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Wells A, Butano V, Phillips M, Davis J, Baker E, Martinie J, Iannitti D. Surgical microwave ablation of 397 neuroendocrine liver metastases: a retrospective cohort analysis of 16 years of experience. Surg Endosc 2024; 38:6743-6752. [PMID: 39384658 DOI: 10.1007/s00464-024-11021-4] [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: 03/06/2024] [Accepted: 06/30/2024] [Indexed: 10/11/2024]
Abstract
BACKGROUND Neuroendocrine tumors (NET) constitute a heterogeneous group of malignancies whose incidence has been on the rise over the past two decades, currently documented at 5.25 per 100,000. Liver metastasis develops in over 60% of NET patients. Even after resection recurrence rates are high, underscoring the importance of parenchymal-sparing interventions. In this study, we conducted 105 surgical microwave ablations and examined outcomes related to survival and local recurrence. METHODS Retrospective review of patients who underwent a surgical microwave ablation (MWA) at a single-center, high-volume institution from September 2007 through December 2022 using a prospective database. Primary outcome was overall survival. RESULTS A total of 105 operations were performed on 94 patients, with 397 tumors undergoing MWA. Median tumor size was 1.3 cm (range 0.3-8.0), and the median number of tumors ablated was 2 (range 1-12). Laparoscopic approach was utilized 69.5% of the time. The most common concomitant procedure performed was hepatectomy (33.3%) and cholecystectomy (23.8%). Clavien-Dindo grade III or IV complications occurred in 9 patients (9.6%). Mortality within 30 days occurred in 1 patient (1.1%). The rate of incomplete ablation was 0.3% per tumor. Local recurrence occurred in 2.8% of tumors. Median OS was 9.43 years [95% CI 4.23-14.63 years], with a 5- and 10-year survival probability of 70.2% and 48.2%, respectively. CONCLUSION Surgical MWA offers an efficacious, parenchymal-sparing treatment of hepatic metastasis of NET, with low rates of incomplete ablation and local recurrence per tumor.
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Affiliation(s)
- Alexandra Wells
- Division of HPB Surgery, Department of Surgery, Atrium Health Carolinas Medical Center, 1025 Morehead Medical Drive, Suite 600, Charlotte, NC, 28204, USA
| | - Vincent Butano
- Division of HPB Surgery, Department of Surgery, Atrium Health Carolinas Medical Center, 1025 Morehead Medical Drive, Suite 600, Charlotte, NC, 28204, USA
| | - Michael Phillips
- Division of HPB Surgery, Department of Surgery, Atrium Health Carolinas Medical Center, 1025 Morehead Medical Drive, Suite 600, Charlotte, NC, 28204, USA
| | - Joshua Davis
- Division of HPB Surgery, Department of Surgery, Atrium Health Carolinas Medical Center, 1025 Morehead Medical Drive, Suite 600, Charlotte, NC, 28204, USA
| | - Erin Baker
- Division of HPB Surgery, Department of Surgery, Atrium Health Carolinas Medical Center, 1025 Morehead Medical Drive, Suite 600, Charlotte, NC, 28204, USA
| | - John Martinie
- Division of HPB Surgery, Department of Surgery, Atrium Health Carolinas Medical Center, 1025 Morehead Medical Drive, Suite 600, Charlotte, NC, 28204, USA
| | - David Iannitti
- Division of HPB Surgery, Department of Surgery, Atrium Health Carolinas Medical Center, 1025 Morehead Medical Drive, Suite 600, Charlotte, NC, 28204, USA.
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Modica R, La Salvia A, Liccardi A, Cozzolino A, Di Sarno A, Russo F, Colao A, Faggiano A. Dyslipidemia, lipid-lowering agents and neuroendocrine neoplasms: new horizons. Endocrine 2024; 85:520-531. [PMID: 38509261 PMCID: PMC11291585 DOI: 10.1007/s12020-024-03767-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 02/29/2024] [Indexed: 03/22/2024]
Abstract
PURPOSE Neuroendocrine neoplasms (NENs) are a heterogeneous group of malignancies originating from cells with a neuroendocrine phenotype. The complex relationship between lipid metabolism and cancer is gaining interest and a potential anti-cancer effect of lipid lowering agents is being considered. This review aims to discuss the current understanding and treatment of dyslipidaemia in NENs, focusing on the role of lipid lowering agents, including new therapeutic approaches, and future perspectives as possible tool in cancer prevention and tumor-growth control. METHODS We performed an electronic-based search using PubMed updated until December 2023, summarizing the available evidence both in basic and clinical research about lipid lowering agents in NENs. RESULTS Dyslipidemia is an important aspect to be considered in NENs management, although randomized studies specifically addressing this topic are lacking, unlike other cancer types. Available data mainly regard statins, and in vitro studies have demonstrated direct antitumor effects, including antiproliferative effects in some cancers, supporting possible pleiotropic effects also in NENs, but data remain conflicting. Ezetimibe, omega 3-fatty acids, fibrates and inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) may enhance the regulation of lipid homeostasis, as demonstrated in other cancers. CONCLUSIONS Targeting dyslipidemia in NENs should be part of the multidisciplinary management and an integrated approach may be the best option for both metabolic and tumor control. Whether lipid lowering agents may directly contribute to tumor control remains to be confirmed with specific studies, focusing on association with other metabolic risk, disease stage and primary site.
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Affiliation(s)
- Roberta Modica
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, 80131, Naples, Italy.
| | - Anna La Salvia
- National Center for Drug Research and Evaluation, National Institute of Health (ISS), 00161, Rome, Italy
| | - Alessia Liccardi
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, 80131, Naples, Italy
| | - Alessia Cozzolino
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - Antonella Di Sarno
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, 80131, Naples, Italy
| | - Flaminia Russo
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, ENETS Center of Excellence, Sapienza University of Rome, 00189, Rome, Italy
| | - Annamaria Colao
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, 80131, Naples, Italy
- UNESCO Chair, Education for Health and Sustainable Development, Federico II University, 80131, Naples, Italy
| | - Antongiulio Faggiano
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, ENETS Center of Excellence, Sapienza University of Rome, 00189, Rome, Italy
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Vaughn H, Major H, Kadera E, Keck K, Dunham T, Qian Q, Brown B, Scott A, Bellizzi AM, Braun T, Breheny P, Quelle DE, Howe JR, Darbro B. Functional Copy-Number Alterations as Diagnostic and Prognostic Biomarkers in Neuroendocrine Tumors. Int J Mol Sci 2024; 25:7532. [PMID: 39062773 PMCID: PMC11277019 DOI: 10.3390/ijms25147532] [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] [Received: 06/11/2024] [Revised: 06/29/2024] [Accepted: 07/05/2024] [Indexed: 07/28/2024] Open
Abstract
Functional copy-number alterations (fCNAs) are DNA copy-number changes with concordant differential gene expression. These are less likely to be bystander genetic lesions and could serve as robust and reproducible tumor biomarkers. To identify candidate fCNAs in neuroendocrine tumors (NETs), we integrated chromosomal microarray (CMA) and RNA-seq differential gene-expression data from 31 pancreatic (pNETs) and 33 small-bowel neuroendocrine tumors (sbNETs). Tumors were resected from 47 early-disease-progression (<24 months) and 17 late-disease-progression (>24 months) patients. Candidate fCNAs that accurately differentiated these groups in this discovery cohort were then replicated using fluorescence in situ hybridization (FISH) on formalin-fixed, paraffin-embedded (FFPE) tissues in a larger validation cohort of 60 pNETs and 82 sbNETs (52 early- and 65 late-disease-progression samples). Logistic regression analysis revealed the predictive ability of these biomarkers, as well as the assay-performance metrics of sensitivity, specificity, and area under the curve. Our results indicate that copy-number changes at chromosomal loci 4p16.3, 7q31.2, 9p21.3, 17q12, 18q21.2, and 19q12 may be used as diagnostic and prognostic NET biomarkers. This involves a rapid, cost-effective approach to determine the primary tumor site for patients with metastatic liver NETs and to guide risk-stratified therapeutic decisions.
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Affiliation(s)
- Hayley Vaughn
- Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA 52242, USA; (H.V.); (T.B.)
- Stead Family Department of Pediatrics, University of Iowa Health Care, Iowa City, IA 52242, USA; (H.M.); (E.K.); (T.D.); (Q.Q.)
| | - Heather Major
- Stead Family Department of Pediatrics, University of Iowa Health Care, Iowa City, IA 52242, USA; (H.M.); (E.K.); (T.D.); (Q.Q.)
| | - Evangeline Kadera
- Stead Family Department of Pediatrics, University of Iowa Health Care, Iowa City, IA 52242, USA; (H.M.); (E.K.); (T.D.); (Q.Q.)
| | - Kendall Keck
- Department of Surgery, University of Iowa Health Care, Iowa City, IA 52242, USA; (K.K.); (A.S.); (J.R.H.)
| | - Timothy Dunham
- Stead Family Department of Pediatrics, University of Iowa Health Care, Iowa City, IA 52242, USA; (H.M.); (E.K.); (T.D.); (Q.Q.)
| | - Qining Qian
- Stead Family Department of Pediatrics, University of Iowa Health Care, Iowa City, IA 52242, USA; (H.M.); (E.K.); (T.D.); (Q.Q.)
| | - Bartley Brown
- Department of Biomedical Engineering, University of Iowa, Iowa City, IA 52242, USA;
| | - Aaron Scott
- Department of Surgery, University of Iowa Health Care, Iowa City, IA 52242, USA; (K.K.); (A.S.); (J.R.H.)
| | | | - Terry Braun
- Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA 52242, USA; (H.V.); (T.B.)
- Department of Biomedical Engineering, University of Iowa, Iowa City, IA 52242, USA;
| | - Patrick Breheny
- Department of Biostatistics, University of Iowa, Iowa City, IA 52242, USA;
| | - Dawn E. Quelle
- Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, IA 52242, USA;
| | - James R. Howe
- Department of Surgery, University of Iowa Health Care, Iowa City, IA 52242, USA; (K.K.); (A.S.); (J.R.H.)
| | - Benjamin Darbro
- Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA 52242, USA; (H.V.); (T.B.)
- Stead Family Department of Pediatrics, University of Iowa Health Care, Iowa City, IA 52242, USA; (H.M.); (E.K.); (T.D.); (Q.Q.)
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Corti F, Rossi RE, Cafaro P, Passarella G, Turla A, Pusceddu S, Coppa J, Oldani S, Guidi A, Longarini R, Cortinovis DL. Emerging Treatment Options for Neuroendocrine Neoplasms of Unknown Primary Origin: Current Evidence and Future Perspectives. Cancers (Basel) 2024; 16:2025. [PMID: 38893145 PMCID: PMC11171242 DOI: 10.3390/cancers16112025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 05/19/2024] [Accepted: 05/22/2024] [Indexed: 06/21/2024] Open
Abstract
Among neuroendocrine neoplasms (NENs), a non-negligible proportion (9-22%) is represented by sufferers of NENs of unknown primary origin (UPO), a poor prognostic group with largely unmet clinical needs. In the absence of standard therapeutic algorithms, current guidelines suggest that the treatment of UPO-NENs should be based on tumor clinical-pathological characteristics, disease burden, and patient conditions. Chemotherapy represents the backbone for the treatment of high-grade poorly differentiated UPO-NENs, usually providing deep but short-lasting responses. Conversely, the spectrum of available systemic therapy options for well-differentiated UPO-NENs may range from somatostatin analogs in indolent low-grade tumors, to peptide receptor radioligand therapy, tyrosine kinase inhibitors (TKIs), or chemotherapy for more aggressive tumors or in case of high disease burden. In recent years, molecular profiling has provided deep insights into the molecular landscape of UPO-NENs, with both diagnostic and therapeutic implications. Although preliminary, interesting activity data have been provided about upfront chemoimmunotherapy, the use of immune checkpoint inhibitors (ICIs), and the combination of ICIs plus TKIs in this setting. Here, we review the literature from the last 30 years to examine the available evidence about the treatment of UPO-NENs, with a particular focus on future perspectives, including the expanding scenario of targeted agents in this setting.
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Affiliation(s)
- Francesca Corti
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori, Via G.B. Pergolesi 33, 20900 Monza, Italy; (P.C.); (G.P.); (A.T.); (A.G.); (R.L.); (D.L.C.)
| | - Roberta Elisa Rossi
- Gastroenterology and Endoscopy Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy;
| | - Pietro Cafaro
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori, Via G.B. Pergolesi 33, 20900 Monza, Italy; (P.C.); (G.P.); (A.T.); (A.G.); (R.L.); (D.L.C.)
| | - Gaia Passarella
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori, Via G.B. Pergolesi 33, 20900 Monza, Italy; (P.C.); (G.P.); (A.T.); (A.G.); (R.L.); (D.L.C.)
| | - Antonella Turla
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori, Via G.B. Pergolesi 33, 20900 Monza, Italy; (P.C.); (G.P.); (A.T.); (A.G.); (R.L.); (D.L.C.)
| | - Sara Pusceddu
- Gastro-Entero-Pancreatic and Neuroendocrine Unit 1, Department of Medical Oncology, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy; (S.P.); (S.O.)
| | - Jorgelina Coppa
- Hepatology and Hepato-Pancreatic-Biliary Surgery and Liver Transplantation Unit, Fondazione IRCCS, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy;
| | - Simone Oldani
- Gastro-Entero-Pancreatic and Neuroendocrine Unit 1, Department of Medical Oncology, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy; (S.P.); (S.O.)
| | - Alessandro Guidi
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori, Via G.B. Pergolesi 33, 20900 Monza, Italy; (P.C.); (G.P.); (A.T.); (A.G.); (R.L.); (D.L.C.)
| | - Raffaella Longarini
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori, Via G.B. Pergolesi 33, 20900 Monza, Italy; (P.C.); (G.P.); (A.T.); (A.G.); (R.L.); (D.L.C.)
| | - Diego Luigi Cortinovis
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori, Via G.B. Pergolesi 33, 20900 Monza, Italy; (P.C.); (G.P.); (A.T.); (A.G.); (R.L.); (D.L.C.)
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Melhorn P, Mazal P, Wolff L, Kretschmer-Chott E, Raderer M, Kiesewetter B. From biology to clinical practice: antiproliferative effects of somatostatin analogs in neuroendocrine neoplasms. Ther Adv Med Oncol 2024; 16:17588359241240316. [PMID: 38529270 PMCID: PMC10962050 DOI: 10.1177/17588359241240316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 02/27/2024] [Indexed: 03/27/2024] Open
Abstract
Somatostatin analogs (SSA), specifically octreotide and lanreotide, have demonstrated antiproliferative effects in patients with neuroendocrine tumors (NET), a group of rare malignancies of diverse origin and presentation. A prominent feature of NET cells is the expression of G protein-coupled receptors called somatostatin receptors (SSTR). Although these SSTR are not uniformly present in NET, they can be instrumental in the diagnosis and treatment of NET. Apart from their application in nuclear imaging and radionuclide therapy, SSA have proven invaluable in the treatment of hormonal syndromes associated with certain NET (antisecretory effects of SSA), but it took more than two decades to convincingly demonstrate the antiproliferative effects of SSA in metastatic NET with the two pivotal studies PROMID and CLARINET. The current review summarizes three decades of SSA treatment and provides an overview of the clinical trial landscape for SSA monotherapy and combination therapy, including clinical implications and quality of life aspects, as well as ongoing fields of research.
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Affiliation(s)
- Philipp Melhorn
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Peter Mazal
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Ladislaia Wolff
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Elisabeth Kretschmer-Chott
- Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Markus Raderer
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria
| | - Barbara Kiesewetter
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
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Zhang J, Wang Y, Wang L, You L, Zhang T. Pancreatic ductal adenocarcinoma chemoresistance: From metabolism reprogramming to novel treatment. Chin Med J (Engl) 2024; 137:408-420. [PMID: 37545027 PMCID: PMC10876258 DOI: 10.1097/cm9.0000000000002758] [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: 03/28/2023] [Indexed: 08/08/2023] Open
Abstract
ABSTRACT As pancreatic cancer (PC) is highly malignant, its patients tend to develop metastasis at an early stage and show a poor response to conventional chemotherapies. First-line chemotherapies for PC, according to current guidelines, include fluoropyrimidine- and gemcitabine-based regimens. Accumulating research on drug resistance has shown that biochemical metabolic aberrations in PC, especially those involving glycolysis and glutamine metabolism, are highly associated with chemoresistance. Additionally, lipid metabolism is a major factor in chemoresistance. However, emerging compounds that target these key metabolic pathways have the potential to overcome chemoresistance. This review summarizes how PC develops chemoresistance through aberrations in biochemical metabolism and discusses novel critical targets and pathways within cancer metabolism for new drug research.
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Affiliation(s)
- Jingcheng Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Yutong Wang
- Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Lejunzi Wang
- Department of Anaesthesia, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Taiping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Clinical Immunology Centre, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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Egidi MJ, Krug S, Haybaeck J, Michl P, Griesmann H. Anti-angiogenic therapy using the multi-tyrosine kinase inhibitor Regorafenib enhances tumor progression in a transgenic mouse model of ß-cell carcinogenesis. Br J Cancer 2023; 129:1225-1237. [PMID: 37620408 PMCID: PMC10575939 DOI: 10.1038/s41416-023-02389-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 07/12/2023] [Accepted: 07/31/2023] [Indexed: 08/26/2023] Open
Abstract
BACKGROUND Pancreatic neuroendocrine tumors (PNETs) represent a distinct hypervascularized tumor entity, often diagnosed at metastatic stage. Therapeutic efficacy of anti-angiogenic multi-kinase inhibitors is frequently limited by primary or acquired resistance in vivo. This study aimed to characterize the molecular mode of action as well as resistance mechanisms to the anti-angiogenic multi-tyrosine kinase inhibitor (TKI) Regorafenib in vitro and in vivo. METHODS In vitro, human and murine pancreatic neuroendocrine cell lines were comparatively treated with Regorafenib and other TKIs clinically used in PNETs. Effects on cell viability and proliferation were analyzed. In vivo, transgenic RIP1Tag2 mice were treated with Regorafenib at two different time periods during carcinogenesis and its impact on angiogenesis and tumor progression was evaluated. RESULTS Compared to the established TKI therapies with Sunitinib and Everolimus, Regorafenib showed the strongest effects on cell viability and proliferation in vitro, but was unable to induce apoptosis. Unexpectedly and in contrast to these in vitro findings, Regorafenib enhanced proliferation during early tumor development in RIP1Tag2 mice and had no significant effect in late tumor progression. In addition, invasiveness was increased at both time points. Mechanistically, we could identify an upregulation of the pro-survival protein Bcl-2, the induction of the COX2-PGE2-pathway as well as the infiltration of CSF1R positive immune cells into the tumors as potential resistance mechanisms following Regorafenib treatment. DISCUSSION Our data identify important tumor cell-autonomous and stroma-dependent mechanisms of resistance to antiangiogenic therapies.
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Affiliation(s)
- Maren Juliane Egidi
- Clinic for Internal Medicine I, Martin-Luther University Halle/Wittenberg, Ernst-Grube-Straße 40, D 06120, Halle, Germany
| | - Sebastian Krug
- Clinic for Internal Medicine I, Martin-Luther University Halle/Wittenberg, Ernst-Grube-Straße 40, D 06120, Halle, Germany
- Department of Internal Medicine IV, Heidelberg University Hospital, Heidelberg, Germany
| | - Johannes Haybaeck
- Department of Pathology, Neuropathology, and Molecular Pathology, Medical University of Innsbruck, Innsbruck, Austria
- Diagnostic & Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Patrick Michl
- Clinic for Internal Medicine I, Martin-Luther University Halle/Wittenberg, Ernst-Grube-Straße 40, D 06120, Halle, Germany.
- Department of Internal Medicine IV, Heidelberg University Hospital, Heidelberg, Germany.
| | - Heidi Griesmann
- Clinic for Internal Medicine I, Martin-Luther University Halle/Wittenberg, Ernst-Grube-Straße 40, D 06120, Halle, Germany
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Zhang V, Taparra K, Fisher G, Aparici C, Soltys SG. Definitive Treatment of Brain Metastases From a Neuroendocrine Tumor With Peptide Receptor Radionuclide Therapy With 177Lutetium DOTATATE: A Case Report. Cureus 2023; 15:e45327. [PMID: 37849592 PMCID: PMC10577096 DOI: 10.7759/cureus.45327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/13/2023] [Indexed: 10/19/2023] Open
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare malignancies that arise from secretory endocrine cells of the gastroenteropancreatic system. Clinical outcomes have improved for patients with GEP-NETs due to the development and recent FDA approval of 177Lutetium DOTATATE. However, the response of brain metastases from GEP-NETs from 177Lutetium DOTATATE is unreported. We present the case of an 81-year-old man with low-grade small bowel GEP-NET with liver and brain metastases treated with a total of six cycles of 177Lutetium DOTATATE. With over three years of follow-up from his initial treatment, his brain metastases have had complete or partial responses, with no need for brain radiotherapy or radiosurgery.
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Affiliation(s)
- Vivian Zhang
- Department of Radiation Oncology, Stanford University, Stanford, USA
| | - Kekoa Taparra
- Department of Radiation Oncology, Stanford University, Stanford, USA
| | - George Fisher
- Department of Medicine and Medical Oncology, Stanford University, Stanford, USA
| | - Carina Aparici
- Department of Nuclear Medicine and Molecular Imaging, Stanford University, Stanford, USA
| | - Scott G Soltys
- Department of Radiation Oncology, Stanford University, Stanford, USA
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Kiesewetter B, Melhorn P, Macheiner S, Wolff L, Kretschmer-Chott E, Haug A, Mazal P, Raderer M. Does the dose matter? Antiproliferative efficacy and toxicity of everolimus in patients with neuroendocrine tumors - Experiences from a tertiary referral center. J Neuroendocrinol 2023; 35:e13319. [PMID: 37485760 DOI: 10.1111/jne.13319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 05/12/2023] [Accepted: 06/26/2023] [Indexed: 07/25/2023]
Abstract
The mTOR-inhibitor everolimus has been approved for the treatment of advanced neuroendocrine tumors (NETs) but is associated with relevant toxicities in clinical practice. Hence, optimal treatment sequencing and the impact of dose reductions have yet to be clarified. This retrospective analysis assessed patients with advanced, well-differentiated NET treated with everolimus at the Medical University of Vienna. The primary objective was to evaluate the efficacy of everolimus in a real-world cohort. A total of 52 patients treated with everolimus for advanced NET grade 1 (G1) or G2 (or typical or atypical carcinoid) 2010-2021 were included in this analysis. The most common sites of origin were pancreas (44%) and lung (29%). The initial dose was decided by the treating physician based on clinical assessment and 25 patients (48%) each were started at 10 mg/day and 5 mg/day. Median progression-free survival (PFS) following everolimus in the overall cohort was 9.8 months (95% CI: 4.3-15.3), with a statistically significant PFS difference (p = .03) between NET G1/typical carcinoids (42.9 months) and NET G2/atypical carcinoids (8.9 months). PFS was numerically but not significantly shorter in patients treated with a reduced dose (7.5 months vs. 12.4 months, p = .359). Even in this mixed full/half dose cohort, 93% developed treatment-related side effects (mostly grade I, no grade IV), 63% had dose reductions or interruptions, and five stopped due to toxicity. Median survival following treatment was 40.9 months (95% CI: 21.5-60.3) and no difference with regard to dosing was observed (p = .517). These data from an unselected patient cohort show long-term outcomes similar to those reported in the pivotal studies. Comparing everolimus starting dose, median PFS did not significantly differ for patients treated at a lower dose. While this finding is limited by the sample size and warrants prospective verification, initiating therapy at a reduced dose might be practicable and safe in a distinct subset of patients.
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Affiliation(s)
- Barbara Kiesewetter
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria
| | - Philipp Melhorn
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria
| | - Simon Macheiner
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria
| | - Ladislaia Wolff
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria
| | - Elisabeth Kretschmer-Chott
- Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria
| | - Alexander Haug
- Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria
| | - Peter Mazal
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Markus Raderer
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria
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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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11
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Taban Akça K, Çınar Ayan İ, Çetinkaya S, Miser Salihoğlu E, Süntar İ. Autophagic mechanisms in longevity intervention: role of natural active compounds. Expert Rev Mol Med 2023; 25:e13. [PMID: 36994671 PMCID: PMC10407225 DOI: 10.1017/erm.2023.5] [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: 07/31/2022] [Revised: 11/14/2022] [Accepted: 03/06/2023] [Indexed: 03/31/2023]
Abstract
The term 'autophagy' literally translates to 'self-eating' and alterations to autophagy have been identified as one of the several molecular changes that occur with aging in a variety of species. Autophagy and aging, have a complicated and multifaceted relationship that has recently come to light thanks to breakthroughs in our understanding of the various substrates of autophagy on tissue homoeostasis. Several studies have been conducted to reveal the relationship between autophagy and age-related diseases. The present review looks at a few new aspects of autophagy and speculates on how they might be connected to both aging and the onset and progression of disease. Additionally, we go over the most recent preclinical data supporting the use of autophagy modulators as age-related illnesses including cancer, cardiovascular and neurodegenerative diseases, and metabolic dysfunction. It is crucial to discover important targets in the autophagy pathway in order to create innovative therapies that effectively target autophagy. Natural products have pharmacological properties that can be therapeutically advantageous for the treatment of several diseases and they also serve as valuable sources of inspiration for the development of possible new small-molecule drugs. Indeed, recent scientific studies have shown that several natural products including alkaloids, terpenoids, steroids, and phenolics, have the ability to alter a number of important autophagic signalling pathways and exert therapeutic effects, thus, a wide range of potential targets in various stages of autophagy have been discovered. In this review, we summarised the naturally occurring active compounds that may control the autophagic signalling pathways.
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Affiliation(s)
- Kevser Taban Akça
- Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Ankara, Türkiye
| | - İlknur Çınar Ayan
- Department of Medical Biology, Medical Faculty, Necmettin Erbakan University, Meram, Konya, Türkiye
| | - Sümeyra Çetinkaya
- Biotechnology Research Center of Ministry of Agriculture and Forestry, Yenimahalle, Ankara, Türkiye
| | - Ece Miser Salihoğlu
- Biochemistry Department, Faculty of Pharmacy, Gazi University, Ankara, Türkiye
| | - İpek Süntar
- Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Ankara, Türkiye
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12
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Chen G, Hong X, He W, Ou L, Chen B, Zhong W, Lin Y, Luo X. The construction and analysis of tricarboxylic acid cycle related prognostic model for cervical cancer. Front Genet 2023; 14:1092276. [PMID: 36968582 PMCID: PMC10033772 DOI: 10.3389/fgene.2023.1092276] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 02/08/2023] [Indexed: 03/29/2023] Open
Abstract
Introduction: Cervical cancer (CC) is the fourth most common malignant tumor in term of in incidence and mortality among women worldwide. The tricarboxylic acid (TCA) cycle is an important hub of energy metabolism, networking one-carbon metabolism, fatty acyl metabolism and glycolysis. It can be seen that the reprogramming of cell metabolism including TCA cycle plays an indispensable role in tumorigenesis and development. We aimed to identify genes related to the TCA cycle as prognostic markers in CC. Methods: Firstly, we performed the differential expressed analysis the gene expression profiles associated with TCA cycle obtained from The Cancer Genome Atlas (TCGA) database. Differential gene list was generated and cluster analysis was performed using genes with detected fold changes >1.5. Based on the subclusters of CC, we analysed the relationship between different clusters and clinical information. Next, Cox univariate and multivariate regression analysis were used to screen genes with prognostic characteristics, and risk scores were calculated according to the genes with prognostic characteristics. Additionally, we analyzed the correlation between the predictive signature and the treatment response of CC patients. Finally, we detected the expression of ench prognostic gene in clinical CC samples by quantitative polymerase chain reaction (RT-qPCR). Results: We constructed a prognostic model consist of seven TCA cycle associated gene (ACSL1, ALDOA, FOXK2, GPI, MDH1B, MDH2, and MTHFD1). Patients with CC were separated into two groups according to median risk score, and high-risk group had a worse prognosis compared to the low-risk group. High risk group had lower level of sensitivity to the conventional chemotherapy drugs including cisplatin, paclitaxel, sunitinib and docetaxel. The expression of ench prognostic signature in clinical CC samples was verified by qRT-PCR. Conclusion: There are several differentially expressed genes (DEGs) related to TCA cycle in CC. The risk score model based on these genes can effectively predict the prognosis of patients and provide tumor markers for predicting the prognosis of CC.
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Affiliation(s)
- Guanqiao Chen
- Guangzhou Medical University, Guangzhou, China
- Department of Gynecology, Guangdong Women and Children Medical Hospital, Guangzhou, China
| | - Xiaoshan Hong
- Department of Gynecology, Guangdong Women and Children Medical Hospital, Guangzhou, China
| | - Wanshan He
- Guangzhou Medical University, Guangzhou, China
- Department of Gynecology, Guangdong Women and Children Medical Hospital, Guangzhou, China
| | - Lingling Ou
- Guangzhou Medical University, Guangzhou, China
- Department of Gynecology, Guangdong Women and Children Medical Hospital, Guangzhou, China
| | - Bin Chen
- Guangzhou Medical University, Guangzhou, China
- Department of Gynecology, Guangdong Women and Children Medical Hospital, Guangzhou, China
| | - Weitao Zhong
- Department of Surgical Neonatal Intensive Care Unit, Guangzhou Women and Children’s Medical Center, Guangzhou, China
| | - Yu Lin
- Nanfang Hospital, Southern Medical University, Guangzhou, China
- Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Yu Lin, ; Xiping Luo,
| | - Xiping Luo
- Guangzhou Medical University, Guangzhou, China
- Department of Gynecology, Guangdong Women and Children Medical Hospital, Guangzhou, China
- *Correspondence: Yu Lin, ; Xiping Luo,
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13
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Muttillo EM, Mazzarella G, Picardi B, Rossi S, Cinelli L, Diana M, Baiocchini A, Felli E, Pessaux P, Felli E, Muttillo IA. Treatment strategies for neuroendocrine liver metastases: a systematic review. HPB (Oxford) 2022; 24:1832-1843. [PMID: 35794053 DOI: 10.1016/j.hpb.2022.06.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 03/19/2022] [Accepted: 06/15/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Gastroenteropancreatic neuroendocrine tumors are often diagnosed when metastatic. The liver is the main site of metastases. Unfortunately, optimal management of neuroendocrine liver metastases remains a topic of debate. The aim of this study was to make a systematic review of the current literature about the results of the different treatments of neuroendocrine liver metastases. METHODS A systematic review was conducted for English language publications from 1995 to 2021. Outcomes were analyzed according to survival, disease-free survival, and in the case of systemic therapies, progression-free survival. RESULTS 5509 patients were analyzed in the review. 67% of patients underwent surgery achieving 5 years overall survival despite only 30% percent without a recurrence. 60% of patients that had received a transplant reached 5 years survival with a low disease-free survival rate (20%). Five-year survival rate was 36.2% for patients undergoing loco-regional therapies. CONCLUSION Surgical resection is the best treatment when metastases are resectable, with the highest rate of survival, although liver transplantation shows good results for patients not eligible for surgery. Loco-regional therapies may be useful when surgical resection is contraindicated, or selectively used as a bridge to surgery or transplantation. Systemic therapies are indicated in patients for whom curative treatment cannot be obtained.
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Affiliation(s)
- Edoardo M Muttillo
- Department of Surgical Sciences, Sapienza University of Rome, Rome, Italy; Research Institute Against Digestive Cancer (IRCAD), Strasbourg, France
| | - Gennaro Mazzarella
- Department of General and Emergency Surgery, Ospedale San Filippo Neri, Rome, Italy
| | - Biagio Picardi
- Department of General and Emergency Surgery, Ospedale San Filippo Neri, Rome, Italy
| | - Stefano Rossi
- Department of General and Emergency Surgery, Ospedale San Filippo Neri, Rome, Italy
| | | | - Michele Diana
- Research Institute Against Digestive Cancer (IRCAD), Strasbourg, France
| | | | - Eric Felli
- Hepatology, Department of Biomedical Research, Inselspital, University of Bern, Bern, Switzerland
| | - Patrick Pessaux
- Research Institute Against Digestive Cancer (IRCAD), Strasbourg, France; HPB Unit, Digestive Surgery Department, Nouvel Hopital Civil, University of Strasbourg, Strasbourg, France
| | - Emanuele Felli
- Research Institute Against Digestive Cancer (IRCAD), Strasbourg, France; Service Chirurgie Digestive et Transplantation Hépatique Hopital Trousseau CHU Tours, France
| | - Irnerio A Muttillo
- Department of General and Emergency Surgery, Ospedale San Filippo Neri, Rome, Italy.
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14
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Mohindroo C, McAllister F, De Jesus-Acosta A. Genetics of Pancreatic Neuroendocrine Tumors. Hematol Oncol Clin North Am 2022; 36:1033-1051. [PMID: 36154786 DOI: 10.1016/j.hoc.2022.07.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Pancreatic neuroendocrine tumors (pNETs) represent a relatively rare disease; however, the incidence has been increasing during the last 2 decades. Next generation sequencing has greatly increased our understanding of driver mutations in pNETs. Sporadic pNETs have consistently presented with mutations in MEN1, DAXX/ATRX, and genes related to the mammalian target of rapamycin pathway. Inherited pNETs have traditionally been associated with multiple endocrine neoplasia type 1, von Hippel-Lindau syndrome, neurofibromatosis type 1, and tuberous sclerosis complex. The current review expands on the existing knowledge and the relevant updates on the genetics of pNETs.
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Affiliation(s)
- Chirayu Mohindroo
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Unit 1360, Houston, TX 77030, USA; Department of Internal Medicine, Sinai Hospital of Baltimore, 2435 W. Belvedere Ave, Ste 56, Baltimore, MD 21215, USA
| | - Florencia McAllister
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Unit 1360, Houston, TX 77030, USA; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ana De Jesus-Acosta
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, CRB1, 1650 Orleans Street, CRB1 Rm 409, Baltimore, MD 21287.
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Modica R, Liccardi A, Minotta R, Cannavale G, Benevento E, Colao A. Therapeutic strategies for patients with neuroendocrine neoplasms: current perspectives. Expert Rev Endocrinol Metab 2022; 17:389-403. [PMID: 35822906 DOI: 10.1080/17446651.2022.2099840] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 07/06/2022] [Indexed: 10/17/2022]
Abstract
INTRODUCTION Neuroendocrine neoplasms (NENs) are a heterogeneous group of malignancies mainly arising in the gastroenteropancreatic (GEP) and bronchopulmonary systems, with steadily increasing incidence. The therapeutic landscape has widened and the therapeutic strategy should be based on new sequences and combinations, still debated. AREAS COVERED Herein, we provide an overview of current approved pharmacological treatments in patients with NENs, with the aim to summarize evidence of efficacy of the main different options in GEP and pulmonary NENs, principally focusing on somatostatin analogs (SSAs), targeted therapy with everolimus and sunitinib, peptide receptor radionuclide therapy (PRRT) and chemotherapy. We discuss biological rationale and toxicities, including current indications according to differentiation and placement in the therapeutic algorithm, clinical trials, and combinations. Furthermore, we recommend areas for further research. EXPERT OPINION Therapeutic management of patients with NENs represents a challenge for clinicians and the identification of effective sequences and combinations is of utmost importance. Major efforts should be directed to early identify and overcome resistance and to limit toxicity. The progress in the therapeutic management of NENs grows faster and the choice of the best approach should be based on randomized clinical trials, as well as on long-term, real-world data.
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Affiliation(s)
- Roberta Modica
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Alessia Liccardi
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Roberto Minotta
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Giuseppe Cannavale
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Elio Benevento
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Annamaria Colao
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
- UNESCO Chair, Education for Health and Sustainable Development, Federico II University, Naples, Italy
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Abstract
OBJECTIVES Neuroendocrine tumors (NETs) are characterized by their expression of vascular endothelial growth factor (VEGF). This trial investigated the activity of Ziv-aflibercept, a recombinant protein that binds to and inhibits the activity of VEGF, in patients with advanced NETs (NCT01782443). METHODS A single-arm, phase II trial enrolling patients with advanced, progressive extrapancreatic NET. Patients were treated with Ziv-aflibercept 4 mg/kg intravenously on day 1 and 15 of a 28-day cycle; the starting dose was reduced to 2 mg/kg on days 1 and 15 of a 28-day cycle because of hypertension-related events. The primary end point was progression-free survival. RESULTS The trial enrolled 19 patients (13 male:6 female). Patients received a median of 7 cycles (range, 1-18 cycles). The median progression free survival was 11.8 months (95% confidence interval, 3.2-16.1 months), and the median overall survival was 36.4 months (95% confidence interval, 16.1-not reached). Best responses by Response Evaluation Criteria in Solid Tumors 1.1 are as follows: 1 (5%) partial response, 13 (68%) stable disease, 2 (10%) with progressive disease, and 3 (15%) unevaluable. Hypertension occurred in 18 patients (95%), including grade 3-4 hypertension in 12 patients (63%). CONCLUSIONS Although the progression free survival is similar to other VEGF inhibitors in NET, toxicity may preclude further investigation.
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Ali MA, Shah SS, Tahir N, Rehman S, Saeed M, Bajwa SF, Ali R, Aiman W, Anwar MY. Efficacy and toxicity of surufatinib in neuroendocrine tumors: A systematic review and meta-analysis. J Neuroendocrinol 2022; 34:e13149. [PMID: 35665971 DOI: 10.1111/jne.13149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 12/12/2021] [Accepted: 04/15/2022] [Indexed: 02/05/2023]
Abstract
The incidence and prevalence of neuroendocrine neoplasms (NENs) has increased in the US in recent decades. These are well-vascularized tumors, but no antiangiogenic drug has been approved for treatment of extra-pancreatic NENs. The aim is to assess efficacy and safety of surufatinib in pancreatic and extra-pancreatic NETs. We searched PubMed, Embase, Cochrane Library, Web of Science and Clinicaltrials.gov. Clinical trials and observational studies that provided safety and efficacy data in clinical terms were included. Characteristics of the study, baseline characteristics of participants, treatment drugs, measures of efficacy, and toxicity (≥grade 3 adverse effects) were extracted. The meta-analysis was performed using the "R" programming language. Risk ratio (RR) of objective response (OR)/partial response (PR) was 8.55 (95% CI: 1.68-43.66, I2 = 0) in favor of surufatinib. The hazard ratio (HR) of progression-free survival (PFS) was 0.48 (95% CI: 0.25-0.92, I2 = 77%) in favor of surufatinib. The risk of ≥grade 3 adverse effects: diarrhea, hypertension, hypertriglyceridemia, proteinuria, and vomiting were high with the use of surufatinib. Quality of life (QoL) was similar in surufatinib and placebo groups except for the diarrhea that was high with surufatinib. Lack of randomized clinical trials in non-Chinese population. Surufatinib is well tolerated and is more effective than placebo in both pancreatic and extra-pancreatic NETs. More multicenter randomized, double-blinded clinical trials are needed to confirm these results.
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Affiliation(s)
- Muhammad Ashar Ali
- Beth Israel Deconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Syed S Shah
- University of Kentucky, Lexington, Kentucky, USA
| | - Nayha Tahir
- Rosalind Franklin University of Medical Sciences/Chicago Medical School, North Chicago, Illinois, USA
| | - Sana Rehman
- Shaikh Khalifa Bin Zayed Al Nahyan Medical and Dental College, Lahore, Pakistan
| | | | | | - Rimsha Ali
- Rawalpindi Medical College, Rawalpindi, Pakistan
| | - Wajeeha Aiman
- Beth Israel Deconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
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Abdelhamed W, El-Kassas M. Fibrolamellar hepatocellular carcinoma: A rare but unpleasant event. World J Gastrointest Oncol 2022; 14:1103-1114. [PMID: 35949219 PMCID: PMC9244987 DOI: 10.4251/wjgo.v14.i6.1103] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 03/19/2022] [Accepted: 05/08/2022] [Indexed: 02/06/2023] Open
Abstract
Fibrolamellar carcinoma (FLC) is a rare variant of hepatocellular carcinoma (HCC), comprising 1%-9% of all HCCs. FLC is a poorly understood malignancy, which seems to be more prevalent in young patients with no underlying liver diseases. The term "fibrolamellar" is derived from thick fibrous collagen bands surrounding the tumor cells. Unlike HCC, cirrhosis and viral hepatitis infection are not predisposing to FLC, and it is not associated with elevations in serum alpha-fetoprotein. FLC patients often present with vague abdominal pain, nausea, malaise, and weight loss. Most cases present are at an advanced stage at the time of initial diagnosis. However, curative treatment options can still be offered to up to 70% of patients. Surgery (resection/liver transplantation) is the mainstay of treatment and the only potentially curative option. FLCs have been less chemo-responsive than the conventional HCC, however, in advanced cases, multimodality treatments can be effective. Recent advances in molecular studies of FLC have found a unique DNAJB1-PRKACA fusion transcript in most of the cases studied. The review aims to describe clinical characteristics, diagnostic methods, and therapeutic modalities for this rare tumor to raise awareness among clinicians and surgeons.
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Affiliation(s)
- Walaa Abdelhamed
- Department of Endemic Medicine, Sohag University, Sohag 14322, Egypt
| | - Mohamed El-Kassas
- Department of Endemic Medicine, Faculty of Medicine, Helwan University, Cairo 11795, Egypt
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Buchholz M, Strotmann J, Majchrzak-Stiller B, Hahn S, Peters I, Horn J, Müller T, Höhn P, Uhl W, Braumann C. New Therapy Options for Neuroendocrine Carcinoma of the Pancreas—The Emergent Substance GP-2250 and Gemcitabine Prove to Be Highly Effective without the Development of Secondary Resistances In Vitro and In Vivo. Cancers (Basel) 2022; 14:cancers14112685. [PMID: 35681665 PMCID: PMC9179328 DOI: 10.3390/cancers14112685] [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: 04/26/2022] [Revised: 05/20/2022] [Accepted: 05/25/2022] [Indexed: 11/22/2022] Open
Abstract
Simple Summary Neuroendocrine carcinoma of the pancreas is a highly aggressive form of neuroendocrine tumor associated with poor survival and increasing occurrence. GP-2250 is an emergent substance showing antineoplastic properties, especially in combination with Gemcitabine. This study was the first to evaluate the antineoplastic effects of GP-2250 on pancreatic neuroendocrine carcinoma. The combination of GP-2250 and Gemcitabine showed highly synergistic effects in a cell culture model, as well as in mice, without the development of secondary resistances. These findings form the basis for further clinical evaluation of a highly promising combination therapy. Abstract Neuroendocrine carcinoma of the pancreas (pNEC) is an aggressive form of neuroendocrine tumor characterized by a rising incidence without an increase in survival rates. GP-2250 is an oxathiazinane derivate possessing antineoplastic effects, especially in combination with Gemcitabine on the pancreatic adenocarcinoma. The cytotoxic effects of the monotherapy of GP-2250 (GP-2250mono) and Gemcitabine (Gemmono), as well as the combination therapy of both, were studied in vitro using an MTT-assay on the QGP-1 and BON-1 cell lines, along with in vivo studies on a murine xenograft model of QGP-1 and a patient-derived xenograft model (PDX) of Bo99. In vitro, Gemmono and GP-2250mono showed a dose-dependent cytotoxicity. The combination of GP-2250 and Gemcitabine exhibited highly synergistic effects. In vivo, the combination therapy obtained a partial response in QGP-1, while GP-2250mono and Gemmono showed progressive disease or stable disease, respectively. In Bo99 PDX, the combination therapy led to a partial response, while the monotherapy resulted in progressive disease. No development of secondary resistances was observed, as opposed to monotherapy. This study was the first to evaluate the effects of the emerging substance GP-2250 on pNEC. The substance showed synergism in combination with Gemcitabine. The combination therapy proved to be effective in vitro and in vivo, without the development of secondary resistances.
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Affiliation(s)
- Marie Buchholz
- Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany; (J.S.); (B.M.-S.); (I.P.); (J.H.); (P.H.); (W.U.); (C.B.)
- Correspondence: ; Tel.: +49-234-509-6236
| | - Johanna Strotmann
- Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany; (J.S.); (B.M.-S.); (I.P.); (J.H.); (P.H.); (W.U.); (C.B.)
| | - Britta Majchrzak-Stiller
- Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany; (J.S.); (B.M.-S.); (I.P.); (J.H.); (P.H.); (W.U.); (C.B.)
| | - Stephan Hahn
- Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, 44780 Bochum, Germany;
| | - Ilka Peters
- Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany; (J.S.); (B.M.-S.); (I.P.); (J.H.); (P.H.); (W.U.); (C.B.)
| | - Julian Horn
- Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany; (J.S.); (B.M.-S.); (I.P.); (J.H.); (P.H.); (W.U.); (C.B.)
| | | | - Philipp Höhn
- Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany; (J.S.); (B.M.-S.); (I.P.); (J.H.); (P.H.); (W.U.); (C.B.)
| | - Waldemar Uhl
- Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany; (J.S.); (B.M.-S.); (I.P.); (J.H.); (P.H.); (W.U.); (C.B.)
| | - Chris Braumann
- Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany; (J.S.); (B.M.-S.); (I.P.); (J.H.); (P.H.); (W.U.); (C.B.)
- Department of General, Visceral and Vascular Surgery, Evangelische Kliniken Gelsenkirchen, Akademisches Lehrkrankenhaus der Universität Duisburg-Essen, 45879 Gelsenkirchen, Germany
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Wei H, Sun Z, Ye X, Yu J, Ye Y, Wang Z. Establishment of a prediction model for disease progression within one year in newly diagnosed multiple myeloma patients. Hematology 2022; 27:575-582. [PMID: 35617129 DOI: 10.1080/16078454.2022.2067940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Multiple myeloma is still an incurable disease In the past decade, with the continuous progress of treatment methods, the progression-free survival of patients has been prolonged, but some patients still progress in the early stage of the disease. Our research analyses the clinical laboratory indicators of newly diagnosed multiple myeloma (NDMM) patients, to obtain the relevant factors of disease progression within one year in MM patients and to establish a prediction model. 108 MM patients treated in our hospital from January 2015 to January 2020 were retrospectively analyzed. After univariate and multivariate logistic regression analyses, the related factors of disease progression within one year in NDMM patients were obtained, and a prediction model was established. Treatment regimen containing at least two targeted drugs (OR = 0.226, 95% CI 0.068-0.753), increased lactate dehydrogenase(LDH, OR = 3.452, 95% CI 1.101-10.826) and increased serum corrected calcium(OR = 4.466, 95% CI 1.346-14.811) were identified as potential predictors by statistical analysis. The prediction model was obtained: x = -2.042-1.489 × treatment regimen (including at least two targeted drug assignment as 1, otherwise 0) + 1.239 ×LDH (U/L, lactate dehydrogenase elevation assignment as 1, normal as 0) +1.496 × serum corrected calcium (mmol/L, serum corrected calcium elevation assignment as 1, normal as 0). Receiver operating characteristic curve analysis showed that the model has good predictive performance. The possibility of disease progression within one year can be predicted by the prediction model. The model can be used as a reference for clinicians to make individualized treatment plans for patients so that patients can obtain better treatment effects.
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Affiliation(s)
- Huahua Wei
- Department of Hematology, Shangrao People's Hospital, Shangrao, People's Republic of China
| | - Zhihuang Sun
- Department of Orthopedics, Shangrao People's Hospital, Shangrao, People's Republic of China
| | - Xiaoying Ye
- Department of Hematology, Shangrao People's Hospital, Shangrao, People's Republic of China
| | - Jieni Yu
- Department of Hematology, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, People's Republic of China
| | - Yinhai Ye
- Department of Blood Transfusion, The First Affiliated Hospital of Xiamen University, Xiamen, People's Republic of China
| | - Zifeng Wang
- Department of Hematology, Shangrao People's Hospital, Shangrao, People's Republic of China
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21
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Dai M, Mullins CS, Lu L, Alsfasser G, Linnebacher M. Recent advances in diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms. World J Gastrointest Surg 2022; 14:383-396. [PMID: 35734622 PMCID: PMC9160679 DOI: 10.4240/wjgs.v14.i5.383] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 01/17/2022] [Accepted: 04/29/2022] [Indexed: 02/06/2023] Open
Abstract
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a rare group of tumors originating from neuroendocrine cells of the digestive system. Their incidence has increased over the last decades. The specific pathogenetic mechanisms underlying GEP-NEN development have not been completely revealed. Unfunctional GEP-NENs are usually asymptomatic; some grow slowly and thus impede early diagnosis, which ultimately results in a high rate of misdiagnosis. Therefore, many GEP-NEN patients present with later staged tumors. Motivated hereby, research attention for diagnosis and treatment for GEP-NENs increased in recent years. The result of which is great progress in clinical diagnosis and treatment. According to the most recent clinical guidelines, improved grading standards can accurately define poorly differentiated grade 3 neuroendocrine tumors and neuroendocrine carcinomas (NECs), which are subclassified into large and small cell NECs. Combining different functional imaging methods facilitates precise diagnosis. The expression of somatostatin receptors helps to predict prognosis. Genetic analyses of mutations affecting death domain associated protein (DAXX), multiple endocrine neoplasia type 1 (MEN 1), alpha thalassemia/intellectual disability syndrome X-linked (ATRX), retinoblastoma transcriptional corepressor 1 (RB 1), and mothers against decapentaplegic homolog 4 (SMAD 4) help distinguishing grade 3 NENs from poorly differentiated NECs. The aim of this review is to summarize the latest research progress on diagnosis and treatment of GEP-NENs.
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Affiliation(s)
- Meng Dai
- Clinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany
| | - Christina S Mullins
- Clinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany
| | - Lili Lu
- Clinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany
| | - Guido Alsfasser
- Clinic of General Surgery, Rostock University Medical Center, 18057 Rostock, Germany
| | - Michael Linnebacher
- Clinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany
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22
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Crook C, Zhang YH, Li D. Pharmacotherapeutic Management of Well-Differentiated Neuroendocrine Tumors in Older Patients: Current Status and Potential Therapies. Drugs Aging 2022; 39:257-269. [PMID: 35332446 DOI: 10.1007/s40266-022-00934-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/11/2022] [Indexed: 12/01/2022]
Abstract
Neuroendocrine tumors are a rare and heterogenous group of neoplasms that arise from hormone-producing cells throughout the body, with the greatest increase in incidence occurring among older adults aged ≥ 65 years. Despite this, there is currently a lack of data regarding the safety and efficacy of systemic treatment for older adults with neuroendocrine tumors. In this review, we provide a synopsis of the current standard-of-care pharmacotherapeutic treatments for neuroendocrine tumors, with an emphasis on available data in older adults. The benefits of various systemic options such as somatostatin analogs, tryptophan hydroxylase inhibition, molecular targeted agents, peptide receptor radionuclide therapy, and chemotherapy were similar between older adults compared to younger patients. However, real-world data regarding tolerance in the older adult population with neuroendocrine tumors are needed. Future development of novel systemic therapies in the neuroendocrine tumor treatment landscape and their inclusion of and potential impact on older adults living with neuroendocrine tumors is warranted.
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Affiliation(s)
- Christiana Crook
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, 1500 E Duarte Road, Duarte, CA, 91010, USA
| | - Ya-Han Zhang
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, 1500 E Duarte Road, Duarte, CA, 91010, USA
| | - Daneng Li
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, 1500 E Duarte Road, Duarte, CA, 91010, USA.
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23
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Neuroendocrine Tumors: a Relevant Clinical Update. Curr Oncol Rep 2022; 24:703-714. [PMID: 35254612 DOI: 10.1007/s11912-022-01217-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/19/2021] [Indexed: 11/03/2022]
Abstract
PURPOSE OF REVIEW The field of neuroendocrine oncology has changed much since the time of Oberndorfer first described and coined the term carcinoid. The purpose of this review is to summarize recent findings and highlight clinically relevant updates in the management of NENs, particularly those that are practice changing. RECENT FINDINGS Neuroendocrine tumors (NETs) have replaced carcinoid tumor, for the most part. The classification of neuroendocrine neoplasms (NENs) improved, and the epidemiological understanding of this disease group also expanded with global collaborations and maturation of large tumor registries. Clarity in the utility of some NET biomarkers continues to be evolving. Knowledge of molecular drivers of tumorigenesis increases, and scientific/technological advancements lead the way to multiple drug approvals for the treatment of advanced NETs. The incidence and prevalence of NENs continue to increase, and patients are living longer. Better understanding of molecular drivers and further understanding of the role of immunotherapy in NENs will further elevate the level of care and transform care for all patients with NENs.
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24
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Marchese U, Gaillard M, Pellat A, Tzedakis S, Abou Ali E, Dohan A, Barat M, Soyer P, Fuks D, Coriat R. Multimodal Management of Grade 1 and 2 Pancreatic Neuroendocrine Tumors. Cancers (Basel) 2022; 14:433. [PMID: 35053593 PMCID: PMC8773540 DOI: 10.3390/cancers14020433] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/11/2022] [Accepted: 01/13/2022] [Indexed: 12/13/2022] Open
Abstract
Pancreatic neuroendocrine tumors (p-NETs) are rare tumors with a recent growing incidence. In the 2017 WHO classification, p-NETs are classified into well-differentiated (i.e., p-NETs grade 1 to 3) and poorly differentiated neuroendocrine carcinomas (i.e., p-NECs). P-NETs G1 and G2 are often non-functioning tumors, of which the prognosis depends on the metastatic status. In the localized setting, p-NETs should be surgically managed, as no benefit for adjuvant chemotherapy has been demonstrated. Parenchymal sparing resection, including both duodenum and pancreas, are safe procedures in selected patients with reduced endocrine and exocrine long-term dysfunction. When the p-NET is benign or borderline malignant, this surgical option is associated with low rates of severe postoperative morbidity and in-hospital mortality. This narrative review offers comments, tips, and tricks from reviewing the available literature on these different options in order to clarify their indications. We also sum up the overall current data on p-NETs G1 and G2 management.
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Affiliation(s)
- Ugo Marchese
- Department of Digestive, Hepatobiliary and Pancreatic Surgery, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (M.G.); (S.T.); (D.F.)
| | - Martin Gaillard
- Department of Digestive, Hepatobiliary and Pancreatic Surgery, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (M.G.); (S.T.); (D.F.)
| | - Anna Pellat
- Gastroenterology and Digestive Oncology Unit, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.P.); (E.A.A.); (R.C.)
| | - Stylianos Tzedakis
- Department of Digestive, Hepatobiliary and Pancreatic Surgery, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (M.G.); (S.T.); (D.F.)
| | - Einas Abou Ali
- Gastroenterology and Digestive Oncology Unit, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.P.); (E.A.A.); (R.C.)
| | - Anthony Dohan
- Department of Radiology, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.D.); (M.B.); (P.S.)
| | - Maxime Barat
- Department of Radiology, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.D.); (M.B.); (P.S.)
| | - Philippe Soyer
- Department of Radiology, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.D.); (M.B.); (P.S.)
| | - David Fuks
- Department of Digestive, Hepatobiliary and Pancreatic Surgery, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (M.G.); (S.T.); (D.F.)
| | - Romain Coriat
- Gastroenterology and Digestive Oncology Unit, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.P.); (E.A.A.); (R.C.)
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25
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Bou Zerdan M, Hamouche R, Bouferraa Y, Chouairy C, Gholam D. Everolimus in poorly differentiated neuroendocrine carcinoma of unknown primary: A case report. SAGE Open Med Case Rep 2022; 10:2050313X221106987. [PMID: 35783669 PMCID: PMC9247284 DOI: 10.1177/2050313x221106987] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 05/26/2022] [Indexed: 12/20/2022] Open
Abstract
Malignancies with unknown primaries contribute to a small yet significant
percentage of overall tumors. Neuroendocrine carcinomas, a rare disease with a
poor prognosis, have been known to present as an unknown primary. Treatment
consists of cytotoxic chemotherapy but given the latter’s high toxicity profile
new treatment options are being explored. In this case report, we describe a
case of a patient with poorly differentiated neuroendocrine carcinoma of unknown
primary treated with compassionate oral everolimus after his refusal of
intravenous chemotherapy.
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Affiliation(s)
- Maroun Bou Zerdan
- Department of Internal Medicine, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Ramzi Hamouche
- Yale-Waterbury Internal Medicine Residency Program, Waterbury, CT, USA
| | - Youssef Bouferraa
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Camil Chouairy
- Department of Pathology, Saint George Hospital University Medical Center, Beirut, Lebanon
| | - Dany Gholam
- Department of Hematology and Oncology, Saint George Hospital University Medical Center (SGHUMC), Beirut, Lebanon
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26
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Study Protocol for a Trial: A Single-Arm, Open-Labeled Study Evaluating Transcatheter Arterial Embolization Plus Everolimus Combination Therapy for Patients With Liver Metastasis of Gastroenteropancreatic Neuroendocrine Tumors. Clin Med Insights Oncol 2022; 16:11795549221127750. [DOI: 10.1177/11795549221127750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 09/05/2022] [Indexed: 11/09/2022] Open
Abstract
Background: The number of patients with non-functional neuroendocrine tumors (NETs) has increased recently, and the rate of liver metastasis of NETs is about 20% in patients at the first diagnosis. Transcatheter arterial embolization (TAE) and everolimus are therapies with reported efficacy, but few reports have described their combined treatment. We therefore aim to evaluate the efficacy and safety of combination therapy with everolimus and TAE in patients with liver metastasis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in a prospective study. Methods: We design a single-arm, open-label, prospective study to evaluate the efficacy and safety of combination therapy with everolimus and TAE in patients with liver metastases of GEP-NETs. The study started in June 2021 at Okayama University Hospital and is expected to enroll 18 patients over a 2-year period. Discussion: This study is a prospective study investigating a new treatment method for a rare disease called GEP-NETs. We may obtain useful information that contributes to the treatment guidelines in this study. However, NET is a rare disease, and although the number of cases is statistically established, it may not be possible to accurately assess causality. TRIAL REGISTRATION NUMBER: jRCT1061210015.
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27
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Keihanian T, Othman M. Epidemiology, Pathogenesis, and Prognosis of Pancreatic Neuroendocrine Tumors. HEPATO-PANCREATO-BILIARY MALIGNANCIES 2022:623-637. [DOI: 10.1007/978-3-030-41683-6_36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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28
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Mileva M, Wimana Z, Flamen P, Karfis I. Everolimus-induced somatostatin receptor overexpression in a rectal neuroendocrine tumor patient may promote somatostatin receptor-guided radionuclide therapy (peptide receptor radiotherapy) as an additional treatment option. World J Nucl Med 2021; 20:316-318. [PMID: 34703403 PMCID: PMC8488891 DOI: 10.4103/wjnm.wjnm_120_20] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 09/17/2020] [Accepted: 09/27/2020] [Indexed: 12/15/2022] Open
Abstract
We present a case of Grade II, well-differentiated rectal neuroendocrine tumor in a 39-year-old patient. Following different sequential treatment modalities, the disease progressed both on metabolic (18F-fluorodeoxyglucose positron emission tomography-computed tomography [18F-FDG PET/CT]) and somatostatin receptor (SSTR)-imaging (68Ga-DOTA-Tyr3-octreotate [68Ga-DOTATATE] PET/CT), and the patient received three cycles of peptide receptor radiotherapy (PRRT). Two years later, upon new progression due to the appearance of metabolically active, 68Ga-DOTATATE PET/CT-negative liver lesions, targeted treatment with everolimus was introduced. Further morphologic and metabolic progression occurred 4 months after everolimus initiation, however, this time liver lesions demonstrated increased SSTR-expression on68Ga-DOTATATE PET/CT. Thus, the patient became eligible for a second PRRT course.
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Affiliation(s)
- Magdalena Mileva
- Department of Nuclear Medicine, Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium
| | - Zéna Wimana
- Department of Nuclear Medicine, Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium
| | - Patrick Flamen
- Department of Nuclear Medicine, Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium
| | - Ioannis Karfis
- Department of Nuclear Medicine, Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium
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29
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Hayes AR, Chan DLH, Chan BA, Pavlakis N. The quality of clinical trials in neuroendocrine tumours; have we learnt from our mistakes? An evaluation of phase II and phase III clinical trials. J Neuroendocrinol 2021; 33:e13015. [PMID: 34397130 DOI: 10.1111/jne.13015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 07/09/2021] [Accepted: 07/12/2021] [Indexed: 11/30/2022]
Abstract
The quality and reporting of neuroendocrine tumour (NET) clinical trials has previously been found to be heterogeneous impairing trial interpretability. We aimed to perform an updated review of the quality of phase II/III clinical trials in NET to assess if trial design and reporting have improved since 2011. We performed a PubMed search for phase II/III trials evaluating systemic anticancer therapies or liver-directed therapies published between 2011 and 2018. Data collected comprised administrative data, study population characteristics, endpoints, reporting and statistical design parameters, and results. Sixty studies were included (5218 patients): 50 phase II and 10 phase III trials. Study populations were heterogeneous: 52% of trials allowed tumours from various primary sites, 28% allowed both well- and poorly-differentiated tumour morphology or did not specify, and 57% did not report proliferative indices and/or tumour grade in ≥80% of the study population. Only 36% of trials mandated radiological disease progression on participant enrolment using a validated measure. Statistical design and primary endpoint were clearly defined in 67% and 88% of trials, respectively. Toxicity (88%), radiological response rate (85%) and progression-free survival/time to progression (82%) were well reported in a majority of trials, but health-related quality of life was included in the minority. Of the randomised trials (n = 11), study populations were more homogeneous and study design was more often clearly defined; however, only 45% mandated radiological progression at baseline as measured per Response Evaluation Criteria In Solid Tumours, and reporting of health-related quality of life (55%) remained suboptimal. The design and reporting of NET clinical trials, predominantly of single-arm phase II trials, remains suboptimal and has not considerably improved over time despite the growth in our knowledge of the biology and unique characteristics of NETs. Higher quality is seen in randomised trials, although certain design and reporting elements remain inadequate in some studies. We must prioritise the design and conduct of NET clinical trials to effectively inform future research and guide practice change.
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Affiliation(s)
- Aimee R Hayes
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK
- The University of Sydney, Camperdown, NSW, Australia
| | - David L H Chan
- The University of Sydney, Camperdown, NSW, Australia
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal North Shore Hospital, St Leonards, NSW, Australia
| | - Bryan A Chan
- School of Medicine and Dentistry, Griffith University, Adem Crosby Cancer Centre, Sunshine Coast University Hospital, Birtinya, QLD, Australia
| | - Nick Pavlakis
- The University of Sydney, Camperdown, NSW, Australia
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal North Shore Hospital, St Leonards, NSW, Australia
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30
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Hijioka S, Morizane C, Ikeda M, Ishii H, Okusaka T, Furuse J. Current status of medical treatment for gastroenteropancreatic neuroendocrine neoplasms and future perspectives. Jpn J Clin Oncol 2021; 51:1185-1196. [PMID: 34038547 PMCID: PMC8326384 DOI: 10.1093/jjco/hyab076] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 05/03/2021] [Indexed: 12/16/2022] Open
Abstract
Neuroendocrine neoplasms (NENs) constitute a heterogeneous group of tumors. In this review, we summarize the results of various clinical trials that have been conducted to investigate the efficacy and safety of various therapeutic options for NENs. Based on the encouraging results obtained from these trials, various therapeutic options have been established for the treatment of NENs, including somatostatin analogs (SSAs), molecularly targeted drugs and cytotoxic agents. In addition, peptide receptor radionucleotide therapy has recently been evaluated for the treatment of various NENs. We also discuss the approach for selecting the appropriate drugs and sequence of treatment with the various drug classes, as recommended by different treatment guidelines. Finally, we discuss the scope for future research in this field, especially into the merits of combination therapy with molecularly targeted drugs plus SSAs, along with ongoing studies.
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Affiliation(s)
- Susumu Hijioka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Chigusa Morizane
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hiroshi Ishii
- Department of Gastroenterology, Chiba Cancer Center, Chiba, Japan
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Junji Furuse
- Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan
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31
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Metastatic well-differentiated pancreatic neuroendocrine tumors to the liver: a narrative review of systemic and surgical management. JOURNAL OF PANCREATOLOGY 2021. [DOI: 10.1097/jp9.0000000000000068] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
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32
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Yoshimura M, Seki K, Bychkov A, Fukuoka J. Molecular Pathology of Pulmonary Large Cell Neuroendocrine Carcinoma: Novel Concepts and Treatments. Front Oncol 2021; 11:671799. [PMID: 33968782 PMCID: PMC8100606 DOI: 10.3389/fonc.2021.671799] [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: 02/24/2021] [Accepted: 03/31/2021] [Indexed: 01/14/2023] Open
Abstract
Pulmonary large cell neuroendocrine carcinoma (LCNEC) is an aggressive neoplasm with poor prognosis. Histologic diagnosis of LCNEC is not always straightforward. In particular, it is challenging to distinguish small cell lung carcinoma (SCLC) or poorly differentiated carcinoma from LCNEC. However, histological classification for LCNEC as well as their therapeutic management has not changed much for decades. Recently, genomic and transcriptomic analyses have revealed different molecular subtypes raising hopes for more personalized treatment. Two main molecular subtypes of LCNEC have been identified by studies using next generation sequencing, namely type I with TP53 and STK11/KEAP1 alterations, alternatively called as non-SCLC type, and type II with TP53 and RB1 alterations, alternatively called as SCLC type. However, there is still no easy way to classify LCNEC subtypes at the actual clinical level. In this review, we have discussed histological diagnosis along with the genomic studies and molecular-based treatment for LCNEC.
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Affiliation(s)
| | - Kurumi Seki
- Department of Pathology, Kameda Medical Center, Kamogawa, Japan
| | - Andrey Bychkov
- Department of Pathology, Kameda Medical Center, Kamogawa, Japan
- Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Junya Fukuoka
- Department of Pathology, Kameda Medical Center, Kamogawa, Japan
- Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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33
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Chu H, Shi Y, Liu J, Huang D, Zhang J, Dou C. Update in clinical management for gallbladder neuroendocrine carcinoma. Medicine (Baltimore) 2021; 100:e25449. [PMID: 33832150 PMCID: PMC8036038 DOI: 10.1097/md.0000000000025449] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 03/10/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Gallbladder neuroendocrine carcinoma (GB-NEC) is rare and there are few reports at present. We sought to review the current knowledge of GB-NEC and provide recommendations for clinical management. METHODS A systemic literature research was conducted in the websites of Pubmed, Medline, Web of Science, CNKI, Wanfang Data using the keywords including gallbladder combined with neuroendocrine carcinoma or neuroendocrine tumor or neuroendocrine neoplasm. Two reviewers independently screened the articles by reading the title, abstract and full-text. RESULTS In computed tomography (CT) and magnetic resonance imaging (MRI) examination, a well-defined margin, gallbladder replacing type with larger hepatic and lymphatic metastases could be helpful for differential diagnosis of GB-NEC and gallbladder adenocarcinoma (GB-ADC). Older age, unmarried status, large tumor size (>5 cm), positive margins, and distant Surveillance, Epidemiology and End result (SEER) stage are independently associated with poor survival. Surgical resection remains as the preferred and primary treatment. The potential survival benefit of lymphadenectomy for patients remains controversial. Platinum-based postoperative adjuvant chemotherapy may improve the survival. The efficacy of other treatments including immunotherapy, targeted therapy and somatostatin analogue needs further investigation. CONCLUSION Typical imaging features could be helpful for preoperative diagnosis. Age, margin status, tumor size, marital status, histopathologic subtype and SEER stage may be independent predictors for the survival. Remarkable advances regarding the treatment for GB-NEC have been achieved in recent years. Further studies are needed to investigate the survival benefit of lymphadenectomy for patients with GB-NEC.
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Affiliation(s)
- Hongwu Chu
- Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou
- Qingdao University, Qingdao
| | - Ying Shi
- Obstetrics and Gynecology, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Junwei Liu
- Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou
| | - Dongsheng Huang
- Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou
| | - Jungang Zhang
- Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou
| | - Changwei Dou
- Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou
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Targeted Cancer Therapy: What's New in the Field of Neuroendocrine Neoplasms? Cancers (Basel) 2021; 13:cancers13071701. [PMID: 33916707 PMCID: PMC8038369 DOI: 10.3390/cancers13071701] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/29/2021] [Accepted: 03/31/2021] [Indexed: 12/18/2022] Open
Abstract
Neuroendocrine tumors (NETs) are a heterogeneous family of neoplasms of increasing incidence and high prevalence due to their relatively indolent nature. Their wide anatomic distribution and their characteristic ability to secrete hormonally active substances pose unique challenges for clinical management. They are also characterized by the common expression of somatostatin receptors, a target that has been extremely useful for diagnosis and treatment (i.e., somatostatin analogues (SSAs) and peptide-receptor radionuclide therapy (PRRT)). Chemotherapy is of limited use for NETs of non-pancreatic origin, and the only approved targeted agents for advanced progressive NETs are sunitinib for those of pancreatic origin, and everolimus for lung, gastrointestinal and pancreatic primaries. Despite recent therapeutic achievements, thus, systemic treatment options remain limited. In this review we will discuss the state-of-the-art targeted therapies in the field of NETs, and also future perspectives of novel therapeutic drugs or strategies in clinical development, including recently presented results from randomized trials of yet unapproved antiangiogenic agents (i.e., pazopanib, surufatinib and axitinib), PRRT including both approved radiopharmaceuticals (177Lu-Oxodotreotide) and others in development (177Lu-Edotreotide, 177Lu-Satoreotide Tetraxetan), immunotherapy and other innovative targeted strategies (antibody-drug conjugates, bites,…) that shall soon improve the landscape of personalized treatment options in NET patients.
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Yoo C, Oh CR, Kim ST, Bae WK, Choi HJ, Oh DY, Lee MA, Ryoo BY. Systemic Treatment of Advanced Gastroenteropancreatic Neuroendocrine Tumors in Korea: Literature Review and Expert Opinion. Cancer Res Treat 2021; 53:291-300. [PMID: 33421978 PMCID: PMC8053871 DOI: 10.4143/crt.2020.1233] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 12/28/2020] [Indexed: 02/06/2023] Open
Abstract
Neuroendocrine tumors (NETs) are a group of malignancies arising from neuroendocrine cells and frequently originate in the gastrointestinal tract and pancreas. Although curative resection is the main treatment for localized disease, systemic therapy is needed for relapsed or metastatic/unresectable gastroenteropancreatic NETs (GEP-NETs). Although there are several NET treatment guidelines from various countries, the geographical discrepancies between patient clinical characteristics, the regulatory approval status for therapeutic agents, and medical practices necessitate specific guidelines for Korean patients. We here provide a consensus review of the diagnosis, staging and systemic treatment of Korean GEP-NET patients. Systemic therapy options and the current Korean expert consensus on these treatments, including somatostatin analogs, targeted therapies such as everolimus and sunitinib, peptide receptor radionuclide treatments, and cytotoxic chemotherapies are addressed.
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Affiliation(s)
- Changhoon Yoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul,
Korea
| | - Chung Ryul Oh
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul,
Korea
| | - Seung-Tae Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul,
Korea
| | - Woo Kyun Bae
- Division of Hematology-Oncology, Department of Internal Medicine, Chonnam National University Medical School, Gwangju,
Korea
| | - Hye-Jin Choi
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul,
Korea
| | - Do-Youn Oh
- Division of Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul,
Korea
| | - Myung-Ah Lee
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, Catholic Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul,
Korea
| | - Baek-Yeol Ryoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul,
Korea
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Rinzivillo M, De Felice I, Magi L, Annibale B, Panzuto F. Octreotide long-acting release (LAR) in combination with other therapies for treatment of neuroendocrine neoplasia: a systematic review. J Gastrointest Oncol 2021; 12:845-855. [PMID: 34012671 PMCID: PMC8107603 DOI: 10.21037/jgo-20-292] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND In the last decades, the incidence of neuroendocrine neoplasia (NEN) increased from 1 to 5 new diagnoses/100,000 persons/year. The synthetic somatostatin analogues (SSAs) represent the first-choice treatment for both functionally active and inactive gastro-enteric-pancreatic NEN. This systematic review examines the role of octreotide long-acting release (LAR) in combination with other therapies for NEN management. METHODS Primary outcomes were the disease control rate and the progression free survival (PFS), defined as the time between treatment initiation and progression of disease. Secondary outcomes were overall survival (OS) and safety. RESULTS This systematic review identified 13 studies, concerning the use of octreotide LAR in association with other therapies in advanced NENs and included 1,206 patients. Patients were treated with octreotide LAR in combination with other drugs, mainly with everolimus (404 patients, 35%), but even with Peptide Receptor Radionuclide Therapy, bevacizumab, interferon or fluoride-derivatives. Disease control was observed in 85% cases with SSAs in combination with other therapies; PFS ranged from 15 to 16.4 months and OS from 25 to 61.9 months. SSAs are very well tolerated drugs, with few side effects which are usually mild, not requiring drug withdrawn. CONCLUSIONS The review summarizes the effectiveness and available safety data on octreotide LAR in combination with other therapies in patients with NEN and may provide suggestions to address the therapeutic strategy. Further comparative head-to-head studies are needed to understand which is the best combination treatment for patients with progressive NEN after failure of first-line therapy.
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Affiliation(s)
- Maria Rinzivillo
- Digestive Disease Unit, Sant’ Andrea University Hospital, ENETS Center of Excellence, Rome, Italy
| | - Ilaria De Felice
- Digestive Disease Unit, Sant’ Andrea University Hospital, ENETS Center of Excellence, Rome, Italy
| | - Ludovica Magi
- Digestive Disease Unit, Sant’ Andrea University Hospital, ENETS Center of Excellence, Rome, Italy
| | - Bruno Annibale
- Digestive Disease Unit, Sant’ Andrea University Hospital, Department of Medical-Surgical Sciences and Translational Medicine, Sapienza University of Rome, ENETS Center of Excellence, Rome, Italy
| | - Francesco Panzuto
- Digestive Disease Unit, Sant’ Andrea University Hospital, ENETS Center of Excellence, Rome, Italy
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Asa SL, La Rosa S, Basturk O, Adsay V, Minnetti M, Grossman AB. Molecular Pathology of Well-Differentiated Gastro-entero-pancreatic Neuroendocrine Tumors. Endocr Pathol 2021; 32:169-191. [PMID: 33459926 DOI: 10.1007/s12022-021-09662-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/03/2021] [Indexed: 12/17/2022]
Abstract
Well differentiated neuroendocrine tumors (NETs) arising in the gastrointestinal and pancreaticobiliary system are the most common neuroendocrine neoplasms. Studies of the molecular basis of these lesions have identified genetic mutations that predispose to familial endocrine neoplasia syndromes and occur both as germline events and in sporadic tumors. The mutations often involve epigenetic regulators rather than the oncogenes and tumor suppressors that are affected in other malignancies. Somatic copy number alterations and miRNAs have also been implicated in the development and progression of some of these tumors. The molecular profiles differ by location, but many are shared by tumors in other sites, including those outside the gastroenteropancreatic system. The approach to therapy relies on both the neuroendocrine nature of these tumors and the identification of specific alterations that can serve as targets for precision oncologic approaches.
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Affiliation(s)
- Sylvia L Asa
- Department of Pathology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA.
| | - Stefano La Rosa
- Institute of Pathology, University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Olca Basturk
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Volkan Adsay
- Department of Pathology and Research Center for Translational Medicine (KUTTAM), Koç University Hospital, Istanbul, Turkey
| | - Marianna Minnetti
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Ashley B Grossman
- Green Templeton College, University of Oxford and ENETS Centre of Excellence, Royal Free Hospital, London, UK
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A literature-based treatment algorithm for low-grade neuroendocrine liver metastases. HPB (Oxford) 2021; 23:63-70. [PMID: 32448647 DOI: 10.1016/j.hpb.2020.04.012] [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] [Received: 07/19/2019] [Revised: 03/03/2020] [Accepted: 04/20/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND The optimal timing of treatment of liver metastases from low-grade neuroendocrine tumors (LG-NELM) varies significantly due to numerous treatment modalities and the literature supporting various treatment(s). This study sought to create and validate a literature-based treatment algorithm for LG-NELM. METHODS A treatment algorithm to maximize overall survival (OS) was designed using peer-reviewed articles evaluating treatment of LG-NELM. This algorithm was retrospectively applied to patients treated for LG-NELM at our institution. Deviation was determined based on whether or not a patient received treatment consistent with that recommended by the algorithm. Patients who did and did not deviate from the algorithm were compared with respect to OS and number of treatments. RESULTS Applying our algorithm to a 149-patient cohort, 57 (38%) deviated from recommended treatment. Deviation occurred in the form of alternative (28, 49%) versus additional procedures (29, 51%). Algorithm deviators underwent significantly more procedures than non-deviators (median 1 vs. 2, p < 0.001). Cox model indicated no difference in OS associated with algorithm deviation (HR 1.19, p = 0.58) when controlling for age and tumor characteristics. CONCLUSION This literature-based algorithm helps standardize treatment protocols in patients with LG-NELM and can reduce cost and risk by minimizing unnecessary procedures. Prospective implementation and validation is required.
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Wang J, Doherty G. Neuroendocrine Tumors: Stomach. ENDOCRINE SURGERY COMPREHENSIVE BOARD EXAM GUIDE 2021:661-679. [DOI: 10.1007/978-3-030-84737-1_26] [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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Targeted Therapies in the Management of Well-Differentiated Digestive and Lung Neuroendocrine Neoplasms. Curr Treat Options Oncol 2020; 21:96. [PMID: 33029680 DOI: 10.1007/s11864-020-00794-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/25/2020] [Indexed: 01/05/2023]
Abstract
OPINION STATEMENT Ongoing advances in our understanding of neuroendocrine tumor (NET) biology, genetics, and immunology, will continue to expand the availability of targeted therapies, thus improving the outcomes of patients. Well-differentiated neuroendocrine tumors (NETs) are grouped into pancreatic and non-pancreatic NETs (includes GI and thoracic NETs) for treatment considerations (Fig. 1). For panNETs, initial therapy is driven by the need of radiographic response, and targeted agents are typically reserved for second and third line based on the toxicity profile. Treatment options for non-pancreatic NETs are also expanding and while SSAs are the typical first-line option, everolimus and PRRT both remain approved therapies for future lines, and VEGF TKIs are showing promising results in research settings. Sequencing these agents and best time to incorporate peptide receptor radio therapy into the management algorithm remains an unmet need.
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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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Roberto GA, Rodrigues CMB, Peixoto RD, Younes RN. Gastric neuroendocrine tumor: A practical literature review. World J Gastrointest Oncol 2020; 12:850-856. [PMID: 32879663 PMCID: PMC7443841 DOI: 10.4251/wjgo.v12.i8.850] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 05/05/2020] [Accepted: 07/19/2020] [Indexed: 02/05/2023] Open
Abstract
Gastric neuroendocrine tumors are gastric neoplasms originating from enterochromaffin type cells and are inserted in a larger group, named gastroenteropancreatic neuroendocrine tumors. They are considered rare and variable in terms of their clinical, morphological and functional characteristics and may be indolent or aggressive. They are classified into types I, II and III, according to their pathophysiology, behavior and treatment. Their diagnosis occurs, in most cases, incidentally during upper digestive endoscopies, presenting as simple gastric polyps. Most cases (type I and type II) are related to hypergastrinemia, can be multiple and are treated by endoscopic resection, whenever possible. The use of somatostatin analogs for tumor control may be one of the options for therapy, in addition to total or subtotal gastrectomy for selected cases. Adjuvant chemotherapy is only reserved for poorly differentiated neuroendocrine carcinomas. Although rare, gastric neuroendocrine tumors have an increasing incidence over the years, therefore deserving more comprehensive studies on its adequate treatment. The present study reviews and updates management recommendations for gastric neuroendocrine tumors.
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Affiliation(s)
- Gabriel Antonio Roberto
- Bachelor Medicine, União das Faculdades dos Grandes Lagos, São José do Rio Preto 15030070, Brazil
| | | | - Renata D’Alpino Peixoto
- Department of Oncology, Hospital Alemão Oswaldo Cruz, São Paulo 01327001, Brazil
- Universidade Nove de Julho, São Paulo 01327001, Brazil
| | - Riad Naim Younes
- Department of Thoracic Surgery, Hospital Alemão Oswaldo Cruz, São Paulo 01327001, Brazil
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Wu Z, Wang Z, Zheng Z, Bi J, Wang X, Feng Q. Risk Factors for Lymph Node Metastasis and Survival Outcomes in Colorectal Neuroendocrine Tumors. Cancer Manag Res 2020; 12:7151-7164. [PMID: 32848469 PMCID: PMC7429107 DOI: 10.2147/cmar.s256723] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 07/14/2020] [Indexed: 12/21/2022] Open
Abstract
Objective The aim of our study was to analyze the factors affecting lymph node metastasis (LNM) and the prognosis of colorectal neuroendocrine tumors (NETs). Patients and Methods A retrospective analysis was conducted to collect the clinical data of 135 patients with colorectal NETs from January 2000 to December 2018, including clinical manifestations, pathological results, treatment methods, etc. Follow-up was regularly performed to observe the recurrence and metastasis of tumors and to identify the clinical and pathological features of colorectal NETs, risk factors for LNM and survival outcomes. Results Among 135 patients, there were 57 (42.2) patients with LNM, and the independent risk factors for LNM in the multivariable analyses were tumor diameter ≥2 cm (P= 0.040) and tumor grade G3 (P=0.001). Patients were followed up for 1 to 190 months, and of the 133 patients who were successfully followed up, the 5-year OS was 71.7%, and the 5-year PFS was 69.0%. The multivariate analysis for survival outcomes showed that age ≥65 years (P=0.002/<0.001) and lymph node metastasis (P=0.018/0.025) were independent risk factors affecting 5-year PFS and OS in colorectal neuroendocrine tumors. Tumors in the colon (P=0.022), moderately positive (++) CgA (P=0.010) and strongly positive (+++) CgA (P=0.007) were independent risk factors for poor 5-year PFS in patients with colorectal NETs. Conclusion Rectal NETs have a better prognosis than colonic neuroendocrine tumors. Tumor diameter and tumor grade are independent risk factors for LNM in colorectal neuroendocrine tumors. Age, tumor location, lymph node status and a positive level of the neuroendocrine marker CgA are independent risk factors that affect the prognosis of colorectal NETs.
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Affiliation(s)
- Zijian Wu
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Zhijie Wang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Zhaoxu Zheng
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Jianjun Bi
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Xishan Wang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Qiang Feng
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
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Gut P. Oncological management of advanced neuroendocrine tumours (Review). Mol Clin Oncol 2020; 13:8. [PMID: 32754322 DOI: 10.3892/mco.2020.2078] [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: 02/07/2020] [Accepted: 06/02/2020] [Indexed: 11/06/2022] Open
Abstract
The oncological principles of managing patients with gastroenteropancreatic neuroendocrine tumours (GEP-NETs) depends on a number of factors and requires a multidisciplinary approach. Recent data have provided additional therapeutic options, including biotherapy, traditional chemotherapy and novel targeted agents. Somatostatin analogues (SSAs) inhibit multiple cellular functions, including secretion, motility and proliferation. Interferon appears to act through several mechanisms, with antisecretory effects, immunomodulatory effects and antiproliferative functions, the latter inhibiting direct growth or attenuating angiogenesis. Opinions on when to commence chemotherapy for well differentiated GEP-NETs varies among experts. In previous years, reserving chemotherapy for patients with progressive disease (well differentiated, inoperable and/or metastatic GEP-NETs) was reasonably well argued for. Most well differentiated endocrine tumours are richly vascular and many express vascular endothelial growth factor (VEGF) receptors. In a xenograft model of a human carcinoid, treatment with an anti-VEGF monoclonal antibody was revealed to inhibit tumour growth and metastasis. As the role of angiogenesis and hypoxic-associated factors appears to be associated with tumour aggressiveness, strategies using agents which target angiogenesis have been developed. Mammalian target of rapamycin (mTOR) is a conserved serine-threonine kinase that regulates the cell cycle and metabolism in response to environmental factors. In addition, mTOR inhibition suppression was demonstrated to suppress NET growth. Each patient requires an individual approach to the choice of therapy, which should be selected depending on the severity of disease.
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Affiliation(s)
- Paweł Gut
- Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, Poznań 60-355, Poland
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45
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Tsoli M, Alexandraki K, Xanthopoulos C, Kassi E, Kaltsas G. Medical Treatment of Gastrointestinal Neuroendocrine Neoplasms. Horm Metab Res 2020; 52:614-620. [PMID: 32108932 DOI: 10.1055/a-1110-7251] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Neuroendocrine neoplasms (NENs) are rare tumours that arise mainly in the gastrointestinal or pulmonary system. Most NENs are well-differentiated and may obtain prolonged survival besides the presence of metastatic disease; however, a subset (poorly differentiated NENs) may display a truly aggressive behaviour exhibiting a poor prognosis. The recently developed classification systems along with advances in functional imaging have helped stratify patients to the administration of appropriate therapeutic options. Surgery is the mainstay of treatment of NENs, but in recent decades there has been a considerable evolution of medical treatments that are used for locally advanced or metastatic disease not amenable to surgical resection. Long acting somatostatin analogues are the main therapeutic modality for patients with functioning and well-differentiated low grade NENs exhibiting symptomatic control and mainly stabilisation of tumour growth. Other systemic treatments include chemotherapy, molecular targeted agents, interferon-α, peptide receptor radionuclide therapy (PRRT), and immunotherapy. In addition, new agents such as telotristat may be used for the control of symptoms of carcinoid syndrome. The choice and/or sequence of therapeutic agents should be individualized according to tumour origin and differentiation, disease burden, presence of clinical symptoms and patients' performance status in the context of a multidisciplinary approach. Recent advances in the molecular pathogenesis of NENs set the field for a more personalised treatment approach.
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Affiliation(s)
- Marina Tsoli
- 1st Department of Propaedeutic and Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Krystallenia Alexandraki
- 1st Department of Propaedeutic and Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Christos Xanthopoulos
- 1st Department of Propaedeutic and Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Eva Kassi
- 1st Department of Propaedeutic and Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
- Department of Biological Chemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - Gregory Kaltsas
- 1st Department of Propaedeutic and Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
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Trevisi E, La Salvia A, Daniele L, Brizzi MP, De Rosa G, Scagliotti GV, Di Maio M. Neuroendocrine breast carcinoma: a rare but challenging entity. Med Oncol 2020; 37:70. [PMID: 32712767 PMCID: PMC7382662 DOI: 10.1007/s12032-020-01396-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Accepted: 07/16/2020] [Indexed: 12/25/2022]
Abstract
Breast carcinoma with neuroendocrine differentiation, also known as neuroendocrine breast carcinoma (NEBC), includes a heterogeneous group of rare tumors, which account for 2–5% of all invasive breast carcinomas. Because of their low incidence, most of the current limited knowledge of these tumors derives from anecdotal case reports or small retrospective series. The diagnosis of NEBC is based on the presence of morphological features similar to gastrointestinal and lung NETs and neuroendocrine markers. NEBCs are usually hormone receptors positive and HER2 negative, but despite this luminal phenotype, most recent studies suggested that NEBC could be associated with worse prognosis compared to invasive breast cancer without neuroendocrine differentiation. Due to its rarity and lack of randomized data, there is little evidence to guide the choice of treatment, so NEBC is currently treated as any invasive breast carcinoma not-otherwise specified. Recently, attempts to molecularly characterize NEBC have been made, in order to provide new targets for a more personalized treatment of this uncommon entity.
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Affiliation(s)
- Elena Trevisi
- Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Regione Gonzole 10, 10043, Orbassano, Turin, Italy.
| | - Anna La Salvia
- Department of Oncology, University Hospital, 12 de Octubre, Madrid, Spain
| | | | - Maria Pia Brizzi
- Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Regione Gonzole 10, 10043, Orbassano, Turin, Italy
| | | | - Giorgio V Scagliotti
- Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Regione Gonzole 10, 10043, Orbassano, Turin, Italy
| | - Massimo Di Maio
- Department of Oncology, University of Turin, Ordine Mauriziano Hospital, Torino, Italy
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Megdanova-Chipeva VG, Lamarca A, Backen A, McNamara MG, Barriuso J, Sergieva S, Gocheva L, Mansoor W, Manoharan P, Valle JW. Systemic Treatment Selection for Patients with Advanced Pancreatic Neuroendocrine Tumours (PanNETs). Cancers (Basel) 2020; 12:E1988. [PMID: 32708210 PMCID: PMC7409353 DOI: 10.3390/cancers12071988] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 06/19/2020] [Accepted: 07/09/2020] [Indexed: 02/07/2023] Open
Abstract
Pancreatic neuroendocrine tumours (PanNETs) are rare diseases and a good example of how research is not only feasible, but also of crucial importance in the scenario of rare tumours. Many clinical trials have been performed over the past two decades expanding therapeutic options for patients with advanced PanNETs. Adequate management relies on optimal selection of treatment, which may be challenging for clinicians due to the fact that multiple options of therapy are currently available. A number of therapies already exist, which are supported by data from phase III studies, including somatostatin analogues and targeted therapies (sunitinib and everolimus). In addition, chemotherapy remains an option, with temozolomide and capecitabine being one of the most popular doublets to use. Peptide receptor radionuclide therapy was successfully implemented in patients with well-differentiated gastro-entero-pancreatic neuroendocrine tumours, but with certain questions waiting to be solved for the management of PanNETs. Finally, the role of immunotherapy is still poorly understood. In this review, the data supporting current systemic treatment options for locally advanced or metastatic PanNETs are summarized. Strategies for treatment selection in patients with PanNETs based on patient, disease, or drug characteristics is provided, as well as a summary of current evidence on prognostic and predictive biomarkers. Future perspectives are discussed, focusing on current and forthcoming challenges and unmet needs of patients with these rare tumours.
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Affiliation(s)
- Vera G. Megdanova-Chipeva
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M204BX, UK; (V.G.M.-C.); (A.B.); (M.G.M.); (J.B.); (W.M.)
- Department of Radiotherapy and Medical Oncology, University Hospital “Queen Yoanna” ISUL, 1000 Sofia, Bulgaria;
- Department of Nuclear Medicine, Radiotherapy and Medical Oncology, Medical University—Sofia, 1000 Sofia, Bulgaria
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M204BX, UK; (V.G.M.-C.); (A.B.); (M.G.M.); (J.B.); (W.M.)
- Division of Cancer Sciences, University of Manchester, Manchester M204BX, UK
| | - Alison Backen
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M204BX, UK; (V.G.M.-C.); (A.B.); (M.G.M.); (J.B.); (W.M.)
- Division of Cancer Sciences, University of Manchester, Manchester M204BX, UK
| | - Mairéad G. McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M204BX, UK; (V.G.M.-C.); (A.B.); (M.G.M.); (J.B.); (W.M.)
- Division of Cancer Sciences, University of Manchester, Manchester M204BX, UK
| | - Jorge Barriuso
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M204BX, UK; (V.G.M.-C.); (A.B.); (M.G.M.); (J.B.); (W.M.)
- Division of Cancer Sciences, University of Manchester, Manchester M204BX, UK
| | - Sonia Sergieva
- Nuclear Medicine Department, SBALOZ, Sofia grad, 1000 Sofia, Bulgaria;
| | - Lilia Gocheva
- Department of Radiotherapy and Medical Oncology, University Hospital “Queen Yoanna” ISUL, 1000 Sofia, Bulgaria;
- Department of Nuclear Medicine, Radiotherapy and Medical Oncology, Medical University—Sofia, 1000 Sofia, Bulgaria
| | - Was Mansoor
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M204BX, UK; (V.G.M.-C.); (A.B.); (M.G.M.); (J.B.); (W.M.)
- Division of Cancer Sciences, University of Manchester, Manchester M204BX, UK
| | - Prakash Manoharan
- Department of Radiology and Nuclear Medicine, The Christie NHS Foundation Trust, Manchester M204BX, UK;
| | - Juan W. Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M204BX, UK; (V.G.M.-C.); (A.B.); (M.G.M.); (J.B.); (W.M.)
- Division of Cancer Sciences, University of Manchester, Manchester M204BX, UK
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mTOR Pathway Expression as Potential Predictive Biomarker in Patients with Advanced Neuroendocrine Tumors Treated with Everolimus. Cancers (Basel) 2020; 12:cancers12051201. [PMID: 32397669 PMCID: PMC7281483 DOI: 10.3390/cancers12051201] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/05/2020] [Accepted: 05/07/2020] [Indexed: 01/05/2023] Open
Abstract
Background. Everolimus (Eve), which is a mammalian target of Rapamicin (mTOR) inhibitor, is part of the therapeutic armamentarium of neuroendocrine tumors (NETs). Currently, there are no validated biomarkers predicting Eve efficacy in NETs. In this study, we explore whether the expression of phosphorilated (p)-mTOR and p70S6-kinase (S6K), a downstream effector of mTOR, correlates with the outcome of patients with NET that were treated with Eve. Methods. Tissue specimens that were derived from NETs treated with Eve at our Institution were examined for the expression levels of p-mTOR and p-S6K by immunohistochemistry. Response rate (RR), progression-free survival (PFS), and overall survival (OS) were analyzed in two groups: p-mTOR/p-S6K positive (group 1) and p-mTOR/p-S6K negative (group 2). Univariate and multivariate Cox regression analysis were performed. Results. Twenty-four patients with advanced NETs that were treated with Eve were included in the analysis. Eight out 24 (33.3%) patients were both p-mTOR and p-S6K positive. A better median PFS and OS in group 1 (18.2 and 39.9 months) as compared to group 2 (13 and 32.4 months) was depicted, with a toxicity profile that was comparable with data literature. Conclusions. Our study suggests that the activation of mTOR pathway can predict better outcomes in patients with NET treated with Eve. However, these results warrant further confirmation in a prospective setting.
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Abstract
The increased incidence and prevalence of neuroendocrine tumors (NETs) over the past few decades has been accompanied by an improvement in overall survival. There are differences in the management of small bowel NETs versus pNETs. The management of all patients with NETs must be individualized based on patient characteristics as well tumor-related factors. This article reviews the role of somatostatin analogues, historical results with chemotherapy in gastroenteropancreatic NETs (GEPNETs), and more recent evidence for the use of cytotoxic chemotherapy in GEPNETs. The article also discusses molecular targeted therapies approved for use in GEPNETs and some ongoing clinical trials.
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Affiliation(s)
- Chandrikha Chandrasekharan
- Division of Medical Oncology, University of Iowa, 200 Hawkins Drive, C GH 32, Iowa City, Iowa 52242, USA.
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50
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Koumarianou A, Pectasides D, Koliou GA, Dionysopoulos D, Kolomodi D, Poulios C, Skondra M, Sgouros J, Pentheroudakis G, Kaltsas G, Fountzilas G. Efficacy and Safety of First-Line Everolimus Therapy Alone or in Combination with Octreotide in Gastroenteropancreatic Neuroendocrine Tumors. A Hellenic Cooperative Oncology Group (HeCOG) Study. BIOLOGY 2020; 9:biology9030051. [PMID: 32182791 PMCID: PMC7150771 DOI: 10.3390/biology9030051] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 02/24/2020] [Accepted: 03/03/2020] [Indexed: 01/17/2023]
Abstract
The purpose of this study was to explore the efficacy and safety of everolimus administered as a first-line treatment in newly diagnosed patients with metastatic or inoperable gastroenteropancreatic neuroendocrine tumors (GEP NETs). This phase II, multicenter, single-arm study included patients with well-differentiated GEP NETs and a Ki67 < 20%. Everolimus, at 10 mg/day, was administered until disease progression; 18 patients (72%) concomitantly received octreotide long-acting release (LAR), at 30 mg/month. The primary endpoint was the 15-month progression-free survival (PFS) rate. Twenty-five patients (grade 1: 11 patients, grade 2: 14 patients) were enrolled between August 2012 and October 2015. At a median follow-up of 58.1 months, the median PFS was 14.6 months, while the 15-month PFS rate was 48%; median overall survival had not been reached yet. Normal baseline chromogranin A (<4 nmol/l) confirmed a longer PFS (HR = 0.25, 95% CI 0.08–0.77, p = 0.016). Seven patients (28%) achieved an objective response (one complete response and six partial responses) in a median of 2.6 months. Twenty-three grade 3–4 events were recorded (14 patients). No fatal reactions occurred. This prospective phase II study unravels the notable activity of everolimus as a first-line treatment in patients with GEP NETS and contributes valuable information about the high activity of the combination of everolimus and octreotide LAR in this setting. Clinical trial information: NCT01648465.
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Affiliation(s)
- Anna Koumarianou
- Hematology Oncology Unit Fourth Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Attikon University Hospital, 12462 Athens, Greece
- Correspondence: ; Tel.: +30-210-583-1687; Fax: +30-210-583-6446
| | - Dimitrios Pectasides
- Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, 11527 Athens, Greece; (D.P.); (M.S.)
| | - Georgia-Angeliki Koliou
- Section of Biostatistics, Hellenic Cooperative Oncology Group, Data Office, 11526 Athens, Greece;
| | - Dimitrios Dionysopoulos
- Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, 56403 Thessaloniki, Greece;
| | - Dionysia Kolomodi
- First Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens, Medical School, Laiko University Hospital, 11527 Athens, Greece; (D.K.); (G.K.)
| | - Christos Poulios
- Department of Pathology, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, 54006 Thessaloniki, Greece;
| | - Maria Skondra
- Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, 11527 Athens, Greece; (D.P.); (M.S.)
| | - Joseph Sgouros
- Third Department of Medical Oncology, Agii Anargiri Cancer Hospital, 14564 Athens, Greece;
| | - George Pentheroudakis
- Department of Medical Oncology, Medical School, University of Ioannina, 45110 Ioannina, Greece;
- Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), 45110 Ioannina, Greece
| | - Gregory Kaltsas
- First Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens, Medical School, Laiko University Hospital, 11527 Athens, Greece; (D.K.); (G.K.)
| | - George Fountzilas
- Aristotle University of Thessaloniki, 54006 Thessaloniki, Greece;
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, 54006 Thessaloniki, Greece
- Department of Medical Oncology, German Oncology Center, Limassol 4108, Cyprus
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