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Ruhwedel T, Rogasch J, Schatka I, Galler M, Steinhagen P, Wetz C, Amthauer H. Beyond similarities: overall survival and prognostic insights from [¹⁷⁷Lu]Lu-DOTATOC therapy in neuroendocrine tumors. Eur J Nucl Med Mol Imaging 2025:10.1007/s00259-025-07221-2. [PMID: 40148509 DOI: 10.1007/s00259-025-07221-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 03/15/2025] [Indexed: 03/29/2025]
Abstract
PURPOSE Therapy with [177Lu]Lu-DOTATATE is well established for neuroendocrine tumors (NET), but its production generates [177mLu], raising concerns about waste disposal due to its longer half-life. In contrast, [177mLu] is not formed during [177Lu]Lu-DOTATOC production. However, data on overall survival (OS) and prognostic factors for [177Lu]Lu-DOTATOC remain limited, and its efficacy compared to [177Lu]Lu-DOTATATE is uncertain. This study aimed to analyze OS and radiological response in NET patients treated with [177Lu]Lu-DOTATOC. METHODS Monocentric, retrospective analysis of 141 patients with NET (grading: 21% G1, 71% G2, 4% G3, 4% grading unknown; primary: 48% small intestine (SI-NET); 27% pancreas (P-NET); 9% colon/rectum; 1% stomach, 7% lung; 9% CUP-NET) receiving PRRT with [177Lu]Lu-DOTATOC. Cox and logistic regression were used to identify prognostic factors for OS or risk of primary progression. RESULTS Death from any cause was observed in 85 of 141 patients (60.3%). Median OS was 55.2 months (SI NET G1-G2: 62.7 months; P-NET G1-G2: 41.2 months; NET G3: 26.3 months). Multivariable Cox regression identified baseline De Ritis Ratio (p < 0.001), ALP (p < 0.001), CgA (p < 0.001) and prior therapy with mTOR-inhibitors (p = 0.005) as significant prognostic factors of OS. Overall response rate was 12% and disease control rate was 72%. In multivariable logistic regression, primary tumor location (p = 0.04) and CgA (p = 0.01) were significant prognostic factors for higher risk of primary progression. CONCLUSION The analysis of OS from routine clinical practice shows that PRRT with [177Lu]Lu-DOTATOC is an effective treatment option for NET patients, while generating minimal [177mLu]. The evaluated prognostic factors could help to identify patients who particularly benefit from shorter follow-up intervals.
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Affiliation(s)
- Tristan Ruhwedel
- Department of Nuclear Medicine, Charité- Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
| | - Julian Rogasch
- Department of Nuclear Medicine, Charité- Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Imke Schatka
- Department of Nuclear Medicine, Charité- Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Markus Galler
- Department of Nuclear Medicine, Charité- Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Peter Steinhagen
- Department of Gastroenterology, Charité- Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Christoph Wetz
- Department of Nuclear Medicine, Charité- Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Holger Amthauer
- Department of Nuclear Medicine, Charité- Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
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Li M, Yuan DH, Yang Z, Lu TX, Zhang L. Retrospective analysis of preoperative tumor marker levels in rectal cancer patients: Implications for diagnosis. World J Gastrointest Surg 2025; 17:100820. [PMID: 40162391 PMCID: PMC11948132 DOI: 10.4240/wjgs.v17.i3.100820] [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: 12/13/2024] [Revised: 01/20/2025] [Accepted: 02/07/2025] [Indexed: 02/24/2025] Open
Abstract
BACKGROUND Early detection of rectal cancer poses significant challenges. Current diagnostic methods, including colonoscopy, imaging techniques, and fecal tests, have limitations such as invasiveness, cost, and varying sensitivity. This study evaluated the diagnostic value of preoperative serum tumor markers in rectal cancer patients. AIM To investigate the value of a multi-marker approach for the preoperative diagnosis of rectal cancer. METHODS A retrospective analysis of 250 patients diagnosed with rectal cancer between July 2022 and July 2024 was conducted. Preoperative alpha-fetoprotein levels, carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), CA19-9, CA15-3, and CA72-4 were analyzed. All blood samples were collected under standardized conditions, including fasting status and proper storage methods, within two weeks before surgery. Diagnostic performance was assessed using receiver operating characteristic curve analysis. Correlations among clinicopathological features were also evaluated. RESULTS CEA demonstrated the highest diagnostic performance among individual tumor markers with an area under the curve (AUC) of 0.78 [95% confidence interval (CI): 0.73-0.83]. However, a combination of CEA, CA19-9, and CA72-4 showed superior performance, achieving an AUC of 0.87 (95%CI: 0.83-0.91). Significant correlations were observed between CEA levels and several clinicopathological features, including tumor stage (P < 0.001), lymph node involvement (P = 0.002), and distant metastasis (P < 0.001). Furthermore, in a subgroup analysis of patients diagnosed after July 2022, the integration of fecal occult blood testing with the tumor marker panel (CEA + CA19-9 + CA72-4) significantly improved diagnostic accuracy, increasing the AUC to 0.91 (95%CI: 0.86-0.96). CONCLUSION A multimarker approach combining CEA, CA19-9, and CA72-4 with fecal occult blood testing enhances the preoperative assessment of patients with rectal cancer. These findings suggest potential improvements in risk stratification and management of patients with rectal cancer.
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Affiliation(s)
- Ming Li
- Clinical Laboratory, Linquan County People’s Hospital, Linquan 236400, Anhui Province, China
| | - Da-Hao Yuan
- Clinical Laboratory, Linquan County People’s Hospital, Linquan 236400, Anhui Province, China
| | - Zhi Yang
- Clinical Laboratory, Linquan County People’s Hospital, Linquan 236400, Anhui Province, China
| | - Teng-Xiang Lu
- Hemodialysis Center, Linquan County People’s Hospital, Linquan 236400, Anhui Province, China
| | - Lei Zhang
- Department of Gastrointestinal Surgery, Linquan County People’s Hospital, Linquan 236400, Anhui Province, China
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Meng QH, Halfdanarson TR, Bornhorst JA, Jann H, Shaheen S, Shi RZ, Schwabe A, Stade K, Halperin DM. Circulating Chromogranin A as a Surveillance Biomarker in Patients with Carcinoids-The CASPAR Study. Clin Cancer Res 2024; 30:5559-5567. [PMID: 39453770 DOI: 10.1158/1078-0432.ccr-24-1875] [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: 06/17/2024] [Revised: 08/09/2024] [Accepted: 10/23/2024] [Indexed: 10/27/2024]
Abstract
PURPOSE Gastroenteropancreatic neuroendocrine tumors (GEP-NET) are relatively indolent but can be more aggressive. The current recommendations for using serum chromogranin A (CgA) for patients with GEP-NET are equivocal. This study was designed to validate an automated CgA immunofluorescence assay for monitoring disease progression in patients with GEP-NET. PATIENTS AND METHODS A prospective, multicenter, blinded observational study was designed to validate an automated CgA immunofluorescence assay for monitoring disease progression in patients with GEP-NET. Tumor progression was evaluated with RECIST 1.1 by CT/MRI. An increase ≥50% above the prior CgA concentration to a value >100 ng/mL in the following CgA concentration was considered positive. RESULTS A total of 153 patients with GEP-NET were enrolled. Using the prespecified cut-off of CgA change for tumor progression, specificity was 93.4% (95% confidence interval, 90.4%-95.5%; P < 0.001), sensitivity 34.4% (25.6%-44.3%), positive predictive value 57.9% (45.0-69.8), negative predictive value 84.3% (80.5-87.6), and AUC 0.73 (0.67-0.79). CONCLUSIONS Changes in serial measurements of serum CgA had a favorable specificity and negative predictive value, making this test a useful adjunct to routine radiographic monitoring.
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Affiliation(s)
- Qing H Meng
- Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Joshua A Bornhorst
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Henning Jann
- Division of Hepatology and Gastroenterology, Medical Department, Charité-Universitätsmedizin, Berlin, Germany
| | - Shagufta Shaheen
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Run Zhang Shi
- Department of Pathology, Stanford University School of Medicine, Stanford, California
| | - Andrej Schwabe
- B·R·A·H·M·S GmbH, part of Thermo Fisher Scientific, Hennigsdorf, Germany
| | - Katrin Stade
- B·R·A·H·M·S GmbH, part of Thermo Fisher Scientific, Hennigsdorf, Germany
| | - Daniel M Halperin
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Yao Z, Chen H. Everolimus in pituitary tumor: a review of preclinical and clinical evidence. Front Endocrinol (Lausanne) 2024; 15:1456922. [PMID: 39736867 PMCID: PMC11682973 DOI: 10.3389/fendo.2024.1456922] [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: 06/29/2024] [Accepted: 11/27/2024] [Indexed: 01/01/2025] Open
Abstract
Although pituitary tumors (PTs) are mostly benign, some PTs are characterized by low surgical resection rates, high recurrence rates, and poor response to conventional treatments and profoundly affect patients' quality of life. Everolimus (EVE) is the only FDA-approved mTOR inhibitor, which can be used for oral treatment. It effectively inhibits tumor cell proliferation and angiogenesis. It has been administered for various neuroendocrine tumors of the digestive tract, lungs, and pancreas. EVE not only suppresses the growth and proliferation of APT cells but also enhances their sensitivity to radiotherapy and chemotherapy. This review introduces the role of the PI3K/AKT/mTOR pathway in the development of APTs, comprehensively explores the current status of preclinical and clinical research of EVE in APTs, and discusses the blood-brain barrier permeability and safety of EVE.
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Affiliation(s)
- Zihong Yao
- The Second Clinical Medical College of Lanzhou University, Lanzhou, Gansu, China
- Department of Endocrinology and Metabolism, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Hui Chen
- Department of Endocrinology and Metabolism, Lanzhou University Second Hospital, Lanzhou, Gansu, China
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Loree JM, Chan D, Lim J, Stuart H, Fidelman N, Koea J, Posavad J, Cummins M, Doucette S, Myrehaug S, Naraev B, Bailey DL, Bellizzi A, Laidley D, Boyle V, Goodwin R, Del Rivero J, Michael M, Pasieka J, Singh S. Biomarkers to Inform Prognosis and Treatment for Unresectable or Metastatic GEP-NENs. JAMA Oncol 2024; 10:1707-1720. [PMID: 39361298 DOI: 10.1001/jamaoncol.2024.4330] [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: 12/20/2024]
Abstract
Importance Evidence-based treatment decisions for advanced gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) require individualized patient-centered decision-making that accounts for patient and cancer characteristics. Objective To create an accessible guidance document to educate clinicians and patients on biomarkers informing prognosis and treatment in unresectable or metastatic GEP-NENs. Methods A multidisciplinary panel in-person workshop was convened to define methods. English language articles published from January 2016 to January 2023 in PubMed (MEDLINE) and relevant conference abstracts were reviewed to investigate prognostic and treatment-informing features in unresectable or metastatic GEP-NENs. Data from included studies were used to form evidence-based recommendations. Quality of evidence and strength of recommendations were determined using the Grading of Recommendations, Assessment, Development and Evaluations framework. Consensus was reached via electronic survey following a modified Delphi method. Findings A total of 131 publications were identified, including 8 systematic reviews and meta-analyses, 6 randomized clinical trials, 29 prospective studies, and 88 retrospective cohort studies. After 2 rounds of surveys, 24 recommendations and 5 good clinical practice statements were developed, with full consensus among panelists. Recommendations focused on tumor and functional imaging characteristics, blood-based biomarkers, and carcinoid heart disease. A single strong recommendation was made for symptomatic carcinoid syndrome informing treatment in midgut neuroendocrine tumors. Conditional recommendations were made to use grade, morphology, primary site, and urinary 5-hydroxyindoleacetic levels to inform treatment. The guidance document was endorsed by the Commonwealth Neuroendocrine Tumour Collaboration and the North American Neuroendocrine Tumor Society. Conclusions and Relevance The study results suggest that select factors have sufficient evidence to inform care in GEP-NENs, but the evidence for most biomarkers is weak. This article may help guide management and identify gaps for future research to advance personalized medicine and improve outcomes for patients with GEP-NENs.
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Affiliation(s)
- Jonathan M Loree
- BC Cancer, Vancouver Centre, Vancouver, British Columbia, Canada
| | - David Chan
- Northern Clinical School, University of Sydney, Sydney, Australia
- ENETS Centre of Excellence, Department of Medical Oncology, Royal North Shore Hospital, St Leonards, New South Wales, Australia
| | - Jennifer Lim
- St George Hospital, Sydney, New South Wales, Australia
- University of New South Wales, Sydney, New South Wales, Australia
- Garvan Institute of Medical Research, Sydney, New South Wales, Australia
| | - Heather Stuart
- University of British Columbia and BC Cancer Agency, Vancouver, British Columbia, Canada
| | | | - Jonathan Koea
- Te Whatu Ora Waitemata and the University of Auckland, Auckland, New Zealand
| | - Jason Posavad
- Canadian Neuroendocrine Tumours Society, Cornwall, Ontario, Canada
| | | | | | - Sten Myrehaug
- Odette Cancer Centre, Toronto, Ontario, Canada
- Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
| | - Boris Naraev
- Tampa General Hospital Cancer Institute, Tampa, Florida
| | - Dale L Bailey
- Department of Nuclear Medicine, Royal North Shore Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
| | | | - David Laidley
- Western University, London, Ontario, Canada
- Lawson Health Research Institute, London, Ontario, Canada
| | - Veronica Boyle
- School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
- Department of Oncology, Auckland City Hospital, Te Whatu Ora Tamaki Makaurau, Auckland, New Zealand
| | - Rachel Goodwin
- Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, Ontario, Canada
| | - Jaydi Del Rivero
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Michael Michael
- NET Unit and ENETS Centre of Excellence, Peter MacCallum Cancer Centre, Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Parkville, Victoria, Australia
| | - Janice Pasieka
- Section of General Surgery, Division of Endocrine Surgery and Surgical Oncology, Department of Surgery and Oncology, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
| | - Simron Singh
- University of Toronto, Toronto, Ontario, Canada
- Sunnybrook Odette Cancer Center, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada
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Mathew D, Sunny SS, Benjamin J, John JR, Jebasingh FK, Georgy JT, Singh A, Oommen R. Outcome of 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy in Progressive Metastatic Neuroendocrine Tumors from a Tertiary Care Center. Indian J Endocrinol Metab 2024; 28:601-610. [PMID: 39881767 PMCID: PMC11774412 DOI: 10.4103/ijem.ijem_372_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 07/14/2024] [Accepted: 09/08/2024] [Indexed: 01/31/2025] Open
Abstract
Introduction Functioning neuroendocrine tumors (NETs) that do not respond to standard therapies are commonly considered for Peptide Receptor Radionuclide Therapy (PRRT). The benefit of 177Lu-DOTATATE PRRT in patients with progressive metastatic NET was analyzed and survival in multi-organ involvement. Methods Forty-one patients with refractory, progressive, or advanced symptomatic NETs, with or without previous treatment modalities were studied. They were treated with 177Lu-DOTATATE IV infusion 150 mCi per dose up to four cycles. Retrospectively, they were assessed for response to PRRT based on clinical, Imaging-Contrast CT/68Ga-DOTATATE PET-CT, and biochemical markers. After treatment, classification based on disease status, symptomatic improvement, and response to treatment based on Chromogranin A level was done. The organs involved and their respective survival benefits, as estimated by Kaplan Meier, were plotted for 60 months. Results The mean serum Chromogranin A level at baseline was 2841 U/ml (Median = 3150). The main site of primary NET was in the pancreas, and the most common site for metastases was the liver. Following PRRT, all patients, except one, reported an improvement in their baseline complaints. Most (82%) reported no new symptoms, and 50% had a reduction in serum Chromogranin A levels. Follow-up imaging showed regression in one patient, static tumor in 18, and progression in rest. Considering radiological and clinical responses, the overall benefit was noticed in 29 (70%) patients. Despite symptomatic improvement, there was no significant survival benefit for those with pancreatic, liver, or nodal metastasis. Conclusion A majority of patients who were treated with PRRT demonstrated clinical, radiological as well as biochemical positive responses warranting an earlier consideration for this well-tolerated treatment modality.
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Affiliation(s)
- David Mathew
- Department of Nuclear Medicine, Christian Medical College, Vellore, Tamil Nadu, India
| | - Saumya S. Sunny
- Department of Nuclear Medicine, Christian Medical College, Vellore, Tamil Nadu, India
| | - Justin Benjamin
- Department of Nuclear Medicine, Christian Medical College, Vellore, Tamil Nadu, India
| | - Junita R. John
- Department of Nuclear Medicine, Christian Medical College, Vellore, Tamil Nadu, India
| | - Felix K. Jebasingh
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, Tamil Nadu, India
| | - Josh T. Georgy
- Department of Medical Oncology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Ashish Singh
- Department of Medical Oncology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Regi Oommen
- Department of Nuclear Medicine, Christian Medical College, Vellore, Tamil Nadu, India
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Hoff CO, Manzi J, Ferreira R, Chauhan A, Housein P, Merchant N, Livingstone A, Vianna R, Abreu P. A neuroendocrine biomarker revolution from monoanalyte to multianalyte biomarkers in non-functioning gastro-entero-pancreatic neuroendocrine neoplasms. Crit Rev Oncol Hematol 2024; 203:104460. [PMID: 39153703 DOI: 10.1016/j.critrevonc.2024.104460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 07/25/2024] [Accepted: 07/26/2024] [Indexed: 08/19/2024] Open
Abstract
Neuroendocrine neoplasms (NENs) arise from neuroendocrine cells in a wide variety of organs. One of the most affected disease sites is the gastrointestinal system, which originates the gastro-entero-pancreatic NENs (GEP-NENs), a heterogenous group of malignancies that are rapidly increasing in incidence. These tumors can be functioning, with secretory activity leading to identifiable clinical syndromes, or non-functioning, with no secretory activity but with local symptoms of tumor growth and metastasis. A limitation in biomarkers is a crucial unmet need in non-secretory NEN management, as clinical decision-making is made more difficult by obstacles in tumor classification, prognostic evaluation, assessment of treatment response and surveillance. The objective of this review is to present existing and novel biomarkers for NENs that can function as prognostic factors and monitor disease progression or regression longitudinally, with a special emphasis on innovative research into novel multianalyte biomarkers.
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Affiliation(s)
- Camilla O Hoff
- University of Sao Paulo Medical School, University of Sao Paulo, Sao Paulo, Brazil; Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, USA
| | - Joao Manzi
- University of Sao Paulo Medical School, University of Sao Paulo, Sao Paulo, Brazil
| | - Raphaella Ferreira
- Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, USA
| | - Aman Chauhan
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, USA
| | - Peter Housein
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, USA
| | - Nipun Merchant
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, USA
| | - Alan Livingstone
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, USA
| | - Rodrigo Vianna
- Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, USA
| | - Phillipe Abreu
- Division of Transplant Surgery, University of Colorado Anschutz Medical Campus, USA.
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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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9
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Ingenerf M, Auernhammer C, Lorbeer R, Winkelmann M, Mansournia S, Mansour N, Hesse N, Heinrich K, Ricke J, Berger F, Schmid-Tannwald C. Utility of clinical and MR imaging parameters for prediction and monitoring of response to capecitabine and temozolomide (CAPTEM) therapy in patients with liver metastases of neuroendocrine tumors. Radiol Oncol 2024; 58:196-205. [PMID: 38613843 PMCID: PMC11165981 DOI: 10.2478/raon-2024-0024] [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: 12/08/2023] [Accepted: 02/20/2024] [Indexed: 04/15/2024] Open
Abstract
BACKGROUND This study explores the predictive and monitoring capabilities of clinical and multiparametric MR parameters in assessing capecitabine and temozolomide (CAPTEM) therapy response in patients with neuroendocrine tumors (NET). PATIENTS AND METHODS This retrospective study (n = 44) assessed CAPTEM therapy response in neuroendocrine liver metastases (NELM) patients. Among 33 monitored patients, as a subgroup of the overall study cohort, pretherapeutic and follow-up MRI data (size, apparent diffusion coefficient [ADC] values, and signal intensities), along with clinical parameters (chromogranin A [CgA] and Ki-67%), were analyzed. Progression-free survival (PFS) served as the reference. Responders were defined as those with PFS ≥ 6 months. RESULTS Most patients were male (75%) and had G2 tumors (76%) with a pancreatic origin (84%). Median PFS was 5.7 months; Overall Survival (OS) was 25 months. Non-responders (NR) had higher Ki-67 in primary tumors (16.5 vs. 10%, p = 0.01) and increased hepatic burden (20% vs. 5%, p = 0.007). NR showed elevated CgA post-treatment, while responders (R) exhibited a mild decrease. ADC changes differed significantly between groups, with NR having decreased ADCmin (-23%) and liver-adjusted ADCmean/ADCmean liver (-16%), compared to R's increases of ADCmin (50%) and ADCmean/ADCmean liver (30%). Receiver operating characteristic (ROC) analysis identified the highest area under the curve (AUC) (0.76) for a single parameter for ∆ ADC mean/liver ADCmean, with a cut-off of < 6.9 (76% sensitivity, 75% specificity). Combining ∆ Size NELM and ∆ ADCmin achieved the best balance (88% sensitivity, 60% specificity) outperforming ∆ Size NELM alone (69% sensitivity, 65% specificity). Kaplan-Meier analysis indicated significantly longer PFS for ∆ ADCmean/ADCmean liver < 6.9 (p = 0.024) and ∆ Size NELM > 0% + ∆ ADCmin < -2.9% (p = 0.021). CONCLUSIONS Survival analysis emphasizes the need for adapted response criteria, involving combined evaluation of CgA, ADC values, and tumor size for monitoring CAPTEM response in hepatic metastasized NETs.
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Affiliation(s)
- Maria Ingenerf
- Department of Radiology, University Hospital, LMU Munich, Germany
| | - Christoph Auernhammer
- ENETS Centre of Excellence, Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System at the University Hospital of Munich (GEPNET-KUM), University Hospital of Munich, Munich, Germany
- Department of Internal Medicine 4, University Hospital, LMU Munich, Munich, Germany
| | - Roberto Lorbeer
- Department of Radiology, University Hospital, LMU Munich, Germany
| | | | - Shiwa Mansournia
- Department of Radiology, University Hospital, LMU Munich, Germany
| | - Nabeel Mansour
- Department of Radiology, University Hospital, LMU Munich, Germany
| | - Nina Hesse
- Department of Radiology, University Hospital, LMU Munich, Germany
| | - Kathrin Heinrich
- Department of Medicine III, University Hospital, University of Munich, Munich, Germany
| | - Jens Ricke
- Department of Radiology, University Hospital, LMU Munich, Germany
- ENETS Centre of Excellence, Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System at the University Hospital of Munich (GEPNET-KUM), University Hospital of Munich, Munich, Germany
| | - Frank Berger
- Department of Radiology, University Hospital, LMU Munich, Germany
| | - Christine Schmid-Tannwald
- Department of Radiology, University Hospital, LMU Munich, Germany
- ENETS Centre of Excellence, Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System at the University Hospital of Munich (GEPNET-KUM), University Hospital of Munich, Munich, Germany
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10
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Mariën L, Islam O, Chhajlani S, Lybaert W, Peeters M, Van Camp G, Op de Beeck K, Vandamme T. The Quest for Circulating Biomarkers in Neuroendocrine Neoplasms: a Clinical Perspective. Curr Treat Options Oncol 2023; 24:1833-1851. [PMID: 37989978 DOI: 10.1007/s11864-023-01147-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2023] [Indexed: 11/23/2023]
Abstract
OPINION STATEMENT Given the considerable heterogeneity in neuroendocrine neoplasms (NENs), it appears unlikely that a sole biomarker exists capable of fully capturing all useful clinical aspects of these tumors. This is reflected in the abundant number of biomarkers presently available for the diagnosis, prognosis, and monitoring of NEN patients. Although assessment of immunohistochemical and radiological markers remains paramount and often obligatory, there has been a notable surge of interest in circulating biomarkers over the years given the numerous benefits associated with liquid biopsies. Currently, the clinic primarily relies on single-analyte assays such as the chromogranin A assay, but these are far from ideal because of limitations such as compromised sensitivity and specificity as well as a lack of standardization. Consequently, the quest for NEN biomarkers continued with the exploration of multianalyte markers, exemplified by the development of the NETest and ctDNA-based analysis. Here, an extensive panel of markers is simultaneously evaluated to identify distinct signatures that could enhance the accuracy of patient diagnosis, prognosis determination, and response to therapy prediction and monitoring. Given the promising results, the development and implementation of these multianalyte markers are expected to usher in a new era of NEN biomarkers in the clinic. In this review, we will outline both clinically implemented and more experimental circulating markers to provide an update on developments in this rapidly evolving field.
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Affiliation(s)
- Laura Mariën
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium
- Integrated Personalized and Precision Oncology Network (IPPON), Center for Oncological Research (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium
| | - Odeta Islam
- Integrated Personalized and Precision Oncology Network (IPPON), Center for Oncological Research (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium
- NETwerk and Department of Oncology, Antwerp University Hospital, Drie Eikenstraat 655, 2650, Edegem, Belgium
| | - Siddharth Chhajlani
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium
- NETwerk and Department of Oncology, Antwerp University Hospital, Drie Eikenstraat 655, 2650, Edegem, Belgium
| | - Willem Lybaert
- NETwerk and Department of Oncology, VITAZ, Lodewijk de Meesterstraat 5, 9100, Sint-Niklaas, Belgium
| | - Marc Peeters
- Integrated Personalized and Precision Oncology Network (IPPON), Center for Oncological Research (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium
- NETwerk and Department of Oncology, Antwerp University Hospital, Drie Eikenstraat 655, 2650, Edegem, Belgium
| | - Guy Van Camp
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium
| | - Ken Op de Beeck
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium
- Integrated Personalized and Precision Oncology Network (IPPON), Center for Oncological Research (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium
| | - Timon Vandamme
- Integrated Personalized and Precision Oncology Network (IPPON), Center for Oncological Research (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium.
- NETwerk and Department of Oncology, Antwerp University Hospital, Drie Eikenstraat 655, 2650, Edegem, Belgium.
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11
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Pavel M, Dromain C, Ronot M, Schaefer N, Mandair D, Gueguen D, Elvira D, Jégou S, Balazard F, Dehaene O, Schutte K. The use of deep learning models to predict progression-free survival in patients with neuroendocrine tumors. Future Oncol 2023; 19:2185-2199. [PMID: 37497644 DOI: 10.2217/fon-2022-1136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/28/2023] Open
Abstract
Aim: The RAISE project assessed whether deep learning could improve early progression-free survival (PFS) prediction in patients with neuroendocrine tumors. Patients & methods: Deep learning models extracted features from CT scans from patients in CLARINET (NCT00353496) (n = 138/204). A Cox model assessed PFS prediction when combining deep learning with the sum of longest diameter ratio (SLDr) and logarithmically transformed CgA concentration (logCgA), versus SLDr and logCgA alone. Results: Deep learning models extracted features other than lesion shape to predict PFS at week 72. No increase in performance was achieved with deep learning versus SLDr and logCgA models alone. Conclusion: Deep learning models extracted relevant features to predict PFS, but did not improve early prediction based on SLDr and logCgA.
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Affiliation(s)
- Marianne Pavel
- Department of Medicine 1, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
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12
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Pellat A, Barat M, Cottereau AS, Terris B, Coriat R. [Well-differentiated neuroendocrine tumors of the digestive tract: Focus on pancreatic neuroendocrine tumors]. Bull Cancer 2023; 110:955-967. [PMID: 36935319 DOI: 10.1016/j.bulcan.2023.03.001] [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: 01/09/2023] [Revised: 02/16/2023] [Accepted: 03/01/2023] [Indexed: 03/19/2023]
Abstract
Pancreatic neuroendocrine tumors are rare tumors showing a rising incidence. They are well-differentiated tumors, classified by grade according to their Ki67 index value (grade 1 to 3). Pancreatic neuroendocrine tumors are mainly sporadic tumors but about 10% arise within endocrine tumor syndromes such as multiple endocrine neoplasia type 1. They can be responsible for functional syndromes or non-specific clinical symptoms depending on tumor extension. However, there is also an increase of incidental diagnoses of nonfunctional pancreatic neuroendocrine tumors with the widespread use of high-quality imaging techniques. About 50 % of pancreatic neuroendocrine tumors are diagnosed at a metastatic stage, with metastases often located in the liver. Chromogranin A, CT-scan and often an abdominal MRI, and functional imaging should be performed for tumor staging and follow-up. Imaging with PET/CT with 68Ga-labeled somatostatin analogues has the highest sensitivity for the diagnosis of pancreatic neuroendocrine tumors, while 18fluorodeoxyglucose PET/CT can sometimes be useful. Overall, they are rather indolent tumors with prolonged survival. Surgery is the recommended treatment in the localized setting, with the exception of small<2cm nonfunctional tumors that can be monitored with imaging techniques. For advanced tumors, there are several available treatments such as somatostatine analogues, chemotherapy, targeted therapies (sunitinib, everolimus), locoregional ablative therapies and Peptide Receptor Radiolabelled Therapy. The treatment strategy will depend on the initial tumor staging, tumor grade, aggressiveness and patient's choice.
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Affiliation(s)
- Anna Pellat
- AP-HP, hôpital Cochin, service de gastroentérologie et d'oncologie digestive, 27, rue du faubourg Saint-Jacques, 75014 Paris, France; Université Paris Cité, 75006 Paris, France.
| | - Maxime Barat
- AP-HP, hôpital Cochin, service de radiologie, 27, rue du faubourg Saint-Jacques, 75014 Paris, France; Université Paris Cité, 75006 Paris, France
| | - Anne-Ségolène Cottereau
- AP-HP, hôpital Cochin, service de médecine nucléaire, 27, rue du faubourg Saint-Jacques, 75014 Paris, France
| | - Benoit Terris
- AP-HP, hôpital Cochin, service d'anatomopathologie, 27, rue du faubourg Saint-Jacques, 75014 Paris, France; Université Paris Cité, 75006 Paris, France
| | - Romain Coriat
- AP-HP, hôpital Cochin, service de gastroentérologie et d'oncologie digestive, 27, rue du faubourg Saint-Jacques, 75014 Paris, France; Université Paris Cité, 75006 Paris, France
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13
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Tsoli M, Koumarianou A, Angelousi A, Kaltsas G. Established and novel circulating neuroendocrine tumor biomarkers for diagnostic, predictive and prognostic use. Best Pract Res Clin Endocrinol Metab 2023; 37:101785. [PMID: 37336711 DOI: 10.1016/j.beem.2023.101785] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/21/2023]
Abstract
The management of neuroendocrine tumors (NETs) represents a clinical challenge due to heterogeneity of their clinical behaviour, molecular biology and response to treatment. Over the years, several circulating biomarkers have been developed for the early diagnosis and follow-up of NETs. The specific secretory products of tumors associated with a secretory syndrome (functioning tumors) may be used as diagnostic and/or prognostic biomarkers while the most common non-specific circulating biomarkers, that may be increased in both functioning and non-functioning tumors, are chromogranin A and the neuron specific enolase. However, the diagnostic accuracy as well as the prognostic and predictive value of these biomarkers are limited and novel techniques of multianalyte analysis of regulators of tumor biology have been developed. The NETest has been most extensively studied and proved to be useful in NET diagnosis, early detection of post-operative recurrence and prediction of response to treatment but further investigation establishing higher level of evidence is required for implementation in clinical practice.
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Affiliation(s)
- Marina Tsoli
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527, Greece.
| | - Anna Koumarianou
- Haematology-Oncology Unit, Fourth Department of Internal Medicine, Attikon Hospital, National and Kapodistrian University of Athens, 12462, Greece
| | - Anna Angelousi
- Unit of Endocrinology, First Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527, Greece
| | - Gregory Kaltsas
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527, Greece
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14
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Elkelany OO, Karaisz FG, Davies B, Krishna SG. An Overview of Pancreatic Neuroendocrine Tumors and an Update on Endoscopic Techniques for Their Management. Curr Oncol 2023; 30:7566-7580. [PMID: 37623030 PMCID: PMC10453483 DOI: 10.3390/curroncol30080549] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 07/25/2023] [Accepted: 07/31/2023] [Indexed: 08/26/2023] Open
Abstract
The growing importance of advanced endoscopy in the diagnosis and treatment of pancreatic neuroendocrine neoplasms (PanNETs) necessitates a comprehensive understanding of various biochemical markers, genetic testing methods, radiological techniques, and treatment approaches that encompass multiple disciplines within and beyond gastrointestinal oncology. This review aims to highlight key aspects of these topics, with a specific focus on emerging EUS-guided procedures for the management of PanNETs.
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Affiliation(s)
- Osama O. Elkelany
- Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Fred G. Karaisz
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Benjamin Davies
- College of Medicine, The Ohio State University, Columbus, OH 43201, USA
| | - Somashekar G. Krishna
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
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15
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Safaroghli-Azar A, Sanaei MJ, Pourbagheri-Sigaroodi A, Bashash D. Phosphoinositide 3-kinase (PI3K) classes: From cell signaling to endocytic recycling and autophagy. Eur J Pharmacol 2023:175827. [PMID: 37269974 DOI: 10.1016/j.ejphar.2023.175827] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 05/19/2023] [Accepted: 05/31/2023] [Indexed: 06/05/2023]
Abstract
Lipid signaling is defined as any biological signaling action in which a lipid messenger binds to a protein target, converting its effects to specific cellular responses. In this complex biological pathway, the family of phosphoinositide 3-kinase (PI3K) represents a pivotal role and affects many aspects of cellular biology from cell survival, proliferation, and migration to endocytosis, intracellular trafficking, metabolism, and autophagy. While yeasts have a single isoform of phosphoinositide 3-kinase (PI3K), mammals possess eight PI3K types divided into three classes. The class I PI3Ks have set the stage to widen research interest in the field of cancer biology. The aberrant activation of class I PI3Ks has been identified in 30-50% of human tumors, and activating mutations in PIK3CA is one of the most frequent oncogenes in human cancer. In addition to indirect participation in cell signaling, class II and III PI3Ks primarily regulate vesicle trafficking. Class III PI3Ks are also responsible for autophagosome formation and autophagy flux. The current review aims to discuss the original data obtained from international research laboratories on the latest discoveries regarding PI3Ks-mediated cell biological processes. Also, we unravel the mechanisms by which pools of the same phosphoinositides (PIs) derived from different PI3K types act differently.
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Affiliation(s)
- Ava Safaroghli-Azar
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad-Javad Sanaei
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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16
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Alexander ES, Ziv E. Neuroendocrine Tumors: Genomics and Molecular Biomarkers with a Focus on Metastatic Disease. Cancers (Basel) 2023; 15:cancers15082249. [PMID: 37190177 DOI: 10.3390/cancers15082249] [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: 03/07/2023] [Revised: 04/08/2023] [Accepted: 04/08/2023] [Indexed: 05/17/2023] Open
Abstract
Neuroendocrine tumors (NETs) are considered rare tumors that originate from specialized endocrine cells. Patients often present with metastatic disease at the time of diagnosis, which negatively impacts their quality of life and overall survival. An understanding of the genetic mutations that drive these tumors and the biomarkers used to detect new NET cases is important to identify patients at an earlier disease stage. Elevations in CgA, synaptophysin, and 5-HIAA are most commonly used to identify NETs and assess prognosis; however, new advances in whole genome sequencing and multigenomic blood assays have allowed for a greater understanding of the drivers of NETs and more sensitive and specific tests to diagnose tumors and assess disease response. Treating NET liver metastases is important in managing hormonal or carcinoid symptoms and is imperative to improve patient survival. Treatment for liver-dominant disease is varied; delineating biomarkers that may predict response will allow for better patient stratification.
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Affiliation(s)
- Erica S Alexander
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Etay Ziv
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
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17
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Mohamed A, Wu S, Hamid M, Mahipal A, Cjakrabarti S, Bajor D, Selfridge JE, Asa SL. Management of Appendix Neuroendocrine Neoplasms: Insights on the Current Guidelines. Cancers (Basel) 2022; 15:295. [PMID: 36612291 PMCID: PMC9818268 DOI: 10.3390/cancers15010295] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/19/2022] [Accepted: 12/26/2022] [Indexed: 01/03/2023] Open
Abstract
Appendiceal neuroendocrine neoplasms (ANENs) usually present as incidental findings at the time of appendectomy for acute appendicitis. They are rare, accounting for only 0.5-1% of intestinal neoplasms; they are found in 0.3-0.9% of all appendectomy specimens. They are usually sporadic tumors. There are several histological types including well-differentiated neuroendocrine tumors (NETs), poorly differentiated neuroendocrine carcinomas (NECs), and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). Histologic differentiation and the grade of well-differentiated NETs correlate with clinical behavior and prognosis. Management varies based on differentiation, aggressiveness, and metastatic potential. There is debate about the optimal surgical management for localized appendiceal NETs that are impacted by many factors including the tumor size, the extent of mesoappendiceal spread, lymphovascular invasion and perineural involvement. In addition, the data to guide therapy in metastatic disease are limited due to the paucity of these tumors. Here, we review the current advances in the management of ANENs within the context of a multidisciplinary approach to these tumors.
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Affiliation(s)
- Amr Mohamed
- Division of Hematology and Medical Oncology, UH Seidman Cancer Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA
| | - Sulin Wu
- Department of Internal Medicine, UH Seidman Cancer Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA
- Department of Medical Genetics, Center for Human Genetics, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Mohamed Hamid
- Department of Stem Cell Biology and Regenerative Medicine, City of Hope Beckman Research Institute, Duarte, CA 91010, USA
| | - Amit Mahipal
- Division of Hematology and Medical Oncology, UH Seidman Cancer Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA
| | - Sakti Cjakrabarti
- Division of Hematology and Medical Oncology, UH Seidman Cancer Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA
| | - David Bajor
- Division of Hematology and Medical Oncology, UH Seidman Cancer Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA
| | - J. Eva Selfridge
- Division of Hematology and Medical Oncology, UH Seidman Cancer Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA
| | - Sylvia L. Asa
- Department of Pathology, UH Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
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18
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Choi JH, Paik WH. Risk Stratification of Pancreatic Neuroendocrine Neoplasms Based on Clinical, Pathological, and Molecular Characteristics. J Clin Med 2022; 11:7456. [PMID: 36556070 PMCID: PMC9786745 DOI: 10.3390/jcm11247456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 12/11/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Pancreatic neuroendocrine neoplasms consist of heterogeneous diseases. Depending on the novel features detected by various modern technologies, their classification and related prognosis predictions continue to change and develop. The role of traditional clinicopathological prognostic factors, including classification systems, is also being refined, and several attempts have been made to predict a more accurate prognosis through novel serum biomarkers, genetic factors, and epigenetic factors that have been identified through various state-of-the-art molecular techniques with multiomics sequencing. In this review article, the latest research results including the traditional approach to prognostic factors and recent advanced strategies for risk stratification of pancreatic neuroendocrine neoplasms based on clinical, pathological, and molecular characteristics are summarized. Predicting prognosis through multi-factorial assessments seems to be more efficacious, and prognostic factors through noninvasive methods are expected to develop further advances in liquid biopsy in the future.
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Affiliation(s)
| | - Woo Hyun Paik
- Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Republic of Korea
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19
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Alsadik S, Gnanasegaran G, Chen L, Quigley AM, Mandair D, Toumpanakis C, Caplin M, Navalkissoor S. Single centre retrospective review of outcome of 177 Lu-DOTATATE peptide receptor radionuclide therapy in the treatment of progressive metastatic neuroendocrine tumours: Survival, toxicity, and prognostic factors. J Neuroendocrinol 2022; 34:e13210. [PMID: 36399420 DOI: 10.1111/jne.13210] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 10/17/2022] [Accepted: 10/18/2022] [Indexed: 11/30/2022]
Abstract
The aim of this study was to evaluate the efficacy and safety of 177 Lu-DOTATATE therapy in advanced metastatic disease. A retrospective analysis of 395 patients (180 female, 215 males, mean age 62) with progressive metastatic neuroendocrine tumours (NETs) who were treated with 177 Lu-DOTATATE was performed. Overall, 115 patients had less than four cycles and 280 completed four cycles of treatment. Progression-free survival (PFS) and overall survival (OS) was performed using Kaplan-Meier analysis. Analysis of survival predictors was performed using Cox regression model. Toxicity was defined using the Common Terminology Criteria for Adverse Events version 5 (CTCAE 5.0). The percentage of patients with liver and skeletal metastases were 91 and 57%, respectively. Median PFS and OS were calculated at 33 months (95% CI: 29-37 months) and 46 months (95% CI: 48-56 months), respectively. End of treatment response assessment was performed using cross sectional imaging demonstrated partial response in 22%, stable disease in 64% and progressive disease in 14% of patients. Overall, grade 3 and 4 bone marrow toxicity was seen in 8%. One patient (0.3%) developed irreversible grade 4 nephrotoxicity. Myelodysplastic disease was recorded in one patient (0.3%). Univariate analysis of PFS predictors showed that body mass index (BMI), baseline chromogranin A (CgA) >400 ng/l, baseline alkaline phosphatase (ALP) >130 mg/dl, liver tumour volume and overall tumour burden were significant. On multivariate analysis only Ki67, high CgA and low BMI retained significance. 177 Lu-DOTATATE is an effective treatment in advanced NETs with generally high-volume metastases. It is well-tolerated. Ki-67, CgA and BMI appear to be predictors for PFS.
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Affiliation(s)
- Shahad Alsadik
- Department of Nuclear Medicine, Royal Free Hospital, London, UK
| | | | - Luohai Chen
- Royal Free London NHS Foundation Trust; Department of Gastroenterology, London, United Kingdom. The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ann-Marie Quigley
- Department of Nuclear Medicine, Royal Free London NHS foundation Trust, London, UK
| | - Dalvinder Mandair
- Neuroendocrine Unit, Royal Free London NHS foundation Trust, London, UK
| | | | - Martyn Caplin
- Neuroendocrine Unit, Royal Free London NHS foundation Trust, London, UK
| | - Shaunak Navalkissoor
- Department of Nuclear Medicine, Royal Free London NHS foundation Trust, London, UK
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20
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Treatment Assessment of pNET and NELM after Everolimus by Quantitative MRI Parameters. Biomedicines 2022; 10:biomedicines10102618. [PMID: 36289880 PMCID: PMC9599819 DOI: 10.3390/biomedicines10102618] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 10/01/2022] [Accepted: 10/11/2022] [Indexed: 11/17/2022] Open
Abstract
Assessment of treatment response to targeted therapies such as everolimus is difficult, especially in slow-growing tumors such as NETs. In this retrospective study, 17 patients with pancreatic neuroendocrine tumors (pNETs) and hepatic metastases (NELMs) (42 target lesions) who received everolimus were analyzed. Intralesional signal intensities (SI) of non-contrast T1w, T2w and DCE imaging, and apparent diffusion coefficients (ADCmean and ADCmin) of DWI, were measured on baseline and first follow-up MRI after everolimus initiation. Response assessment was categorized according to progression-free survival (PFS), with responders (R) showing a PFS of ≥11 months. ADCmin of NELMs decreased in Rs whereas it increased in non-responders (NR). Percentual changes of ADCmin and ADCmean differed significantly between response groups (p < 0.03). By contrast, ADC of the pNETs tended to increase in Rs, while there was no change in NRs. Tumor-to-liver (T/L) ratio of T1 SI of NELMs increased in Rs and decreased in NRs, and percentual changes differed significantly between response groups (p < 0.02). T1 SI of the pNETs tended to decrease in Rs and increase in Ns. The quotient of pretherapeutic and posttherapeutic ADCmin values (DADCmin) and length of everolimus treatment showed significant association with PFS in univariable Cox analysis. In conclusion, quantitative MRI, especially DWI, seems to allow treatment assessment of pNETs with NELMs under everolimus. Interestingly, the responding NELMs showed decreasing ADC values, and there might be an opposite effect on ADC and T1 SI between NELMs and pNETs.
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21
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Kooblall KG, Stokes VJ, Shariq OA, English KA, Stevenson M, Broxholme J, Wright B, Lockstone HE, Buck D, Grozinsky-Glasberg S, Yates CJ, Thakker RV, Lines KE. miR-3156-5p is downregulated in serum of MEN1 patients and regulates expression of MORF4L2. Endocr Relat Cancer 2022; 29:557-568. [PMID: 35900839 PMCID: PMC9422251 DOI: 10.1530/erc-22-0045] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 07/07/2022] [Indexed: 11/28/2022]
Abstract
Multiple endocrine neoplasia type 1 (MEN1), caused by mutations in the MEN1 gene encoding menin, is an autosomal dominant disorder characterised by the combined occurrence of parathyroid, pituitary and pancreatic neuroendocrine tumours (NETs). Development of these tumours is associated with wide variations in their severity, order and ages (from <5 to >80 years), requiring life-long screening. To improve tumour surveillance and quality of life, better circulating biomarkers, particularly for pancreatic NETs that are associated with higher mortality, are required. We, therefore, examined the expression of circulating miRNA in the serum of MEN1 patients. Initial profiling analysis followed by qRT-PCR validation studies identified miR-3156-5p to be significantly downregulated (-1.3 to 5.8-fold, P < 0.05-0.0005) in nine MEN1 patients, compared to matched unaffected relatives. MEN1 knock-down experiments in BON-1 human pancreatic NET cells resulted in reduced MEN1 (49%, P < 0.05), menin (54%, P < 0.05) and miR-3156-5p expression (20%, P < 0.005), compared to control-treated cells, suggesting that miR-3156-5p downregulation is a consequence of loss of MEN1 expression. In silico analysis identified mortality factor 4-like 2 (MOR4FL2) as a potential target of miR-3156-5p, and in vitro functional studies in BON-1 cells transfected with either miR-3156-5p mimic or inhibitors showed that the miR-3156-5p mimic significantly reduced MORF4L2 protein expression (46%, P < 0.005), while miR-3156-5p inhibitor significantly increased MORF4L2 expression (1.5-fold, P < 0.05), compared to control-treated cells, thereby confirming that miR-3156-5p regulates MORF4L2 expression. Thus, the inverse relationship between miR-3156-5p and MORF4L2 expression represents a potential serum biomarker that could facilitate the detection of NET occurrence in MEN1 patients.
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Affiliation(s)
- Kreepa G Kooblall
- OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK
| | - Victoria J Stokes
- OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK
| | - Omair A Shariq
- OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK
| | - Katherine A English
- OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK
| | - Mark Stevenson
- OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK
| | - John Broxholme
- Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK
| | - Benjamin Wright
- Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK
| | - Helen E Lockstone
- Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK
| | - David Buck
- Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK
| | - Simona Grozinsky-Glasberg
- Neuroendocrine Tumor Unit, ENETS Center of Excellence, Endocrinology & Metabolism Department, Hadassah Medical Center and Faculty of Medicine, The Hebrew University of Jerusalem, Israel
| | - Christopher J Yates
- OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK
| | - Rajesh V Thakker
- OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK
- Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK
| | - Kate E Lines
- OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK
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22
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Circulating Angiogenic Markers in Gastroenteropancreatic Neuroendocrine Neoplasms: A Systematic Review. Curr Issues Mol Biol 2022; 44:4001-4014. [PMID: 36135186 PMCID: PMC9497497 DOI: 10.3390/cimb44090274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 08/26/2022] [Accepted: 08/30/2022] [Indexed: 11/30/2022] Open
Abstract
Background: Neuroendocrine neoplasms are a heterogeneous group of tumors that raise challenges in terms of diagnosis, treatment and monitoring. Despite continuous efforts, no biomarker has showed satisfying accuracy in predicting outcome or response to treatment. Methods: We conducted a systematic review to determine relevant circulating biomarkers for angiogenesis in neuroendocrine tumors. We searched three databases (Pubmed, Embase, Web of Science) using the keywords “neuroendocrine” and “biomarkers”, plus specific biomarkers were searched by full and abbreviated name. From a total of 2448 publications, 11 articles met the eligibility criteria. Results: VEGF is the most potent and the most studied angiogenic molecule, but results were highly controversial. Placental growth factor, Angiopoietin 2 and IL-8 were the most consistent markers in predicting poor outcome and aggressive disease behavior. Conclusions: There is no robust evidence so far to sustain the use of angiogenic biomarkers in routine practice, although the results show promising leads.
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23
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Role of Chromogranin A in the Diagnosis and Follow-up of Neuroendocrine Tumors: Real-World Experience. Pancreas 2022; 51:1007-1010. [PMID: 36607947 DOI: 10.1097/mpa.0000000000002132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
OBJECTIVE The aim of this study was to assess the utility of serum chromogranin A (CgA) along the clinical pathway of patients with neuroendocrine tumors (NETs). METHODS A retrospective review of medical records was conducted of patients with NET who had at least 1 measurement of CgA between January 2015 and April 2021 at a large metropolitan Australian hospital. Chromogranin A was classified as increased or decreased if there was at least a 25% change in sequential levels and was compared with disease response by anatomical or functional imaging if within 6 weeks (considered concurrent). RESULTS Of 102 patients with NETs, 67 had at least 1 serum CgA level: 50 had been ordered during diagnostic workup, of which 33 were elevated (sensitivity: 66%; 95% confidence interval, 51%-79%). Of 129 CgA results concurrent with imaging, the sensitivity for detecting progressive disease was 28% (95% confidence interval, 15%-44%). CONCLUSIONS Our findings support previous concerns that CgA adds little value in clinical decision-making.
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Fuksiewicz M, Kowalska M, Kolasinska-Cwikla A, Kotowicz B. Serum levels of neuron-specific enolase as a prognostic factor for disease progression in patients with GET/NEN in the pancreas and the small intestine. Endocr Connect 2022; 11:e210647. [PMID: 35900770 PMCID: PMC9422245 DOI: 10.1530/ec-21-0647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 07/27/2022] [Indexed: 11/17/2022]
Abstract
The aim of this study was to assess the usefulness of neuron-specific enolase (NSE) concentrations as a prognostic factor in patients with neuroendocrine neoplasms and to determine the relationship between NSE and clinicopathological features. Serum NSE levels were measured in 179 NEN patients before treatment. It was found that NSE levels in patients with a primary pancreatic location were higher compared to patients with a small intestine lesion (P = 0.015). NSE levels were significantly higher in patients with primary pancreatic location with histological grade G2 compared with the group with low-grade G1 (P = 0.047). Patients with initial liver involvement showed significantly higher NSE levels compared to patients with tumour location in the pancreas (P = 0.009). Statistical analysis confirmed that higher NSE levels were associated with disease progression (P = 0.001) in both the overall study group and in patients with tumours in the pancreas and small intestine. During treatment monitoring, an increase in median NSE concentrations was observed in patients with persistent progression with subsequent blood draws, and a decrease in NSE concentrations was observed in patients with disease stabilisation. We showed that NSE concentrations have prognostic value for progression-free survival in addition to primary liver involvement. In conclusion, the most important results of the study include the demonstration of an association between NSE concentrations and clinical status, which confirms its usefulness in patient monitoring and as a potential predictive indicator for progression-free survival in patients with NENs.
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Affiliation(s)
- Malgorzata Fuksiewicz
- Laboratory of Tumor Markers, Department of Pathology and Laboratory Diagnostics, The Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Maria Kowalska
- Laboratory of Tumor Markers, Department of Pathology and Laboratory Diagnostics, The Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Agnieszka Kolasinska-Cwikla
- Department of Oncology and Radiotherapy, The Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Beata Kotowicz
- Laboratory of Tumor Markers, Department of Pathology and Laboratory Diagnostics, The Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
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25
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Hope TA, Pavel M, Bergsland EK. Neuroendocrine Tumors and Peptide Receptor Radionuclide Therapy: When Is the Right Time? J Clin Oncol 2022; 40:2818-2829. [PMID: 35649195 PMCID: PMC9390818 DOI: 10.1200/jco.22.00176] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 03/14/2022] [Accepted: 04/18/2022] [Indexed: 12/29/2022] Open
Abstract
Since its approval in 2018 by the US Food and Drug Administration, peptide receptor radionuclide therapy (PRRT) has become a mainstay in the treatment of neuroendocrine tumors. Lutetium-177-DOTATATE, the only approved agent, is indicated for the treatment of gastroenteropancreatic-neuroendocrine tumors. Although patient selection appears straightforward with somatostatin receptor-positron emission tomography, there is considerable complexity when deciding which patients to treat and when to start PRRT. Herein, we review the many factors that affect patient selection, focusing on the optimal patients to treat. Although significant effort has been expended to determine which patients benefit the most from PRRT, a validated predictive biomarker remains elusive. Although PRRT has been used for more than 2 decades in Europe and standards of care exist for safe treatment, there remain numerous questions regarding when PRRT should be used relative to other treatments. It is important to remember that multidisciplinary discussions are essential. Currently, there are a number of ongoing studies looking to assess the efficacy of PRRT compared with other treatment options and to optimize treatment through combination therapy, different dosing strategies, or use of different radionuclides and radioligands.
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Affiliation(s)
- Thomas A. Hope
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA
- Helen Diller Family Comprehensive Cancer Centre, University of California, San Francisco, San Francisco, CA
- Department of Radiology, San Francisco VA Medical Center, San Francisco, CA
| | - Marianne Pavel
- Department of Medicine 1, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Emily K. Bergsland
- Helen Diller Family Comprehensive Cancer Centre, University of California, San Francisco, San Francisco, CA
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA
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26
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Dynamic plasticity of prostate cancer intermediate cells during androgen receptor-targeted therapy. Cell Rep 2022; 40:111123. [PMID: 35905714 DOI: 10.1016/j.celrep.2022.111123] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/25/2022] [Accepted: 06/30/2022] [Indexed: 11/22/2022] Open
Abstract
Treatment-emergent small cell neuroendocrine prostate cancer (t-SCNC) is associated with an epithelial lineage switch from an androgen receptor (AR)-positive to neuroendocrine (NE)-marker-positive status. Understanding the potential for reversibility of this aggressive disease state has been hampered by the paucity of models suitable for studying rate-limiting, transitional, or intermediate tumor cell subpopulations. We define a dual reporter model that measures acute transcriptional changes in response to castration or AR targeting agents. We identify steady-state transcriptional heterogeneity in AR and NE biomarkers, including intermediate subpopulations that are coordinately high for prostate-specific antigen (PSA) and neuron-specific enoclase (NSE) promoter activity. In the presence of castration or AR inhibitors, intermediate cells were necessary and sufficient for therapy-induced conversion of human PC cells to an NSE-high transcriptional status. Using hormone add-back studies, treatment-induced PSA-NSE transcriptional plasticity was reversible in PTEN-deficient PC cells but not in the presence of secondary genetic driver genes, including MYCN.
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27
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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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Lee L, Ramos-Alvarez I, Jensen RT. Predictive Factors for Resistant Disease with Medical/Radiologic/Liver-Directed Anti-Tumor Treatments in Patients with Advanced Pancreatic Neuroendocrine Neoplasms: Recent Advances and Controversies. Cancers (Basel) 2022; 14:1250. [PMID: 35267558 PMCID: PMC8909561 DOI: 10.3390/cancers14051250] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/08/2022] [Accepted: 02/23/2022] [Indexed: 12/14/2022] Open
Abstract
Purpose: Recent advances in the diagnosis, management and nonsurgical treatment of patients with advanced pancreatic neuroendocrine neoplasms (panNENs) have led to an emerging need for sensitive and useful prognostic factors for predicting responses/survival. Areas covered: The predictive value of a number of reported prognostic factors including clinically-related factors (clinical/laboratory/imaging/treatment-related factors), pathological factors (histological/classification/grading), and molecular factors, on therapeutic outcomes of anti-tumor medical therapies with molecular targeting agents (everolimus/sunitinib/somatostatin analogues), chemotherapy, radiological therapy with peptide receptor radionuclide therapy, or liver-directed therapies (embolization/chemoembolization/radio-embolization (SIRTs)) are reviewed. Recent findings in each of these areas, as well as remaining controversies and uncertainties, are discussed in detail, particularly from the viewpoint of treatment sequencing. Conclusions: The recent increase in the number of available therapeutic agents for the nonsurgical treatment of patients with advanced panNENs have raised the importance of prognostic factors predictive for therapeutic outcomes of each treatment option. The establishment of sensitive and useful prognostic markers will have a significant impact on optimal treatment selection, as well as in tailoring the therapeutic sequence, and for maximizing the survival benefit of each individual patient. In the paper, the progress in this area, as well as the controversies/uncertainties, are reviewed.
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Affiliation(s)
- Lingaku Lee
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA; (L.L.); (I.R.-A.)
- National Kyushu Cancer Center, Department of Hepato-Biliary-Pancreatology, Fukuoka 811-1395, Japan
| | - Irene Ramos-Alvarez
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA; (L.L.); (I.R.-A.)
| | - Robert T. Jensen
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA; (L.L.); (I.R.-A.)
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29
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Havasi A, Sur D, Cainap SS, Lungulescu CV, Gavrilas LI, Cainap C, Vlad C, Balacescu O. Current and New Challenges in the Management of Pancreatic Neuroendocrine Tumors: The Role of miRNA-Based Approaches as New Reliable Biomarkers. Int J Mol Sci 2022; 23:1109. [PMID: 35163032 PMCID: PMC8834851 DOI: 10.3390/ijms23031109] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 01/10/2022] [Accepted: 01/18/2022] [Indexed: 12/17/2022] Open
Abstract
Pancreatic neuroendocrine tumors (PanNETs) are rare tumors; however, their incidence greatly increases with age, and they occur more frequently among the elderly. They represent 5% of all pancreatic tumors, and despite the fact that low-grade tumors often have an indolent evolution, they portend a poor prognosis in an advanced stages and undifferentiated tumors. Additionally, functional pancreatic neuroendocrine tumors greatly impact quality of life due to the various clinical syndromes that result from abnormal hormonal secretion. With limited therapeutic and diagnostic options, patient stratification and selection of optimal therapeutic strategies should be the main focus. Modest improvements in the management of pancreatic neuroendocrine tumors have been achieved in the last years. Therefore, it is imperative to find new biomarkers and therapeutic strategies to improve patient survival and quality of life, limiting the disease burden. MicroRNAs (miRNAs) are small endogenous molecules that modulate the expression of thousands of genes and control numerous critical processes involved in tumor development and progression. New data also suggest the implication of miRNAs in treatment resistance and their potential as prognostic or diagnostic biomarkers and therapeutic targets. In this review, we discusses the current and new challenges in the management of PanNETs, including genetic and epigenetic approaches. Furthermore, we summarize the available data on miRNAs as potential prognostic, predictive, or diagnostic biomarkers and discuss their function as future therapeutic targets.
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Affiliation(s)
- Andrei Havasi
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 400015 Cluj-Napoca, Romania; (A.H.); (C.C.)
- 11th Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400015 Cluj-Napoca, Romania;
- MedEuropa Radiotherapy Center, 410191 Oradea, Romania
| | - Daniel Sur
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 400015 Cluj-Napoca, Romania; (A.H.); (C.C.)
- 11th Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400015 Cluj-Napoca, Romania;
| | - Simona Sorana Cainap
- Department of Mother and Child, Pediatric Cardiology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400015 Cluj-Napoca, Romania;
| | | | - Laura-Ioana Gavrilas
- Department of Bromatology, Hygiene, Nutrition, University of Medicine and Pharmacy “Iuliu Hatieganu”, 23 Marinescu Street, 400337 Cluj-Napoca, Romania;
| | - Calin Cainap
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 400015 Cluj-Napoca, Romania; (A.H.); (C.C.)
- 11th Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400015 Cluj-Napoca, Romania;
| | - Catalin Vlad
- Department of Surgery, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 34–36, Republicii Street, 400015 Cluj-Napoca, Romania;
- Department of Oncology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 8, Victor Babes Street, 400012 Cluj-Napoca, Romania
| | - Ovidiu Balacescu
- 11th Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400015 Cluj-Napoca, Romania;
- Department of Genetics, Genomics and Experimental Pathology, The Oncology Institute “Prof. Dr. Ion Chiricuta’’, 400015 Cluj-Napoca, Romania
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30
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Puliani G, Di Vito V, Feola T, Sesti F, Centello R, Pandozzi C, Tarsitano MG, Verrico M, Lenzi A, Isidori AM, Giannetta E, Faggiano A. NETest: A Systematic Review Focusing on the Prognostic and Predictive Role. Neuroendocrinology 2022; 112:523-536. [PMID: 34515175 DOI: 10.1159/000518873] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 08/02/2021] [Indexed: 11/19/2022]
Abstract
The NETest is a standardized and reproducible liquid biopsy for neuroendocrine tumors (NETs). It evaluates the expression of 51 NET genes by real-time polymerase chain reaction, providing an accurate molecular profile of the neoplasm. Diagnostic utility of NETest has been widely demonstrated, while its role in predicting prognosis and treatment response is less studied. This systematic review aims to collect and discuss the available evidence on the prognostic and predictive role of NETest, trying to answer 3 questions, frequently raised in clinical practice. Is NETest able to differentiate stable from progressive disease? Increased NETest levels (at least >40%) correlate with disease progression. Is NETest able to predict tumor progression and tumor response to treatment? Some studies demonstrated that the baseline NETest score >33-40% could predict tumor progression. Moreover, NETest performed after treatment (as peptide receptor radionuclide therapy) could predict treatment response also before radiological findings, since the decrease or stability of NETest score predicts tumor response to treatment. Is NETest able to evaluate tumor recurrence risk after surgery? NETest can predict surgical treatment outcome detecting minimal residual disease after radical surgery, which is characterized by a lower but positive NETest score (20-40%), while a higher score (>33-40%) is associated with nonradical surgery. In conclusion, in addition to its demonstrated diagnostic role, this systematic review highlights the efficacy of NETest to assess disease status at the moment of the NETest execution and to predict tumor recurrence after surgery. The efficacy for other applications should be proven by additional studies.
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Affiliation(s)
- Giulia Puliani
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
- Oncological Endocrinology Unit, IRCCS Regina Elena National Cancer institute, Rome, Italy
| | - Valentina Di Vito
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Tiziana Feola
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
- Neuroendocrinology, Neuromed Institute, IRCCS, Pozzilli, Italy
| | - Franz Sesti
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Roberta Centello
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Carla Pandozzi
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | | | - Monica Verrico
- Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy
| | - Andrea Lenzi
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Andrea M Isidori
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Elisa Giannetta
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Antongiulio Faggiano
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy
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31
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Hayes AR, Furtado O'Mahony L, Quigley AM, Gnanasegaran G, Caplin ME, Navalkissoor S, Toumpanakis C. The Combined Interpretation of 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT in Metastatic Gastroenteropancreatic Neuroendocrine Tumors: A Classification System With Prognostic Impact. Clin Nucl Med 2022; 47:26-35. [PMID: 34874347 DOI: 10.1097/rlu.0000000000003937] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE Gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) are widely heterogeneous in their biological behavior, and predicting prognosis and optimal treatment strategies can be challenging. 68Ga-DOTATATE PET/CT is a sensitive imaging modality for well-differentiated NEN and indicates a favorable prognosis, whereas 18F-FDG PET/CT avidity indicates disease that is potentially more aggressive. There has been emerging interest in the combined interpretation of 68Ga-DOTATATE and 18F-FDG PET and its prognostic significance. We aimed to assess the prognostic utility of a classification system that incorporates the complex findings of 68Ga-DOTATATE and 18F-FDG PET interpreted side-by-side in patients with metastatic GEP NEN. METHODS We defined 3 68Ga-DOTATATE/18F-FDG "dual-tracer PET" groups: D1 (68Ga-DOTATATE positive/18F-FDG negative), D2 (68Ga-DOTATATE positive/18F-FDG positive), and D3 (68Ga-DOTATATE negative/18F-FDG positive). We retrospectively assessed the association between the dual-tracer PET classification and progression-free and overall survival (OS) using Kaplan-Meier analysis. Univariate and multivariate analyses were performed using the Cox proportional hazards model. RESULTS Eighty-seven patients with metastatic GEP NEN and contemporaneous 68Ga-DOTATATE and 18F-FDG PET were included. The dual-tracer PET classification was an independent predictor of OS (multivariate P = 0.016) and also predicted progression-free survival (univariate P = 0.030). Other independent predictors of OS included chromogranin A and World Health Organization (WHO) grade. WHO grade was not associated with OS from the time of dual-tracer PET but was an independent predictor of OS from the date of histological diagnosis (multivariate P = 0.003). CONCLUSION Our study demonstrates that a classification system combining the complex findings of 68Ga-DOTATATE and 18F-FDG PET is correlated with prognosis. Further research is needed to prospectively validate these findings and to explore whether dual-tracer PET scores may also be able to predict response to treatment.
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Affiliation(s)
- Aimee R Hayes
- From the Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital
| | | | | | | | - Martyn E Caplin
- From the Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital
| | | | - Christos Toumpanakis
- From the Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital
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32
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Zhang J, Cao Y, Zhang P, Zhang X, Li J, Zhou J, Wang X, Peng Z, Sun Y, Li J, Shen L, Lu M. Serum Biomarker Status with a Distinctive Pattern in Prognosis of Gastroenteropancreatic Neuroendocrine Carcinoma. Neuroendocrinology 2022; 112:733-743. [PMID: 34592743 PMCID: PMC9533446 DOI: 10.1159/000519948] [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: 05/06/2021] [Accepted: 09/26/2021] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Gastroenteropancreatic neuroendocrine carcinoma (GEPNEC) is a major research focus, but the application of biomarkers to guide its prognostication and management is unsatisfying. Clinical values of conventional serum biomarkers, neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA199) warrant scrutiny. METHODS Patients diagnosed with GEPNEC with baseline NSE, CEA, and CA199 levels provided in Peking University Cancer Hospital were retrospectively studied. Relationships between biomarkers and prognosis were investigated by the χ2 test, Kaplan-Meier analysis, and univariate and multivariate Cox regression analyses. RESULTS A total of 640 GEPNEC patients were enrolled. NSE, CEA, and CA199 were elevated in 59.5%, 28.5%, and 21.3% of the population, respectively. Higher NSE had worse median overall survival (OS) (17.0 months vs. not reached, hazard ratio = 2.77 [2.06, 3.73], p < 0.001), and so did patients with higher CEA and CA199. Multivariable analysis confirmed that NSE and CA199 correlated with OS independently. Baseline NSE level and NSE remission predicted OS and the response of patients with first-line etoposide plus cisplatin (EP) treatment. Furthermore, we combined NSE/CEA/CA199 to segregate GEPNEC into novel subgroups, namely, adenocarcinoma-like NEC (ALN), neuroendocrine-like NEC (NLN), and triple-normal NEC (TNN). The groups shared distinctive clinicopathologic features and prognosis (21.0 months vs. 17.1 months vs. not reached, p < 0.001). The EP regimen remained the priority treatment option in NLN/TNN, while ALN was predisposed to "adenocarcinoma-like chemotherapy." CONCLUSIONS Elevation of NSE, CEA, or CA199 was common and independently indicates poor prognosis in GEPNEC patients. Serum biomarker-based subtypes suggest meaningful clinical implications and appropriate therapeutic approaches, illuminating promising ways to characterize the prognosis of GEPNEC.
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Affiliation(s)
- Jianwei Zhang
- Peking University Cancer Hospital and Institute, Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing, China), Beijing, China
| | - Yanshuo Cao
- Peking University Cancer Hospital and Institute, Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing, China), Beijing, China
| | - Panpan Zhang
- Peking University Cancer Hospital and Institute, Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing, China), Beijing, China
| | - Xiaotian Zhang
- Peking University Cancer Hospital and Institute, Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing, China), Beijing, China
| | - Jian Li
- Peking University Cancer Hospital and Institute, Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing, China), Beijing, China
| | - Jun Zhou
- Peking University Cancer Hospital and Institute, Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing, China), Beijing, China
| | - Xicheng Wang
- Peking University Cancer Hospital and Institute, Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing, China), Beijing, China
| | - Zhi Peng
- Peking University Cancer Hospital and Institute, Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing, China), Beijing, China
| | - Yu Sun
- Peking University Cancer Hospital and Institute, Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing, China
| | - Jie Li
- Peking University Cancer Hospital and Institute, Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing, China), Beijing, China
| | - Lin Shen
- Peking University Cancer Hospital and Institute, Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing, China), Beijing, China
| | - Ming Lu
- Peking University Cancer Hospital and Institute, Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing, China), Beijing, China
- *Ming Lu,
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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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The role of biomarker in pancreatic neuroendocrine tumor. JOURNAL OF PANCREATOLOGY 2021. [DOI: 10.1097/jp9.0000000000000076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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The Role of miRNA in the Pathophysiology of Neuroendocrine Tumors. Int J Mol Sci 2021; 22:ijms22168569. [PMID: 34445276 PMCID: PMC8395312 DOI: 10.3390/ijms22168569] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/16/2021] [Accepted: 08/06/2021] [Indexed: 12/14/2022] Open
Abstract
Neuroendocrine tumors (NETs) represent a tumor group that is both rare and heterogeneous. Prognosis is largely determined by the tumor grading and the site of the primary tumor and metastases. Despite intensive research efforts, only modest advances in diagnostic and therapeutic approaches have been achieved in recent years. For patients with non-respectable tumor stages, prognosis is poor. In this context, the development of novel diagnostic tools for early detection of NETs and prediction of tumor response to therapy as well as estimation of the overall prognosis would greatly improve the clinical management of NETs. However, identification of novel diagnostic molecules is hampered by an inadequate understanding of the pathophysiology of neuroendocrine malignancies. It has recently been demonstrated that microRNA (miRNA), a family of small RNA molecules with an established role in the pathophysiology of quite different cancer entities, may also play a role as a biomarker. Here, we summarize the available knowledge on the role of miRNAs in the development of NET and highlight their potential use as serum-based biomarkers in the context of this disease. We discuss important challenges currently preventing their use in clinical routine and give an outlook on future directions of miRNA research in NET.
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Yu F, Fu J, Zhang C, Wu W, Ai S, Yao X, Meng Q, Huang Y, Lu G, Wang F, Qu W. Use of Chromogranin A for Monitoring Patients With Pancreatic Neuroendocrine Neoplasms. Pancreas 2021; 50:882-889. [PMID: 34347728 DOI: 10.1097/mpa.0000000000001852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVE We aimed to assess the role of serum chromogranin A (CgA) in monitoring disease status and treatment response in patients with pancreatic neuroendocrine neoplasms (pNENs). METHODS We included posttherapy pNENs patients with measured serum CgA levels who underwent 68Ga-labeled tetraazacyclododecanetetraacetic acid-peptide positron emission tomography (PET) imaging between April 2017 and January 2020. Serum CgA levels were determined by enzyme-linked immunosorbent assay. Tumor response was assessed according to the PET response evaluation criteria in solid tumors. RESULTS Seventy-seven patients with 101 events were included in this study. Serum CgA levels were significantly higher in patients with active disease and metastasis. The optimal cutoff values for CgA for active and metastatic pNENs diagnosis after treatment were 52.39 (77.8% sensitivity, 80.7% specificity) and 60.18 ng/mL (73.9% sensitivity, 73.1% specificity), respectively. Based on 18 patients with serial CgA measurements and PET imaging, the optimal changes in CgA levels for predicting disease remission and progression were a 28.5% decrease (71.4% sensitivity, 88.2% specificity) and a 21.0% increase (100.0% sensitivity, 75.0% specificity), respectively. CONCLUSIONS We concluded that serum CgA levels are associated with disease status and treatment response and may thus provide a helpful biomarker for the monitoring and clinical management of patients with pNENs.
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Affiliation(s)
- Fei Yu
- From the Department of Nuclear Medicine
| | | | | | - Wenyu Wu
- From the Department of Nuclear Medicine
| | - Shuyue Ai
- From the Department of Nuclear Medicine
| | | | | | - Yue Huang
- Department of Pathology, Nanjing First Hospital, Nanjing Medical University
| | - Guangming Lu
- Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Feng Wang
- From the Department of Nuclear Medicine
| | - Wei Qu
- From the Department of Nuclear Medicine
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Survival predictors of 177Lu-Dotatate peptide receptor radionuclide therapy (PRRT) in patients with progressive well-differentiated neuroendocrine tumors (NETS). J Cancer Res Clin Oncol 2021; 148:225-236. [PMID: 34110489 PMCID: PMC8752529 DOI: 10.1007/s00432-021-03672-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 05/24/2021] [Indexed: 12/18/2022]
Abstract
Purpose 177Lu-Dotatate is an emerging treatment modality for patients with unresectable or metastatic well-differentiated NETs. This study examines survival predictors in patients who received 177Lu-Dotatate. Methods A retrospective single-center review was conducted, examining 47 individuals with progressive well-differentiated NETs treated with 177Lu-Dotatate (four induction cycles of 5.5 GBq at 10-week intervals followed by eight maintenance cycles of 3.7 GBq at 6-month intervals). Results Median follow-up was 63.1 months with a median progression-free survival (PFS) of 34.1 months. However, median overall survival (OS) was not reached at the time of analysis. The presence of ≥ 5 bone metastases (hazard ratio HR 4.33; p = 0.015), non-gastroenteropancreatic (non-GEP) NETs (HR 3.22; p = 0.025) and development of interim ascites (HR 3.15; p = 0.047) independently predicted a worse OS. Patients with chromogranin A of ≥ 4 × upper limit of normal (ULN) had shorter OS (p < 0.001) and PFS (p = 0.004). Similarly, those with pre-existing ascites demonstrated a worse OS (p = 0.009) and PFS (p = 0.026). Liver metastases involving greater than 50% liver volume and the existence of unusual metastatic locations had a negative impact on OS (p = 0.033) and PFS (p = 0.026), respectively. Conclusion High burden of skeletal and hepatic metastases, non-GEP-NETs, chromogranin A of ≥ 4 × ULN, unusual metastatic sites, pre-existing and interim ascites are predictors of poor outcomes in patients treated with 177Lu-Dotatate. These common indicators can be used for the risk stratification and identification of patients most likely to benefit from PRRT. Trial registration ClinicalTrials.gov identifier: NCT02236910, Retrospectively registered on September, 2014.
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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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Wu W, Chen J, Bai C, Chi Y, Du Y, Feng S, Huo L, Jiang Y, Li J, Lou W, Luo J, Shao C, Shen L, Wang F, Wang L, Wang O, Wang Y, Wu H, Xing X, Xu J, Xue H, Xue L, Yang Y, Yu X, Yuan C, Zhao H, Zhu X, Zhao Y. The Chinese guidelines for the diagnosis and treatment of pancreatic neuroendocrine neoplasms (2020). JOURNAL OF PANCREATOLOGY 2021; 4:1-17. [DOI: 10.1097/jp9.0000000000000064] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Abstract
Pancreatic neuroendocrine neoplasms (pNENs) are highly heterogeneous, and the management of pNENs patients can be intractable. To address this challenge, an expert committee was established on behalf of the Chinese Pancreatic Surgery Association, which consisted of surgical oncologists, gastroenterologists, medical oncologists, endocrinologists, radiologists, pathologists, and nuclear medicine specialists. By reviewing the important issues regarding the diagnosis and treatment of pNENs, the committee concluded evidence-based statements and recommendations in this article, in order to further improve the management of pNENs patients in China.
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Affiliation(s)
- Wenming Wu
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing
| | - Jie Chen
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province
| | - Chunmei Bai
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing
| | - Yihebali Chi
- Department of Medical Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing
| | - Yiqi Du
- Department of Gastroenterology, Changhai Hospital Affiliated to Navy Medical University, Shanghai
| | - Shiting Feng
- Department of Radiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province
| | - Li Huo
- Department of Nuclear Medicine, Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing
| | - Yuxin Jiang
- Department of Ultrasound, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing
| | - Jingnan Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing
| | - Wenhui Lou
- Department of General Surgery, Zhongshan Hospital of Fudan University
| | - Jie Luo
- Department of Pathology, China-Japan Friendship Hospital, Beijing
| | - Chenghao Shao
- Department of Pancreatic-biliary Surgery, Changzheng Hospital, Navy Medical University, Shanghai
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing
| | - Feng Wang
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province
| | - Liwei Wang
- Department of Oncology, Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai
| | - Ou Wang
- Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing
| | - Yu Wang
- Department of Interventional Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province
| | - Huanwen Wu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing
| | - Xiaoping Xing
- Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing
| | - Jianming Xu
- Department of Gastrointestinal Oncology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing
| | - Huadan Xue
- Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing
| | - Ling Xue
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province
| | - Yang Yang
- Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai
| | - Chunhui Yuan
- Department of General Surgery, Peking University Third Hospital, Beijing
| | - Hong Zhao
- Department of Hepatobiliary Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing
| | - Xiongzeng Zhu
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yupei Zhao
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing
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The Prognostic Value of the De Ritis Ratio for Progression-Free Survival in Patients with NET Undergoing [ 177Lu]Lu-DOTATOC-PRRT: A Retrospective Analysis. Cancers (Basel) 2021; 13:cancers13040635. [PMID: 33562643 PMCID: PMC7915791 DOI: 10.3390/cancers13040635] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 01/29/2021] [Accepted: 02/01/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NET) has shown variable response rates between 9% and 39%. Therefore, better criteria are needed that help doctors to identify patients who will show a favorable outcome to PRRT, and which patients may not. The so-called De Ritis ratio, which is calculated using two basic laboratory parameters of liver function, has shown that it can help to predict the patient outcome in various tumor types. This retrospective study included 125 patients with NET who were treated with PRRT. We demonstrated that a high De Ritis ratio and high levels of the tumor marker Chromogranin A (CgA) each improved the prediction of the progression-free survival after treatment. A consequence for clinical care might be that patients with both high De Ritis ratio and high CgA levels may benefit from intensified follow-up imaging after PRRT because they have a higher risk of early progression. Abstract Background: The De Ritis ratio (aspartate aminotransferase [AST]/alanine aminotransferase [ALT]) has demonstrated prognostic value in various cancer entities. We evaluated the prognostic capability of the De Ritis ratio in patients with metastatic neuroendocrine tumors (NET) undergoing peptide receptor radionuclide therapy (PRRT). Methods: Unicentric, retrospective analysis of 125 patients with NET undergoing PRRT with [177Lu]Lu-DOTATOC (female: 37%; median age: 66 years; G1+G2 NET: 95%). The prognostic value regarding progression-free survival (PFS) was analyzed with univariable and multivariable Cox regression. Prognostic accuracy was determined with Harrell’s C index and a likelihood ratio test. Results: Progression, relapse, or death after PRRT was observed in 102/125 patients. Median progression-free survival (PFS) was 15.8 months. Pancreatic or pulmonary origin, high De Ritis ratio, and high Chromogranin A (CgA) significantly predicted shorter PFS in univariable Cox. In multivariable Cox regression, only high De Ritis ratio >0.927 (HR: 1.7; p = 0.047) and high CgA >twice the upper normal limit (HR: 2.1; p = 0.005) remained independent predictors of shorter PFS. Adding the De Ritis ratio to the multivariable Cox model (age, Eastern Cooperative Oncology Group (ECOG) performance status, primary origin, CgA) significantly improved prognostic accuracy (p < 0.001). Conclusions: The De Ritis ratio is simple to obtain in clinical routine and can provide independent prognostic value for PFS in patients with NET undergoing PRRT.
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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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Fröss-Baron K, Garske-Roman U, Welin S, Granberg D, Eriksson B, Khan T, Sandström M, Sundin A. 177Lu-DOTATATE Therapy of Advanced Pancreatic Neuroendocrine Tumors Heavily Pretreated with Chemotherapy: Analysis of Outcome, Safety, and Their Determinants. Neuroendocrinology 2021; 111:330-343. [PMID: 32097917 DOI: 10.1159/000506746] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 02/21/2020] [Indexed: 01/27/2023]
Abstract
OBJECTIVE To retrospectively analyze toxicity, progression-free survival (PFS), overall survival (OS), and their determinants in patients with advanced pancreatic neuroendocrine tumors (PanNETs), previously pretreated with chemothe-r-apy, undergoing peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE. METHODS A total of 102 patients with advanced PanNETs, previously pretreated with one (67%) or several (33%) lines of chemotherapy, were included, of whom 90% had progressive disease and the majority (74.5%) had grade 2 tumors. 177Lu-DOTATATE, 7.4 GBq per cycle, was administered with 6- to 8-week intervals in 88% of patients utilizing a dosimetry-guided protocol until an absorbed dose of 23 Gy to the kidneys was reached. RESULTS A mean dose of 32 ± 10.9 GBq per patient was administered in 1-10 cycles starting a median of 36 months after PanNET diagnosis. The median follow-up was 34 months, the median PFS was 24 months, and the median OS was 42 months from start of PRRT. Independent risk factors for both progression and death were liver tumor burden >50%, more than one line of previous chemotherapy, and elevated alkaline phosphatase. Resection of the primary tumor was linked to longer survival. Bone marrow toxicity grade 3-4 occurred in 10.8%. One patient (1.0%) developed acute myeloid leukemia. Bone marrow toxicity was unrelated to type and length of previous chemotherapy, amount of administered activity, and absorbed dose to the bone marrow. CONCLUSION 177Lu-DOTATATE therapy was feasible, highly effective, and safe in patients with advanced PanNETs heavily pretreated with chemotherapy. More than one line of chemotherapy was a therapy-related independent risk factor for shorter PFS and OS.
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Affiliation(s)
| | - Ulrike Garske-Roman
- Department of Nuclear Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Staffan Welin
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Dan Granberg
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Barbro Eriksson
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Tanweera Khan
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Mattias Sandström
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Anders Sundin
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
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Chromogranin A Expression in Rectal Neuroendocrine Tumors Is Associated With More Aggressive Clinical Behavior and a Poorer Prognosis. Am J Surg Pathol 2020; 44:1496-1505. [PMID: 32735108 DOI: 10.1097/pas.0000000000001526] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Although rectal neuroendocrine tumors (NETs) with an L-cell phenotype and small size are generally less clinically serious, the new 2019 World Health Organization (WHO) classification system has categorized all of these lesions as malignant. Identifying biomarkers of rectal NETs is thus important for stratifying their clinical behavior. Chromogranin A protein expression was assessed in 538 endoscopically or surgically resected rectal NETs and compared with clinicopathologic factors to identify its clinical and prognostic significance. All of the rectal NETs analyzed (100%) were synaptophysin positive, but chromogranin A labeling was only detected in 111 cases (20.6%). Chromogranin A expression in the rectal NETs was more commonly associated with older age (50 y and older; P=0.013), male sex (P=0.002), radical resection (P=0.003), large tumor size (≥1 cm; P=0.038), muscularis propria invasion (P=0.002), lymphovascular (P=0.014) and perineural (P<0.001) invasion, an involved resection margin (P=0.028), and lymph node metastasis (P=0.003). Patients with chromogranin A expression had higher plasma chromogranin A levels (P=0.023) than those without chromogranin A expression during follow-up. The 10-year disease-free survival rate in rectal NET patients with chromogranin A expression (91.5%) was significantly shorter than the negative cases (99.7%) by both univariate (hazard ratio=14.438; 95% confidence interval: 2.911-71.598; P<0.001) and multivariate (hazard ratio=12.099; 95% confidence interval, 2.044-71.608; P=0.006) analyses. In summary, rectal NETs that are positive for chromogranin A are less common than those with synaptophysin expression and show more aggressive clinical behavior. Chromogranin A is therefore a prognostic indicator of higher recurrence risk in patients with endoscopically or surgically resected rectal NETs.
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Liberini V, Huellner MW, Grimaldi S, Finessi M, Thuillier P, Muni A, Pellerito RE, Papotti MG, Piovesan A, Arvat E, Deandreis D. The Challenge of Evaluating Response to Peptide Receptor Radionuclide Therapy in Gastroenteropancreatic Neuroendocrine Tumors: The Present and the Future. Diagnostics (Basel) 2020; 10:E1083. [PMID: 33322819 PMCID: PMC7763988 DOI: 10.3390/diagnostics10121083] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/09/2020] [Accepted: 12/09/2020] [Indexed: 02/07/2023] Open
Abstract
The NETTER-1 study has proven peptide receptor radionuclide therapy (PRRT) to be one of the most effective therapeutic options for metastatic neuroendocrine tumors (NETs), improving progression-free survival and overall survival. However, PRRT response assessment is challenging and no consensus on methods and timing has yet been reached among experts in the field. This issue is owed to the suboptimal sensitivity and specificity of clinical biomarkers, limitations of morphological response criteria in slowly growing tumors and necrotic changes after therapy, a lack of standardized parameters and timing of functional imaging and the heterogeneity of PRRT protocols in the literature. The aim of this article is to review the most relevant current approaches for PRRT efficacy prediction and response assessment criteria in order to provide an overview of suitable tools for safe and efficacious PRRT.
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Affiliation(s)
- Virginia Liberini
- Nuclear Medicine Unit, Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (S.G.); (M.F.); (P.T.); (D.D.)
- Department of Nuclear Medicine, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland;
| | - Martin W. Huellner
- Department of Nuclear Medicine, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland;
| | - Serena Grimaldi
- Nuclear Medicine Unit, Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (S.G.); (M.F.); (P.T.); (D.D.)
| | - Monica Finessi
- Nuclear Medicine Unit, Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (S.G.); (M.F.); (P.T.); (D.D.)
| | - Philippe Thuillier
- Nuclear Medicine Unit, Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (S.G.); (M.F.); (P.T.); (D.D.)
- Department of Endocrinology, University Hospital of Brest, 29200 Brest, France
| | - Alfredo Muni
- Department of Nuclear Medicine, S.S. Biagio e Antonio e C. Arrigo Hospital, 15121 Alessandria, Italy;
| | | | - Mauro G. Papotti
- Pathology Unit, City of Health and Science University Hospital, 10126 Turin, Italy;
- Department of Oncology, University of Turin at Molinette Hospital, 10126 Turin, Italy
| | - Alessandro Piovesan
- Department of Endocrinology, A. O. U. Città della Salute della Scienza of Turin, 10126 Turin, Italy;
| | - Emanuela Arvat
- Oncological Endocrinology, Department of Medical Sciences, University of Turin, 10126 Turin, Italy;
| | - Désirée Deandreis
- Nuclear Medicine Unit, Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (S.G.); (M.F.); (P.T.); (D.D.)
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Asphericity of Somatostatin Receptor Expression in Neuroendocrine Tumors: An Innovative Predictor of Outcome in Everolimus Treatment? Diagnostics (Basel) 2020; 10:diagnostics10090732. [PMID: 32971877 PMCID: PMC7554807 DOI: 10.3390/diagnostics10090732] [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: 08/20/2020] [Revised: 09/14/2020] [Accepted: 09/17/2020] [Indexed: 01/01/2023] Open
Abstract
Background: in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NET), the mTOR inhibitor everolimus is associated with significant improvement in progression-free survival (PFS). This study evaluated the lesional asphericity (ASP) in pretherapeutic somatostatin receptor (SSR) imaging as the first imaging-based prognostic marker for PFS. Methods: this retrospective bicentric cohort study included 30 patients (f = 13, median age, 66.5 (48–81) years) with pretherapeutic [111In-DTPA0]octreotide scintigraphy (Octreoscan®). ASP of functional volumes of up to three leading lesions per patient (n = 74) was calculated after semiautomatic, background-adapted segmentation. Uni- and multivariable Cox regression regarding PFS for clinical factors and the maximum ASP per patient was obtained. Results: all 30 patients showed metachronous or progressive liver metastases. ASP, primary tumor site, metastases pattern, and prior peptide receptor radionuclide therapy (PRRT) were significantly associated with PFS in univariable Cox regression. Only ASP > 12.9% (hazard ratio (HR), 3.33; p = 0.024) and prior PRRT (HR, 0.35; p = 0.043) remained significant in multivariable Cox. Median PFS was 6.7 months for ASP > 12.9% (95% confidence interval (CI), 2.1–11.4 months) versus 14.4 (12.5–16.3) months for ASP ≤ 12.9% (log-rank, p = 0.028). Conclusion: pretherapeutic ASP of SSR positive lesions independently predicted PFS for treatment with everolimus in GEP-NET. ASP may supplement risk-benefit assessment before patient inclusion to treatment.
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Pulvirenti A, Pea A, Chang DK, Jamieson NB. Clinical and Molecular Risk Factors for Recurrence Following Radical Surgery of Well-Differentiated Pancreatic Neuroendocrine Tumors. Front Med (Lausanne) 2020; 7:385. [PMID: 32850899 PMCID: PMC7419466 DOI: 10.3389/fmed.2020.00385] [Citation(s) in RCA: 5] [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: 04/22/2020] [Accepted: 06/22/2020] [Indexed: 12/29/2022] Open
Abstract
Well-differentiated pancreatic neuroendocrine tumors are increasingly diagnosed neoplasms. For localized disease, surgery is the first-line therapy and is curative in most cases. However, although recurrence is a rare event, it can still occur up to 10 years from surgery, worsening the prognosis. Many clinical and pathological factors have been associated with recurrence; however, it is currently unclear how to accurately discern patients at risk for relapse of disease from those that should be considered cured. In this review, we focus on clinical, pathological, and molecular factors associated with recurrence and discuss available prediction tools to assess the risk of recurrence following surgery.
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Affiliation(s)
- Alessandra Pulvirenti
- Unit of General and Pancreatic Surgery, University and Hospital Trust of Verona, Verona, Italy
| | - Antonio Pea
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
- West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom
| | - David K. Chang
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
- West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom
| | - Nigel B. Jamieson
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
- West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom
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Halfdanarson TR, Strosberg JR, Tang L, Bellizzi AM, Bergsland EK, O'Dorisio TM, Halperin DM, Fishbein L, Eads J, Hope TA, Singh S, Salem R, Metz DC, Naraev BG, Reidy-Lagunes DL, Howe JR, Pommier RF, Menda Y, Chan JA. The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Pancreatic Neuroendocrine Tumors. Pancreas 2020; 49:863-881. [PMID: 32675783 DOI: 10.1097/mpa.0000000000001597] [Citation(s) in RCA: 113] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
This article is the result of the North American Neuroendocrine Tumor Society consensus conference on the medical management of pancreatic neuroendocrine tumors from July 19 to 20, 2018. The guidelines panel consisted of medical oncologists, pathologists, gastroenterologists, endocrinologists, and radiologists. The panel reviewed a series of questions regarding the medical management of patients with pancreatic neuroendocrine tumors as well as questions regarding surveillance after resection. The available literature was reviewed for each of the question and panel members voted on controversial topics, and the recommendations were included in a document circulated to all panel members for a final approval.
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Affiliation(s)
| | | | - Laura Tang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Andrew M Bellizzi
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA
| | - Emily K Bergsland
- Department of Medicine, University of California, San Francisco, San Francisco, CA
| | - Thomas M O'Dorisio
- Department of Medicine, Division of Endocrinology, University of Iowa Carver College of Medicine, Iowa City, IA
| | - Daniel M Halperin
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Lauren Fishbein
- Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, Division of Biomedical Informatics and Personalized Medicine, University of Colorado School of Medicine, Aurora, CO
| | - Jennifer Eads
- Division of Hematology and Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
| | - Thomas A Hope
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA
| | - Simron Singh
- Department of Medical Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Riad Salem
- Department of Radiology, Section of Interventional Radiology, Northwestern University, Chicago IL
| | - David C Metz
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | | | | | - James R Howe
- Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA
| | - Rodney F Pommier
- Department of Surgery, Oregon Health and Science University, Portland, OR
| | - Yusuf Menda
- Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, IA
| | - Jennifer A Chan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
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Bocchini M, Nicolini F, Severi S, Bongiovanni A, Ibrahim T, Simonetti G, Grassi I, Mazza M. Biomarkers for Pancreatic Neuroendocrine Neoplasms (PanNENs) Management-An Updated Review. Front Oncol 2020; 10:831. [PMID: 32537434 PMCID: PMC7267066 DOI: 10.3389/fonc.2020.00831] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 04/28/2020] [Indexed: 12/14/2022] Open
Abstract
Pancreatic neuroendocrine tumors (PanNENs) are rare sporadic cancers or develop as part of hereditary syndromes. PanNENs can be both functioning and non-functioning based on whether they produce bioactive peptides. Some PanNENs are well differentiated while others-poorly. Symptoms, thus, depend on both oncological and hormonal causes. PanNEN diagnosis and treatment benefit from and in some instances are guided by biomarker monitoring. However, plasmatic monoanalytes are only suggestive of PanNEN pathological status and their positivity is typically followed by deepen diagnostic analyses through imaging techniques. There is a strong need for new biomarkers and follow-up modalities aimed to improve the outcome of PanNEN patients. Liquid biopsy follow-up, i.e., sequential analysis on tumor biomarkers in body fluids offers a great potential, that need to be substantiated by additional studies focusing on the specific markers and the timing of the analyses. This review provides the most updated panorama on PanNEN biomarkers.
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Affiliation(s)
- Martine Bocchini
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Fabio Nicolini
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Stefano Severi
- Nuclear Medicine and Radiometabolic Units, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Alberto Bongiovanni
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Toni Ibrahim
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Giorgia Simonetti
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Ilaria Grassi
- Nuclear Medicine and Radiometabolic Units, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Massimiliano Mazza
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
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Ma ZY, Gong YF, Zhuang HK, Zhou ZX, Huang SZ, Zou YP, Huang BW, Sun ZH, Zhang CZ, Tang YQ, Hou BH. Pancreatic neuroendocrine tumors: A review of serum biomarkers, staging, and management. World J Gastroenterol 2020; 26:2305-2322. [PMID: 32476795 PMCID: PMC7243647 DOI: 10.3748/wjg.v26.i19.2305] [Citation(s) in RCA: 109] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 03/27/2020] [Accepted: 04/27/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic neuroendocrine tumors (pNETs) are a heterogeneous group of tumors with complicated treatment options that depend on pathological grading, clinical staging, and presence of symptoms related to hormonal secretion. With regard to diagnosis, remarkable advances have been made: Chromogranin A is recommended as a general marker for pNETs. But other new biomarker modalities, like circulating tumor cells, multiple transcript analysis, microRNA profile, and cytokines, should be clarified in future investigations before clinical application. Therefore, the currently available serum biomarkers are insufficient for diagnosis, but reasonably acceptable in evaluating the prognosis of and response to treatments during follow-up of pNETs. Surgical resection is still the only curative therapeutic option for localized pNETs. However, a debulking operation has also been proven to be effective for controlling the disease. As for drug therapy, steroids and somatostatin analogues are the first-line therapy for those with positive expression of somatostatin receptor, while everolimus and sunitinib represent important progress for the treatment of patients with advanced pNETs. Great progress has been achieved in the combination of systematic therapy with local control treatments. The optimal timing of local control intervention, planning of sequential therapies, and implementation of multidisciplinary care remain pending.
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Affiliation(s)
- Zu-Yi Ma
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, China
- Shantou University of Medical College, Shantou 515000, Guangdong Province, China
| | - Yuan-Feng Gong
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, China
| | - Hong-Kai Zhuang
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, China
- Shantou University of Medical College, Shantou 515000, Guangdong Province, China
| | - Zi-Xuan Zhou
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, China
| | - Shan-Zhou Huang
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, China
| | - Yi-Ping Zou
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, China
- Shantou University of Medical College, Shantou 515000, Guangdong Province, China
| | - Bo-Wen Huang
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, China
| | - Zhong-Hai Sun
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, China
- Shantou University of Medical College, Shantou 515000, Guangdong Province, China
| | - Chuan-Zhao Zhang
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, China
| | - Yun-Qiang Tang
- Department of Hepatobiliary Surgery, the Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou 510080, Guangdong Province, China
| | - Bao-Hua Hou
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, China
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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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