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Xu F, Yu D, Guo J, Hu J, Zhao Y, Jiang C, Meng X, Cai J, Zhao Y. From pathology to therapy: A comprehensive review of ATRX mutation related molecular functions and disorders. MUTATION RESEARCH. REVIEWS IN MUTATION RESEARCH 2025; 795:108537. [PMID: 40250797 DOI: 10.1016/j.mrrev.2025.108537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 04/13/2025] [Accepted: 04/15/2025] [Indexed: 04/20/2025]
Abstract
ATRX (alpha-thalassemia/mental retardation, X-linked), a chromatin remodeler, is one of the most commonly mutated genes in human cancer. The ATRX protein functions as a histone chaperone, facilitating the proper folding and assembly of histone proteins into nucleosome cores. Investigations into its molecular mechanisms have significantly advanced our understanding of its roles in diseases associated with chromosomal instability and defective DNA repair. In this comprehensive review, we delineate ATRX's critical function in maintaining heterochromatin integrity and genomic stability under physiological conditions. We further explore the pathogenesis of ATRX-deficient tumors and ATRX syndrome, systematically evaluate current therapeutic strategies for these conditions, and propose novel perspectives on potential targeted therapies for ATRX-mutated malignancies. This review provides useful resource for regarding the etiology and treatment of ATRX deficiency-related diseases.
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Affiliation(s)
- Fan Xu
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, #246 Xuefu Road, Harbin, Heilongjiang Province 150086, PR China; Heilongjiang Provincial Clinical Research Center for Glioma, PR China
| | - Daohan Yu
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, #246 Xuefu Road, Harbin, Heilongjiang Province 150086, PR China; Heilongjiang Provincial Clinical Research Center for Glioma, PR China
| | - Jiazheng Guo
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, #246 Xuefu Road, Harbin, Heilongjiang Province 150086, PR China; Heilongjiang Provincial Clinical Research Center for Glioma, PR China
| | - Jingze Hu
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, #246 Xuefu Road, Harbin, Heilongjiang Province 150086, PR China; Heilongjiang Provincial Clinical Research Center for Glioma, PR China
| | - Yunlei Zhao
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, #246 Xuefu Road, Harbin, Heilongjiang Province 150086, PR China; Heilongjiang Provincial Clinical Research Center for Glioma, PR China
| | - Chuanlu Jiang
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, #246 Xuefu Road, Harbin, Heilongjiang Province 150086, PR China; Heilongjiang Provincial Clinical Research Center for Glioma, PR China; The Sixth Affiliated Hospital of Harbin Medical University, #998 AiYing Street, Harbin, Heilongjiang Province 150023, PR China
| | - Xiangqi Meng
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, #246 Xuefu Road, Harbin, Heilongjiang Province 150086, PR China; Heilongjiang Provincial Clinical Research Center for Glioma, PR China.
| | - Jinquan Cai
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, #246 Xuefu Road, Harbin, Heilongjiang Province 150086, PR China; Heilongjiang Provincial Clinical Research Center for Glioma, PR China.
| | - Yan Zhao
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, #246 Xuefu Road, Harbin, Heilongjiang Province 150086, PR China.
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Huang JY, Cherayil NA, Boyd P, Ali M, Samanani S. A Rare Case of Metastatic Adrenocorticotrophic Hormone - Secreting Pancreatic Neuroendocrine Tumor Causing Ectopic Cushing Syndrome in a 46-Year-Old Woman. AMERICAN JOURNAL OF CASE REPORTS 2025; 26:e945653. [PMID: 40176331 PMCID: PMC11977430 DOI: 10.12659/ajcr.945653] [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: 06/27/2024] [Revised: 02/20/2025] [Accepted: 02/04/2025] [Indexed: 04/04/2025]
Abstract
BACKGROUND Adrenocorticotrophic hormone (ACTH)-secreting pancreatic neuroendocrine tumors (pNETs) are rare and poorly understood entities. Only 1-2% of pancreatic neoplasms are pNETs, and even fewer are hormone-secreting. They can present indolently or with overt Cushing syndrome. Their diagnosis involves complex multi-modal imaging and laboratory evaluation. Management includes medications, such as somatostatin analogs and ketoconazole, as well as surgical resection for definitive treatment. This report describes a 46-year-old woman who presented with overt Cushing syndrome and was ultimately diagnosed with a pNET. CASE REPORT This patient's initial symptoms and laboratory testing were consistent with Cushing syndrome. A high-dose dexamethasone suppression test suggested ectopic ACTH production, and magnetic resonance imaging (MRI) of the brain showed a pituitary microadenoma. However, computed tomography (CT) of the abdomen and endoscopic ultrasound-guided biopsy with immunohistochemistry confirmed a pancreatic mass as the source of ACTH production with potential hepatic metastasis. Her Cushing syndrome was managed with ketoconazole and octreotide. Subsequently, >99% of the pNET was surgically removed, resulting in reversal of her Cushing syndrome. Currently, she is being monitored closely for recurrence. CONCLUSIONS Our management of this ACTH-secreting pNET highlights the complexities of diagnosis and multidisciplinary treatment options, which are underrepresented in the current literature on this rare entity. This case emphasizes the challenges in evaluation, including the importance of early and precise diagnosis in the face of potential confounders.
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Affiliation(s)
- Jessica Y. Huang
- Department of Medicine, The George Washington University, Washington, DC, USA
| | - Nikitha A. Cherayil
- Department of Internal Medicine, The George Washington University, Washington, DC, USA
| | - Paul Boyd
- Department of Medicine, The George Washington University, Washington, DC, USA
| | - Maher Ali
- Department of Pathology, The George Washington University, Washington, DC, USA
| | - Shazia Samanani
- Department of Medicine, The George Washington University, Washington, DC, USA
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Perry RR, Feliberti EC, Hughes MS. Management of Pancreatic Neuroendocrine Tumors: Surgical Strategies and Controversies. Endocr Pract 2024; 30:908-916. [PMID: 39032831 DOI: 10.1016/j.eprac.2024.07.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 06/01/2024] [Accepted: 07/09/2024] [Indexed: 07/23/2024]
Abstract
OBJECTIVE Pancreatic neuroendocrine tumors (PNETs) are uncommon tumors which are increasing in incidence. The management of these tumors continues to evolve. This review examines the current role of surgery in the treatment of these tumors. METHODS Studies published over the past 10 years were identified using several databases including PubMed, MEDLINE, and Science Direct. Search terms included PNETs, treatment, and surgery. Clinical practice guidelines and updates from several major groups were reviewed. RESULTS Surgery continues to have a major role in the treatment of sporadic functional and nonfunctional PNETs. Pancreas-sparing approaches are increasingly accepted as alternatives to formal pancreatic resection in selected patients. Options such as watch and wait or endoscopic ablation may be reasonable alternatives to surgery for non-functional PNETs < 2 cm in size. Surgical decision-making in multiple endocrine neoplasia type 1 patients remains complex and in some situations such as gastrinoma quite controversial. The role of surgery has significantly diminished in patients with advanced disease due to the advent of more effective systemic and liver-directed therapies. However, the optimal treatments and sequencing in advanced disease remain poorly defined, and it has been suggested that surgery is underutilized in these patients. CONCLUSIONS Surgery remains a major treatment modality for PNETs. Given the plethora of available treatments, ongoing controversies and the changing landscape, management has become increasingly complex. An experienced multidisciplinary team which includes surgery is essential to manage these patients.
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Affiliation(s)
- Roger R Perry
- Division of Surgical Oncology, Eastern Virginia Medical School, Norfolk, Virginia.
| | - Eric C Feliberti
- Division of Surgical Oncology, Eastern Virginia Medical School, Norfolk, Virginia
| | - Marybeth S Hughes
- Division of Surgical Oncology, Eastern Virginia Medical School, Norfolk, Virginia
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Mo S, Wang Y, Huang C, Wu W, Qin S. A novel endoscopic ultrasomics-based machine learning model and nomogram to predict the pathological grading of pancreatic neuroendocrine tumors. Heliyon 2024; 10:e34344. [PMID: 39130461 PMCID: PMC11315146 DOI: 10.1016/j.heliyon.2024.e34344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 07/08/2024] [Accepted: 07/08/2024] [Indexed: 08/13/2024] Open
Abstract
OBJECTIVES This research aimed to retrospectively construct and authenticate ultrasomics models using endoscopic ultrasonography (EUS) images for forecasting the pathological grading of pancreatic neuroendocrine tumors (PNETs). METHODS After confirmation through pathological examination, a retrospective analysis of 79 patients was conducted, including 49 with grade 1 PNETs and 30 with grade 2/3 PNETs. These patients were randomized to the training or test cohort in a 6:4 proportion. The least absolute shrinkage and selection operator (LASSO) algorithm was used to reduce the dimensionality of ultrasomics features derived from standard EUS images. These nonzero coefficient features were retained and applied to construct prediction models via eight machine-learning algorithms. The optimum ulstrasomics model was determined, followed by creating and evaluating a nomogram. RESULTS Ultrasomics features of 107 were extracted, and only those with coefficients greater than zero were retained. The XGboost ultrasomics model performed exceptionally well, achieving AUCs of 0.987 and 0.781 in the training and test cohorts, respectively. Furthermore, an effective nomogram was developed and visually represented. Finally, the calibration curves, decision curve analysis (DCA) plots, and clinical impact curve (CIC) displayed in the ulstrasomics model and nomogram demonstrated high accuracy. They provided significant net benefits for clinical decision-making. CONCLUSIONS A novel ulstrasomics model and nomogram were created and certified to predict the pathological grading of PNETs using EUS images. This study has the potential to provide valuable insights that improve the clinical applicability and efficacy of EUS in predicting the grading of PNETs.
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Affiliation(s)
- Shuangyang Mo
- Gastroenterology Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Gastroenterology Department, Liuzhou People's Hospital Affiliated to Guangxi Medical University, Liuzhou, China
| | - Yingwei Wang
- Gastroenterology Department, Liuzhou People's Hospital Affiliated to Guangxi Medical University, Liuzhou, China
| | - Cheng Huang
- Oncology Department, Liuzhou People's Hospital Affiliated to Guangxi Medical University, Liuzhou, China
| | - Wenhong Wu
- Gastroenterology Department, Liuzhou People's Hospital Affiliated to Guangxi Medical University, Liuzhou, China
| | - Shanyu Qin
- Gastroenterology Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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Partelli S, Battistella A, Andreasi V, Muffatti F, Tamburrino D, Pecorelli N, Crippa S, Balzano G, Falconi M. Critical appraisal of the adequacy of surgical indications for non-functioning pancreatic neuroendocrine tumours. BJS Open 2024; 8:zrae083. [PMID: 39107074 PMCID: PMC11303005 DOI: 10.1093/bjsopen/zrae083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 04/22/2024] [Accepted: 06/20/2024] [Indexed: 08/09/2024] Open
Abstract
BACKGROUND The lack of preoperative prognostic factors to accurately predict tumour aggressiveness in non-functioning pancreatic neuroendocrine tumours may result in inappropriate management decisions. This study aimed to critically evaluate the adequacy of surgical treatment in patients with resectable non-functioning pancreatic neuroendocrine tumours and investigate preoperative features of surgical appropriateness. METHODS A retrospective study was conducted on patients who underwent curative surgery for non-functioning pancreatic neuroendocrine tumours at San Raffaele Hospital (2002-2022). The appropriateness of surgical treatment was categorized as appropriate, potential overtreatment and potential undertreatment based on histologic features of aggressiveness and disease relapse within 1 year from surgery (early relapse). RESULTS A total of 384 patients were included. Among them, 230 (60%) received appropriate surgical treatment, whereas the remaining 154 (40%) underwent potentially inadequate treatment: 129 (34%) experienced potential overtreatment and 25 (6%) received potential undertreatment. The appropriateness of surgical treatment was significantly associated with radiological tumour size (P < 0.001), tumour site (P = 0.012), surgical technique (P < 0.001) and year of surgical resection (P < 0.001). Surgery performed before 2015 (OR 2.580, 95% c.i. 1.570 to 4.242; P < 0.001), radiological tumour diameter < 25.5 mm (OR 6.566, 95% c.i. 4.010 to 10.751; P < 0.001) and pancreatic body/tail localization (OR 1.908, 95% c.i. 1.119 to 3.253; P = 0.018) were identified as independent predictors of potential overtreatment. Radiological tumour size was the only independent determinant of potential undertreatment (OR 0.291, 95% c.i. 0.107 to 0.791; P = 0.016). Patients subjected to potential undertreatment exhibited significantly poorer disease-free survival (P < 0.001), overall survival (P < 0.001) and disease-specific survival (P < 0.001). CONCLUSIONS Potential overtreatment occurs in nearly one-third of patients undergoing surgery for non-functioning pancreatic neuroendocrine tumours. Tumour diameter emerges as the sole variable capable of predicting the risk of both potential surgical overtreatment and undertreatment.
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Affiliation(s)
- Stefano Partelli
- Pancreas Translational and Clinical Research Centre, Pancreatic Surgery Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
| | - Anna Battistella
- Pancreas Translational and Clinical Research Centre, Pancreatic Surgery Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
| | - Valentina Andreasi
- Pancreas Translational and Clinical Research Centre, Pancreatic Surgery Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
| | - Francesca Muffatti
- Pancreas Translational and Clinical Research Centre, Pancreatic Surgery Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Domenico Tamburrino
- Pancreas Translational and Clinical Research Centre, Pancreatic Surgery Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Nicolò Pecorelli
- Pancreas Translational and Clinical Research Centre, Pancreatic Surgery Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
| | - Stefano Crippa
- Pancreas Translational and Clinical Research Centre, Pancreatic Surgery Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
| | - Gianpaolo Balzano
- Pancreas Translational and Clinical Research Centre, Pancreatic Surgery Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Massimo Falconi
- Pancreas Translational and Clinical Research Centre, Pancreatic Surgery Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
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Asmundo L, Ambrosini V, Anderson MA, Fanti S, Bradley WR, Campana D, Mojtahed A, Chung R, Mcdermott S, Digumarthy S, Ursprung S, Nikolau K, Fintelmann FJ, Blake M, Fernandez-Del Castillo C, Qadan M, Pandey A, Clark JW, Catalano OA. Clinical Intricacies and Advances in Neuroendocrine Tumors: An Organ-Based Multidisciplinary Approach. J Comput Assist Tomogr 2024; 48:614-627. [PMID: 38626756 DOI: 10.1097/rct.0000000000001596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/18/2024]
Abstract
ABSTRACT Neuroendocrine neoplasms (NENs) are rare neoplasms originating from neuroendocrine cells, with increasing incidence due to enhanced detection methods. These tumors display considerable heterogeneity, necessitating diverse management strategies based on factors like organ of origin and tumor size. This article provides a comprehensive overview of therapeutic approaches for NENs, emphasizing the role of imaging in treatment decisions. It categorizes tumors based on their locations: gastric, duodenal, pancreatic, small bowel, colonic, rectal, appendiceal, gallbladder, prostate, lung, gynecological, and others. The piece also elucidates the challenges in managing metastatic disease and controversies surrounding MEN1-neuroendocrine tumor management. The article underscores the significance of individualized treatment plans, underscoring the need for a multidisciplinary approach to ensure optimal patient outcomes.
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Affiliation(s)
| | | | - Mark A Anderson
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | | | - William R Bradley
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Davide Campana
- Department of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Amirkasra Mojtahed
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Ryan Chung
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Shaunagh Mcdermott
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Subba Digumarthy
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Stephan Ursprung
- Department of Radiology, University Hospital Tuebingen, Tuebingen, Germany
| | - Konstantin Nikolau
- Department of Radiology, University Hospital Tuebingen, Tuebingen, Germany
| | - Florian J Fintelmann
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Michael Blake
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | | | - Motaz Qadan
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Ankur Pandey
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Jeffrey W Clark
- Department of Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Onofrio A Catalano
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
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Mo S, Huang C, Wang Y, Zhao H, Wu W, Jiang H, Qin S. Endoscopic ultrasonography-based intratumoral and peritumoral machine learning radiomics analyses for distinguishing insulinomas from non-functional pancreatic neuroendocrine tumors. Front Endocrinol (Lausanne) 2024; 15:1383814. [PMID: 38952387 PMCID: PMC11215175 DOI: 10.3389/fendo.2024.1383814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 06/05/2024] [Indexed: 07/03/2024] Open
Abstract
OBJECTIVES To develop and validate radiomics models utilizing endoscopic ultrasonography (EUS) images to distinguish insulinomas from non-functional pancreatic neuroendocrine tumors (NF-PNETs). METHODS A total of 106 patients, comprising 61 with insulinomas and 45 with NF-PNETs, were included in this study. The patients were randomly assigned to either the training or test cohort. Radiomics features were extracted from both the intratumoral and peritumoral regions, respectively. Six machine learning algorithms were utilized to train intratumoral prediction models, using only the nonzero coefficient features. The researchers identified the most effective intratumoral radiomics model and subsequently employed it to develop peritumoral and combined radiomics models. Finally, a predictive nomogram for insulinomas was constructed and assessed. RESULTS A total of 107 radiomics features were extracted based on EUS, and only features with nonzero coefficients were retained. Among the six intratumoral radiomics models, the light gradient boosting machine (LightGBM) model demonstrated superior performance. Furthermore, a peritumoral radiomics model was established and evaluated. The combined model, integrating both the intratumoral and peritumoral radiomics features, exhibited a comparable performance in the training cohort (AUC=0.876) and achieved the highest accuracy in predicting outcomes in the test cohorts (AUC=0.835). The Delong test, calibration curves, and decision curve analysis (DCA) were employed to validate these findings. Insulinomas exhibited a significantly smaller diameter compared to NF-PNETs. Finally, the nomogram, incorporating diameter and radiomics signature, was constructed and assessed, which owned superior performance in both the training (AUC=0.929) and test (AUC=0.913) cohorts. CONCLUSION A novel and impactful radiomics model and nomogram were developed and validated for the accurate differentiation of NF-PNETs and insulinomas utilizing EUS images.
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Affiliation(s)
- Shuangyang Mo
- Gastroenterology Department, Liuzhou People’s Hospital Affiliated to Guangxi Medical University, Liuzhou, China
- Gastroenterology Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Cheng Huang
- Oncology Department, Liuzhou People’s Hospital Affiliated to Guangxi Medical University, Liuzhou, China
| | - Yingwei Wang
- Gastroenterology Department, Liuzhou People’s Hospital Affiliated to Guangxi Medical University, Liuzhou, China
| | - Huaying Zhao
- Gastroenterology Department, Liuzhou People’s Hospital Affiliated to Guangxi Medical University, Liuzhou, China
| | - Wenhong Wu
- Gastroenterology Department, Liuzhou People’s Hospital Affiliated to Guangxi Medical University, Liuzhou, China
| | - Haixing Jiang
- Gastroenterology Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Shanyu Qin
- Gastroenterology Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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Patrone R, Mongardini FM, Conzo A, Cacciatore C, Cozzolino G, Catauro A, Lanza E, Izzo F, Belli A, Palaia R, Flagiello L, De Vita F, Docimo L, Conzo G. Pancreatic Neuroendocrine Tumors: What Is the Best Surgical Option? J Clin Med 2024; 13:3015. [PMID: 38792555 PMCID: PMC11121769 DOI: 10.3390/jcm13103015] [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: 04/08/2024] [Revised: 05/08/2024] [Accepted: 05/16/2024] [Indexed: 05/26/2024] Open
Abstract
Background: Pancreatic neuroendocrine tumors (pNETs) represent a rare subset of pancreatic cancer. Functional tumors cause hormonal changes and clinical syndromes, while non-functional ones are often diagnosed late. Surgical management needs multidisciplinary planning, involving enucleation, distal pancreatectomy with or without spleen preservation, central pancreatectomy, pancreaticoduodenectomy or total pancreatectomy. Minimally invasive approaches have increased in the last decade compared to the open technique. The aim of this study was to analyze the current diagnostic and surgical trends for pNETs, to identify better interventions and their outcomes. Methods: The study adhered to the PRISMA guidelines, conducting a systematic review of the literature from May 2008 to March 2022 across multiple databases. Several combinations of keywords were used ("NET", "pancreatic", "surgery", "laparoscopic", "minimally invasive", "robotic", "enucleation", "parenchyma sparing") and relevant article references were manually checked. The manuscript quality was evaluated. Results: The study screened 3867 manuscripts and twelve studies were selected, primarily from Italy, the United States, and China. A total of 7767 surgically treated patients were collected from 160 included centers. The mean age was 56.3 y.o. Enucleation (EN) and distal pancreatectomy (DP) were the most commonly performed surgeries and represented 43.4% and 38.6% of the total interventions, respectively. Pancreatic fistulae, postoperative bleeding, re-operation, and follow-up were recorded and analyzed. Conclusions: Enucleation shows better postoperative outcomes and lower mortality rates compared to pancreaticoduodenectomy (PD) or distal pancreatectomy (DP), despite the similar risks of postoperative pancreatic fistulae (POPF). DP is preferred over enucleation for the pancreas body-tail, while laparoscopic enucleation is better for head pNETs.
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Affiliation(s)
- Renato Patrone
- Hepatobiliary Surgical Oncology Unit, Istituto Nazionale Tumori IRCCS Fondazione Pascale-IRCCS di Napoli, 80131 Naples, Italy; (F.I.); (A.B.); (R.P.); (L.D.); (G.C.)
| | - Federico Maria Mongardini
- Division of General, Oncological, Mini-Invasive and Obesity Surgery, University of Study of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (F.M.M.); (A.C.); (C.C.); (G.C.); (A.C.); (E.L.); (L.F.)
| | - Alessandra Conzo
- Division of General, Oncological, Mini-Invasive and Obesity Surgery, University of Study of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (F.M.M.); (A.C.); (C.C.); (G.C.); (A.C.); (E.L.); (L.F.)
| | - Chiara Cacciatore
- Division of General, Oncological, Mini-Invasive and Obesity Surgery, University of Study of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (F.M.M.); (A.C.); (C.C.); (G.C.); (A.C.); (E.L.); (L.F.)
| | - Giovanni Cozzolino
- Division of General, Oncological, Mini-Invasive and Obesity Surgery, University of Study of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (F.M.M.); (A.C.); (C.C.); (G.C.); (A.C.); (E.L.); (L.F.)
| | - Antonio Catauro
- Division of General, Oncological, Mini-Invasive and Obesity Surgery, University of Study of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (F.M.M.); (A.C.); (C.C.); (G.C.); (A.C.); (E.L.); (L.F.)
| | - Eduardo Lanza
- Division of General, Oncological, Mini-Invasive and Obesity Surgery, University of Study of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (F.M.M.); (A.C.); (C.C.); (G.C.); (A.C.); (E.L.); (L.F.)
| | - Francesco Izzo
- Hepatobiliary Surgical Oncology Unit, Istituto Nazionale Tumori IRCCS Fondazione Pascale-IRCCS di Napoli, 80131 Naples, Italy; (F.I.); (A.B.); (R.P.); (L.D.); (G.C.)
| | - Andrea Belli
- Hepatobiliary Surgical Oncology Unit, Istituto Nazionale Tumori IRCCS Fondazione Pascale-IRCCS di Napoli, 80131 Naples, Italy; (F.I.); (A.B.); (R.P.); (L.D.); (G.C.)
| | - Raffaele Palaia
- Hepatobiliary Surgical Oncology Unit, Istituto Nazionale Tumori IRCCS Fondazione Pascale-IRCCS di Napoli, 80131 Naples, Italy; (F.I.); (A.B.); (R.P.); (L.D.); (G.C.)
| | - Luigi Flagiello
- Division of General, Oncological, Mini-Invasive and Obesity Surgery, University of Study of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (F.M.M.); (A.C.); (C.C.); (G.C.); (A.C.); (E.L.); (L.F.)
| | - Ferdinando De Vita
- Division of Medical Oncology, Department of Internal and Experimental Medicine ‘F. Magrassi’, Università della Campania ‘Luigi Vanvitelli’, 80138 Naples, Italy;
| | - Ludovico Docimo
- Hepatobiliary Surgical Oncology Unit, Istituto Nazionale Tumori IRCCS Fondazione Pascale-IRCCS di Napoli, 80131 Naples, Italy; (F.I.); (A.B.); (R.P.); (L.D.); (G.C.)
| | - Giovanni Conzo
- Hepatobiliary Surgical Oncology Unit, Istituto Nazionale Tumori IRCCS Fondazione Pascale-IRCCS di Napoli, 80131 Naples, Italy; (F.I.); (A.B.); (R.P.); (L.D.); (G.C.)
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Zhang N, He J, Maithel SK, Poultsides G, Rocha F, Weber S, Fields R, Idrees K, Cho C, Lv Y, Zhang XF, Pawlik TM. Accuracy and Prognostic Impact of Nodal Status on Preoperative Imaging for Management of Pancreatic Neuroendocrine Tumors: A Multi-Institutional Study. Ann Surg Oncol 2024; 31:2882-2891. [PMID: 38097878 DOI: 10.1245/s10434-023-14758-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 11/25/2023] [Indexed: 04/10/2024]
Abstract
BACKGROUND We sought to define the accuracy of preoperative imaging to detect lymph node metastasis (LNM) among patients with pancreatic neuroendocrine tumors (pNETs), as well as characterize the impact of preoperative imaging nodal status on survival. METHODS Patients who underwent curative-intent resection for pNETs between 2000 and 2020 were identified from eight centers. Sensitivity and specificity of computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET)-CT, and OctreoScan for LNM were evaluated. The impact of preoperative lymph node status on lymphadenectomy (LND), as well as overall and recurrence-free survival was defined. RESULTS Among 852 patients, 235 (27.6%) individuals had LNM on final histologic examination (hN1). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 12.4%, 98.1%, 71.8%, and 74.4% for CT, 6.3%, 100%, 100%, and 80.1% for MRI, 9.5%, 100%, 100%, and 58.7% for PET, 11.3%, 97.5%, 66.7%, and 70.8% for OctreoScan, respectively. Among patients with any combination of these imaging modalities, overall sensitivity, specificity, PPV, and NPV was 14.9%, 97.9%, 72.9%, and 75.1%, respectively. Preoperative N1 on imaging (iN1) was associated with a higher number of LND (iN1 13 vs. iN0 9, p = 0.003) and a higher frequency of final hN1 versus preoperative iN0 (iN1 72.9% vs. iN0 24.9%, p < 0.001). Preoperative iN1 was associated with a higher risk of recurrence versus preoperative iN0 (median recurrence-free survival, iN1→hN1 47.5 vs. iN0→hN1 92.7 months, p = 0.05). CONCLUSIONS Only 4% of patients with LNM on final pathologic examine had preoperative imaging that was suspicious for LNM. Traditional imaging modalities had low sensitivity to determine nodal status among patients with pNETs.
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Affiliation(s)
- Nan Zhang
- Department of Hepatobiliary Surgery, Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jin He
- Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Shishir K Maithel
- Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | | | - Flavio Rocha
- Department of Surgery, Oregon Health and Science University, Portland, OR, USA
| | - Sharon Weber
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Ryan Fields
- Department of Surgery, Washington University School of Medicine, St. Louis, WI, USA
| | - Kamran Idrees
- Division of Surgical Oncology, Department of Surgery, Vanderbilt University, Nashville, TN, USA
| | - Cliff Cho
- Division of Hepatopancreatobiliary and Advanced Gastrointestinal Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Yi Lv
- Department of Hepatobiliary Surgery, Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xu-Feng Zhang
- Department of Hepatobiliary Surgery, Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
- Division of Surgical Oncology, Department of Surgery, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
| | - Timothy M Pawlik
- Division of Surgical Oncology, Department of Surgery, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
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10
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Liu YL, Zhu HB, Chen ML, Sun W, Li XT, Sun YS. Prediction of the lymphatic, microvascular, and perineural invasion of pancreatic neuroendocrine tumors using preoperative magnetic resonance imaging. World J Gastrointest Surg 2023; 15:2809-2819. [PMID: 38222000 PMCID: PMC10784819 DOI: 10.4240/wjgs.v15.i12.2809] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 11/06/2023] [Accepted: 12/06/2023] [Indexed: 12/27/2023] Open
Abstract
BACKGROUND Significant correlation between lymphatic, microvascular, and perineural invasion (LMPI) and the prognosis of pancreatic neuroendocrine tumors (PENTs) was confirmed by previous studies. There was no previous study reported the relationship between magnetic resonance imaging (MRI) parameters and LMPI. AIM To determine the feasibility of using preoperative MRI of the pancreas to predict LMPI in patients with non-functioning PENTs (NFPNETs). METHODS A total of 61 patients with NFPNETs who underwent MRI scans and lymphadenectomy from May 2011 to June 2018 were included in this retrospective study. The patients were divided into group 1 (n = 34, LMPI negative) and group 2 (n = 27, LMPI positive). The clinical characteristics and qualitative MRI features were collected. In order to predict LMPI status in NF-PNETs, a multivariate logistic regression model was constructed. Diagnostic performance was evaluated by calculating the receiver operator characteristic (ROC) curve with area under ROC, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy. RESULTS There were significant differences in the lymph node metastasis stage, tumor grade, neuron-specific enolase levels, tumor margin, main pancreatic ductal dilatation, common bile duct dilatation, enhancement pattern, vascular and adjacent tissue involvement, synchronous liver metastases, the long axis of the largest lymph node, the short axis of the largest lymph node, number of the lymph nodes with short axis > 5 or 10 mm, and tumor volume between two groups (P < 0.05). Multivariate analysis showed that tumor margin (odds ratio = 11.523, P < 0.001) was a predictive factor for LMPI of NF-PNETs. The area under the receiver value for the predictive performance of combined predictive factors was 0.855. The sensitivity, specificity, PPV, NPV and accuracy of the model were 48.1% (14/27), 97.1% (33/34), 97.1% (13/14), 70.2% (33/47) and 0.754, respectively. CONCLUSION Using preoperative MRI, ill-defined tumor margins can effectively predict LMPI in patients with NF-PNETs.
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Affiliation(s)
- Yu-Liang Liu
- Department of Radiology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Hai-Bin Zhu
- Department of Radiology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Mai-Lin Chen
- Department of Radiology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Wei Sun
- Department of Pathology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Xiao-Ting Li
- Department of Radiology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Ying-Shi Sun
- Department of Radiology, Peking University Cancer Hospital and Institute, Beijing 100142, China
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11
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Clinicopathological Characteristics of Nonfunctional Pancreatic Neuroendocrine Neoplasms and the Effect of Surgical Treatment on the Prognosis of Patients with Liver Metastases: A Study Based on the SEER Database. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:3689895. [PMID: 35720036 PMCID: PMC9200579 DOI: 10.1155/2022/3689895] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/23/2022] [Accepted: 04/11/2022] [Indexed: 12/13/2022]
Abstract
Background The incidence of nonfunctional pancreatic neuroendocrine neoplasms (NF-pNENs) has been increasing annually. This study is aimed at investigating the clinicopathological characteristics and high-risk factors of NF-pNENs and the influence of surgical treatment on the prognosis of NF-pNEN patients with liver metastases. Methods pNEN patients in this study were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. This study analyzed patients diagnosed with NF-pNENs from 2000 to 2017 who met the inclusion criteria. A retrospective analysis of the clinicopathological characteristics of NF-pNEN patients was conducted. Kaplan-Meier method was used to calculate the survival time. A multivariate Cox regression model was used to analyze the survival outcomes and risk factors. Results From 2000 to 2017, the SEER database registered 10576 patients with pNENs and 1774 patients with liver metastases. Cox analysis revealed that age, sex, primary site, grade, tumor stage, surgery, tumor size, and liver metastasis were risk factors of prognosis, with grade being the most influential index. Patients with NF-pNENs with liver metastasis and no metastasis had different primary site, grade, and tumor size. In general, a higher grade was associated with a larger tumor and a greater risk of liver metastasis. Meanwhile, patients with liver metastasis showed that those with tumors originated from the tail of the pancreas had better prognoses than those with tumors originated from other parts. Surgical treatment can improve the prognosis of patients with liver metastases, despite the tumor grade. Conclusions The incidence of pNENs has been increasing annually, and the liver has been the most common site of metastasis. Liver metastasis in patients with NF-pNENs, related to tumor size and grade, affected their long-term survival. Surgery significantly improved the prognosis of patients with liver metastases secondary to NF-pNENs with different grades.
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12
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Marinoni I. Prognostic value of DAXX/ATRX loss of expression and ALT activation in PanNETs: is it time for clinical implementation? Gut 2022; 71:847-848. [PMID: 33975869 PMCID: PMC8995811 DOI: 10.1136/gutjnl-2021-324664] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 04/28/2021] [Accepted: 04/29/2021] [Indexed: 01/26/2023]
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13
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Andreasi V, Ricci C, Partelli S, Guarneri G, Ingaldi C, Muffatti F, Crippa S, Casadei R, Falconi M. Predictors of disease recurrence after curative surgery for nonfunctioning pancreatic neuroendocrine neoplasms (NF-PanNENs): a systematic review and meta-analysis. J Endocrinol Invest 2022; 45:705-718. [PMID: 34773595 DOI: 10.1007/s40618-021-01705-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 11/03/2021] [Indexed: 02/06/2023]
Abstract
PURPOSE Patients submitted to curative surgery for non-functioning pancreatic neuroendocrine neoplasms (NF-PanNENs) exhibit a variable risk of disease relapse. Aims of this meta-analysis were to estimate the rate of disease recurrence and to investigate the risk factors for disease relapse in patients submitted to curative surgery for NF-PanNENs. METHODS Medline/Pubmed and Web of Science databases were searched for relevant studies. A meta-regression analysis was performed to investigate the source of recurrence rate heterogeneity. Pooled hazard ratios (HRs) and 95% confidence intervals (95% CI) were used to assess the effect of each possible prognostic factor on disease-free survival. RESULTS Fifteen studies, involving 2754 patients submitted to curative surgery for NF-PanNENs, were included. The pooled rate of disease recurrence was 21% (95% CI 15-26%). Study quality (Odds ratio, OR 0.94, P = 0.016) and G3-PanNENs rate (OR 2.18, P = 0.040) independently predicted the recurrence rate variability. Nodal metastases (HR 1.63, P < 0.001), tumor grade G2-G3 (G1 versus G2: HR 1.72, P < 0.001, G1 versus G3 HR 2.57, P < 0.001), microvascular (HR 1.25, P = 0.046) and perineural (HR 1.29, P = 0.019) invasion were identified as significant prognostic factors. T stage (T1-T2 versus T3-T4, P = 0.253) and status of resection margins (R0 versus R1, P = 0.173) did not show any significant relationship with NF-PanNENs recurrence. CONCLUSION Disease relapse occurs in approximately one out of five patients submitted to curative surgery for NF-PanNENs. Nodal involvement, tumor grade, microvascular and perineural invasion are relevant prognostic factors, that should be taken into account for follow-up and for possible trials investigating adjuvant or neoadjuvant treatments.
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Affiliation(s)
- V Andreasi
- Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Hospital Neuroendocrine Tumor Group (ENETS Center of Excellence), IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Via Olgettina 60, 20132, Milan, Italy
| | - C Ricci
- Division of Pancreatic Surgery, IRCCS Azienda Ospedaliero Universitaria Di Bologna, Bologna, Italy
- Department of Internal Medicine and Surgery (DIMEC), S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - S Partelli
- Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Hospital Neuroendocrine Tumor Group (ENETS Center of Excellence), IRCCS San Raffaele Scientific Institute, Milan, Italy.
- Vita-Salute San Raffaele University, Via Olgettina 60, 20132, Milan, Italy.
| | - G Guarneri
- Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Hospital Neuroendocrine Tumor Group (ENETS Center of Excellence), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - C Ingaldi
- Division of Pancreatic Surgery, IRCCS Azienda Ospedaliero Universitaria Di Bologna, Bologna, Italy
- Department of Internal Medicine and Surgery (DIMEC), S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - F Muffatti
- Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Hospital Neuroendocrine Tumor Group (ENETS Center of Excellence), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - S Crippa
- Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Hospital Neuroendocrine Tumor Group (ENETS Center of Excellence), IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Via Olgettina 60, 20132, Milan, Italy
| | - R Casadei
- Division of Pancreatic Surgery, IRCCS Azienda Ospedaliero Universitaria Di Bologna, Bologna, Italy
- Department of Internal Medicine and Surgery (DIMEC), S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - M Falconi
- Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Hospital Neuroendocrine Tumor Group (ENETS Center of Excellence), IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Via Olgettina 60, 20132, Milan, Italy
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Inoue M, Kim M, Inoue T, Tait M, Byrne T, Nitschké M, Murer P, Cha H, Subramanian A, De Silva N, Chiaverotti T, McDonald DM. Oncolytic vaccinia virus injected intravenously sensitizes pancreatic neuroendocrine tumors and metastases to immune checkpoint blockade. Mol Ther Oncolytics 2022; 24:299-318. [PMID: 35118189 PMCID: PMC8783073 DOI: 10.1016/j.omto.2021.12.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 12/17/2021] [Indexed: 02/07/2023] Open
Abstract
This study determined the influence of intravenous (i.v.) oncolytic vaccinia virus mpJX-594 (mpJX) on antitumor activity of anti-programmed death receptor-1 antibody (aPD1) in functional and metastatic pancreatic neuroendocrine tumors (PanNETs). One i.v. dose of mpJX, engineered for mice with the same plasmid design as clinical virus Pexa-Vec, was administered alone or with repeated dosing of aPD1 (mpJX+aPD1) to two contrasting genetic models of PanNET: one developing benign insulin-secreting tumors (RIP1-Tag2;C57BL/6J mice) and the other developing liver metastases (RIP1-Tag2;AB6F1 mice). Experiments revealed that aPD1 had synergistic actions with mpJX on CD8+ T cell and natural killer (NK) cell influx, apoptosis, and suppression of proliferation in PanNETs. After mpJX+aPD1, the 53-fold increase in apoptosis (5 days) and 85% reduction in proliferation (20 days) exceeded the sum of mpJX and aPD1 given separately. mpJX+aPD1 also stabilized blood insulin and glucose in mice with functional PanNETs, regressed liver metastases in mice with aggressive PanNETs, and prolonged survival of both. The findings revealed that mpJX+aPD1 converted “cold” PanNETs into immunogenic tumors with widespread cytotoxic T cell influx, tumor cell killing, and suppression of proliferation. Reduction of tumor insulin secretion from functional PanNETs prolonged survival, and anti-metastatic actions on aggressive PanNETs reduced the metastatic burden to less than before treatment. The findings support the efficacy of the vaccinia virus with aPD1 for functional and metastatic PanNETs.
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Affiliation(s)
- Mitsuko Inoue
- UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA 94143-0452, USA
| | - Minah Kim
- UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA 94143-0452, USA
| | - Tomoyoshi Inoue
- UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA 94143-0452, USA
| | - Madeline Tait
- UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA 94143-0452, USA
| | - Thomas Byrne
- UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA 94143-0452, USA
| | - Maximilian Nitschké
- UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA 94143-0452, USA
| | - Patrizia Murer
- UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA 94143-0452, USA
| | - Howard Cha
- UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA 94143-0452, USA
| | - Aishwarya Subramanian
- UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA 94143-0452, USA
| | - Naomi De Silva
- SillaJen Biotherapeutics Inc., San Francisco, CA 94111, USA
| | | | - Donald M McDonald
- UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA 94143-0452, USA
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Better Management for Neuroendocrine Neoplasms: A Complex Task Ahead. J Clin Med 2021; 10:jcm10091859. [PMID: 33922910 PMCID: PMC8123141 DOI: 10.3390/jcm10091859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 04/22/2021] [Indexed: 11/16/2022] Open
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Fernandez CJ, Agarwal M, Pottakkat B, Haroon NN, George AS, Pappachan JM. Gastroenteropancreatic neuroendocrine neoplasms: A clinical snapshot. World J Gastrointest Surg 2021; 13. [PMID: 33796213 PMCID: PMC7993001 DOI: 10.4240/wjgs.v13.i3.231&set/a 886074439+803088391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/16/2023] Open
Abstract
Our understanding about the epidemiological aspects, pathogenesis, molecular diagnosis, and targeted therapies of neuroendocrine neoplasms (NENs) have drastically advanced in the past decade. Gastroenteropancreatic (GEP) NENs originate from the enteroendocrine cells of the embryonic gut which share common endocrine and neural differentiation factors. Most NENs are well-differentiated, and slow growing. Specific neuroendocrine biomarkers that are used in the diagnosis of functional NENs include insulin, glucagon, vasoactive intestinal polypeptide, gastrin, somatostatin, adrenocorticotropin, growth hormone releasing hormone, parathyroid hormone-related peptide, serotonin, histamine, and 5-hydroxy indole acetic acid (5-HIAA). Biomarkers such as pancreatic polypeptide, human chorionic gonadotrophin subunits, neurotensin, ghrelin, and calcitonin are used in the diagnosis of non-functional NENs. 5-HIAA levels correlate with tumour burden, prognosis and development of carcinoid heart disease and mesenteric fibrosis, however several diseases, medications and edible products can falsely elevate the 5-HIAA levels. Organ-specific transcription factors are useful in the differential diagnosis of metastasis from an unknown primary of well-differentiated NENs. Emerging novel biomarkers include circulating tumour cells, circulating tumour DNA, circulating micro-RNAs, and neuroendocrine neoplasms test (NETest) (simultaneous measurement of 51 neuroendocrine-specific marker genes in the peripheral blood). NETest has high sensitivity (85%-98%) and specificity (93%-97%) for the detection of gastrointestinal NENs, and is useful for monitoring treatment response, recurrence, and prognosis. In terms of management, surgery, radiofrequency ablation, symptom control with medications, chemotherapy and molecular targeted therapies are all considered as options. Surgery is the mainstay of treatment, but depends on factors including age of the individual, location, stage, grade, functional status, and the heredity of the tumour (sporadic vs inherited). Medical management is helpful to alleviate the symptoms, manage inoperable lesions, suppress postoperative tumour growth, and manage recurrences. Several molecular-targeted therapies are considered second line to somatostatin analogues. This review is a clinical update on the pathophysiological aspects, diagnostic algorithm, and management of GEP NENs.
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Affiliation(s)
- Cornelius J Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, United Kingdom
| | - Mayuri Agarwal
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, United Kingdom
| | - Biju Pottakkat
- Department of Surgical Gastroenterology, Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), Puducherry 605006, India
| | - Nisha Nigil Haroon
- Department of Endocrinology and Internal Medicine, Northern Ontario School of Medicine, Sudbury P3E 2C6, Ontario, Canada
| | - Annu Susan George
- Department of Medical Oncology, VPS Lakeshore Hospital, Cochin 682040, Kerala, India
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, PR2 9HT, Preston, The University of Manchester, Oxford Road M13 9PL, Manchester Metropolitan University, All Saints Building M15 6BH, Manchester, United Kingdom.
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Fernandez CJ, Agarwal M, Pottakkat B, Haroon NN, George AS, Pappachan JM. Gastroenteropancreatic neuroendocrine neoplasms: A clinical snapshot. World J Gastrointest Surg 2021; 13:231-255. [PMID: 33796213 PMCID: PMC7993001 DOI: 10.4240/wjgs.v13.i3.231] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/17/2021] [Accepted: 03/02/2021] [Indexed: 02/06/2023] Open
Abstract
Our understanding about the epidemiological aspects, pathogenesis, molecular diagnosis, and targeted therapies of neuroendocrine neoplasms (NENs) have drastically advanced in the past decade. Gastroenteropancreatic (GEP) NENs originate from the enteroendocrine cells of the embryonic gut which share common endocrine and neural differentiation factors. Most NENs are well-differentiated, and slow growing. Specific neuroendocrine biomarkers that are used in the diagnosis of functional NENs include insulin, glucagon, vasoactive intestinal polypeptide, gastrin, somatostatin, adrenocorticotropin, growth hormone releasing hormone, parathyroid hormone-related peptide, serotonin, histamine, and 5-hydroxy indole acetic acid (5-HIAA). Biomarkers such as pancreatic polypeptide, human chorionic gonadotrophin subunits, neurotensin, ghrelin, and calcitonin are used in the diagnosis of non-functional NENs. 5-HIAA levels correlate with tumour burden, prognosis and development of carcinoid heart disease and mesenteric fibrosis, however several diseases, medications and edible products can falsely elevate the 5-HIAA levels. Organ-specific transcription factors are useful in the differential diagnosis of metastasis from an unknown primary of well-differentiated NENs. Emerging novel biomarkers include circulating tumour cells, circulating tumour DNA, circulating micro-RNAs, and neuroendocrine neoplasms test (NETest) (simultaneous measurement of 51 neuroendocrine-specific marker genes in the peripheral blood). NETest has high sensitivity (85%-98%) and specificity (93%-97%) for the detection of gastrointestinal NENs, and is useful for monitoring treatment response, recurrence, and prognosis. In terms of management, surgery, radiofrequency ablation, symptom control with medications, chemotherapy and molecular targeted therapies are all considered as options. Surgery is the mainstay of treatment, but depends on factors including age of the individual, location, stage, grade, functional status, and the heredity of the tumour (sporadic vs inherited). Medical management is helpful to alleviate the symptoms, manage inoperable lesions, suppress postoperative tumour growth, and manage recurrences. Several molecular-targeted therapies are considered second line to somatostatin analogues. This review is a clinical update on the pathophysiological aspects, diagnostic algorithm, and management of GEP NENs.
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Affiliation(s)
- Cornelius J Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, United Kingdom
| | - Mayuri Agarwal
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, United Kingdom
| | - Biju Pottakkat
- Department of Surgical Gastroenterology, Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), Puducherry 605006, India
| | - Nisha Nigil Haroon
- Department of Endocrinology and Internal Medicine, Northern Ontario School of Medicine, Sudbury P3E 2C6, Ontario, Canada
| | - Annu Susan George
- Department of Medical Oncology, VPS Lakeshore Hospital, Cochin 682040, Kerala, India
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, PR2 9HT, Preston, The University of Manchester, Oxford Road M13 9PL, Manchester Metropolitan University, All Saints Building M15 6BH, Manchester, United Kingdom
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