homolog 1 (ASCL1) in a dose-dependent manner. Moreover, the gene expression analysis showed that the compound treatment reduced c-Kit proto-oncogene expression in the NET cell lines. Induction of apoptosis could also have been caused by the inhibition of c-Kit expression, in addition to the known mechanisms such as damage of DNA by topoisomerase II inhibition for this class of compounds. In summary, makaluvamine analogs DHN-II-84 and DHN-III-14 induced apoptosis, decreased neuroendocrine tumor markers, and showed promising antitumor activity in pulmonary, thyroid, and pancreatic NET cell lines, and hold potential to be developed as an effective treatment to combat neuroendocrine tumors.
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Affiliation(s)
- Zviadi Aburjania
- Department of Surgery, University of Alabama at Birmingham, 1824 6th Avenue S., Birmingham, AL 35233, USA; (Z.A.); (J.D.W.); (S.J.); (H.C.); (J.B.R.)
| | - Jason D. Whitt
- Department of Surgery, University of Alabama at Birmingham, 1824 6th Avenue S., Birmingham, AL 35233, USA; (Z.A.); (J.D.W.); (S.J.); (H.C.); (J.B.R.)
| | - Samuel Jang
- Department of Surgery, University of Alabama at Birmingham, 1824 6th Avenue S., Birmingham, AL 35233, USA; (Z.A.); (J.D.W.); (S.J.); (H.C.); (J.B.R.)
| | - Dwayaja H. Nadkarni
- Department of Chemistry, University of Alabama at Birmingham, 901 14th Street S., Birmingham, AL 35294, USA;
| | - Herbert Chen
- Department of Surgery, University of Alabama at Birmingham, 1824 6th Avenue S., Birmingham, AL 35233, USA; (Z.A.); (J.D.W.); (S.J.); (H.C.); (J.B.R.)
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294, USA
| | - J. Bart Rose
- Department of Surgery, University of Alabama at Birmingham, 1824 6th Avenue S., Birmingham, AL 35233, USA; (Z.A.); (J.D.W.); (S.J.); (H.C.); (J.B.R.)
| | - Sadanandan E. Velu
- Department of Chemistry, University of Alabama at Birmingham, 901 14th Street S., Birmingham, AL 35294, USA;
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294, USA
- Correspondence: (S.E.V.); (R.J.-S.); Tel.: +1-(205)-975-2478 (S.E.V.); +1-(205)-975-3507 (R.J.-S.); Fax: +1-(205)-934-2543 (S.E.V.); +1-(205)-934-0135 (R.J.-S.)
| | - Renata Jaskula-Sztul
- Department of Surgery, University of Alabama at Birmingham, 1824 6th Avenue S., Birmingham, AL 35233, USA; (Z.A.); (J.D.W.); (S.J.); (H.C.); (J.B.R.)
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294, USA
- Correspondence: (S.E.V.); (R.J.-S.); Tel.: +1-(205)-975-2478 (S.E.V.); +1-(205)-975-3507 (R.J.-S.); Fax: +1-(205)-934-2543 (S.E.V.); +1-(205)-934-0135 (R.J.-S.)
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Gupta S, Iorgulescu JB, Hoffman S, Catalino M, Bernstock JD, Chua M, Segar DJ, Fandino LB, Laws ER, Smith TR. The diagnosis and management of primary and iatrogenic soft tissue sarcomas of the sella. Pituitary 2020; 23:558-572. [PMID: 32613388 DOI: 10.1007/s11102-020-01062-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
PURPOSE Soft tissue sarcoma (STS) of the sella is exceptionally rare. We conducted a case series, literature review, and nationwide analysis of primary and iatrogenic (radiation-associated) STS of the sella to define the clinical course of this entity. METHODS This study employed a multi-institutional retrospective case review, literature review, and nationwide analysis using the National Cancer Database (NCDB). RESULTS We report five patients who were diagnosed at three institutions with malignant STS of the sella. All patients presented with symptoms related to mass effect in the sellar region. All tumors extended to the suprasellar space, with the majority displaying extension into the cavernous sinus. All patients underwent an operation via a transsphenoidal approach with a goal of maximal safe tumor resection in four patients and biopsy for 1 patient. Histopathologic evaluation demonstrated STS in all patients. Post-operative adjuvant radiotherapy and chemotherapy were given to 2 and 1 out of 4 patients with known post-operative clinical course, respectively. The 1-year and 5-year overall survival rates were 100% (5/5) and 25% (1/4). Twenty-two additional reports of primary, non-iatrogenic STS of the sella were identified in the literature. Including the three cases from our series, treatment included resection in all cases, and adjuvant radiotherapy and chemotherapy were utilized in 50% (12/24) and 17% (4/24) of cases, respectively. The national prevalence of malignant STS is estimated to be 0.01% among all pituitary and sellar tumors within the NCDB. CONCLUSIONS We report the prevalence and survival rates of STS of the sella. Multimodal therapy, including maximal safe resection, chemotherapy, and radiotherapy are necessary to optimize outcomes for this uncommon pathology.
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Affiliation(s)
- Saksham Gupta
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
- Computational Neurosciences Outcome Center, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - J Bryan Iorgulescu
- Computational Neurosciences Outcome Center, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, 02115, USA
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA
| | - Samantha Hoffman
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Michael Catalino
- Department of Neurosurgery, University of North Carolina Medical Center, Chapel Hill, NC, 27599, USA
| | - Joshua D Bernstock
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Melissa Chua
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - David J Segar
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Luis Bradley Fandino
- Department of Orthopedic Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Edward R Laws
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Timothy R Smith
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.
- Computational Neurosciences Outcome Center, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, 02115, USA.
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Shi H, Jiang C, Zhang Q, Qi C, Yao H, Lin R. Clinicopathological heterogeneity between primary and metastatic sites of gastroenteropancreatic neuroendocrine neoplasm. Diagn Pathol 2020; 15:108. [PMID: 32917216 PMCID: PMC7488304 DOI: 10.1186/s13000-020-01030-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Accepted: 09/04/2020] [Indexed: 12/11/2022] Open
Abstract
Background Chromogranin A (CgA), synaptophysin (Syn) and the Ki-67 index play significant roles in diagnosis or the evaluation of the proliferative activity of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). However, little is known about whether these biological markers change during tumor metastasis and whether such changes have effect on prognosis. Methods We analyzed 35 specimens of both primary and metastatic tumor from 779 patients who had been diagnosed as GEP-NENs at Wuhan Union Hospital from August 2011 to October 2019. The heterogeneity of CgA, Syn and Ki-67 index was evaluated by immunohistochemical analysis. Results Among these 779 patients, the three most common sites of NENs in the digestive tract were the pancreas, rectum and stomach. Metastases were found in 311 (39.9%) patients. Among the 35 patients with both primary and metastatic pathological specimens, differences in the Ki-67 level were detected in 54.3% of the patients, while 37.1% showed a difference in CgA and only 11.4% showed a difference in Syn. Importantly, due to the difference in the Ki-67 index between primary and metastatic lesions, the WHO grade was changed in 8.6% of the patients. In addition, a Kaplan–Meier survival analysis showed that patients with Ki-67 index variation had a shorter overall survival (p = 0.0346), while neither Syn variation nor CgA variation was related to patient survival (p = 0.7194, p = 0.4829). Conclusions Our data indicate that primary and metastatic sites of GEP-NENs may exhibit pathological heterogeneity. Ki-67 index variation is closely related to the poor prognosis of patients with tumor metastasis, but neither Syn variation nor CgA variation is related to patient prognosis. Therefore, clinicopathologic evaluation of the primary tumor and metastatic sites could be helpful for predicting the prognosis.
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Affiliation(s)
- Huiying Shi
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chen Jiang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Qin Zhang
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Cuihua Qi
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Hailing Yao
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Rong Lin
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Almas T, Inayat F, Ehtesham M, Khan MK. Primary hepatic neuroendocrine tumour masquerading as a giant haemangioma: an unusual presentation of a rare disease. BMJ Case Rep 2020; 13:13/9/e236153. [PMID: 32900712 DOI: 10.1136/bcr-2020-236153] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Primary hepatic neuroendocrine tumour is an exceedingly rare entity. We hereby delineate the case of a 45-year-old Balti descent woman who hails from a land-locked village situated in the foothills of the Pakistani Himalayas. The patient presented to our medical centre with a hepatic mass. She underwent extensive diagnostic workup. The consistent findings of an abdominal CT scan, coupled with her clinical history, insinuated a preoperative diagnosis of atypical hepatic haemangioma. After a detailed discussion in a multidisciplinary meeting, a standard right hemihepatectomy was performed. She had an uneventful postoperative recovery and was discharged in stable condition after 1 week. Surprisingly, pathological examination and immunohistochemistry of the resected specimen divulged the diagnosis of a grade II primary hepatic neuroendocrine tumour. Her somatostatin-receptor scintigraphy and Gallium-68 DOTATATE positron emission tomography scan excluded residual hepatic or additional body lesions. Regular follow-ups over the past 4 years demonstrated unremarkable radiological findings with no recurrence to date.
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Affiliation(s)
- Talal Almas
- Royal College of Surgeons in Ireland, Dublin, Ireland
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Ebert A, König J, Frommer L, Schuppan D, Kahaly GJ. Chromogranin Serves as Novel Biomarker of Endocrine and Gastric Autoimmunity. J Clin Endocrinol Metab 2020; 105:5841628. [PMID: 32436949 DOI: 10.1210/clinem/dgaa288] [Citation(s) in RCA: 10] [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: 01/23/2020] [Accepted: 05/18/2020] [Indexed: 02/06/2023]
Abstract
CONTEXT The glycoprotein chromogranin A (CgA) is expressed by endocrine and neuroendocrine cells. High levels of serum CgA serve as markers of neuroendocrine tumors (NET), but its role in autoimmunity has not been assessed. OBJECTIVE To investigate CgA utility as a marker of endocrine autoimmunity. METHODS CgA serum levels were evaluated in 807 consecutive unselected participants (cross-sectional study) with the time-resolved amplified cryptate emission technology. RESULTS Serum CgA concentrations were increased in 66%, 39%, 38%, and 24% of patients with NET, type 1 diabetes (T1D), autoimmune gastritis (AG) and autoimmune polyendocrinopathy (AP), respectively. Compared with healthy participant controls (C), the odds of positive CgA measurement were up to 28 times higher in the disease groups. In detail, the odds ratios (ORs) for positive CgA levels were 27.98, 15.22, 7.32 (all P < 0.0001) and 3.89 (P = 0.0073) in patients with NET, T1D, AG, and AP, respectively. In AG, CgA and serum gastrin correlated positively (r = 0.55; P < 0.0001). The area under the receiver operating characteristic curve to predict AG was higher for parietal cell antibody (PCA) positivity than for CgA (0.84 vs 0.67; P < 0.0001). However, in combination with PCA and intrinsic factor autoantibodies, CgA independently improved prediction of AG (OR 6.5; P = 0.031). An impact of age on CgA positivity and on CgA value was detected (P < 0.0001) while current smoking significantly increased CgA serum levels by 25% (P = 0.0080). CONCLUSION CgA qualifies as a novel biomarker for T1D, AP, and AG.
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Affiliation(s)
- Antonia Ebert
- Department of Medicine I, Johannes Gutenberg University (JGU) Medical Center, Mainz, Germany
| | - Jochem König
- Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), Johannes Gutenberg University Medical Center, Mainz, Germany
| | - Lara Frommer
- Department of Medicine I, Johannes Gutenberg University (JGU) Medical Center, Mainz, Germany
| | - Detlef Schuppan
- Institute for Translational Immunology and Research Center for Immunotherapy (FZI), Johannes Gutenberg University Medical Center, Mainz, Germany
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - George J Kahaly
- Department of Medicine I, Johannes Gutenberg University (JGU) Medical Center, Mainz, Germany
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Warsinggih, Liliyanto, Prihantono, Ariani GDW, Faruk M. Colorectal neuroendocrine tumors: A case series. Int J Surg Case Rep 2020; 72:411-417. [PMID: 32563832 PMCID: PMC7306531 DOI: 10.1016/j.ijscr.2020.06.030] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 06/07/2020] [Accepted: 06/07/2020] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION Neuroendocrine tumors (NET) of the colon and sigmoid colon are uncommon compared to colorectal adenocarcinoma. Few reports have been made of NET of the colon and sigmoid colon that presents with peritonitis and large bowel obstruction. CASE PRESENTATION Here, we report two cases of NET of the colon and sigmoid colon, which were diagnosed and treated at our institution. In our first case, a 66-year-old man with a history of abdominal distension was diagnosed with NET via histopathology of the sigmoid colon. The second case involved a 45-year-old woman with the chief complaints of abdominal distention and inability to defecate; specimen histopathology of the descending colon showed neuroendocrine carcinoma features. Clinical outcome was very poor in our patients: eight months after the resection, the second patient demonstrated a sign of metastasis on the liver. CONCLUSION An uncommon case of colon and sigmoid colon carcinoma with neuroendocrine and diagnostic difficulties precludes an exact description of the initial diagnostic criteria and management. Thus, our case series offers an overview of initial symptoms, radiological and histopathological features for early diagnosis, and proper management of NET.
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Affiliation(s)
- Warsinggih
- Division of Digestive, Department of Surgery, Faculty of Medicine, Hasanuddin University Makassar, Indonesia.
| | - Liliyanto
- Division of Digestive, Department of Surgery, Faculty of Medicine, Hasanuddin University Makassar, Indonesia.
| | - Prihantono
- Division of Oncology, Department of Surgery, Faculty of Medicine, Hasanuddin University Makassar, Indonesia.
| | - Gusti Deasy Wilda Ariani
- Department of Anatomic Pathology, Faculty of Medicine, Hasanuddin University Makassar, Indonesia.
| | - Muhammad Faruk
- Department of Surgery, Faculty of Medicine, Hasanuddin University Makassar, Indonesia.
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Papalou O, Peppa M, Kandaraki E, Diamanti-Kandarakis E, Nikou G. The Diagnostic Value of Chromogranin A in Neuroendocrine Neoplasms is Potentiated by Clinical Factors and Inflammatory Markers. ENDOCRINES 2020; 1:1-12. [DOI: 10.3390/endocrines1010001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025] Open
Abstract
Objective: Neuroendocrine neoplasms (NENs) are a heterogenous group of indolent tumors, with variable clinical behavior and steadily rising incidence. The aim of this study is to investigate the clinical and laboratory factors that contribute in predicting the aggressiveness and invasiveness of NENs. Special focus is given to clinical parameters that would enhance the diagnostic value of chromogranin A (CgA), via formalizing an integrated probability model, which would contribute to the timely and accurate identification of patients at high risk for metastatic disease at initial diagnosis. Designs and Methods: We identified a total of 93 patients with NENs, recruited at a specialized academic center in Athens, Greece. Anthropometric, clinical, laboratory, and pathological data were obtained from every patient before any therapeutic intervention. Results: Age over 50 years and male gender were accompanied by increased risk for metastases at the time of initial diagnosis. Additionally, when these parameters were combined with CgA levels, they were shown to enhance the predictive capacity of CgA. Different patient scenarios combining age, gender, and CgA levels are associated with different probabilities for metastatic disease, demonstrated schematically in a gradually escalating model, as age and CgA levels increase in both males and females. The lowest risk is observed in women aged <50 years old with CgA levels <200 ng/dl (6.5%), while the highest one is in males over 50 years old with CgA > 200 ng/dl (62.9%). Finally, it was shown that c-reactive protein (CRP) can predict disease extent at the time of diagnosis. Conclusions: CgA levels can not only be used as a direct predictor of tumor load in patients with NENs, but also, when interpolated with the effects of age and gender, cumulatively predict whether a NEN would be metastatic or not at the time of initial diagnosis, via a risk-escalating probability model.
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Affiliation(s)
- Olga Papalou
- Department of Endocrinology, Diabetes and Metabolism, Hygeia Hospital, 15123 Athens, Greece
| | - Melpomeni Peppa
- Endocrine and Metabolic Bone Disorders Unit, 2nd Department of Internal Medicine and Research Institute and Diabetes Center, Attikon University Hospital, 12462 Athens, Greece
| | - Eleni Kandaraki
- Department of Endocrinology, Diabetes and Metabolism, Hygeia Hospital, 15123 Athens, Greece
- School of Medicine, European University Cyprus (EUC), Nicosia 2404, Cyprus
| | | | - George Nikou
- Section of Neuroendocrine Tumors—3rd Department of Internal Medicine, National and Kapodistrian University of Athens, “Sotiria” Hospital, 11527 Athens, Greece
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Maggio I, Mollica V, Brighi N, Lamberti G, Manuzzi L, Ricci AD, Campana D. The functioning side of the pancreas: a review on insulinomas. J Endocrinol Invest 2020; 43:139-148. [PMID: 31368049 DOI: 10.1007/s40618-019-01091-w] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 07/24/2019] [Indexed: 12/19/2022]
Abstract
PURPOSE Insulinomas are a rare type of neuroendocrine tumors, originating in the pancreas, difficult to diagnose and to treat. Due to its rarity, insulinomas are a not well-known pathological entity; thus, the diagnostic process is frequently a medical challenge with many possible differential diagnoses. The diagnostic process varies between non-invasive procedures, such as the fasting test or imaging techniques, and invasive ones. Insulinomas are rarely malignant, but the glycemic imbalance correlated with this tumor can frequently alter the quality of life of the patients and the consequent hypoglycemia can be extremely dangerous. Moreover, insulinomas can be associated with different genetic syndromes, such as Multiple Endocrine Neoplasia 1, accompanied by other specific symptoms. There are many different treatment strategies, depending on the need to control symptoms or control diseases progression, the only curative one being surgery. METHODS AND RESULTS We reviewed the evidences present in the literature on insulinomas and reported its main clinical characteristics and management strategies. CONCLUSION The aim of this review of the literature is to present the current knowledge on insulinomas, exploring the main clinical characteristics, the diagnostic tools, and the therapeutic strategies.
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Affiliation(s)
- I Maggio
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - V Mollica
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - N Brighi
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
- NET Team Bologna ENETS Center of Excellence, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - G Lamberti
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - L Manuzzi
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - A D Ricci
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - D Campana
- NET Team Bologna ENETS Center of Excellence, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy.
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy.
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Asban A, Patel AJ, Reddy S, Wang T, Balentine CJ, Chen H. Cancer of the Endocrine System. ABELOFF'S CLINICAL ONCOLOGY 2020:1074-1107.e11. [DOI: 10.1016/b978-0-323-47674-4.00068-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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36
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Malczewska A, Kidd M, Matar S, Kos-Kudła B, Bodei L, Oberg K, Modlin IM. An Assessment of Circulating Chromogranin A as a Biomarker of Bronchopulmonary Neuroendocrine Neoplasia: A Systematic Review and Meta-Analysis. Neuroendocrinology 2020; 110:198-216. [PMID: 31266019 DOI: 10.1159/000500525] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 04/23/2019] [Indexed: 11/19/2022]
Abstract
BACKGROUND Management of bronchopulmonary neuroendocrine neoplasia (NEN; pulmonary carcinoids [PCs], small-cell lung cancer [SCLC], and large cell neuroendocrine carcinoma) is hampered by the paucity of biomarkers. Chromogranin A (CgA), the default neuroendocrine tumor biomarker, has undergone wide assessment in gastroenteropancreatic neuroendocrine tumors. OBJECTIVES To evaluate CgA in lung NEN, define its clinical utility as a biomarker, assess its diagnostic, prognostic, and predictive efficacy, as well as its accuracy in the identification of disease recurrence. METHODS A systematic review of PubMed was undertaken using the preferred reporting items for systematic reviews and meta-analyses guidelines. No language restrictions were applied. Overall, 33 original scientific papers and 3 case reports, which met inclusion criteria, were included in qualitative analysis, and meta-analysis thereafter. All studies, except 2, were retrospective. Meta-analysis statistical assessment by generic inverse variance methodology. RESULTS Ten different CgA assay types were reported, without consistency in the upper limit of normal (ULN). For PCs (n = 16 studies; median patient inclusion 21 [range 1-200, total: 591 patients]), the CgA diagnostic sensitivity was 34.5 ± 2.7% with a specificity of 93.8 ± 4.7. CgA metrics were not available separately for typical or atypical carcinoids. CgA >100 ng/mL (2.7 × ULN) and >600 ng/mL (ULN unspecified) were anecdotally prognostic for overall survival (n = 2 retrospective studies). No evidence was presented for predicting treatment response or identifying post-surgery residual disease. For SCLC (n = 19 studies; median patient inclusion 23 [range 5-251, total: 1,241 patients]), the mean diagnostic sensitivity was 59.9 ± 6.8% and specificity 79.4 ± 3.1. Extensive disease typically exhibited higher CgA levels (diagnostic accuracy: 61 ± 2.5%). An elevated CgA was prognostic for overall survival (n = 4 retrospective studies). No prospective studies evaluating predictive benefit or prognostic utility were identified. CONCLUSION The available data are scarce. An assessment of all published data showed that CgA exhibits major limitations as an effective and accurate biomarker for either PC or SCLC. Its utility especially for localized PC/limited SCLC (when surgery is potentially curative), is limited. The clinical value of CgA remains to be determined. This requires validated, well-constructed, multicenter, prospective, randomized studies. An assessment of all published data indicates that CgA does not exhibit the minimum required metrics to function as a clinically useful biomarker for lung NENs.
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Affiliation(s)
- Anna Malczewska
- Department of Endocrinology and Neuroendocrine Tumors, Medical University of Silesia, Katowice, Poland
| | - Mark Kidd
- Wren Laboratories, Branford, Connecticut, USA
| | - Somer Matar
- Wren Laboratories, Branford, Connecticut, USA
| | - Beata Kos-Kudła
- Department of Endocrinology and Neuroendocrine Tumors, Medical University of Silesia, Katowice, Poland
| | - Lisa Bodei
- Memorial Sloan Kettering Cancer Centre, New York, New York, USA
| | - Kjell Oberg
- Department of Endocrine Oncology, University Hospital, Uppsala, Sweden
| | - Irvin M Modlin
- Yale University School of Medicine, New Haven, Connecticut, USA,
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The American Society of Colon and Rectal Surgeons, Clinical Practice Guidelines for the Management of Appendiceal Neoplasms. Dis Colon Rectum 2019; 62:1425-1438. [PMID: 31725580 DOI: 10.1097/dcr.0000000000001530] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Touitou Y, Lambrozo J, Mauvieux B, Riedel M. Evaluation in humans of ELF-EMF exposure on chromogranin A, a marker of neuroendocrine tumors and stress. Chronobiol Int 2019; 37:60-67. [PMID: 31682468 DOI: 10.1080/07420528.2019.1683857] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Chromogranin A (CgA), which is a major protein in adrenal chromaffin cells and adrenergic neurons, is a clinically relevant endocrine and neuroendocrine tumor marker including pheochromocytomas, neuroblastomas, and related neurogenic tumors. In this study, we looked at the effect in humans of chronic daily exposure to a 50-Hz magnetic field. We examined in 15 men (38.0 ± 0.9 years) the effects of chronic daily exposure to a 50-Hz magnetic field for 1-20 yrs both at home and at work. EMDEX II dosimeters were used to record magnetic field all day long every 30 s. for 1 week. The weekly geometric mean of the individual exposures ranged from 0.1 to 2.6 μT. Blood samples were taken hourly between 20:00 h and 08:00 h. CgA patterns of exposed subjects were compared to age-matched controls. The results of exposed subjects were compared with those for 15 unexposed men who served as controls and whose individual exposure was ten times lower ranging from 0.004 to 0.092 μT. This work shows that in the control group the serum CgA levels exhibited a nighttime peak with a progressive decline of the serum concentrations and a nadir in the morning. Both the profile and the serum concentrations of CgA, a marker of neuroendocrine tumors and stress, did not appear to be impaired in the subjects chronically exposed over a long period (up to 20 yrs) to magnetic fields though a trend toward lower levels were found at the highest exposure (>0.3 μT). This does not rule out, however, that the potential deleterious risk of ELF-EMF on frail populations such as children and the elderly may be greater at low exposure and should hence be documented, at least for their residential exposure.
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Affiliation(s)
- Yvan Touitou
- Unité de Chronobiologie, Fondation A. de Rothschild, Paris, France
| | - Jacques Lambrozo
- Unité de Chronobiologie, Fondation A. de Rothschild, Paris, France
| | - Benoit Mauvieux
- Unité de Chronobiologie, Fondation A. de Rothschild, Paris, France.,INSERM UMR U1075, Université de Caen, Caen, France
| | - Marc Riedel
- Unité de Chronobiologie, Fondation A. de Rothschild, Paris, France.,EA 2114, Université de Tours, Tours, France
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Alsadik S, Yusuf S, AL-Nahhas A. Peptide Receptor Radionuclide Therapy for Pancreatic Neuroendocrine Tumours. Curr Radiopharm 2019; 12:126-134. [PMID: 30714538 DOI: 10.2174/1874471012666190201164132] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 05/15/2018] [Accepted: 10/19/2018] [Indexed: 12/29/2022]
Abstract
Background:
The incidence of pancreatic Neuroendocrine Tumours (pNETs) has increased
considerably in the last few decades. The characteristic features of this tumour and the development of
new investigative and therapeutic methods had a great impact on its management.
Objective:
The aim of this review is to investigate the outcome of Peptide Receptor Radionuclide Therapy
(PRRT) in the treatment of pancreatic neuroendocrine tumours.
Methods:
A comprehensive literature search strategy was used based on two databases (SCOPUS, and
PubMed). We considered all studies published in English, evaluating the use of PRRT (177Luteciuim-
DOTA-conjugated peptides and 90Yetrium- DOTA- conjugated peptides) in the treatment of pancreatic
neuroendocrine tumours as a standalone entity or as a subgroup within the wider category of Gastroenteropancreatic
Neuroendocrine Tumours (GEP NETs).
Results:
PRRT was found to be an effective treatment modality as a monotherapy or in combination
with other therapies in the treatment of non-operable and metastatic pNETs where other options are
limited. Complete response was reported to be between 2-6% while partial response was achieved in up
to 60% of cases. Survival analysis was also impressive. Progression Free Survival (PFS) reached a mean
of 34 months and Overall Survival (OS) of 53 months. PRRT also proved to improve patients’ Quality
of Life (QoL). Acute and sub-acute side effects like nephrotoxicity and haematotoxicity are usually mild
and reversible.
Conclusion:
PRRT is well tolerated and effective treatment option for non-operable and/or metastatic
pNETs. Side effects are usually mild and reversible. Larger randomized controlled trails need to be done
to compare PRRT with other treatment modalities and to provide more detailed guidelines regarding
patient selections, the choice of PRRT, follow up and response assessment to maximum potential benefit.
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Affiliation(s)
- Shahad Alsadik
- Department of Nuclear Medicine, Hammersmith Hospital, Imperial College NHS Trust, London, United Kingdom
| | - Siraj Yusuf
- Department of Nuclear Medicine, Hammersmith Hospital, Imperial College NHS Trust, London, United Kingdom
| | - Adil AL-Nahhas
- Department of Nuclear Medicine, Hammersmith Hospital, Imperial College NHS Trust, London, United Kingdom
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40
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Hopper AD, Jalal M, Munir A. Recent advances in the diagnosis and management of pancreatic neuroendocrine tumours. Frontline Gastroenterol 2019; 10:269-274. [PMID: 31290854 PMCID: PMC6583562 DOI: 10.1136/flgastro-2018-101006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 09/12/2018] [Accepted: 09/14/2018] [Indexed: 02/06/2023] Open
Abstract
The incidence of pancreatic neuroendocrine tumours (PNET) is rising mainly due to the increased use of cross-sectional imaging. Although many PNETs are asymptomatic and non-functioning, the overall 5-year survival is still less than 50%. In this article, we review the advances in diagnosis, classification and staging of PNET that have evolved with the development of new cross-sectional imaging methods and biopsy techniques. With accurate classification, evidence-based, individualised prognostic outcomes and treatments are able to be given which are also discussed.
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Affiliation(s)
- Andrew D Hopper
- Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK
| | - Mustafa Jalal
- Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK
| | - Alia Munir
- Department of Endocrinology, Royal Hallamshire Hospital, Sheffield, UK
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Ye S, Ma L, Zhang R, Liu F, Jiang P, Xu J, Cao H, Du X, Lin F, Cheng L, Zhou X, Shi Z, Liu Y, Huang Y, Wang Z, Li C. Plasma proteomic and autoantibody profiles reveal the proteomic characteristics involved in longevity families in Bama, China. Clin Proteomics 2019; 16:22. [PMID: 31139026 PMCID: PMC6526601 DOI: 10.1186/s12014-019-9242-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 05/15/2019] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Chinese Bama Yao Autonomous County is a well-known longevity region in the world. In the past 30 years, population and genome studies were undertaken to investigate the secret of longevity and showed that longevity is the result of a combination of multiple factors, such as genetic, environmental and other causes. In this study, characteristics of the blood plasma proteomic and autoantibody profiles of people from Bama longevity family were investigated. METHODS Sixty-six plasma donors from Chinese Bama longevity area were recruited in this study. Thirty-three offsprings of longevous families were selected as case studies (Longevous group) and 33 ABO (blood type), age, and gender-matched subjects from non-longevous families were selected as controls (Normal group). Each group contains 3 biological replicates. Tandem mass tag-based proteomic technique was used to investigate the differentially expressed plasma proteins between the two groups. The auto-reactive IgG antibody profiles of the 3 pooled samples in each group were revealed by human proteome microarrays with 17,000 recombinant human proteins. RESULTS Firstly, 525 plasma proteins were quantified and 12 proteins were discovered differentially expressed between the two groups. Secondly, more than 500 proteins were recognized by plasma antibodies, 14 proteins ware differentially reacted with the autoantibodies in the two groups. Bioinformatics analysis showed some of the differential proteins and targeted autoantigens were involved in cancer, cardiovascular disease and immunity. CONCLUSIONS Proteomic and autoantibody profiles varied between the offspring of longevous and normal families which are from the same area and shared the same environmental factors. The identified differences were reported to be involved in several physiological and pathological pathways. The identified proteins will contribute to a better understanding of the proteomic characteristics of people from Bama longevous area and a revelation of the molecular mechanisms of longevity.
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Affiliation(s)
- Shengliang Ye
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, 610052 China
| | - Li Ma
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, 610052 China
| | - Rong Zhang
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, 610052 China
| | - Fengjuan Liu
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, 610052 China
| | - Peng Jiang
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, 610052 China
| | - Jun Xu
- Shanghai RAAS Blood Products Co. Ltd, Shanghai, 201401 China
| | - Haijun Cao
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, 610052 China
| | - Xi Du
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, 610052 China
| | - Fangzhao Lin
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, 610052 China
| | - Lu Cheng
- Shanghai RAAS Blood Products Co. Ltd, Shanghai, 201401 China
| | - Xuefeng Zhou
- Shanghai RAAS Blood Products Co. Ltd, Shanghai, 201401 China
| | - Zhihui Shi
- Shanghai RAAS Blood Products Co. Ltd, Shanghai, 201401 China
| | - Yeheng Liu
- Shanghai RAAS Blood Products Co. Ltd, Shanghai, 201401 China
| | | | - Zongkui Wang
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, 610052 China
| | - Changqing Li
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, 610052 China
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Guo Z, Wang Y, Xiang S, Wang S, Chan FL. Chromogranin A is a predictor of prognosis in patients with prostate cancer: a systematic review and meta-analysis. Cancer Manag Res 2019; 11:2747-2758. [PMID: 31114331 PMCID: PMC6497897 DOI: 10.2147/cmar.s190678] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 02/15/2019] [Indexed: 12/30/2022] Open
Abstract
Background: The prognostic value of chromogranin-A (CHGA) as a biomarker of prostate cancer (PCa) has been evaluated extensively. However, to date the results still remain controversial. This study aims to perform a meta-analysis on previous studies in order to determine whether CHGA would be a biomarker for survival in PCa patients. Methods: MEDLINE, Embase, Web of Science, and Cochrane Library databases were searched to identify eligible studies published before September 2018, regarding the association of CHGA gene expression with survival outcomes in patients with PCa. Multivariate adjusted HRs and associated 95% CIs were calculated using random effects models. Results: Ten cohort studies involving 3,172 patients were finally included. According to the included studies, circulating CHGA levels were tested in serum, plasma, and tissues. The results showed an association between high CHGA expression and worse overall survival (OS) (HR=1.24, 95% CI: 1.07-1.44; P=0.004; I 2=77.6%) in PCa patients. However, no significant association was observed between increasing CHGA expression and shorter progression-free survival (HR=1.73, 95% CI: 0.92-3.28; P=0.090; I 2=73.9%). The results of sensitivity analysis validated the rationality and reliability of our analysis. Conclusion: Current evidence indicates that high CHGA expression is a potential marker for poor OS in PCa. Future studies are needed to explore tailored treatments that directly target CHGA for the improvement of survival in men with PCa.
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Affiliation(s)
- Zhenlang Guo
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China
| | - Yuliang Wang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, People's Republic of China
| | - Songtao Xiang
- Department of Urology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China
| | - Shusheng Wang
- Department of Urology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China
| | - Franky Leung Chan
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, People's Republic of China
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Goudey B, Fung BJ, Schieber C, Faux NG. A blood-based signature of cerebrospinal fluid Aβ 1-42 status. Sci Rep 2019; 9:4163. [PMID: 30853713 PMCID: PMC6409361 DOI: 10.1038/s41598-018-37149-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 12/03/2018] [Indexed: 12/22/2022] Open
Abstract
It is increasingly recognized that Alzheimer's disease (AD) exists before dementia is present and that shifts in amyloid beta occur long before clinical symptoms can be detected. Early detection of these molecular changes is a key aspect for the success of interventions aimed at slowing down rates of cognitive decline. Recent evidence indicates that of the two established methods for measuring amyloid, a decrease in cerebrospinal fluid (CSF) amyloid β1-42 (Aβ1-42) may be an earlier indicator of Alzheimer's disease risk than measures of amyloid obtained from Positron Emission Tomography (PET). However, CSF collection is highly invasive and expensive. In contrast, blood collection is routinely performed, minimally invasive and cheap. In this work, we develop a blood-based signature that can provide a cheap and minimally invasive estimation of an individual's CSF amyloid status using a machine learning approach. We show that a Random Forest model derived from plasma analytes can accurately predict subjects as having abnormal (low) CSF Aβ1-42 levels indicative of AD risk (0.84 AUC, 0.78 sensitivity, and 0.73 specificity). Refinement of the modeling indicates that only APOEε4 carrier status and four plasma analytes (CGA, Aβ1-42, Eotaxin 3, APOE) are required to achieve a high level of accuracy. Furthermore, we show across an independent validation cohort that individuals with predicted abnormal CSF Aβ1-42 levels transitioned to an AD diagnosis over 120 months significantly faster than those with predicted normal CSF Aβ1-42 levels and that the resulting model also validates reasonably across PET Aβ1-42 status (0.78 AUC). This is the first study to show that a machine learning approach, using plasma protein levels, age and APOEε4 carrier status, is able to predict CSF Aβ1-42 status, the earliest risk indicator for AD, with high accuracy.
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Affiliation(s)
- Benjamin Goudey
- IBM Research Australia, Carlton, Victoria, Australia
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Parkville, Victoria, Australia
- Department of Computing and Information System, The University of Melbourne, Parkville, Victoria, Australia
| | - Bowen J Fung
- IBM Research Australia, Carlton, Victoria, Australia
- School of Psychological Sciences, University of Melbourne, Parkville, Victoria, Australia
| | | | - Noel G Faux
- IBM Research Australia, Carlton, Victoria, Australia.
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
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44
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Chromogranin A usefulness in small non-functioning pancreatic neuroendocrine tumors surgical management. Surgery 2019; 166:952. [PMID: 30683505 DOI: 10.1016/j.surg.2018.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 12/07/2018] [Indexed: 11/23/2022]
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45
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Raoof M, Jutric Z, Melstrom LG, Lee B, Li D, Warner SG, Fong Y, Singh G. Prognostic significance of Chromogranin A in small pancreatic neuroendocrine tumors. Surgery 2018; 165:760-766. [PMID: 30447803 DOI: 10.1016/j.surg.2018.10.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 10/03/2018] [Accepted: 10/15/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND The incidence of nonfunctional pancreatic neuroendocrine tumors ≤2cm is rising. The biologic behavior of these tumors is variable; thus, their management remains controversial. Chromogranin A upregulation is a useful diagnostic biomarker of neuroendocrine tumors; however, the prognostic significance of Chromogranin A is unclear. The objective of this study was to determine whether Chromogranin A levels have prognostic value in pancreatic neuroendocrine tumor patients and may help guide management. METHODS We evaluated the National Cancer Database over a 10-year period (2004-2013). Patients with pancreatic neuroendocrine tumors measuring ≤2cm, without distant metastases, were identified and categorized as Chromogranin A high (>420ng/mL) or Chromogranin A low (≤420ng/mL), and those lacking data on Chromogranin A levels were excluded from the study. Univariate and multivariate analyses were performed using Cox proportional hazards model. Cut-point determination was performed using the Contal and O'Quigley method. RESULTS Of the 445 eligible patients, 352 (79%) were Chromogranin A low and 93 (21%) were Chromogranin A high. Median Chromogranin A level was 71ng/mL (interquartile range, 24-294ng/mL). Chromogranin levels were associated with clinical nodal status and grade. Furthermore, on multivariate analysis, Chromogranin A levels (Chromogranin A high versus Chromogranin A low) independently predicted overall survival after controlling for tumor size, grade, clinical nodal status, and academic status of the facility (hazard ratio: 7.90, 95%CI: 2.34-26.69, P = .001). The greatest benefit of surgical resection was noted in patients in the Chromogranin A high subgroup (log-rank P <.001). CONCLUSION Serum Chromogranin A levels can be incorporated in surgical decision-making for patients with small pancreatic neuroendocrine tumors. Patients in the Chromogranin A low group can be considered for observation, whereas patients in the Chromogranin A high group should be strongly considered for resection.
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Affiliation(s)
- Mustafa Raoof
- Department of Surgery, City of Hope National Medical Center, Duarte, CA
| | - Zeljka Jutric
- Department of Surgery, University of California, Irvine, CA
| | - Laleh G Melstrom
- Department of Surgery, City of Hope National Medical Center, Duarte, CA
| | - Byrne Lee
- Department of Surgery, City of Hope National Medical Center, Duarte, CA
| | - Daneng Li
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA
| | - Susanne G Warner
- Department of Surgery, City of Hope National Medical Center, Duarte, CA
| | - Yuman Fong
- Department of Surgery, City of Hope National Medical Center, Duarte, CA
| | - Gagandeep Singh
- Department of Surgery, City of Hope National Medical Center, Duarte, CA.
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The Levels of Tumor Markers in Pancreatic Neuroendocrine Carcinoma and Their Values in Differentiation Between Pancreatic Neuroendocrine Carcinoma and Pancreatic Ductal Adenocarcinoma. Pancreas 2018; 47:1290-1295. [PMID: 30308534 DOI: 10.1097/mpa.0000000000001181] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVES The levels of tumor markers in pancreatic neuroendocrine carcinoma (PNEC) are unknown, and imaging findings of PNEC and pancreatic ductal adenocarcinoma (PDAC) have overlaps. In this study, we show the tumor markers in PNEC and evaluate their values for distinguishing PNEC from PDAC. METHODS Thirty-three cases of PDAC and 21 cases of PNEC were retrospectively evaluated. The demographic information and clinical data were reviewed. RESULTS Pancreatic neuroendocrine carcinoma was usually misdiagnosed (57.1%) as PDAC based on imaging findings. Abnormal carbohydrate antigen (CA) 19-9, carcinoembryonic antigen (CEA), and α-fetoprotein (AFP) were observed in 19.0% to 28.6% of PNECs. Abnormal CA 19-9 and CA 125 levels were more common in PDAC than in PNEC (P < 0.05). Higher level of AFP was more common in PNEC than in PDAC (33.3% vs 3.0%, P < 0.05). The cutoff value of CA 19-9 for detecting PNEC was calculated as 38.5 U/mL or less with 0.788 sensitivity and 0.800 specificity. Carbohydrate antigen 19-9 (odds ratio [OR], 22.9; 95% confidence interval [CI], 2.94-179.3), AFP (OR, 0.08; 95% CI, 0.012-0.564), and CA 125 (OR, 17.4; 95% CI, 1.13-267.3) were predictors in differentiating PDAC from PNEC. CONCLUSIONS Carbohydrate antigen 19-9, AFP, and CA 125 have potential for distinguishing hypovascularized PNEC from PDAC.
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Corrias G, Monti S, Horvat N, Tang L, Basturk O, Saba L, Mannelli L. Imaging features of malignant abdominal neuroendocrine tumors with rare presentation. Clin Imaging 2018; 51:59-64. [PMID: 29448120 PMCID: PMC6082726 DOI: 10.1016/j.clinimag.2018.02.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 01/30/2018] [Accepted: 02/02/2018] [Indexed: 01/07/2023]
Abstract
BACKGROUND Gastroenteropancreatic neuroendocrine tumors (NETs) are rare entities arising from neuroendocrine cells in the gastroenteric tract and pancreas. The purpose of this article is to present four cases of gastroenteropancreatic NETs that featured a challenging diagnosis. CASE PRESENTATION We report a case series of four NETs, each with different features. All NETs were suspected based on clinical and biochemical data. The workup of the abnormalities was performed with CT, PET or MRI. CONCLUSION The diagnosis of NETs is challenging and generally based on clinical manifestations, blood biochemical tests, imaging techniques, and pathology.
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Affiliation(s)
- Giuseppe Corrias
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Department of Radiology, University of Cagliari, Via Università, 40, 09124 Cagliari, CA, Italy
| | | | - Natally Horvat
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Department of Radiology, Hospital Sírio-Libanês, São Paulo, SP, Brazil; Department of Radiology, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Laura Tang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
| | - Olca Basturk
- Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
| | - Luca Saba
- Department of Radiology, University of Cagliari, Via Università, 40, 09124 Cagliari, CA, Italy
| | - Lorenzo Mannelli
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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48
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Kay RG, Challis BG, Casey RT, Roberts GP, Meek CL, Reimann F, Gribble FM. Peptidomic analysis of endogenous plasma peptides from patients with pancreatic neuroendocrine tumours. RAPID COMMUNICATIONS IN MASS SPECTROMETRY : RCM 2018; 32:1414-1424. [PMID: 29857350 PMCID: PMC6099210 DOI: 10.1002/rcm.8183] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 05/15/2018] [Accepted: 05/18/2018] [Indexed: 05/04/2023]
Abstract
RATIONALE Diagnosis of pancreatic neuroendocrine tumours requires the study of patient plasma with multiple immunoassays, using multiple aliquots of plasma. The application of mass spectrometry based techniques could reduce the cost and amount of plasma required for diagnosis. METHODS Plasma samples from two patients with pancreatic neuroendocrine tumours were extracted using an established acetonitrile-based plasma peptide enrichment strategy. The circulating peptidome was characterised using nano and high flow rate liquid chromatography/mass spectrometry (LC/MS) analyses. To assess the diagnostic potential of the analytical approach, a large sample batch (68 plasmas) from control subjects, and aliquots from subjects harbouring two different types of pancreatic neuroendocrine tumour (insulinoma and glucagonoma), were analysed using a 10-min LC/MS peptide screen. RESULTS The untargeted plasma peptidomics approach identified peptides derived from the glucagon prohormone, chromogranin A, chromogranin B and other peptide hormones and proteins related to control of peptide secretion. The glucagon prohormone derived peptides that were detected were compared against putative peptides that were identified using multiple antibody pairs against glucagon peptides. Comparison of the plasma samples for relative levels of selected peptides showed clear separation between the glucagonoma and the insulinoma and control samples. CONCLUSIONS The combination of the organic solvent extraction methodology with high flow rate analysis could potentially be used to aid diagnosis and monitor treatment of patients with functioning pancreatic neuroendocrine tumours. However, significant validation will be required before this approach can be clinically applied.
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Affiliation(s)
- Richard G. Kay
- Institute of Metabolic ScienceMetabolic Research LaboratoriesAddenbrooke's Hospital, Hills RoadCambridgeCB2 0QQUK
| | - Benjamin G. Challis
- Institute of Metabolic ScienceWolfson Diabetes and Endocrine CentreAddenbrooke's HospitalCambridgeUK
- IMED Biotech Unit, Clinical Discovery Unit, AstraZenecaUK
| | - Ruth T. Casey
- Institute of Metabolic ScienceWolfson Diabetes and Endocrine CentreAddenbrooke's HospitalCambridgeUK
| | - Geoffrey P. Roberts
- Institute of Metabolic ScienceMetabolic Research LaboratoriesAddenbrooke's Hospital, Hills RoadCambridgeCB2 0QQUK
| | - Claire L. Meek
- Institute of Metabolic ScienceMetabolic Research LaboratoriesAddenbrooke's Hospital, Hills RoadCambridgeCB2 0QQUK
| | - Frank Reimann
- Institute of Metabolic ScienceMetabolic Research LaboratoriesAddenbrooke's Hospital, Hills RoadCambridgeCB2 0QQUK
| | - Fiona M. Gribble
- Institute of Metabolic ScienceMetabolic Research LaboratoriesAddenbrooke's Hospital, Hills RoadCambridgeCB2 0QQUK
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49
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Genç CG, Jilesen APJ, Nieveen van Dijkum EJM, Klümpen HJ, van Eijck CHJ, Drozdov I, Malczewska A, Kidd M, Modlin I. Measurement of circulating transcript levels (NETest) to detect disease recurrence and improve follow-up after curative surgical resection of well-differentiated pancreatic neuroendocrine tumors. J Surg Oncol 2018; 118:37-48. [PMID: 30114319 DOI: 10.1002/jso.25129] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 05/13/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Recurrence of pancreatic neuroendocrine tumors (pNET) after surgery is common. Strategies to detect recurrence have limitations. We investigated the role of clinical criteria and the multigene polymerase chain reaction-based NETest during post-operative follow-up of pNET. METHODS We studied 3 groups of resections: R0 with no recurrence (n = 11), R0 with recurrence (n = 12), and R1 with no recurrence (n = 12). NETest levels (>40%) were compared with chromogranin A (CgA) and clinicopathological criteria (CC; grade, lymph node metastases, size). Nonparametric, receiver operating characteristics, logistic regression, and predictive feature importance analyses were performed. RESULTS NETest was higher in R0 with recurrence (56 ± 8%) compared with R1 with no recurrence (39 ± 6%) and R0 with no recurrence (28 ± 6%, P < .005). NETest positively correlated with recurrence (area under the curve: 0.82), CgA was not (area under the curve: 0.51 ± 0.09). Multiple regression analysis defined factor impact as highest for NETest (P < .005) versus CC (P < .03) and CgA (P = .23). NETest gave false positive or negative recurrence in 18% using a 40% cutoff. Logistic regression modeling of CC was 83% accurate; it was 91% when the NETest was included. Combining CC and NETest was approximately 2× more effective than individual CC alone (increase in R 2 value from 43% to 80%). CONCLUSIONS A multigene blood test facilitates effective identification of pNET recurrence, prediction of disease relapse, and outperforms CgA.
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Affiliation(s)
- Cansu G Genç
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
| | - Anneke P J Jilesen
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
| | | | - Heinz-Josef Klümpen
- Department of Medical Oncology, Academic Medical Center, Amsterdam, The Netherlands.,Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | | | | | - Anna Malczewska
- Department of Endocrinology and Neuroendocrine Tumours, Medical University of Silesia, Katowice, Poland
| | - Mark Kidd
- Wren Laboratories, Branford, Connecticut
| | - Irvin Modlin
- Department of Surgery, Yale University School of Medicine, New Haven, Connecticut
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Abstract
Primary hepatic neuroendocrine neoplasms (PHNENs) represent a kind of rare liver tumor and its clinical features and prognosis remain unclear. This study aims to reveal the long-term therapeutic outcome of PHNEN and to present its prognostic feature.A retrospective designed, single-center study containing 22 patients with PHNENs receiving surgical resections was done. Clinical data were reviewed and long-term follow-up was updated. Survival analysis was tried to find the prognostic factors.Nine patients recurred (recurrence rate = 40.9%) and 6 patients died on the disease. The actual 1-, 3-, and 5-year recurrence-free survival rate were 86.4%, 63.6%, and 52.9%, respectively. The 1-, 3-, and 5-year overall survival rate were 95.5%, 81.8%, and 64.7%, respectively. Median overall survival for group G1, G2, and G3 were 69, 67, and 42 months, respectively.Patients with PHNEN can have a long survival after radical surgical resection, especially when the tumor proliferative grade exhibits lower (G1/2).
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Affiliation(s)
| | - Qian Zhao
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | | | - Feng Xie
- Department of Hepatobiliary Surgery
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