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Landoni L, Paiella S, Marchetti A, Fontana M, Corvino G, Maistri G, Gronchi F, Cattelani A, Casciani F, Cingarlini S, D'Onofrio M, De Robertis Lombardi R, Malleo G, Salvia R. Somatostatin analogs for resectable pancreatic neuroendocrine tumors in high-risk surgical patients: Data from a single-center cohort. Pancreatology 2025:S1424-3903(25)00066-3. [PMID: 40328552 DOI: 10.1016/j.pan.2025.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 02/08/2025] [Accepted: 04/01/2025] [Indexed: 05/08/2025]
Abstract
OBJECTIVES To evaluate the use of long-acting somatostatin-analogs (SSA) for treating non-advanced, resectable pancreatic neuroendocrine tumors (PNETs) with indications to surgery, in high-risk patients who were not candidates for surgery. METHODS Patients diagnosed with histology-proven, non-advanced G1/low-G2 68Ga-TC/PET-positive PNETs >20 mm who did not undergo surgery due to comorbidities/old age/high-risk surgical profile, which were treated with SSA at a single, high-volume institution were included. The efficacy of SSA was evaluated using the analysis of tumor growth rate (TGR). "Negative TGRTx-TpreSSA" was defined as the first time point after the initiation of SSA when a negative TGRTx-TpreSSA was observed. RESULTS Between 2014 and 2024, 20 patients were treated with long-acting SSA. The median age was 76 (IQR 72-80), and the median ASA score was 3 (IQR 3-3). Fifteen patients (75 %) received Lanreotide, and five (25 %) octreotide acetate (Sandostatin® LAR). The median overall survival was 68.5 months (IQR 60-99). In four patients (20 %), SSA were interrupted when the tumor had shrunk below 2 cm. In one of them, SSA reintroduction was necessary due to disease progression (after 14 months). In two patients (10 %), the treatment was interrupted due to side effects. In one of these, the disease progressed until death at 87 years old. At the last follow-up, sixteen patients were alive, 3 had died (1 death of disease), and 13 were receiving SSA. T2 PNETs presented a significantly faster response to SSA therapy compared to T3 (Median time to "Negative TGRTx-TpreSSA": 6 [95 % CI 5, na] vs 52 [95 % CI 19, na] months, respectively; p = 0.0092) CONCLUSION: In patients at high surgical risk, with localized, resectable, G1 or low-G2, 68Ga-TC/PET-positive PNETs >20 mm, SSA can obtain disease control with a manageable safety profile.
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Affiliation(s)
- Luca Landoni
- Unit of Pancreatic Surgery, University of Verona Hospital Trust, Verona, Italy
| | - Salvatore Paiella
- Pancreatic Surgery Unit, Department of Surgery, Dentistry, Paediatrics and Gynecology, University of Verona, Verona, Italy
| | - Alessio Marchetti
- Unit of Pancreatic Surgery, University of Verona Hospital Trust, Verona, Italy
| | - Michele Fontana
- Unit of Pancreatic Surgery, University of Verona Hospital Trust, Verona, Italy
| | - Gaetano Corvino
- Unit of Pancreatic Surgery, University of Verona Hospital Trust, Verona, Italy
| | - Giulia Maistri
- Unit of Pancreatic Surgery, University of Verona Hospital Trust, Verona, Italy
| | - Federico Gronchi
- Unit of Pancreatic Surgery, University of Verona Hospital Trust, Verona, Italy
| | - Alice Cattelani
- Unit of Pancreatic Surgery, University of Verona Hospital Trust, Verona, Italy
| | - Fabio Casciani
- Unit of Pancreatic Surgery, University of Verona Hospital Trust, Verona, Italy
| | - Sara Cingarlini
- Department of Medicine, Section of Oncology, University and Hospital Trust of Verona, Verona, Italy
| | - Mirko D'Onofrio
- Department of Radiology, Ospedale G.B. Rossi AOUI Verona, Verona, Italy; Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Riccardo De Robertis Lombardi
- Department of Radiology, Ospedale G.B. Rossi AOUI Verona, Verona, Italy; Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Giuseppe Malleo
- Pancreatic Surgery Unit, Department of Surgery, Dentistry, Paediatrics and Gynecology, University of Verona, Verona, Italy
| | - Roberto Salvia
- Pancreatic Surgery Unit, Department of Engineering for Innovation Medicine (DIMI), University of Verona, Verona, Italy.
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Massironi S, Albertelli M, Hasballa I, Paravani P, Ferone D, Faggiano A, Danese S. "Cold" Somatostatin Analogs in Neuroendocrine Neoplasms: Decoding Mechanisms, Overcoming Resistance, and Shaping the Future of Therapy. Cells 2025; 14:245. [PMID: 39996718 PMCID: PMC11854070 DOI: 10.3390/cells14040245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 01/28/2025] [Accepted: 02/04/2025] [Indexed: 02/26/2025] Open
Abstract
BACKGROUND Neuroendocrine neoplasms (NENs) represent a heterogeneous group of tumors that pose significant therapeutic challenges due to their potential for progression, metastasis, and hormonal syndromes. Somatostatin analogs (SSAs) have emerged as a cornerstone in NEN treatment, offering both antisecretory and antiproliferative effects by targeting somatostatin receptors (SSTRs). Despite their proven efficacy, intrinsic and acquired resistance mechanisms, including receptor downregulation, tumor heterogeneity, and microenvironmental influences, limit their long-term effectiveness. Recent advances, including high-dose SSA regimens and novel formulations, have aimed to optimize their therapeutic utility and address these limitations. Body of the review. This review explores the cellular and molecular mechanisms underlying the antitumor effects of SSAs, including receptor-mediated signaling pathways, cell cycle arrest, apoptosis induction, and antiangiogenesis. The role of SSAs in combination therapies with mTOR inhibitors and peptide receptor radionuclide therapy (PRRT) is analyzed, emphasizing their synergistic potential. Key clinical trials, such as RADIANT-2, EVERLAR, and NETTER-1, support the efficacy of these approaches, demonstrating improved outcomes when SSAs are combined with targeted agents or radiolabeled therapies. Emerging strategies include high-dose SSA regimens, particularly in progressive cases with low Ki67 indices. Finally, novel formulations, including oral octreotide, paltusotine, and subcutaneous depot formulations like CAM2029, offer improved pharmacokinetics, bioavailability, and patient adherence. Ongoing clinical trials, including SORENTO, further evaluate their efficacy and safety profiles. CONCLUSIONS This paper provides a comprehensive analysis of the cellular and molecular mechanisms of SSAs. SSAs remain integral to the management of NENs, providing effective tumor stabilization and symptom control. However, resistance mechanisms and tumor heterogeneity necessitate innovative approaches, including high-dose regimens, combination strategies, and next-generation formulations. Future research should focus on refining these strategies to optimize patient outcomes, enhance long-term efficacy, and expand the therapeutic landscape for NENs.
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Affiliation(s)
- Sara Massironi
- Faculty of Medicine and Surgery, Vita e Salute San Raffaele University, Via Olgettina, 20132 Milan, Italy;
- Gastroenterology Unit, Istituti Ospedalieri Bergamaschi, 24046 Bergamo, Italy
| | - Manuela Albertelli
- Endocrinology, Department of Internal Medicine and Medical Specialties (DiMI), University of Genova, 16132 Genova, Italy (I.H.); (D.F.)
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy
| | - Iderina Hasballa
- Endocrinology, Department of Internal Medicine and Medical Specialties (DiMI), University of Genova, 16132 Genova, Italy (I.H.); (D.F.)
| | - Piero Paravani
- Unit of Endocrinology, Department of Clinical and Molecular Medicine, ENETS Center of Excellence, Sant’Andrea Hospital, Sapienza University, 00189 Rome, Italy; (P.P.); (A.F.)
| | - Diego Ferone
- Endocrinology, Department of Internal Medicine and Medical Specialties (DiMI), University of Genova, 16132 Genova, Italy (I.H.); (D.F.)
| | - Antongiulio Faggiano
- Unit of Endocrinology, Department of Clinical and Molecular Medicine, ENETS Center of Excellence, Sant’Andrea Hospital, Sapienza University, 00189 Rome, Italy; (P.P.); (A.F.)
| | - Silvio Danese
- Faculty of Medicine and Surgery, Vita e Salute San Raffaele University, Via Olgettina, 20132 Milan, Italy;
- Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy
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Lauricella E, Vilisova S, Chaoul N, Giglio A, D'Angelo G, Porta C, Cives M. The current status of somatostatin analogs in the treatment of neuroendocrine tumors and future perspectives. Expert Rev Neurother 2025; 25:245-258. [PMID: 39415322 DOI: 10.1080/14737175.2024.2417419] [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: 07/31/2024] [Accepted: 10/13/2024] [Indexed: 10/18/2024]
Abstract
INTRODUCTION Somatostatin analogs (SSAs) were developed as antisecretory agents to palliate hormonal symptoms in patients with functioning neuroendocrine tumors (NETs). Their antiproliferative activity has been established in the phase 3 PROMID and CLARINET trials. SSAs currently represent the standard first-line therapy for the majority of well-differentiated G1/G2 gastroenteropancreatic NETs as well as for pulmonary NETs. AREAS COVERED An update on the clinical applications of established SSAs for the treatment of NETs is provided. Perspectives on emerging nonpeptide SSAs such as paltusotine and innovative formulations of octreotide (CAM2029) are included. EXPERT OPINION SSAs represent the cornerstone of treatment for both functioning and nonfunctioning NETs. While standard-dose SSAs have a defined place in the therapeutic algorithm of well-differentiated NETs, uncertainties remain on how to best integrate above-label doses of SSAs in the treatment sequence, particularly when tumor control is the goal. Octreotide and lanreotide appear to be clinically interchangeable, and no signs of superiority of one agent over the other has been observed so far. Whether SSAs may be exploited in the maintenance setting following more aggressive treatments, whether continuing SSAs beyond-progression after first-line therapy could be an effective treatment strategy, and whether new-generation SSAs such as pasireotide could overcome resistance to established SSAs are key areas of investigation.
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Affiliation(s)
- Eleonora Lauricella
- Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy
| | - Sofija Vilisova
- Department of Oncology, Pauls Stradins Clinical University Hospital, Riga, Latvia
| | - Nada Chaoul
- Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy
| | - Andrea Giglio
- Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy
| | - Gabriella D'Angelo
- Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy
| | - Camillo Porta
- Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, Bari, Italy
| | - Mauro Cives
- Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, Bari, Italy
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Marasco M, Dell'Unto E, Laviano A, Campana D, Panzuto F. Gastrointestinal side effects of somatostatin analogs in neuroendocrine tumors: a focused review. J Gastroenterol Hepatol 2024; 39:1737-1744. [PMID: 38783558 DOI: 10.1111/jgh.16638] [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] [Revised: 04/06/2024] [Accepted: 05/16/2024] [Indexed: 05/25/2024]
Abstract
Neuroendocrine tumors (NETs) are a group of well-differentiated heterogeneous neoplasms characterized by slow progression and distinct clinical and biological behavior. In the majority of patients with NET, first-line treatment is represented by somatostatin analogs (SSAs) that, despite being drugs with high tolerability (even at high doses) and providing to carcinoid symptoms control and anti-proliferative effects, may present some side effects, with potential impact on quality of life and nutritional status. The most frequent side effects are represented by gastrointestinal events in particular alterations in bowel habits (diarrhea and constipation), abdominal pain, exocrine pancreatic insufficiency, and cholelithiasis. Considering the relative rarity of NETs, literature about frequency and standard clinical management of adverse events SSA-related is still lacking and heterogeneous. The aim of this review is to arm gastroenterologists and other physicians treating NET patients with essential knowledge on the side effects of SSAs. By identifying and managing these adverse events early, healthcare professionals can offer optimal care, avert foreseeable complications, and ensure the best outcomes for patients. Without such early recognition, there is a risk of diminishing the patient's quality of life and their ability to sustain treatment over time.
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Affiliation(s)
- Matteo Marasco
- Department of Medical-Surgical Sciences and Translational Medicine, Sapienza University of Rome, Digestive Disease Unit, ENETS Center of Excellence, Sant'Andrea University Hospital, Rome, Italy
- PhD in Translational Medicine and Oncology, Sapienza University of Rome, Rome, Italy
| | - Elisabetta Dell'Unto
- Department of Medical-Surgical Sciences and Translational Medicine, Sapienza University of Rome, Digestive Disease Unit, ENETS Center of Excellence, Sant'Andrea University Hospital, Rome, Italy
| | - Alessandro Laviano
- Department of Translational and Precision Medicine, Sapienza University of Rome, Clinical Nutrition Unit, Sant'Andrea University Hospital, Rome, Italy
| | - Davide Campana
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum - University of Bologna, Medical Oncology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Francesco Panzuto
- Department of Medical-Surgical Sciences and Translational Medicine, Sapienza University of Rome, Digestive Disease Unit, ENETS Center of Excellence, Sant'Andrea University Hospital, Rome, Italy
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Lamberti G, Panzuto F, Pavel M, O'Toole D, Ambrosini V, Falconi M, Garcia-Carbonero R, Riechelmann RP, Rindi G, Campana D. Gastric neuroendocrine neoplasms. Nat Rev Dis Primers 2024; 10:25. [PMID: 38605021 DOI: 10.1038/s41572-024-00508-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/27/2024] [Indexed: 04/13/2024]
Abstract
Gastric neuroendocrine neoplasms (gNENs) display peculiar site-specific features among all NENs. Their incidence and prevalence have been rising in the past few decades. gNENs comprise gastric neuroendocrine carcinomas (gNECs) and gastric neuroendocrine tumours (gNETs), the latter further classified into three types. Type I anatype II gNETs are gastrin-dependent and develop in chronic atrophic gastritis and as part of Zollinger-Ellison syndrome within a multiple endocrine neoplasia type 1 syndrome (MEN1), respectively. Type III or sporadic gNETs develop in the absence of hypergastrinaemia and in the context of a near-normal or inflamed gastric mucosa. gNECs can also develop in the context of variable atrophic, relatively normal or inflamed gastric mucosa. Each gNEN type has different clinical characteristics and requires a different multidisciplinary approach in expert dedicated centres. Type I gNETs are managed mainly by endoscopy or surgery, whereas the treatment of type II gNETs largely depends on the management of the concomitant MEN1. Type III gNETs may require both locoregional approaches and systemic treatments; NECs are often metastatic and therefore require systemic treatment. Specific data regarding the systemic treatment of gNENs are lacking and are derived from the treatment of intestinal NETs and NECs. An enhanced understanding of molecular and clinical pathophysiology is needed to improve the management and outcomes of patients' gNETs.
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Affiliation(s)
- Giuseppe Lamberti
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum - University of Bologna, Bologna, Italy
- Medical Oncology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Francesco Panzuto
- Department of Medical-Surgical Sciences and Translational Medicine, Sapienza University of Rome, Rome, Italy
- Digestive Disease Unit, Sant'Andrea University Hospital, ENETS Center of Excellence, Rome, Italy
| | - Marianne Pavel
- Department of Medicine 1, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Dermot O'Toole
- National Centre for Neuroendocrine Tumours, ENETS Centre of Excellence, St. Vincent's University Hospital, Dublin, Ireland
- Trinity College Dublin, St. James Hospital, Dublin, Ireland
| | - Valentina Ambrosini
- Nuclear Medicine, Alma Mater Studiorum University of Bologna, Bologna, Italy
- Nuclear Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Massimo Falconi
- Pancreatic Surgery, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Rocio Garcia-Carbonero
- Medicine Department, Universidad Complutense de Madrid, Madrid, Spain
- Oncology Department, Hospital Universitario 12 de Octubre, Imas12, Madrid, Spain
| | | | - Guido Rindi
- Section of Anatomic Pathology, Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Woman and Child Health Sciences and Public Health, Anatomic Pathology Unit, Fondazione Policlinico Universitario A. Gemelli - IRCCS, ENETS Center of Excellence, Rome, Italy
| | - Davide Campana
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum - University of Bologna, Bologna, Italy.
- Medical Oncology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
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Faggiano A. Long-acting somatostatin analogs and well differentiated neuroendocrine tumors: a 20-year-old story. J Endocrinol Invest 2024; 47:35-46. [PMID: 37581846 PMCID: PMC10776682 DOI: 10.1007/s40618-023-02170-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 07/28/2023] [Indexed: 08/16/2023]
Abstract
PURPOSE The specific indications of somatostatin analogs (SSAs) in patients with neuroendocrine tumor (NET) emerged over the time. The objective of this review is to summarize and discuss the most relevant data concerning long-acting SSAs in NET. METHODS A narrative review was performed including publications focusing on therapy with the long-acting octreotide, lanreotide, and pasireotide in patients with NET. RESULTS Long-acting SSAs confirm to be a manageable and widely used tool in patients with NET. Both long-acting octreotide and lanreotide are safe as the short-acting formulations, while patient compliance and adherence is further improved. Together with some randomized phase-3 trials, many retrospective and prospective studies have been performed in the last 20 years revealing a variable but substantial impact on progression free survival, not only in gastroenteropancreatic but also in lung and unknown primary NETs. The most frequent tumor response to SSAs is stable disease, but an objective response can be observed, more frequently by using high-dose schedules and in MEN1-related pancreatic NETs. Low tumor burden, low tumor grade (G1 and low G2), good performance status and use as first-line therapy are the main predictive factors to SSAs in NET patients. Pasireotide has been evaluated in few studies. This compound remains a promising SSA and would deserve to be further evaluated as a potential additional indication in NET therapy. CONCLUSIONS Long-acting SSAs are an effective and safe initial therapy of patients with well differentiated NET, allowing tumor growth as well as symptoms control for long-time in selected patients.
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Affiliation(s)
- A Faggiano
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Sant'Andrea Hospital, ENETS Center of Excellence, Via di Grottarossa 1038, 00189, Rome, Italy.
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Ghorbani M, Hekmatdoost A, Darabi Z, Sadeghi A, Yari Z. Dietary inflammatory index and risk of gallstone disease in Iranian women: a case-control study. BMC Gastroenterol 2023; 23:311. [PMID: 37710148 PMCID: PMC10500896 DOI: 10.1186/s12876-023-02943-9] [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: 05/20/2023] [Accepted: 08/31/2023] [Indexed: 09/16/2023] Open
Abstract
BACKGROUND Considering inflammation as a primary occurrence in gallstone formation, this study aimed to determine the relation between serum biomarkers of inflammation and oxidative stress, and dietary Inflammatory Index (DII) score with the risk of gallstone disease (GD) among Iranian women. MATERIALS AND METHODS Present BMI-matched case-control study was performed among 75 women with GD and 75 healthy controls. Biochemical parameters were measured by standard laboratory methods. A validated food frequency questionnaire (FFQ) was used to assess the usual intake of participants. DII score was calculated for all participants. The linear and logistic regression were used to examine the association of DII with serum inflammatory biomarkers and the odds ratio of GD, respectively. RESULTS The mean serum levels of high-sensitivity C-reactive protein (hs-CRP) and Malondialdehyde (MDA) were significantly (P < 0.001) higher in GD patients compared to control subjects. Women in the highest tertile of DII compared to the lowest tertile had lower intake of macronutrients, minerals, vitamins garlic, onion, pepper and fiber. Moreover, the odd of GD was significantly higher in the third tertile of the DII versus the first tertile after adjustment of potential confounders (OR: 17.47; 95% CI: 4.64-65.72). Also, a positive and significant relationship was found between the serum level of inflammatory biomarkers with the risk of GD and the inflammatory score of the diet (P < 0.001). CONCLUSION Our data indicate that higher DII score, and serum inflammatory and oxidative stress biomarkers are related to higher risk of GD in Iranian women.
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Affiliation(s)
- Moloud Ghorbani
- Department of Community Nutrition, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Azita Hekmatdoost
- Clinical Nutrition and Dietetics Department, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences Tehran, Tehran, Iran
| | - Zahra Darabi
- Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Amir Sadeghi
- Department of Adult Gastroenterology and Hepatology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Yari
- Department of Nutrition Research, National Nutrition and Food Technology Research Institute, Faculty of Nutrition Sciences & Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Kupietzky A, Dover R, Mazeh H. Surgical aspects of small intestinal neuroendocrine tumors. World J Gastrointest Surg 2023; 15:566-577. [PMID: 37206065 PMCID: PMC10190731 DOI: 10.4240/wjgs.v15.i4.566] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 02/25/2023] [Accepted: 03/27/2023] [Indexed: 04/22/2023] Open
Abstract
Small intestinal neuroendocrine tumors (NETs) are a heterogeneous group of epithelial tumors with a predominant neuroendocrine differentiation. Although NETs are usually considered rare neoplasms, small intestinal NETs are the most common primary malignancy of the small bowel, with an increasing prevalence worldwide during the course of the past few decades. The indolent nature of these tumors often leads to a delayed diagnosis, resulting in over one-third of patients presenting with synchronous metastases. Primary tumor resection remains the only curative option for this type of tumor. In this review article, the various surgical aspects for the excision of small intestinal NETs are discussed.
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Affiliation(s)
- Amram Kupietzky
- Department of Surgery, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91240, Israel
| | - Roi Dover
- Department of Surgery, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91240, Israel
| | - Haggi Mazeh
- Department of Surgery, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91240, Israel
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Chemotherapy in Well Differentiated Neuroendocrine Tumors (NET) G1, G2, and G3: A Narrative Review. J Clin Med 2023; 12:jcm12020717. [PMID: 36675645 PMCID: PMC9861419 DOI: 10.3390/jcm12020717] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 01/08/2023] [Accepted: 01/13/2023] [Indexed: 01/19/2023] Open
Abstract
Neuroendocrine tumors (NETs) are rare neoplasms with a wide spectrum of clinical behavior, from the long survival of well-differentiated NETs to the dismal prognosis of high-grade neuroendocrine carcinomas (NECs), being G3 NETs a recently recognized intermediate entity. While the role of chemotherapy is well established in NECs, data on NETs mostly derives from small studies, experts' opinions, and extrapolating results from small-cell lung cancer studies. This narrative review aims to summarize available evidence about the use of chemotherapy in the setting of G1-2 NETs and G3 NETs. We performed literature research in PubMed Library for all articles published up to September 2022 about the efficacy of chemotherapy in NETs. Treatment regimens with STZ-5FU, CAPTEM, and anti-metabolite-based treatment are the most active and tolerated in gastroenteropancreatic NETs (GEP-NETs) G1-G2, while platinum-based regimens (FOLFOX/XELOX) and TEM/CAPTEM showed the best activity in thoracic NETs. Solid evidence about chemotherapy efficacy in G3 NETs is still lacking. Literature data support the use of chemotherapy in low-intermediate grade NETs after the failure of other therapies or if tumor shrinkage is needed. Studies assessing G3 NETs independently from NECs are needed to better understand the role of chemotherapy in this setting.
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The Antiproliferative Activity of High-Dose Somatostatin Analogs in Gastro-Entero-Pancreatic Neuroendocrine Tumors: A Systematic Review and Meta-Analysis. J Clin Med 2022; 11:jcm11206127. [PMID: 36294448 PMCID: PMC9605244 DOI: 10.3390/jcm11206127] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/13/2022] [Accepted: 10/14/2022] [Indexed: 11/18/2022] Open
Abstract
Background: The antiproliferative activity of a high dose of somatostatin analogs (HD-SSA) in treating gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) remains under debate. Methods: A systematic review and proportion meta-analysis were made. The primary endpoint was the efficacy measured as incidence density ratio (IDR) at one year. The secondary endpoints were the disease control rate (DCR) and severe adverse events (SAEs). The heterogeneity (I2), when high (>50%), was interpreted by performing a univariate metaregression analysis, analyzing as covariates: type and design of the study, location (Europe or USA), sample size, grading according to 2017 WHO, the metastatic disease rate, previous therapy including surgery, and quality of the study. Results: A total of 11 studies with 783 patients were included. The IDR was 62 new progressions of 100 patients treated with HD-SSA every one year. The heterogeneity was high. The study’s year, type and design, primary tumor, grading, previous treatments, and quality of the studies did not influence the IDR. The IDR was significantly higher in USA centers and studies with more than 50 patients. The IDR was lower when a high rate of metastatic patients was present in the studies. The DCR was 45%. The heterogeneity was high. The DCR was lower in USA studies and in prospective trials. Conclusion: Given the limited efficacy of HD-SSA in preventing the disease progression in unresectable GEP-NENs after failure of standard dose SSA, the use of this therapeutic approach is advisable in selected cases when other antiproliferative treatments are not feasible.
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Lee BJH, Yap QV, Low JK, Chan YH, Shelat VG. Cholecystectomy for asymptomatic gallstones: Markov decision tree analysis. World J Clin Cases 2022; 10:10399-10412. [PMID: 36312509 PMCID: PMC9602237 DOI: 10.12998/wjcc.v10.i29.10399] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 05/13/2022] [Accepted: 09/01/2022] [Indexed: 02/05/2023] Open
Abstract
Gallstones are a common public health problem, especially in developed countries. There are an increasing number of patients who are diagnosed with gallstones due to increasing awareness and liberal use of imaging, with 22.6%-80% of gallstone patients being asymptomatic at the time of diagnosis. Despite being asymptomatic, this group of patients are still at life-long risk of developing symptoms and complications such as acute cholangitis and acute biliary pancreatitis. Hence, while early prophylactic cholecystectomy may have some benefits in selected groups of patients, the current standard practice is to recommend cholecystectomy only after symptoms or complications occur. After reviewing the current evidence about the natural course of asymptomatic gallstones, complications of cholecystectomy, quality of life outcomes, and economic outcomes, we recommend that the option of cholecystectomy should be discussed with all asymptomatic gallstone patients. Disclosure of material information is essential for patients to make an informed choice for prophylactic cholecystectomy. It is for the patient to decide on watchful waiting or prophylactic cholecystectomy, and not for the medical community to make a blanket policy of watchful waiting for asymptomatic gallstone patients. For patients with high-risk profiles, it is clinically justifiable to advocate cholecystectomy to minimize the likelihood of morbidity due to complications.
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Affiliation(s)
- Brian Juin Hsien Lee
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore S308232, Singapore
| | - Qai Ven Yap
- Biostatistics Unit, Yong Loo Lin School of Medicine, National University of Singapore, Singapore S117597, Singapore
| | - Jee Keem Low
- Department of General Surgery, Tan Tock Seng Hospital, Singapore S308433, Singapore
| | - Yiong Huak Chan
- Biostatistics Unit, Yong Loo Lin School of Medicine, National University of Singapore, Singapore S117597, Singapore
| | - Vishal G Shelat
- Department of General Surgery, Tan Tock Seng Hospital, Singapore S308433, Singapore
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Lisotti A, Napoleon B, Fabbri C, Anderloni A, Linguerri R, Bacchilega I, Fusaroli P. Treatment of acute cholecystitis in high-risk surgical patients. Minerva Gastroenterol (Torino) 2022; 68:154-161. [PMID: 33793158 DOI: 10.23736/s2724-5985.21.02854-3] [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] [Indexed: 12/07/2022]
Abstract
INTRODUCTION Acute cholecystitis (AC) is the most common biliary stone disease complication. While there is consensus regarding cholecystectomy for AC, gallbladder drainage is indicated in elderly or high-risk surgical patients. EVIDENCE ACQUISITION We systematically reviewed available evidence in the field of EUS-guided gallbladder drainage (EUS-GBD) for AC in high-risk surgical patients. The studies were classified according to their level of evidence (LE) according to the Oxford Centre for Evidence Based Medicine classification. EVIDENCE SYNTHESIS Literature search retrieved 175 manuscripts; most of them were expert opinions (LE V, N.=53) or case-series (LE IV, N.=29). There was no meta-analysis of RCT (LE Ia), while two randomized controlled trials (LE Ib) demonstrated that EUS-GBD was superior to percutaneous transhepatic-GBD (PT-GBD) regarding long-term outcomes (adverse events, recurrent cholecystitis, and reintervention). Several meta-analyses of cohort studies (LE IIa, N.=11) were designed to compare the three available drainage strategies (endoscopic, echoendoscopic and percutaneous) and to assess the pooled risk of adverse events. Comparison between surgery and EUS-GBD was done in a single retrospective study with a propensity score analysis (LE III). The outcomes of conversion from PT-GBD to EUS-GBD were covered by few retrospective studies (LE III). Several manuscripts (N.=69) were published on EUS-GBD as a rescue strategy in case of malignant biliary obstruction. CONCLUSIONS The levels of evidence of EUS-GBD in the literature have evolved from initial descriptive studies to recent randomized controlled trials and meta-analysis of cohort studies. While several articles addressed the comparison among different techniques for GBD, in our opinion some topics and questions have not been adequately investigated. are still debated.
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Affiliation(s)
- Andrea Lisotti
- Unit of Gastroenterology, Department of Medical and Surgical Sciences, Hospital of Imola, University of Bologna, Bologna, Italy -
| | - Bertrand Napoleon
- Department of Gastroenterology, Jean Mermoz Hospital, Ramsay Générale de Santé, Lyon, France
| | - Carlo Fabbri
- Unit of Gastroenterology, Hospital of Forli-Cesena, AUSL Romagna, Forli-Cesena, Italy
| | - Andrea Anderloni
- Unit of Digestive Endoscopy, Division of Gastroenterology, IRCCS Humanitas Clinic, Rozzano, Milan, Italy
| | | | - Igor Bacchilega
- Intensive Care Unit, Hospital of Imola, Imola, Bologna, Italy
| | - Pietro Fusaroli
- Unit of Gastroenterology, Department of Medical and Surgical Sciences, Hospital of Imola, University of Bologna, Bologna, Italy
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13
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Lee L, Ramos-Alvarez I, Jensen RT. Predictive Factors for Resistant Disease with Medical/Radiologic/Liver-Directed Anti-Tumor Treatments in Patients with Advanced Pancreatic Neuroendocrine Neoplasms: Recent Advances and Controversies. Cancers (Basel) 2022; 14:1250. [PMID: 35267558 PMCID: PMC8909561 DOI: 10.3390/cancers14051250] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/08/2022] [Accepted: 02/23/2022] [Indexed: 12/14/2022] Open
Abstract
Purpose: Recent advances in the diagnosis, management and nonsurgical treatment of patients with advanced pancreatic neuroendocrine neoplasms (panNENs) have led to an emerging need for sensitive and useful prognostic factors for predicting responses/survival. Areas covered: The predictive value of a number of reported prognostic factors including clinically-related factors (clinical/laboratory/imaging/treatment-related factors), pathological factors (histological/classification/grading), and molecular factors, on therapeutic outcomes of anti-tumor medical therapies with molecular targeting agents (everolimus/sunitinib/somatostatin analogues), chemotherapy, radiological therapy with peptide receptor radionuclide therapy, or liver-directed therapies (embolization/chemoembolization/radio-embolization (SIRTs)) are reviewed. Recent findings in each of these areas, as well as remaining controversies and uncertainties, are discussed in detail, particularly from the viewpoint of treatment sequencing. Conclusions: The recent increase in the number of available therapeutic agents for the nonsurgical treatment of patients with advanced panNENs have raised the importance of prognostic factors predictive for therapeutic outcomes of each treatment option. The establishment of sensitive and useful prognostic markers will have a significant impact on optimal treatment selection, as well as in tailoring the therapeutic sequence, and for maximizing the survival benefit of each individual patient. In the paper, the progress in this area, as well as the controversies/uncertainties, are reviewed.
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Affiliation(s)
- Lingaku Lee
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA; (L.L.); (I.R.-A.)
- National Kyushu Cancer Center, Department of Hepato-Biliary-Pancreatology, Fukuoka 811-1395, Japan
| | - Irene Ramos-Alvarez
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA; (L.L.); (I.R.-A.)
| | - Robert T. Jensen
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA; (L.L.); (I.R.-A.)
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14
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Lisotti A, Linguerri R, Bacchilega I, Cominardi A, Marocchi G, Fusaroli P. EUS-guided gallbladder drainage in high-risk surgical patients with acute cholecystitis-procedure outcomes and evaluation of mortality predictors. Surg Endosc 2022; 36:569-578. [PMID: 33507383 PMCID: PMC7842173 DOI: 10.1007/s00464-021-08318-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 01/09/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Recent evidences suggest that gallbladder drainage is the treatment of choice in elderly or high-risk surgical patients with acute cholecystitis (AC). Despite better outcomes compared to other approaches, endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) is burdened by high mortality. The aim of the study was to evaluate predictive factors for mortality in high-risk surgical patients who underwent EUS-GBD for AC. METHODS A retrospective analysis of a prospectively maintained database was performed. Electrocautery-enhanced lumen-apposing metal stents were used; all recorded variables were evaluated as potential predictive factors for mortality. RESULTS Thirty-four patients underwent EUS for suspected AC and 25 (44% male, age 78) were finally included. Technical, clinical success rate and adverse events rate were 92%, 88%, and 16%, respectively. 30-day and 1-year mortality were 12% and 32%. On univariate analysis, age-adjusted Charlson Comorbidity Index (CCI) (OR 20.8[4-68.2]), acute kidney injury (AKI) (OR 21.4[2.6-52.1]) and clinical success (OR 8.9[1.2-11.6]) were related to 30-day mortality. On multivariate analysis, CCI and AKI were independently related to long-term mortality. Kaplan-Meier curves showed an increased long-term mortality in patients with CCI > 6 (hazard ratio 7.6[1.7-34.6]) and AKI (hazard ratio 11.3[1.4-91.5]). CONCLUSIONS Severe comorbidities and AKI were independent predictive factors confirming of long-term mortality after EUS-GBD. Outcomes of EUS-GBD appear more influenced by patients' conditions rather than by procedure success.
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Affiliation(s)
- Andrea Lisotti
- Department of Medical and Surgical Sciences, Gastroenterology Unit, Hospital of Imola, University of Bologna, Via Montericco 4, 40026, Imola, BO, Italy.
| | | | | | - Anna Cominardi
- Department of Medical and Surgical Sciences, Gastroenterology Unit, Hospital of Imola, University of Bologna, Via Montericco 4, 40026, Imola, BO, Italy
| | - Gianmarco Marocchi
- Department of Medical and Surgical Sciences, Gastroenterology Unit, Hospital of Imola, University of Bologna, Via Montericco 4, 40026, Imola, BO, Italy
| | - Pietro Fusaroli
- Department of Medical and Surgical Sciences, Gastroenterology Unit, Hospital of Imola, University of Bologna, Via Montericco 4, 40026, Imola, BO, Italy
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15
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Han ZH, He ZM, Chen WH, Wang CY, Wang Q. Octreotide-induced acute life-threatening gallstones after vicarious contrast medium excretion: A case report. World J Clin Cases 2021; 9:7484-7489. [PMID: 34616816 PMCID: PMC8464451 DOI: 10.12998/wjcc.v9.i25.7484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 05/12/2021] [Accepted: 07/16/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Octreotide is widely used for the treatment of acromegaly, neuroendocrine tumors, and secretory diarrhea. However, long-term octreotide treatment can increase the incidence of gallstones. Vicarious contrast medium excretion (VCME) through the hepatobiliary system is well known. However, few studies have reported octreotide-induced acute gallstones following VCME.
CASE SUMMARY A 69-year-old man presented with left lower back pain and hematuria caused by a fall. The patient had a history of polycystic kidney disease. VCME occurred following renal artery embolization for a ruptured polycystic kidney. After 5 d of treatment with octreotide, the patient developed acute gallstones and intrahepatic cholestasis which further induced pancreatitis and cholangitis. He was discharged after hemodialysis, antibiotics, and supportive treatments.
CONCLUSION For patients with a high-risk of VCME, octreotide should be cautiously administered and carefully monitored.
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Affiliation(s)
- Zong-Hong Han
- Department of Interventional Radiology, The First People’s Hospital of Changzhou, Changzhou 213003, Jiangsu Province, China
| | - Zhong-Ming He
- Department of Interventional Radiology, The First People’s Hospital of Changzhou, Changzhou 213003, Jiangsu Province, China
| | - Wen-Hua Chen
- Department of Interventional Radiology, The First People’s Hospital of Changzhou, Changzhou 213003, Jiangsu Province, China
| | - Cao-Ye Wang
- Department of Interventional Radiology, The First People’s Hospital of Changzhou, Changzhou 213003, Jiangsu Province, China
| | - Qi Wang
- Department of Interventional Radiology, The First People’s Hospital of Changzhou, Changzhou 213003, Jiangsu Province, China
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16
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Demographic, Chemical, and Helicobacter pylori Positivity Assessment in Different Types of Gallstones and the Bile in a Random Sample of Cholecystectomied Iranian Patients with Cholelithiasis. Can J Gastroenterol Hepatol 2021; 2021:3351352. [PMID: 34422710 PMCID: PMC8371640 DOI: 10.1155/2021/3351352] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/30/2021] [Accepted: 08/04/2021] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND The occurrence of stones in the gallbladder or common bile duct and the symptoms and complications they cause is called gallstone disease. The symptoms of gallstone disease range from mild, nonspecific symptoms to a severe right quadrant abdominal pain. Characteristics of gallstone types in an Iranian population have not been well studied before and there are very limited studies on the demographic pattern of stone types in our country, so this study is one of the first studies on its kind on the epidemiology of gallstone types in Iran. As information on chemical components of the stone will help in the management and prevention of gallstones, in this study, we aimed to do chemical component analysis of gallstones including cholesterol, bilirubin, and calcium. Given the conflicting reports about the relationship between H. pylori infections and gallstone formation, this study aimed to investigate the relationship between H. pylori positivity in the bile specimen of Iranian patients with cholelithiasis and formation and type of stone. METHODS This prospective study reviewed a total of 196 patients who underwent cholecystectomy for symptomatic cholelithiasis at Shahid Beheshti Training and Research Hospital affiliated to the Yasuj University of Medical Sciences between September 2015 and May 2018. Chemical analysis of gallstone components performed using the colorimetry method. Microbiological analysis for H. pylori was done using the OnSite H. pylori Ag Rapid Test on the bile sample. For the validation test of bile, the H. pylori Rapid Stool Ag Test on stool was used, and Cohen's Kappa statistical analysis was done next. RESULTS There were significant associations between the stone types and age, chemical composition of the stones such as calcium, cholesterol, and bilirubin levels, and also H. pylori positivity and cholesterol and bilirubin levels; however, no significant association was found between the stone types and sex, H. pylori positivity and age, sex, stone types, and calcium level. The main bile and validity tests were matched to the substantial agreement according to Cohen's Kappa analysis. The most common drugs used were proton pump inhibitors, nonsteroidal anti-inflammatory drugs, antihypertensive drugs, and oral contraceptives. CONCLUSIONS This study suggested that the chemical composition of the stones could predict the presence of bacteria, there is no correlation between H. pylori and gallstone formation, and some of the drugs could be predisposing factors for gallstones. This work provides an objective basis for further research into gallbladder stone formation; meanwhile, it has great significance in the treatment and prevention of gallbladder stones. Trial registration. The project was found to be in accordance to the ethical principles and the national norms and standards for conducting research in Iran with the approval ID IR.YUMS.REC.1399.147 and date 2020.09.23, and this project is the result of a residency dissertation to obtain the specialty in general surgery, which has been registered with the research project number 960159 in the Vice Chancellor for Research and Technology Development of the Yasuj University of Medical Sciences, Yasuj, Iran, URL: https://ethics.research.ac.ir/EthicsProposalViewEn.php?id=160634.
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17
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Prophylactic cholecystectomy is not mandatory in patients candidate to the resection for small intestine neuroendocrine neoplasms: a propensity score-matched and cost-minimization analysis. Updates Surg 2021; 74:991-998. [PMID: 34224086 PMCID: PMC9213268 DOI: 10.1007/s13304-021-01123-2] [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: 04/22/2021] [Accepted: 06/21/2021] [Indexed: 11/18/2022]
Abstract
To evaluate two competitive strategies in patients undergoing resection of Small-intestine neuroendocrine neoplasms (Si-NEN): prophylactic cholecystectomy (PC) versus On-demand delayed (OC) cholecystectomy. None comparative studies are available. This is a retrospective study based on 247 Si-NENs candidates for the primary tumor resection. Patients were divided into two arms: PC and OC. Propensity score matching was performed, reporting the d value. The primary outcome was the rehospitalization rate for any cause. The secondary endpoints were: the rehospitalization rate for biliary stone disease (BSD), the mean number of rehospitalization (any cause and BSD), the complication rate (all and severe). A P value < 0.05 was considered significant, and the number needed to treat (NNT) < 10 was considered clinically relevant. Before matching, 52 (21.1%) were in the PC arm and 195 (78.9%) in the OC group. The two arms have a sub-optimal balance for age (d = 0.575), symptoms (d = 0.661), ENETS TNM stage (d = 0.661). After matching, we included 52 patients in PC and 104 in OC one. The two groups are well balanced (all d values < 0.5). The rehospitalization rate was similar in the two groups (36% vs 31; P = 0.594; NNT = 21). The rehospitalization rate for BSD was lower in the PC arm than OC one (0% vs 7%) without statistical significance (P = 0.096) and relevance (NNT = 15). The mean number of readmission (any cause and BSD) and the complication rate (all and severe) were similar. PC was not mandatory in patients having Si-NEN and candidates to the resection of primary tumors.
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18
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Aapkes SE, de Haas RJ, Bernts LHP, Blijdorp CJ, Dekker SEI, van Gastel MDA, Meijer E, Veldman A, Drenth JPH, Gansevoort RT. Incident Gallstones During Somatostatin Analog Treatment are Associated with Acute Biliary Complications Especially After Discontinuation. Drugs R D 2021; 21:179-188. [PMID: 33779943 PMCID: PMC8206401 DOI: 10.1007/s40268-021-00342-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/10/2021] [Indexed: 12/23/2022] Open
Abstract
INTRODUCTION Gallstones are a known adverse effect of somatostatin analogs, but the exact incidence and clinical implications are unknown. OBJECTIVES The aim of this study was to investigate the incidence of gallstones on imaging and related complications in unbiased trial data. METHODS Data from the DIPAK 1 trial, in which 305 polycystic kidney disease patients were randomized to standard of care (SoC) or lanreotide for 120 weeks, were used. Magnetic resonance imaging (MRI) was performed at baseline and end of treatment and was assessed for the presence, number, and size of gallstones. For all patients who had gallstones at the end of the trial, we obtained follow-up after the trial. RESULTS Of 249 patients with data available, 11 patients randomized to lanreotide and four randomized to SoC had gallstones at baseline. During the study, new gallstones were formed in 19/124 patients using lanreotide (15%) and 1/125 patients receiving SoC (1%). The odds ratio for gallstone formation with lanreotide use was 25.9 (95% confidence interval 3.37-198.8; p < 0.001). Gallstones during lanreotide treatment were multiple (> 20 stones in 69% of patients) and small (≤ 3 mm in 63% of patients). Of the 19 patients with incident gallstones during lanreotide treatment, 9 experienced gallstone-associated complications, 8 of whom experienced gallstone-associated complications after discontinuation of treatment (median time after discontinuation 2.5 years). In patients with gallstones at baseline and in patients receiving SoC, no complications occurred. CONCLUSIONS Treatment with a somatostatin analog leads to the formation of multiple, small gallstones that are associated with severe complications, especially after discontinuation of therapy. CLINICAL TRIAL REGISTRY WEBSITE AND TRIAL NUMBER ClinicalTrials.gov ( https://clinicaltrials.gov ); NCT01616927.
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Affiliation(s)
- Sophie E Aapkes
- Department of Nephrology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands
| | - Robbert J de Haas
- Department of Radiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Lucas H P Bernts
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Charles J Blijdorp
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Sosha E I Dekker
- Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | - Maatje D A van Gastel
- Department of Nephrology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands
| | - Esther Meijer
- Department of Nephrology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands
| | - Abigail Veldman
- Department of Nephrology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ron T Gansevoort
- Department of Nephrology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.
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Prencipe N, Bona C, Cuboni D, Parasiliti-Caprino M, Berton AM, Fenoglio LM, Gasco V, Ghigo E, Grottoli S. Biliary adverse events in acromegaly during somatostatin receptor ligands: predictors of onset and response to ursodeoxycholic acid treatment. Pituitary 2021; 24:242-251. [PMID: 33164134 PMCID: PMC7966199 DOI: 10.1007/s11102-020-01102-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/23/2020] [Indexed: 01/03/2023]
Abstract
PURPOSE Somatostatin receptor ligands (SRL) are the first-line medical treatment for acromegaly. Gallbladder alterations are one of most important SRL side effect, but according to some authors growth hormone hypersecretion itself is a risk factor for gallstones. This single center, longitudinal retrospective study evaluated the incidence and the predictors of biliary adverse events (BAE) in acromegaly during SRL therapy and their response to ursodeoxycholic acid (UDCA). METHODS 91 acromegaly patients with indication to SRL were enrolled. Evaluations of acromegaly activity (GH, IGF-I, IGF-I/ULN) and metabolic profile were collected before starting treatment, yearly during follow-up and at BAE onset. In patients developing BAE we searched for predictors of UDCA effectiveness. RESULTS 61.5% of patients developed BAE (58.9% cholelithiasis; 41.1% only sludge). IGF-I and IGF-I/ULN proved to be positive predictor of BAE, which occur about 5 years after SRL starting. None of metabolic markers proved to be associated with BAE. Only five patients (5.5%) underwent cholecystectomy for symptomatic cholelithiasis. 71% of patients started UDCA treatment, achieving regression of BAE in 60% of cases (88% in patients developing only sludge and 30% in patients affected by cholelithiasis, p < 0.001). BMI and obesity were negative predictors of UDCA efficacy. In 50% of the subjects BAE resolved after 36 months of therapy with a lower rate if cholelithiasis was present. CONCLUSION Biliary stone disease is a frequent SRL adverse event, although it is often symptomless. Ultrasound follow-up mainly in the first 5 years of therapy, early UDCA starting and proper lifestyle represent a valid strategy in their detection and management.
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Affiliation(s)
- N Prencipe
- Division of Endocrinology, Diabetology and Metabolism, Department of Medical Science, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy.
| | - C Bona
- Division of Endocrinology, Diabetology and Metabolism, Department of Medical Science, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy
| | - D Cuboni
- Division of Endocrinology, Diabetology and Metabolism, Department of Medical Science, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy
| | - M Parasiliti-Caprino
- Division of Endocrinology, Diabetology and Metabolism, Department of Medical Science, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy
| | - A M Berton
- Division of Endocrinology, Diabetology and Metabolism, Department of Medical Science, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy
| | - L M Fenoglio
- Division of Internal Medicine, Santa Croce and Carle General Teaching Hospital, Cuneo, Italy
| | - V Gasco
- Division of Endocrinology, Diabetology and Metabolism, Department of Medical Science, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy
| | - E Ghigo
- Division of Endocrinology, Diabetology and Metabolism, Department of Medical Science, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy
| | - S Grottoli
- Division of Endocrinology, Diabetology and Metabolism, Department of Medical Science, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy
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Araz M, Baltacioglu MH, Saglam S, Ozguven MA, Kucuk NO. Gallbladder Uptake Mimicking Liver Metastasis on 177Lu-DOTATATE Posttherapy Scan Gallbladder Uptake on 177Lu-DOTATATE Scan. Clin Nucl Med 2021; 46:e154-e155. [PMID: 33512839 DOI: 10.1097/rlu.0000000000003475] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
We represent the case of a 61-year-old man with atypical carcinoid tumor of the lung. On posttherapy 177Lu-DOTATATE whole-body scan, focal intense uptake in the inferomedial side of the liver was detected. Pretherapy 68Ga-DOTATATE PET/CT showed no sign of liver metastasis, and posttherapy diagnostic dynamic liver MRI is used to exclude metastatic liver disease. Focal intense uptake was attributed to physiological gallbladder uptake.
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Affiliation(s)
- Mine Araz
- From the Department of Nuclear Medicine, Ankara University Medical School, Ankara
| | | | - Sezer Saglam
- Department of Medical Oncology, Demiroglu Bilim University, Istanbul
| | | | - Nuriye Ozlem Kucuk
- From the Department of Nuclear Medicine, Ankara University Medical School, Ankara
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21
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Shamsi BH, Chatoo M, Xu XK, Xu X, Chen XQ. Versatile Functions of Somatostatin and Somatostatin Receptors in the Gastrointestinal System. Front Endocrinol (Lausanne) 2021; 12:652363. [PMID: 33796080 PMCID: PMC8009181 DOI: 10.3389/fendo.2021.652363] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 02/19/2021] [Indexed: 01/03/2023] Open
Abstract
Somatostatin (SST) and somatostatin receptors (SSTRs) play an important role in the brain and gastrointestinal (GI) system. SST is produced in various organs and cells, and the inhibitory function of somatostatin-containing cells is involved in a range of physiological functions and pathological modifications. The GI system is the largest endocrine organ for digestion and absorption, SST-endocrine cells and neurons in the GI system are a critical effecter to maintain homeostasis via SSTRs 1-5 and co-receptors, while SST-SSTRs are involved in chemo-sensory, mucus, and hormone secretion, motility, inflammation response, itch, and pain via the autocrine, paracrine, endocrine, and exoendocrine pathways. It is also a power inhibitor for tumor cell proliferation, severe inflammation, and post-operation complications, and is a first-line anti-cancer drug in clinical practice. This mini review focuses on the current function of producing SST endocrine cells and local neurons SST-SSTRs in the GI system, discusses new development prognostic markers, phosphate-specific antibodies, and molecular imaging emerging in diagnostics and therapy, and summarizes the mechanism of the SST family in basic research and clinical practice. Understanding of endocrines and neuroendocrines in SST-SSTRs in GI will provide an insight into advanced medicine in basic and clinical research.
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Affiliation(s)
- Bilal Haider Shamsi
- Department of Neurobiology, Department of Neurology of the Second Affiliated Hospital, School of Brain Science and Brain Medicine, Hangzhou, China
| | - Mahanand Chatoo
- Department of Neurobiology, Department of Neurology of the Second Affiliated Hospital, School of Brain Science and Brain Medicine, Hangzhou, China
| | - Xiao Kang Xu
- Department of Neurobiology, Department of Neurology of the Second Affiliated Hospital, School of Brain Science and Brain Medicine, Hangzhou, China
| | - Xun Xu
- College of Renji, Wenzhou Medical University, Wenzhou, China
| | - Xue Qun Chen
- Department of Neurobiology, Department of Neurology of the Second Affiliated Hospital, School of Brain Science and Brain Medicine, Hangzhou, China
- National Health Commission (NHC) and Chinese Academy of Medical Sciences (CAMS) Key Laboratory of Medical Neurobiology, Ministry of Education (MOE), Frontier Science Center for Brain Research and Brain Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China
- *Correspondence: Xue Qun Chen,
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Surgery and Perioperative Management in Small Intestinal Neuroendocrine Tumors. J Clin Med 2020; 9:jcm9072319. [PMID: 32708330 PMCID: PMC7408509 DOI: 10.3390/jcm9072319] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 07/14/2020] [Accepted: 07/16/2020] [Indexed: 12/19/2022] Open
Abstract
Small-intestinal neuroendocrine tumors (SI-NETs) are the most prevalent small bowel neoplasms with an increasing frequency. In the multimodal management of SI-NETs, surgery plays a key role, either in curative intent, even if R0 resection is feasible in only 20% of patients due to advanced stage at diagnosis, or palliative intent. Surgeons must be informed about the specific surgical management of SI-NETs according to their hormonal secretion, their usual dissemination at the time of diagnosis and the need for bowel-preserving surgery to avoid short bowel syndrome. The aim of this paper is to review the surgical indications and techniques, and perioperative and postoperative management of SI-NETs.
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23
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Jerram KL. Sialithosis from octreotide. BMJ Support Palliat Care 2020; 10:223. [DOI: 10.1136/bmjspcare-2019-002111] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 01/24/2020] [Indexed: 11/03/2022]
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de Mestier L, Lepage C, Baudin E, Coriat R, Courbon F, Couvelard A, Do Cao C, Frampas E, Gaujoux S, Gincul R, Goudet P, Lombard-Bohas C, Poncet G, Smith D, Ruszniewski P, Lecomte T, Bouché O, Walter T, Cadiot G. Digestive Neuroendocrine Neoplasms (NEN): French Intergroup clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, GTE, RENATEN, TENPATH, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFR). Dig Liver Dis 2020; 52:473-492. [PMID: 32234416 DOI: 10.1016/j.dld.2020.02.011] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 02/08/2020] [Accepted: 02/24/2020] [Indexed: 12/11/2022]
Abstract
INTRODUCTION This document is a summary of the French Intergroup guidelines regarding the management of digestive neuroendocrine neoplasms (NEN) published in February 2020 (www.tncd.org). METHODS All French medical societies involved in the management of NEN took part in this work. Recommendations were graded into four categories (A, B, C or D), according to the level of evidence found in the literature until May 2019. RESULTS The management of NEN is challenging because of their heterogeneity and the increasing complexity of diagnostic and therapeutic procedures. Pathological analysis is required for their diagnostic and prognostic characterization, which mainly relies on differentiation, grade and stage. The two main emergency situations are functioning syndromes and poorly-differentiated carcinoma. Chromogranin A is the main biochemical marker of NET, although of limited clinical interest. Initial characterization relies on morphological and isotopic imaging. The treatment of localized NET relies on watchful follow-up and local or surgical resection depending on its supposed aggressiveness. Treatment options for metastatic disease include surgery, somatostatin analogues, chemotherapy, targeted therapies, organ-driven locoregional therapies and peptide-receptor radionuclide therapy. As specific predictive factors of treatment efficacy are yet to be identified and head-to-head comparisons have not or only rarely been performed, the therapeutic strategy currently depends on prognostic factors. Cumulative toxicity and the impact of treatment on quality of life must be considered since survival is relatively long in most patients with NET. CONCLUSION These guidelines are proposed to achieve the most beneficial therapeutic strategy in clinical practice as the therapeutic landscape of NEN is becoming ever more complex. These recommendations are permanently being reviewed.
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Affiliation(s)
- Louis de Mestier
- Department of Gastroenterology-Pancreatology, ENETS Centre of Excellence, Beaujon Hospital (APHP) and Université de Paris, Clichy, France
| | - Come Lepage
- Department of Gastroenterology and Digestive Oncology, Dijon University Hospital, EPICAD INSERM LNC UMR 1231, University of Burgundy Dijon, France
| | - Eric Baudin
- Department of Nuclear Medicine and Endocrine Oncology, Gustave-Roussy Institute, Villejuif, France
| | - Romain Coriat
- Department of Gastroenterology and Digestive Oncology, Cochin Hospital (APHP) and Université de Paris, Paris, France
| | - Frédéric Courbon
- Department of Nuclear Medicine, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
| | - Anne Couvelard
- Department of Pathology of Bichat-Beaujon Hospitals (APHP), ENETS Centre of Excellence and Université de Paris, Paris, France
| | - Christine Do Cao
- Department of Endocrinology, Hôpital Claude Huriez, Lille University Hospital, Lille, France
| | - Eric Frampas
- Department of Radiology, Nantes University Hospital, Nantes, France
| | - Sébastien Gaujoux
- Department of Endocrine and Pancreatic Surgery, Cochin Hospital (APHP) and University of Paris, Paris, France
| | - Rodica Gincul
- Department of Gastroenterology, Ramsay Générale de Santé, Hôpital Privé Jean Mermoz, Lyon, France
| | - Pierre Goudet
- Department of Endocrine Surgery, Dijon University Hospital and University of Burgundy, Dijon, France
| | - Catherine Lombard-Bohas
- Department of Oncology, ENETS Centre of Excellence, Hospices Civils de Lyon and Lyon University, Lyon, France
| | - Gilles Poncet
- Department of Digestive Surgery, ENETS Centre of Excellence, Edouard Herriot Hospital and Lyon University, Lyon, France
| | - Denis Smith
- Department of Digestive Oncology, Haut-Lévèque Hospital and University of Bordeaux, Pessac, France
| | - Philippe Ruszniewski
- Department of Gastroenterology-Pancreatology, ENETS Centre of Excellence, Beaujon Hospital (APHP) and Université de Paris, Clichy, France
| | - Thierry Lecomte
- Department of Gastroenterology and Digestive Oncology, Tours University Hospital, Tours, France
| | - Olivier Bouché
- Department of Hepato-Gastroenterology and Digestive Oncology, Robert Debré University Hospital, Reims, France
| | - Thomas Walter
- Department of Oncology, ENETS Centre of Excellence, Hospices Civils de Lyon and Lyon University, Lyon, France
| | - Guillaume Cadiot
- Department of Hepato-Gastroenterology and Digestive Oncology, Robert Debré University Hospital, Reims, France.
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Brighi N, Panzuto F, Modica R, Gelsomino F, Albertelli M, Pusceddu S, Massironi S, Lamberti G, Rinzivillo M, Faggiano A, Spallanzani A, Ferone D, Prinzi N, Rossi RE, Annibale B, Colao AM, Campana D. Biliary Stone Disease in Patients with Neuroendocrine Tumors Treated with Somatostatin Analogs: A Multicenter Study. Oncologist 2020; 25:259-265. [PMID: 32162819 PMCID: PMC7066710 DOI: 10.1634/theoncologist.2019-0403] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 10/03/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Somatostatin analogs (SSAs) are the mainstay of neuroendocrine tumor (NET) treatment. Biliary stone disease is reported as a common side effect of SSAs, with a frequency ranging from 10% to 63%. Studies on SSA-treated patients for acromegaly report an increased incidence of biliary stone disease compared with the general population, whereas data on patients with NETs are few. Guidelines are based on weak evidence, thus resulting in conflicting recommendations. The aim of the study is to evaluate biliary stone disease incidence, complications, and risk factors in a large population of SSA-treated patients with NETs. MATERIALS AND METHODS A retrospective analysis of a prospectively collected database was performed. Patients with a diagnosis of NET in seven dedicated centers from 1995 to 2017 were included at the time of SSA start. RESULTS A total of 754 SSA-treated patients were evaluated. Patients with history of cholecystectomy or with known biliary stone disease were excluded; 478 patients were included. Among them, 118 patients (24.7%) received prophylactic ursodeoxycholic acid (UDCA). During the study period, 129 patients (27.0%) developed biliary stone disease; of them, 36 (27.9%) developed biliary complications. On multivariate analysis, primary gastrointestinal (GI)-NET (hazard ratio [HR] 1.76) and related surgery (HR 1.58) were independent risk factors for biliary stone disease. CONCLUSION We report a high incidence of biliary stone disease particularly in GI-NET or GI surgery. UDCA prophylaxis does not seem to have a protective role. Our data suggest that all patients with primary GI-NET or undergoing abdominal surgery should be considered for prophylactic cholecystectomy; no conclusion could be drawn on the indication of prophylactic cholecystectomy in patients with primary pancreatic or thoracic NET for whom abdominal surgery is not planned. IMPLICATIONS FOR PRACTICE The results of this study confirm an increased rate of gallstones development and related complications in patients with neuroendocrine tumors (NETs) treated with somatostatin analogs (SSAs). NETs of the gastrointestinal (GI) tract and related surgery are independent risk factors for biliary stone disease development. Therefore, all patients with primary GI-NET or undergoing abdominal surgery should be considered for prophylactic cholecystectomy. Data on other subgroups are not exhaustive, and management also evaluating additional clinical features (life expectancy, surgical and anesthesiological risks) should be considered. Prophylactic treatment with ursodeoxycholic acid does not seem to be a protective factor for SSA-related biliary stone disease.
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Affiliation(s)
- Nicole Brighi
- NET Team Bologna ENETS Center of Excellence, S. Orsola‐Malpighi University Hospital, Alma Mater Studiorum University of BolognaBolognaItaly
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCSMeldolaItaly
| | - Francesco Panzuto
- Digestive Disease Unit, Sant'Andrea University Hospital, ENETS Center of ExcellenceRomeItaly
| | - Roberta Modica
- Clinical Medicine and Surgery Department ‐ Federico II UniversityNaplesItaly
| | - Fabio Gelsomino
- Department of Oncology and Hematology, University Hospital of ModenaModenaItaly
| | - Manuela Albertelli
- Endocrinology Department (DiMi), San Martino University HospitalGenovaItaly
| | - Sara Pusceddu
- Department of Medical Oncology, Fondazione IRCCS Istituto Tumori Milano, ENETS Center of ExcellenceMilanItaly
| | - Sara Massironi
- Gastroenterology and Endoscopy Department, Fondazione IRCCS Ca' Granda, Ospedale Maggiore PoliclinicoMilanItaly
| | - Giuseppe Lamberti
- NET Team Bologna ENETS Center of Excellence, S. Orsola‐Malpighi University Hospital, Alma Mater Studiorum University of BolognaBolognaItaly
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola‐Malpighi University HospitalBolognaItaly
| | - Maria Rinzivillo
- Digestive Disease Unit, Sant'Andrea University Hospital, ENETS Center of ExcellenceRomeItaly
| | | | - Andrea Spallanzani
- Department of Oncology and Hematology, University Hospital of ModenaModenaItaly
| | - Diego Ferone
- Endocrinology Department (DiMi), San Martino University HospitalGenovaItaly
| | - Natalie Prinzi
- Department of Medical Oncology, Fondazione IRCCS Istituto Tumori Milano, ENETS Center of ExcellenceMilanItaly
| | - Roberta Elisa Rossi
- Gastroenterology and Endoscopy Department, Fondazione IRCCS Ca' Granda, Ospedale Maggiore PoliclinicoMilanItaly
| | - Bruno Annibale
- Digestive Disease Unit, Sant'Andrea University Hospital, ENETS Center of ExcellenceRomeItaly
| | - Anna Maria Colao
- Clinical Medicine and Surgery Department ‐ Federico II UniversityNaplesItaly
| | - Davide Campana
- NET Team Bologna ENETS Center of Excellence, S. Orsola‐Malpighi University Hospital, Alma Mater Studiorum University of BolognaBolognaItaly
- Department of Medical and Surgical Sciences, S. Orsola‐Malpighi University HospitalBolognaItaly
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Lamberti G, Faggiano A, Brighi N, Tafuto S, Ibrahim T, Brizzi MP, Pusceddu S, Albertelli M, Massironi S, Panzuto F, Badalamenti G, Riccardi F, Butturini G, Gelsomino F, De Divitiis C, Modica R, Bongiovanni A, La Salvia A, Torchio M, Colao A, Ferone D, Campana D. Nonconventional Doses of Somatostatin Analogs in Patients With Progressing Well-Differentiated Neuroendocrine Tumor. J Clin Endocrinol Metab 2020; 105:dgz035. [PMID: 31545377 DOI: 10.1210/clinem/dgz035] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 09/20/2019] [Indexed: 02/08/2023]
Abstract
PURPOSE To evaluate the antiproliferative activity and safety of nonconventional high doses of somatostatin analogs (HD-SSA) in patients with well-differentiated gastroenteropancreatic (GEP) neuroendocrine tumors (NET) with radiological disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria on a previous treatment. METHODS A retrospective analysis of prospectively maintained databases from 13 Italian NET-dedicated centers was performed. Main inclusion criteria were: well-differentiated G1 or G2 GEP-NET, progressive disease on a previous treatment, and subsequent treatment with HD-SSA (either by increased administered dose [dose intensity] or shortened interval between administrations [dose density]). Main endpoints were progression-free survival (PFS) and safety. RESULTS Of 198 patients, 140 matched inclusion criteria and were included in the analysis. Overall, median PFS was 31 months. Use of HD-SSA as second-line treatment was associated with reduced risk for progression or death compared with third- or further-line treatment (HR: 2.12; P = 0.004). There was no difference in PFS between HD-SSA by increased dose density (N = 133; 95%) or intensity (N = 7; 5%). Partial response according to RECIST criteria was observed in 12 patients (8.6%), and stable disease was achieved in 106 (75.7%) patients. Adverse events occurred in 21 patients (15.0%), 2 of whom had grade 3 biliary stone disease. No patients discontinued HD-SSA treatment due to adverse events. CONCLUSIONS HD-SSA is an active and safe treatment option in patients with progressive well-differentiated GEP-NET. The high rate of objective responses observed deserves prospective validation in ad hoc clinical trials.
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Affiliation(s)
- Giuseppe Lamberti
- NET Team Bologna ENETS Center of Excellence, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | | | - Nicole Brighi
- NET Team Bologna ENETS Center of Excellence, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | | | - Toni Ibrahim
- Osteoncology and Rare Tumors Center- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCSS, Meldola, Italy
| | | | - Sara Pusceddu
- Department of medical oncology, Fondazione IRCCS Istituto Tumori Milano, ENETS Center of Excellence, Milan, Italy
| | - Manuela Albertelli
- Endocrinology Department of Internal Medicine and Medical Specialties (DiMi), San Martino University Hospital, Genova, Italy
| | - Sara Massironi
- Gastroenterology and Endoscopy Department, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Francesco Panzuto
- Digestive Disease Unit, Sant'Andrea University Hospital, ENETS Center of Excellence, Rome, Italy
| | - Giuseppe Badalamenti
- Medical Oncology, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy
| | | | | | - Fabio Gelsomino
- Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | | | - Roberta Modica
- Clinical medicine and Surgery Department - Federico II University, Naples, Italy
| | - Alberto Bongiovanni
- Osteoncology and Rare Tumors Center- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCSS, Meldola, Italy
| | | | - Martina Torchio
- Department of medical oncology, Fondazione IRCCS Istituto Tumori Milano, ENETS Center of Excellence, Milan, Italy
| | - Annamaria Colao
- Clinical medicine and Surgery Department - Federico II University, Naples, Italy
| | - Diego Ferone
- Endocrinology Department of Internal Medicine and Medical Specialties (DiMi), San Martino University Hospital, Genova, Italy
| | - Davide Campana
- NET Team Bologna ENETS Center of Excellence, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy
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27
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Larouche V, Akirov A, Alshehri S, Ezzat S. Management of Small Bowel Neuroendocrine Tumors. Cancers (Basel) 2019; 11:cancers11091395. [PMID: 31540509 PMCID: PMC6770692 DOI: 10.3390/cancers11091395] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 09/08/2019] [Accepted: 09/15/2019] [Indexed: 12/20/2022] Open
Abstract
Several important landmark trials have reshaped the landscape of non-surgical management of small bowel neuroendocrine tumors over the last few years, with the confirmation of the antitumor effect of somatostatin analogue therapy in PROMID and CLARINET trials as well as the advent of therapies with significant potential such as mammalian target of rapamycin inhibitor (mTor) everolimus (RADIANT trials) and peptide receptor radionuclide therapy (PRRT) with 177-Lutetium (NETTER-1 trial). This narrative summarizes the recommended management strategies of small bowel neuroendocrine tumors. We review the main evidence behind each recommendation as well as compare and contrast four major guidelines, namely the 2016 Canadian Consensus guidelines, the 2017 North American Neuroendocrine Tumor Society guidelines, the 2018 National Comprehensive Cancer Network guidelines, and the 2016 European Neuroendocrine Tumor Society guidelines. Different clinical situations will be addressed, from loco-regional therapy to metastatic unresectable disease. Carcinoid syndrome, which is mostly managed by somatostatin analogue therapy and the serotonin antagonist telotristat etiprate for refractory diarrhea, as well as neuroendocrine carcinoma will be reviewed. However, several questions remain unanswered, such as the optimal management of neuroendocrine carcinomas or the effect of combining and sequencing of the aforementioned modalities where more randomized controlled trials are needed.
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Affiliation(s)
- Vincent Larouche
- Endocrine Oncology Site Group, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON M5G2C1, Canada; (A.A.); (S.A.); (S.E.)
- Division of Endocrinology and Metabolism, Department of Medicine, Jewish General Hospital, McGill University, Montreal, QC H3T1E2, Canada
- Correspondence: ; Tel.: +1-(514)-340-8222 (ext. 28521)
| | - Amit Akirov
- Endocrine Oncology Site Group, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON M5G2C1, Canada; (A.A.); (S.A.); (S.E.)
- Department of Medicine, Institute of Endocrinology, Beilinson Hospital, Petach Tikva 4941492, Israel
- Department of Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Sameerah Alshehri
- Endocrine Oncology Site Group, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON M5G2C1, Canada; (A.A.); (S.A.); (S.E.)
| | - Shereen Ezzat
- Endocrine Oncology Site Group, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON M5G2C1, Canada; (A.A.); (S.A.); (S.E.)
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Bergeron E, Bensoussan M. Massively distended, necrotic and hemorrhagic gallbladder in a long-term octreotide-treated patient with added everolimus. Int J Surg Case Rep 2019; 61:107-110. [PMID: 31352317 PMCID: PMC6664011 DOI: 10.1016/j.ijscr.2019.07.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 07/11/2019] [Indexed: 12/12/2022] Open
Abstract
Somatostatin analogs and immunosuppressants promote gallstones formation. Severe cholecystitis can develop during long-term treatment of metastatic carcinoid cancer. There is no proof that severe cholecystitis is caused by somatostatin analogs and immunosuppressants. Introduction Long-term treatment with somatostatin analogs, such as octreotide, is well known to promote gallstones formation. Immunosuppressive therapy in renal transplantation is also associated with increased occurrence of gallstones. But acute cholecystitis develops only in a few cholelithiasis patients. However, it is not known whether long-term somatostatin analog therapy and immunosuppressants aggravate the severity of disease if the patient develops cholecystitis. Case presentation We present a case of severe cholecystitis in a patient with metastatic carcinoid cancer on octreotide long-acting release therapy for seven years with newly added immunosuppressant, everolimus. Discussion Cholelithiasis as well as cholecystitis develop more often in patients on somatostatin analogs and immunosuppressants than in general population. However, morbidity remains negligible. Conclusion No conclusion can be drawn on the contribution of somatostatin analogs and immunosuppressant in the occurrence of severe cholecystitis. Prophylactic cholecystectomy is not indicated in patients with this medication.
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Affiliation(s)
- Eric Bergeron
- Departments of Surgery and Gastroenterology, Charles-LeMoyne Hospital, Greenfield Park, Canada.
| | - Michael Bensoussan
- Departments of Surgery and Gastroenterology, Charles-LeMoyne Hospital, Greenfield Park, Canada
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