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Fayyaz F, Reardon MF, Byrne L. Insulinoma as a cause of seizure-like activity and spontaneous hypoglycaemia. BMJ Case Rep 2023; 16:e250799. [PMID: 36627134 PMCID: PMC9835887 DOI: 10.1136/bcr-2022-250799] [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] [Accepted: 12/16/2022] [Indexed: 01/11/2023] Open
Abstract
A woman in her 60s presented to our hospital with recurrent episodes of confusion and double vision with spontaneous recovery to baseline within 10 min. Her initial workup was unremarkable, and she was diagnosed with complex partial seizures and commenced on levetiracetam. The following week, she re-presented with a recurrence of her symptoms, associated with spontaneous hypoglycaemia, with blood glucose levels of 1.9 mmol/L. She was found to have endogenously elevated serum insulin and C peptide levels, which were concomitantly associated with hypoglycaemia. An initial diagnosis of insulinoma was made and she was commenced on diazoxide. MRI and endoscopic ultrasound revealed 16 mm insulinoma in her uncinate process. She underwent surgical resection and remained symptom free at follow-up. This case highlights the importance of blood glucose measurements in patients presenting with neuroglycopenic symptoms and outlines the workup and management of insulinoma.
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Affiliation(s)
- Fahd Fayyaz
- Medicine, Wexford General Hospital, Wexford, Ireland
| | | | - Luke Byrne
- Cardiology, Tallaght University Hospital, Dublin, Ireland
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2
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Haslerud T. SPECT/CT in Neuroendrocrine Tumours. CLINICAL APPLICATIONS OF SPECT-CT 2022:95-118. [DOI: 10.1007/978-3-030-65850-2_6] [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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Comparative Preclinical Evaluation of HER2-Targeting ABD-Fused Affibody ® Molecules 177Lu-ABY-271 and 177Lu-ABY-027: Impact of DOTA Position on ABD Domain. Pharmaceutics 2021; 13:pharmaceutics13060839. [PMID: 34200197 PMCID: PMC8226825 DOI: 10.3390/pharmaceutics13060839] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/04/2021] [Accepted: 06/04/2021] [Indexed: 12/12/2022] Open
Abstract
Radiolabeled Affibody-based targeting agent 177Lu-ABY-027, a fusion of an anti-HER2 Affibody molecule with albumin binding domain (ABD) site-specifically labeled at the C-terminus, has demonstrated a promising biodistribution profile in mice; binding of the construct to albumin prevents glomerular filtration and significantly reduces renal uptake. In this study, we tested the hypothesis that site-specific positioning of the chelator at helix 1 of ABD, at a maximum distance from the albumin binding site, would further increase the strength of binding to albumin and decrease the renal uptake. The new construct, ABY-271 with DOTA conjugated at the back of ABD, has been labelled with 177Lu. Targeting properties of 177Lu-ABY-271 and 177Lu-ABY-027 were compared directly. 177Lu-ABY-271 specifically accumulated in SKOV-3 xenografts in mice. The tumor uptake of 177Lu-ABY-271 exceeded uptake in any other organ 24 h and later after injection. However, the renal uptake of 177Lu-ABY-271 was two-fold higher than the uptake of 177Lu-ABY-027. Thus, the placement of chelator on helix 1 of ABD does not provide desirable reduction of renal uptake. To conclude, minimal modification of the design of Affibody molecules has a strong effect on biodistribution, which cannot be predicted a priori. This necessitates extensive structure-properties relationship studies to find an optimal design of Affibody-based targeting agents for therapy.
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Ramonaheng K, van Staden JA, du Raan H. The effect of calibration factors and recovery coefficients on 177Lu SPECT activity quantification accuracy: a Monte Carlo study. EJNMMI Phys 2021; 8:27. [PMID: 33738605 PMCID: PMC7973313 DOI: 10.1186/s40658-021-00365-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 02/08/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Different gamma camera calibration factor (CF) geometries have been proposed to convert SPECT data into units of activity concentration. However, no consensus has been reached on a standardised geometry. The CF is dependent on the selected geometry and is further affected by partial volume effects. This study investigated the effect of two CF geometries and their corresponding recovery coefficients (RCs) on the quantification accuracy of 177Lu SPECT images using Monte Carlo simulations. METHODS The CF geometries investigated were (i) a radioactive-sphere surrounded by non-radioactive water (sphere-CF) and (ii) a cylindrical phantom uniformly filled with radioactive water (cylinder-CF). Recovery coefficients were obtained using the sphere-CF and cylinder-CF, yielding the sphere-RC and cylinder-RC values, respectively, for partial volume correction (PVC). The quantification accuracy was evaluated using four different-sized spheres (15.6-65.4 ml) and a kidney model with known activity concentrations inside a cylindrical, torso and patient phantom. Images were reconstructed with the 3D OS-EM algorithm incorporating attenuation, scatter and detector-response corrections. Segmentation was performed using the physical size and a small cylindrical volume inside the cylinder for the sphere-CF and cylinder-CF, respectively. RESULTS The sphere quantification error (without PVC) was better for the sphere-CF (≤ - 5.54%) compared to the cylinder-CF (≤ - 20.90%), attributed to the similar geometry of the quantified and CF spheres. Partial volume correction yielded comparable results for the sphere-CF-RC (≤ 3.47%) and cylinder-CF-RC (≤ 3.53%). The accuracy of the kidney quantification was poorer (≤ 22.34%) for the sphere-CF without PVC compared to the cylinder-CF (≤ 2.44%). With PVC, the kidney quantification results improved and compared well for the sphere-CF-RC (≤ 3.50%) and the cylinder-CF-RC (≤ 3.45%). CONCLUSION The study demonstrated that upon careful selection of CF-RC combinations, comparable quantification errors (≤ 3.53%) were obtained between the sphere-CF-RC and cylinder-CF-RC, when all corrections were applied.
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Affiliation(s)
- Keamogetswe Ramonaheng
- Department of Medical Physics, Faculty of Health Sciences, University of the Free State, PO Box 339, Bloemfontein, 9300, South Africa.
| | - Johannes A van Staden
- Department of Medical Physics, Faculty of Health Sciences, University of the Free State, PO Box 339, Bloemfontein, 9300, South Africa
| | - Hanlie du Raan
- Department of Medical Physics, Faculty of Health Sciences, University of the Free State, PO Box 339, Bloemfontein, 9300, South Africa
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Wyld D, Wan MH, Moore J, Dunn N, Youl P. Epidemiological trends of neuroendocrine tumours over three decades in Queensland, Australia. Cancer Epidemiol 2019; 63:101598. [DOI: 10.1016/j.canep.2019.101598] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 08/19/2019] [Accepted: 09/05/2019] [Indexed: 01/23/2023]
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Tsoli M, Chatzellis E, Koumarianou A, Kolomodi D, Kaltsas G. Current best practice in the management of neuroendocrine tumors. Ther Adv Endocrinol Metab 2019; 10:2042018818804698. [PMID: 30800264 PMCID: PMC6378464 DOI: 10.1177/2042018818804698] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 09/05/2018] [Indexed: 12/13/2022] Open
Abstract
Neuroendocrine neoplasms are rare tumors that display marked heterogeneity with varying natural history, biological behavior, response to therapy and prognosis. Their management is complex, particularly as a number of them may be associated with a secretory syndrome and involve a variety of options. A number of factors such as proliferation rate, degree of differentiation, functionality and extent of the disease are mostly utilized to tailor treatment accordingly, ideally in the context of a multidisciplinary team. In addition, a number of relevant scientific societies have published therapeutic guidelines in an attempt to direct and promote evidence-based treatment. Surgery remains the treatment of choice with an intention to cure while it may also be recommended in some cases of metastatic disease and difficult to control secretory syndromes. Long-acting somatostatin analogs constitute the main treatment for the majority of functioning tumors, whereas specific evolving agents such as telotristat may be used for the control of carcinoid syndrome and related sequelae. In patients with advanced disease not amenable to surgical resection, treatment options include locoregional therapies, long-acting somatostatin analogs, molecular targeted agents, radionuclides, chemotherapy and recently immunotherapy, alone or in combination. However, the ideal time of treatment initiation, sequence of administration of different therapies and identification of robust prognostic markers to select the most appropriate treatment for each individual patient still need to be defined.
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Affiliation(s)
| | - Eleftherios Chatzellis
- First Department of Propaedeutic Internal
Medicine, Laiko General Hospital, National and Kapodistrian University of
Athens, Athens, Greece
| | - Anna Koumarianou
- Fourth Department of Internal Medicine, Attikon
University General Hospital, Athens, Greece
| | - Dionysia Kolomodi
- First Department of Propaedeutic Internal
Medicine, Laiko General Hospital, National and Kapodistrian University of
Athens, Athens, Greece
| | - Gregory Kaltsas
- First Department of Propaedeutic Internal
Medicine, Laiko General Hospital, National and Kapodistrian University of
Athens, Athens, Greece
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Abstract
This article reviews the role of surgical and medical management in patients with Zollinger-Ellison syndrome (ZES) due to a gastrin-secreting neuroendocrine tumor (gastrinoma). It concentrates on the status at present but also briefly reviews the changes over time in treatment approaches. Generally, surgical and medical therapy are complementary today; however, in some cases, such as patients with ZES and multiple endocrine neoplasia type 1, the treatment approach remains controversial.
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Affiliation(s)
- Jeffrey A Norton
- Department of Surgery, Stanford University School of Medicine, 291 campus Drive, Stanford, CA 94305-5101, USA
| | - Deshka S Foster
- Department of Surgery, Stanford University School of Medicine, 291 campus Drive, Stanford, CA 94305-5101, USA
| | - Tetsuhide Ito
- Neuroendocrine Tumor Centra, Fukuoka Sanno Hospital, International University of Health and Welfare, 3-6-45 Momochihama, Sawara-Ku, Fukuoka 814-0001, Japan
| | - Robert T Jensen
- Digestive Diseases Branch, NIDDK, National Institutes of Health, Building 10, Room 9C-103, Bethesda, MD 20892-1804, USA.
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Müller C, Domnanich KA, Umbricht CA, van der Meulen NP. Scandium and terbium radionuclides for radiotheranostics: current state of development towards clinical application. Br J Radiol 2018; 91:20180074. [PMID: 29658792 PMCID: PMC6475947 DOI: 10.1259/bjr.20180074] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Currently, different radiometals are in use for imaging and therapy in nuclear medicine: 68Ga and 111In are examples of nuclides for positron emission tomography (PET) and single photon emission computed tomography (SPECT), respectively, while 177Lu and 225Ac are used for β−- and α-radionuclide therapy. The application of diagnostic and therapeutic radionuclides of the same element (radioisotopes) would utilize chemically-identical radiopharmaceuticals for imaging and subsequent treatment, thereby enabling the radiotheranostic concept. There are two elements which are of particular interest in this regard: Scandium and Terbium. Scandium presents three radioisotopes for theranostic application. 43Sc (T1/2 = 3.9 h) and 44Sc (T1/2 = 4.0 h) can both be used for PET, while 47Sc (T1/2 = 3.35 d) is the therapeutic match—also suitable for SPECT. Currently, 44Sc is most advanced in terms of production, as well as with pre-clinical investigations, and has already been employed in proof-of-concept studies in patients. Even though the production of 43Sc may be more challenging, it would be advantageous due to the absence of high-energetic γ-ray emission. The development of 47Sc is still in its infancy, however, its therapeutic potential has been demonstrated preclinically. Terbium is unique in that it represents four medically-interesting radioisotopes. 155Tb (T1/2 = 5.32 d) and 152Tb (T1/2 = 17.5 h) can be used for SPECT and PET, respectively. Both radioisotopes were produced and tested preclinically. 152Tb has been the first Tb isotope that was tested (as 152Tb-DOTATOC) in a patient. Both radionuclides may be of interest for dosimetry purposes prior to the application of radiolanthanide therapy. The decay properties of 161Tb (T1/2 = 6.89 d) are similar to 177Lu, but the coemission of Auger electrons make it attractive for a combined β−/Auger electron therapy, which was shown to be effective in preclinical experiments. 149Tb (T1/2 = 4.1 h) has been proposed for targeted α-therapy with the possibility of PET imaging. In terms of production, 161Tb and 155Tb are most promising to be made available at the large quantities suitable for future clinical translation. This review article is dedicated to the production routes, the methods of separating the radioisotopes from the target material, preclinical investigations and clinical proof-of-concept studies of Sc and Tb radionuclides. The availability, challenges of production and first (pre)clinical application, as well as the potential of these novel radionuclides for future application in nuclear medicine, are discussed.
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Affiliation(s)
- Cristina Müller
- 1 Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut , Villigen-PSI , Switzerland
| | | | - Christoph A Umbricht
- 1 Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut , Villigen-PSI , Switzerland
| | - Nicholas P van der Meulen
- 1 Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut , Villigen-PSI , Switzerland.,2 Laboratory of Radiochemistry, Paul Scherrer Institut , Villigen-PSI , Switzerland
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Aristizabal Prada ET, Heinzle V, Knösel T, Nölting S, Spöttl G, Maurer J, Spitzweg C, Angele M, Schmidt N, Beuschlein F, Stalla GK, Blaser R, Kuhn KA, Auernhammer CJ. Tropomyosin receptor kinase: a novel target in screened neuroendocrine tumors. Endocr Relat Cancer 2018; 25:547-560. [PMID: 29563190 DOI: 10.1530/erc-17-0201] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 03/21/2018] [Indexed: 01/27/2023]
Abstract
Tropomyosin receptor kinase (Trk) inhibitors are investigated as a novel targeted therapy in various cancers. We investigated the in vitro effects of the pan-Trk inhibitor GNF-5837 in human neuroendocrine tumor (NET) cells. The human neuroendocrine pancreatic BON1, bronchopulmonary NCI-H727 and ileal GOT1 cell lines were treated with GNF-5837 alone and in combination with everolimus. Cell viability decreased in a time- and dose-dependent manner in GOT1 cells in response to GNF-5837 treatment, while treatment in BON1 and NCI-H727 cells showed no effect on cellular viability. Trk receptor expression determined GNF-5837 sensitivity. GNF-5837 caused downregulation of PI3K-Akt-mTOR signaling, Ras-Raf-MEK-ERK signaling, the cell cycle and increased apoptotic cell death. The combinational treatment of GNF-5837 with everolimus showed a significant enhancement in inhibition of cell viability vs single substance treatments, due to a cooperative PI3K-Akt-mTOR and Ras-Raf-MEK-ERK pathway downregulation, as well as an enhanced cell cycle component downregulation. Immunohistochemical staining for Trk receptors were performed using a tissue microarray containing 107 tumor samples of gastroenteropancreatic NETs. Immunohistochemical staining with TrkA receptor and pan-Trk receptor antibodies revealed a positive staining in pancreatic NETs in 24.2% (8/33) and 33.3% (11/33), respectively. We demonstrated that the pan-Trk inhibitor GNF-5837 has promising anti-tumoral properties in human NET cell lines expressing the TrkA receptor. Immunohistochemical or molecular screening for Trk expression particularly in pancreatic NETs might serve as predictive marker for molecular targeted therapy with Trk inhibitors.
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Affiliation(s)
- Elke Tatjana Aristizabal Prada
- Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Munich, Germany
- Department of Internal Medicine 2, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
- Department of Internal Medicine 4, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Vera Heinzle
- Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Munich, Germany
- Department of Internal Medicine 2, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Thomas Knösel
- Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Munich, Germany
- Institute of Pathology, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Svenja Nölting
- Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Munich, Germany
- Department of Internal Medicine 2, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
- Department of Internal Medicine 4, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Gerald Spöttl
- Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Munich, Germany
- Department of Internal Medicine 2, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
- Department of Internal Medicine 4, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Julian Maurer
- Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Munich, Germany
- Department of Internal Medicine 2, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
- Department of Internal Medicine 4, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Christine Spitzweg
- Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Munich, Germany
- Department of Internal Medicine 2, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
- Department of Internal Medicine 4, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Martin Angele
- Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Munich, Germany
- Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Nina Schmidt
- Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Munich, Germany
- Department of Internal Medicine 2, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
- Department of Internal Medicine 4, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Felix Beuschlein
- Department of Internal Medicine 4, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
- Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, Universitätsspital Zürich, Zurich, Switzerland
| | - Günter K Stalla
- Clinical Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany
| | - Rainer Blaser
- Institute of Medical Statistics and Epidemiology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Klaus A Kuhn
- Institute of Medical Statistics and Epidemiology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Christoph J Auernhammer
- Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Munich, Germany
- Department of Internal Medicine 2, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
- Department of Internal Medicine 4, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
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Camilli M, Papadimitriou K, Nogueira A, Incorvaia L, Galvano A, D'Antonio F, Ferri J, Santini D, Silvestris N, Russo A, Peeters M, Rolfo C. Molecular profiling of pancreatic neuroendocrine tumors (pNETS) and the clinical potential. Expert Rev Gastroenterol Hepatol 2018; 12:471-478. [PMID: 29629846 DOI: 10.1080/17474124.2018.1463157] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Pancreatic neuroendocrine tumors (pNETs) represent a small part of pancreatic neoplasms, and the knowledge about their indolent clinical course remains a subject of investigation. They occur sporadically or as part of familial cancer syndromes and are classified by WHO in 3 categories. There is ongoing research to understand their molecular profiling and leading mutations. Areas covered: The aim of this review is to clarify the overall aspects of tumorigenesis, to expose the latest developments in understanding the course of the disease and the possible therapeutic implications of these. The review also discusses functional and non-functional pNETs and associated inherited syndromes as well as pNET molecular profiling and its possible guidance in the use of targeted therapy. Expert commentary: In the next decade, a more extensive application of new technologies will help improve quality of life and survival, individualizing treatment protocols and identifying which therapeutic strategy is more suitable for each kind of NET.
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Affiliation(s)
| | | | - Amanda Nogueira
- c Phase I-Early Clinical Trials Unit, Oncology Department , Antwerp University Hospital & Center for Oncological Research (CORE) , Antwerp , Belgium
| | - Lorena Incorvaia
- d Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology , University of Palermo , Palermo , Italy
| | - Antonio Galvano
- d Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology , University of Palermo , Palermo , Italy
| | - Federica D'Antonio
- a Department of Oncology , University Campus Biomedico of Rome , Rome , Italy
| | - Jose Ferri
- c Phase I-Early Clinical Trials Unit, Oncology Department , Antwerp University Hospital & Center for Oncological Research (CORE) , Antwerp , Belgium
| | - Daniele Santini
- c Phase I-Early Clinical Trials Unit, Oncology Department , Antwerp University Hospital & Center for Oncological Research (CORE) , Antwerp , Belgium
| | - Nicola Silvestris
- e Medical Oncology Department , Oncological institute Giovanni Paolo II , Bari , Italy
| | - Antonio Russo
- d Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology , University of Palermo , Palermo , Italy
| | - Marc Peeters
- b Oncology Department , Antwerp University Hospital , Edegem , Belgium
| | - Christian Rolfo
- c Phase I-Early Clinical Trials Unit, Oncology Department , Antwerp University Hospital & Center for Oncological Research (CORE) , Antwerp , Belgium
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11
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Lisova K, Sergeev M, Evans-Axelsson S, Stuparu AD, Beykan S, Collins J, Jones J, Lassmann M, Herrmann K, Perrin D, Lee JT, Slavik R, van Dam RM. Microscale radiosynthesis, preclinical imaging and dosimetry study of [ 18F]AMBF 3-TATE: A potential PET tracer for clinical imaging of somatostatin receptors. Nucl Med Biol 2018; 61:36-44. [PMID: 29747035 DOI: 10.1016/j.nucmedbio.2018.04.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 03/28/2018] [Accepted: 04/01/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Peptides labeled with positron-emitting isotopes are emerging as a versatile class of compounds for the development of highly specific, targeted imaging agents for diagnostic imaging via positron-emission tomography (PET) and for precision medicine via theranostic applications. Despite the success of peptides labeled with gallium-68 (for imaging) or lutetium-177 (for therapy) in the clinical management of patients with neuroendocrine tumors or prostate cancer, there are significant advantages of using fluorine-18 for imaging. Recent developments have greatly simplified such labeling: in particular, labeling of organotrifluoroborates via isotopic exchange can readily be performed in a single-step under aqueous conditions and without the need for HPLC purification. Though an automated synthesis has not yet been explored, microfluidic approaches have emerged for 18F-labeling with high speed, minimal reagents, and high molar activity compared to conventional approaches. As a proof-of-concept, we performed microfluidic labeling of an octreotate analog ([18F]AMBF3-TATE), a promising 18F-labeled analog that could compete with [68Ga]Ga-DOTATATE with the advantage of providing a greater number of patient doses per batch produced. METHODS Both [18F]AMBF3-TATE and [68Ga]Ga-DOTATATE were labeled, the former by microscale methods adapted from manual labeling, and were imaged in mice bearing human SSTR2-overexpressing, rat SSTR2 wildtype, and SSTR2-negative xenografts. Furthermore, a dosimetry analysis was performed for [18F]AMBF3-TATE. RESULTS The micro-synthesis exhibited highly-repeatable performance with radiochemical conversion of 50 ± 6% (n = 15), overall decay-corrected radiochemical yield of 16 ± 1% (n = 5) in ~40 min, radiochemical purity >99%, and high molar activity. Preclinical imaging with [18F]AMBF3-TATE in SSTR2 tumor models correlated well with [68Ga]Ga-DOTATATE. The favorable biodistribution, with the highest tracer accumulation in the bladder followed distantly by gastrointestinal tissues, resulted in 1.26 × 10-2 mSv/MBq maximal estimated effective dose in human, a value lower than that reported for current clinical 18F- and 68Ga-labeled compounds. CONCLUSIONS The combination of novel chemical approaches to 18F-labeling and microdroplet radiochemistry have the potential to serve as a platform for greatly simplified development and production of 18F-labeled peptide tracers. Favorable preclinical imaging and dosimetry of [18F]AMBF3-TATE, combined with a convenient synthesis, validate this assertion and suggest strong potential for clinical translation.
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Affiliation(s)
- Ksenia Lisova
- Physics in Biology and Medicine Interdepartmental Graduate Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Maxim Sergeev
- Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Susan Evans-Axelsson
- Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Imaging Division, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Andreea D Stuparu
- Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Imaging Division, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Seval Beykan
- Department of Nuclear Medicine, University of Würzburg, Würzburg, Germany
| | - Jeffrey Collins
- Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Jason Jones
- Physics in Biology and Medicine Interdepartmental Graduate Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Michael Lassmann
- Department of Nuclear Medicine, University of Würzburg, Würzburg, Germany
| | - Ken Herrmann
- Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Imaging Division, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center (JCCC), UCLA, Los Angeles, CA, USA
| | - David Perrin
- Department of Chemistry, University of British Columbia, Vancouver, BC, Canada
| | - Jason T Lee
- Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center (JCCC), UCLA, Los Angeles, CA, USA.
| | - Roger Slavik
- Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Imaging Division, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center (JCCC), UCLA, Los Angeles, CA, USA.
| | - R Michael van Dam
- Physics in Biology and Medicine Interdepartmental Graduate Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center (JCCC), UCLA, Los Angeles, CA, USA.
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Peptide Receptor Radionuclide Therapy With 177Lu-Octreotate in Patients With Somatostatin Receptor Expressing Neuroendocrine Tumors: Six Years' Assessment. Clin Nucl Med 2017; 42:436-443. [PMID: 28263217 DOI: 10.1097/rlu.0000000000001629] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVES Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues is a promising treatment for patients with inoperable, well to moderately differentiated metastatic neuroendocrine tumors (NETs). In continuation of our novel study with the radionuclide lutetium Lu, we now present further results of Lu DOTATATE therapy in managing NETs and other somatostatin receptor-expressing tumors in a larger and more diverse patient group. PATIENTS AND METHODS One hundred forty-four consecutive patients (85 men and 59 women; age range, 11-87 years; mean age, 58.5 years) with histologically confirmed NET were enrolled. One hundred forty-three patients received at least 1 cycle of treatment. Among them, 132 were deemed evaluable by having at least 1 cycle of treatment and a posttreatment MRI or CT scan for assessment based on modified Response Evaluation Criteria in Solid Tumors. Response to therapy was evaluated in terms of progression-free survival, overall survival, as well as radiologic, biochemical, and clinical responses. Further, analysis of symptoms was reviewed during therapy and also in subsequent follow-ups for safety evaluation. Renal, gastrointestinal (GI), hepatic, and hematological adverse events were evaluated using National Cancer Institute common toxicities criteria V4.03, through full blood panels, as well as consultation with patients for any symptoms and/or adverse events. RESULTS As of July 2016, median progression-free survival was about to be reached. Of 28 patients who have completed Lu DOTATATE therapy (completion of 4 or more cycles of treatment and all designated follow-ups), no patient showed complete response (CR), 8 patients (28.57%) showed partial response (PR), 16 patients (57.14%) showed stable disease (SD), and progressive disease (PD) was observed in 4 patients (14.28%). The objective response rate (CR + PR) of this group was 28.57% (n = 8) with a cumulative disease control (CR + PR + SD) of 85.71% (n = 24).Among 132 evaluable patients, assessment of treatment response using modified Response Evaluation Criteria in Solid Tumors criteria revealed CR in none of the patients, PR in 12 patients (9.09%), SD in 66 patients (50%), whereas PD, which included patients who passed away, was observed in 54 patients (40.90%), yielding an objective response rate of 9.09% (n = 12) and a cumulative disease control rate of 59.09% (n = 78).Symptoms including abdominal pain, diarrhea, flushing, and fatigue improved in over 50% of the patients, whereas weight loss improved in 28.26% of the patients. No grade 3 or grade 4 renal toxicities were found, though eleven grade 3 and five grade 4 hematological as well as three grade 3 hepatotoxicities were reported. Grade 3 hematotoxicity lasted an average of 2.7 months, and grade 4 lasted for only 0.9 months, whereas grade 3 hepatotoxicity lasted an average of 3.1 months. CONCLUSIONS Lu-octreotate peptide receptor radionuclide therapy has shown promising potential as a safe and effective targeted therapy in inoperable, well to moderately differentiated metastatic neuroendocrine cancers. The results of the multicenter randomized clinical trial conducted in United States and Europe are concordant with current study.
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13
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Neuzillet C, de Mestier L, Rousseau B, Mir O, Hebbar M, Kocher HM, Ruszniewski P, Tournigand C. Unravelling the pharmacologic opportunities and future directions for targeted therapies in gastro-intestinal cancers part 2: Neuroendocrine tumours, hepatocellular carcinoma, and gastro-intestinal stromal tumours. Pharmacol Ther 2017; 181:49-75. [PMID: 28723416 DOI: 10.1016/j.pharmthera.2017.07.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Until the 1990s, cytotoxic chemotherapy has been the cornerstone of medical therapy for gastrointestinal (GI) cancers. Better understanding of the cancer cell molecular biology has led to the therapeutic revolution of targeted therapies, i.e. monoclonal antibodies or small molecule inhibitors directed against proteins that are specifically overexpressed or mutated in cancer cells. These agents, being more specific to cancer cells, were expected to be less toxic than conventional cytotoxic agents. However, their effects have sometimes been disappointing, due to intrinsic or acquired resistance mechanisms, or to an activity restricted to some tumour settings, illustrating the importance of patient selection and early identification of predictive biomarkers of response to these therapies. Targeted agents have provided clinical benefit in many GI cancer types. Particularly, some GI tumours are considered chemoresistant and targeted therapies have offered a new therapeutic base for their management. Hence, somatostatin receptor-directed strategies, sorafenib, and imatinib have revolutioned the management of neuroendocrine tumours (NET), hepatocellular carcinoma (HCC), and gastrointestinal stromal tumours (GIST), respectively, and are now used as first-line treatment in many patients affected by these tumours. However, these agents face problems of resistances and identification of predictive biomarkers from imaging and/or biology. We propose a comprehensive two-part review providing a panoramic approach of the successes and failures of targeted agents in GI cancers to unravel the pharmacologic opportunities and future directions for these agents in GI oncology. In this second part, we will focus on NET, HCC, and GIST, whose treatment relies primarily on targeted therapies.
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Affiliation(s)
- Cindy Neuzillet
- INSERM UMR1149, Beaujon University Hospital (Assistance Publique-Hôpitaux de Paris, AP-HP), Paris 7 Diderot University, 100 Boulevard du Général Leclerc, 92110 Clichy, France; Department of Medical Oncology, Henri Mondor University Hospital (AP-HP), Paris Est Créteil University (UPEC), 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France; Tumour Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom; Barts and The London HPB Centre, The Royal London Hospital, Whitechapel, London E1 1BB, United Kingdom.
| | - Louis de Mestier
- INSERM UMR1149, Beaujon University Hospital (Assistance Publique-Hôpitaux de Paris, AP-HP), Paris 7 Diderot University, 100 Boulevard du Général Leclerc, 92110 Clichy, France; Department of Gastroenterology and Pancreatology, Beaujon University Hospital (AP-HP), Paris 7 Diderot University, 100 Boulevard du Général Leclerc, 92110 Clichy, France
| | - Benoît Rousseau
- Department of Medical Oncology, Henri Mondor University Hospital (AP-HP), Paris Est Créteil University (UPEC), 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France; Institut Mondor de Recherche Biomédicale, INSERM UMR955 Team 18, Paris Est Créteil University (UPEC), 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France
| | - Olivier Mir
- Department of Cancer Medicine - Sarcoma Group, Department of Early Drug Development (DITEP) - Phase 1 Unit, Gustave Roussy Cancer Campus, University of Paris Sud, 114, Rue Edouard Vaillant, 94800 Villejuif, France
| | - Mohamed Hebbar
- Department of Medical Oncology, Lille University Hospital, 1, Rue Polonovski, 59037 Lille, France
| | - Hemant M Kocher
- Tumour Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom; Barts and The London HPB Centre, The Royal London Hospital, Whitechapel, London E1 1BB, United Kingdom
| | - Philippe Ruszniewski
- INSERM UMR1149, Beaujon University Hospital (Assistance Publique-Hôpitaux de Paris, AP-HP), Paris 7 Diderot University, 100 Boulevard du Général Leclerc, 92110 Clichy, France
| | - Christophe Tournigand
- Department of Medical Oncology, Henri Mondor University Hospital (AP-HP), Paris Est Créteil University (UPEC), 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France
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Abstract
OBJECTIVE This article reviews recent developments in targeted radionuclide therapy (TRT) approaches directed to malignant liver lesions, bone metastases, neuroendocrine tumors, and castrate-resistant metastatic prostate cancer and discusses challenges and opportunities in this field. CONCLUSION TRT has been employed since the first radioiodine thyroid treatment almost 75 years ago. Progress in the understanding of the complex underlying biology of cancer and advances in radiochemistry science, multimodal imaging techniques including the concept of "see and treat" within the framework of theranostics, and universal traction with the notion of precision medicine have all contributed to a resurgence of TRT.
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Popa E, Schnoll‐Sussman F, Jesudian A, Nandakumar G, Shah MA. Uncommon Cancers of the Stomach. TEXTBOOK OF UNCOMMON CANCER 2017:395-415. [DOI: 10.1002/9781119196235.ch27] [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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Peptide Receptor Radionuclide Therapy Outcomes in a North American Cohort With Metastatic Well-Differentiated Neuroendocrine Tumors. Pancreas 2017; 46:151-156. [PMID: 27759712 PMCID: PMC5595066 DOI: 10.1097/mpa.0000000000000734] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES The objective of this study was to describe the outcomes of patients in the University of Iowa Neuroendocrine Tumor (NET) Database treated with peptide receptor radionuclide therapy (PRRT). METHODS One hundred thirty-five patients from the University of Iowa NET Database who received PRRT were analyzed, their characteristics were described, and survival was calculated. RESULTS The median age at diagnosis was 51 years, and 64% were men. The primary tumor was located in the small bowel (SBNET) in 37.8%, in the pancreas (PNET) in 26.0%, in the lung in 13.3%, in unknown primary in 9.6%, and in other sites in 13.3%. A radiographic response of any magnitude was observed in 65.8%, 11.1% had a mixed response, and 15.4% showed progression. The overall survival (OS) from the first PRRT was 40 months, and the median time to progression was 23.9 months. Higher pretreatment chromogranin A and pancreastatin levels predicted inferior OS. CONCLUSIONS Peptide receptor radionuclide therapy resulted in a relatively long OS and time to progression in heavily pretreated North American patients with advanced NETs. Elevated pretreatment chromogranin A and pancreastatin predicted shorter OS after therapy. Peptide receptor radionuclide therapy is a valuable treatment option in patients with advanced NETs, especially SBNETS.
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Pancreatic Neuroendocrine Neoplasms: Basic Biology, Current Treatment Strategies and Prospects for the Future. Int J Mol Sci 2017; 18:ijms18010143. [PMID: 28098761 PMCID: PMC5297776 DOI: 10.3390/ijms18010143] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Revised: 12/25/2016] [Accepted: 01/05/2017] [Indexed: 02/07/2023] Open
Abstract
Pancreatic neuroendocrine neoplasms (pNENs) are rare tumors accounting for only 1%–2% of all pancreatic tumors. pNENs are pathologically heterogeneous and are categorized into three groups (neuroendocrine tumor: NET G1, NET G2; and neuroendocrine carcinoma: NEC) on the basis of the Ki-67 proliferation index and the mitotic count according to the 2010 World Health Organization (WHO) classification of gastroenteropancreatic NENs. NEC in this classification includes both histologically well-differentiated and poorly differentiated subtypes, and modification of the WHO 2010 classification is under discussion based on genetic and clinical data. Genomic analysis has revealed NETs G1/G2 have genetic alterations in chromatin remodeling genes such as MEN1, DAXX and ATRX, whereas NECs have an inactivation of TP53 and RB1, and these data suggest that different treatment approaches would be required for NET G1/G2 and NEC. While there are promising molecular targeted drugs, such as everolimus or sunitinib, for advanced NET G1/G2, treatment stratification based on appropriate predictive and prognostic biomarkers is becoming an important issue. The clinical outcome of NEC is still dismal, and a more detailed understanding of the genetic background together with preclinical studies to develop new agents, including those already under investigation for small cell lung cancer (SCLC), will be needed to improve the prognosis.
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Waligórska-Stachura J, Gut P, Sawicka-Gutaj N, Liebert W, Gryczyńska M, Baszko-Błaszyk D, Blanco-Gangoo AR, Ruchała M. Growth hormone–secreting macroadenoma of the pituitary gland successfully treated with the radiolabeled somatostatin analog 90Y-DOTATATE: case report. J Neurosurg 2016; 125:346-9. [DOI: 10.3171/2015.6.jns15363] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Pituitary tumors causing acromegaly are usually macroadenomas at the time of diagnosis, and they can grow aggressively, infiltrating surrounding tissues. Difficulty in achieving complete tumor removal at surgery can lead toward a strong tendency for recurrence, making it necessary to consider a means of treatment other than those currently used such as somatostatin analogs (SSAs), growth hormone (GH) receptor antagonist, surgical removal, and radiotherapy. The purpose of this paper is to describe a patient diagnosed with an aggressive, giant GH-secreting tumor refractory to medical therapy but ultimately treated with the radiolabeled somatostatin analog 90Y-DOTATATE.
A 26-year-old male with an invasive macroadenoma of the pituitary gland (5.6 × 2.5 × 3.6 cm) and biochemically confirmed acromegaly underwent 2 partial tumor resections: the first used the transsphenoidal approach and the second used the transcranial method. The patient received SSAs pre- and postoperatively. Because of the progression in pituitary tumor size, he underwent classic irradiation of the tumor (50 Gy). One and a half years later, the patient presented with clinically and biochemically active disease, and the tumor size was still 52 mm in diameter (height). Two neurosurgeons disqualified him from further surgical procedures. After confirming the presence of somatostatin receptors in the pituitary tumor by using 68Ga-DOTATATE PET/CT, we treated the patient 4 times with an SSA bound with 90Y-DOTATATE. After this treatment, the patient attained partial biochemical remission and a reduction in the tumor mass for the first time.
Treatment with an SSA bound with 90Y-DOTATATE may be a promising option for some aggressive GH-secreting pituitary adenomas when other methods have failed.
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Affiliation(s)
| | - Paweł Gut
- Departments of 1Endocrinology, Metabolism and Internal Medicine and
| | | | - Włodzimierz Liebert
- 2Neurosurgery and Neurotraumatology, Poznań University of Medical Sciences, Poznań, Poland
| | - Maria Gryczyńska
- Departments of 1Endocrinology, Metabolism and Internal Medicine and
| | | | | | - Marek Ruchała
- Departments of 1Endocrinology, Metabolism and Internal Medicine and
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Keutgen XM, Babic B, Nilubol N. Management of pancreatic neuroendocrine tumors. INTERNATIONAL JOURNAL OF ENDOCRINE ONCOLOGY 2016. [DOI: 10.2217/ije-2016-0002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Pancreatic neuroendocrine tumors (pNETs) are rare tumors that have a better prognosis than their exocrine counterpart, but frequently present with advanced disease. Management of pNETs has evolved considerably over the past decade. Surgical resection remains the only potentially curative option for patients with pNETs. Patients who have locoregionally advanced and/or metastatic pNETs require additional treatments. These include liver-directed (transarterial (chemo)-embolization, selective intraarterial radio therapy) and systemic therapies (somatostatin analogs, targeted therapy such as tyrosine-kinase inhibitors and mammalian target of rapamycin inhibitor, peptide receptor radionuclide therapy and cytotoxic chemotherapy). The aim of this article is to review the current treatment options as well as potential future therapeutic perspectives for patients with pNETs.
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Affiliation(s)
- Xavier M Keutgen
- Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Bruna Babic
- Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Naris Nilubol
- Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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Kesavan M, Turner JH. Myelotoxicity of Peptide Receptor Radionuclide Therapy of Neuroendocrine Tumors: A Decade of Experience. Cancer Biother Radiopharm 2016; 31:189-98. [PMID: 27419665 DOI: 10.1089/cbr.2016.2035] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
AIM This review of the literature, and the authors' own decade of experience with lutetium-177-octreotate-capecitabine±temozolomide peptide receptor radionuclide therapy (PRRT)-chemotherapy of GEPNETs, analyses the risk of both short- and long-term hematotoxicity. BACKGROUND Myelodysplastic syndrome (MDS) and acute leukemia (AL) have been associated with PRRT in heavily pretreated patients with a history of exposure to alkylating agents. Commenced 15 years ago, PRRT is now becoming established as first- and second-line therapy for gastroentero pancreatic neuroendocrine tumors (GEPNETs), and early treatment minimizes myelotoxicity, which is the most significant potential adverse event following PRRT. RESULTS Sixteen key articles involving primary research were identified. A total of 2225 patients were treated (2104 treated with PRRT monotherapy and 121 with PRRT combined with chemotherapy). The average age of patients in these studies ranged from 53 to 64 years with median duration of follow-up ranging from 6 to 62 months. Short-term myelotoxicity was observed in 221 patients (10%), occurring in 213 of 2104 patients treated with PRRT monotherapy and 8 of 121 patients treated with PRRT combined with chemotherapy. Acute toxicity manifested as modest self-limited grade 3/4 toxicity (CTCAE or WHO), most often affecting platelets during the first cycle of treatment. Toxicity manifesting early was easily managed with dose modification or therapy cessation and was ameliorated by appropriate patient selection. MDS/AL was a rare stochastic event occurring in 32 (1.4%) patients. Where bone marrow biopsy was performed, cases of MDS displayed cytogenetic abnormalities, consistent with secondary MDS. Factors associated with myelotoxicity included age >70 years, impaired renal function, baseline cytopenias, prior number of therapies, prior chemotherapy (alkylating agents), and prior radiotherapy. CONCLUSION Early therapy with PRRT-containing regimens improves outcomes, minimizes myelotoxicity, and renders the risk of MDS and AL negligible.
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Affiliation(s)
- Murali Kesavan
- School of Medicine and Pharmacology, The University of Western Australia , Crawley, Australia
| | - J Harvey Turner
- School of Medicine and Pharmacology, The University of Western Australia , Crawley, Australia
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Moreno P, Ramos-Álvarez I, Moody TW, Jensen RT. Bombesin related peptides/receptors and their promising therapeutic roles in cancer imaging, targeting and treatment. Expert Opin Ther Targets 2016; 20:1055-73. [PMID: 26981612 DOI: 10.1517/14728222.2016.1164694] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Despite remarkable advances in tumor treatment, many patients still die from common tumors (breast, prostate, lung, CNS, colon, and pancreas), and thus, new approaches are needed. Many of these tumors synthesize bombesin (Bn)-related peptides and over-express their receptors (BnRs), hence functioning as autocrine-growth-factors. Recent studies support the conclusion that Bn-peptides/BnRs are well-positioned for numerous novel antitumor treatments, including interrupting autocrine-growth and the use of over-expressed receptors for imaging and targeting cytotoxic-compounds, either by direct-coupling or combined with nanoparticle-technology. AREAS COVERED The unique ability of common neoplasms to synthesize, secrete, and show a growth/proliferative/differentiating response due to BnR over-expression, is reviewed, both in general and with regard to the most frequently investigated neoplasms (breast, prostate, lung, and CNS). Particular attention is paid to advances in the recent years. Also considered are the possible therapeutic approaches to the growth/differentiation effect of Bn-peptides, as well as the therapeutic implication of the frequent BnR over-expression for tumor-imaging and/or targeted-delivery. EXPERT OPINION Given that Bn-related-peptides/BnRs are so frequently ectopically-expressed by common tumors, which are often malignant and become refractory to conventional treatments, therapeutic interventions using novel approaches to Bn-peptides and receptors are being explored. Of particular interest is the potential of reproducing with BnRs in common tumors the recent success of utilizing overexpression of somatostatin-receptors by neuroendocrine-tumors to provide the most sensitive imaging methods and targeted delivery of cytotoxic-compounds.
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Affiliation(s)
- Paola Moreno
- a Digestive Diseases Branch, Cell Biology Section, NIDDK , National Institutes of Health , Bethesda , MD , USA
| | - Irene Ramos-Álvarez
- a Digestive Diseases Branch, Cell Biology Section, NIDDK , National Institutes of Health , Bethesda , MD , USA
| | - Terry W Moody
- b Center for Cancer Research, Office of the Director , NCI, National Institutes of Health , Bethesda , MD , USA
| | - Robert T Jensen
- a Digestive Diseases Branch, Cell Biology Section, NIDDK , National Institutes of Health , Bethesda , MD , USA
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Folkert IW, Hernandez P, Roses RE. Multidisciplinary management of nonfunctional neuroendocrine tumor of the pancreas. World J Gastroenterol 2016; 22:3105-3116. [PMID: 27003988 PMCID: PMC4789986 DOI: 10.3748/wjg.v22.i11.3105] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Revised: 01/05/2016] [Accepted: 01/11/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatic neuroendocrine tumors (PNETs) are a rare and diverse group of tumors; nonfunctional (NF) PNETs account for the majority of cases. Most patients with NF-PNETs have metastatic disease at the time of presentation. A variety of treatment modalities exist, including medical, liver directed, and surgical treatments. Aggressive surgical management is associated with prolonged survival, however available data are limited by selection bias and the frequent combination of PNETs with carcinoid tumors. Although few patients with metastatic disease will be cured, application of currently available therapies in a multidisciplinary setting can lead to excellent outcomes with prolonged patient survival.
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Pancreatic neuroendocrine tumors: Challenges in an underestimated disease. Crit Rev Oncol Hematol 2016; 101:193-206. [PMID: 27021395 DOI: 10.1016/j.critrevonc.2016.03.013] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2015] [Revised: 02/24/2016] [Accepted: 03/09/2016] [Indexed: 12/20/2022] Open
Abstract
Pancreatic neuroendocrine tumours (PanNETs) are considered a relatively unusual oncologic entity. Due to its relative good prognosis, surgery remains the goal standard therapy not only in localized disease but also in the setting of locally or metastatic disease. Most of the patients are diagnosed in metastatic scenario, where multidisciplinary approach based on surgery, chemotherapies, liver-directed and/or molecular targeted therapies are commonly used. Owing to a deeper molecular knowledge of this disease, these targeted therapies are nowadays widely implemented, being the likely discovery of predictive biomarkers that would allow its use in other settings. This review is focused on describing the different classifications, etiology, prognostic biomarkers and multidisciplinary approaches that are typically used in PanNET.
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Abstract
When diagnosed at an early stage, resection of pancreatic neuroendocrine tumors (NETs) is often curative. Unfortunately, curative surgery is rarely an option for patients with metastatic disease. Multiple options are available for the management of patients with advanced pancreatic NETs, including surgery, liver-directed therapy, and systemic therapies. Because of the heterogeneity of disease biology and presentation, a multidisciplinary approach to management is critical. Treatment with somatostatin analogs, sunitinib, everolimus, and alkylating agents provide effective systemic therapeutic options for patients. Future studies to evaluate the optimal timing, sequence, and combination of therapies, as well as to identify predictors of response, are warranted.
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Moody TW, Nuche-Berenguer B, Jensen RT. Vasoactive intestinal peptide/pituitary adenylate cyclase activating polypeptide, and their receptors and cancer. Curr Opin Endocrinol Diabetes Obes 2016; 23:38-47. [PMID: 26702849 PMCID: PMC4844466 DOI: 10.1097/med.0000000000000218] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW To summarize the roles of vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase activating polypeptide (PACAP) and their receptors (VPAC1, VPAC2, PAC1) in human tumors as well as their role in potential novel treatments. RECENT FINDINGS Considerable progress has been made in understanding of the effects of VIP/PACAP on growth of various tumors as well as in the signaling cascades involved, especially in the role of transactivation of the epidermal growth factor family. The overexpression of VPAC1/2 and PAC1 on a number of common neoplasms (breast, lung, prostate, central nervous system and neuroblastoma) is receiving increased attention both as a means of tumor imaging the location and extent of these tumors, as well as for targeted directed treatment, by coupling cytotoxic agents to VIP/PACAP analogues. SUMMARY VIP/PACAP has prominent growth effects on a number of common neoplasms, which frequently overexpressed the three subtypes of their receptors. The increased understanding of their signaling cascades, effect on tumor growth/differentiation and the use of the overexpression of these receptors for localization/targeted cytotoxic delivery are all suggesting possible novel tumor treatments.
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Affiliation(s)
- Terry W Moody
- aDepartment of Health and Human Services, National Cancer Institute, Center for Cancer Research, Office of the Director bNational Institutes of Health, National Institute of Diabetes, Digestive and Kidney Disease, Digestive Diseases Branch, Bethesda, Maryland, USA
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Hauck L, Bitzer M, Malek N, Plentz RR. Subgroup analysis of patients with G2 gastroenteropancreatic neuroendocrine tumors. Scand J Gastroenterol 2016; 51:55-9. [PMID: 26137871 DOI: 10.3109/00365521.2015.1064994] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Neuroendocrine tumors (NET) are malignancies with an increasing incidence rate. NETs are graded or classified by the expression level of Ki67, a proliferation marker in Grade 1 and 2 tumors. Out of 120 patients who visited our hospital between 2003 and 2012, 40 were classified as G2 NET. This study was mainly designed to investigate a new threshold for optimising the Ki67 system. Patients were subdivided into two new groups according to Ki67 (group 1 = 3-9%, group 2 = 10-20%). Twenty-five patients were allocated to group 1 and 15 to group 2. The primary tumor originated in 46% from the foregut and 68% NET were functionally active. Patients were treated in 88 versus 60% by surgery, 48 versus 80% by somatostatin analogs, 0 versus 20% by chemotherapy, 2,5 versus 0% by Everolimus and 32 versus 47% underwent peptide receptor radionuclide therapy. Group 1 patients showed a significantly (p = 0.01) better survival compared with group 2 and also a significant difference of Chromogranin A (p = 0.03) and alkaline phosphatase (p = 0.01). In addition, all patients with elevated lactate dehydrogenase showed a significantly (p = 0.03) shorter survival. Prognostic relevance of G2 NETs may be improved by using a new boundary. Patients with Ki67 of 3-9% showed a better response to current treatment methods and significantly longer survival compared to group 2. Thus, our data clearly show that patients with higher G2 proliferation index should be treated differently. Finally, LDH has been found to be a new prognostic factor in patients with G2 NET.
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Affiliation(s)
- Lisa Hauck
- a Department of Internal Medicine I, University Hospital , Tübingen, Germany
| | - Michael Bitzer
- a Department of Internal Medicine I, University Hospital , Tübingen, Germany
| | - Nisar Malek
- a Department of Internal Medicine I, University Hospital , Tübingen, Germany
| | - Ruben R Plentz
- a Department of Internal Medicine I, University Hospital , Tübingen, Germany
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Brolin G, Gustafsson J, Ljungberg M, Gleisner KS. Pharmacokinetic digital phantoms for accuracy assessment of image-based dosimetry in (177)Lu-DOTATATE peptide receptor radionuclide therapy. Phys Med Biol 2015. [PMID: 26215085 DOI: 10.1088/0031-9155/60/15/6131] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Patient-specific image-based dosimetry is considered to be a useful tool to limit toxicity associated with peptide receptor radionuclide therapy (PRRT). To facilitate the establishment and reliability of absorbed-dose response relationships, it is essential to assess the accuracy of dosimetry in clinically realistic scenarios. To this end, we developed pharmacokinetic digital phantoms corresponding to patients treated with (177)Lu-DOTATATE. Three individual voxel phantoms from the XCAT population were generated and assigned a dynamic activity distribution based on a compartment model for (177)Lu-DOTATATE, designed specifically for this purpose. The compartment model was fitted to time-activity data from 10 patients, primarily acquired using quantitative scintillation camera imaging. S values for all phantom source-target combinations were calculated based on Monte-Carlo simulations. Combining the S values and time-activity curves, reference values of the absorbed dose to the phantom kidneys, liver, spleen, tumours and whole-body were calculated. The phantoms were used in a virtual dosimetry study, using Monte-Carlo simulated gamma-camera images and conventional methods for absorbed-dose calculations. The characteristics of the SPECT and WB planar images were found to well represent those of real patient images, capturing the difficulties present in image-based dosimetry. The phantoms are expected to be useful for further studies and optimisation of clinical dosimetry in (177)Lu PRRT.
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Affiliation(s)
- Gustav Brolin
- Department of Medical Radiation Physics, Clinical Sciences Lund, Lund University, Sweden
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The current place and indications of 131I-metaiodobenzylguanidine therapy in the era of peptide receptor radionuclide therapy: determinants to consider for evolving the best practice and envisioning a personalized approach. Nucl Med Commun 2015; 36:1-7. [PMID: 25299467 DOI: 10.1097/mnm.0000000000000209] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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Baum RP, Puranik AD, Kulkarni HR. Peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors: current state and future perspectives. INTERNATIONAL JOURNAL OF ENDOCRINE ONCOLOGY 2015. [DOI: 10.2217/ije.15.5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The heterogeneous nature of neuroendocrine tumors, their indolent course and lack of therapeutic options for the management of advanced cases – together form the Achilles heel for oncologists. Somatostatin receptor-specific imaging with Ga-68 labeled peptides has provided an opportunity for management of advanced cancers with their therapeutic radionuclide counterparts (Lu-177/Y-90 labeled peptides). Molecular imaging with positron emission tomography/computed tomography is accepted technique for treatment response assessment, since the radiolabels for imaging and therapy are same, thereby depicting accurate response. We have compiled and reviewed our experience of last 8–10 years in the use of these novel radiolabeled peptides in the treatment of neuroendocrine tumors, focusing on the survival, toxicity profiles and the recent advances and improvements.
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Affiliation(s)
- Richard P Baum
- THERANOSTICS Center of Molecular Radiotherapy & Molecular Imaging, Zentralklinik Bad Berka, Germany
| | - Ameya D Puranik
- THERANOSTICS Center of Molecular Radiotherapy & Molecular Imaging, Zentralklinik Bad Berka, Germany
| | - Harshad R Kulkarni
- THERANOSTICS Center of Molecular Radiotherapy & Molecular Imaging, Zentralklinik Bad Berka, Germany
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Wolin EM. Treatment options for advanced pancreatic neuroendocrine tumors: what is on the horizon? INTERNATIONAL JOURNAL OF ENDOCRINE ONCOLOGY 2015. [DOI: 10.2217/ije.14.30] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Abstract: Treatment options for patients with advanced or metastatic pancreatic tumors (pNET) have expanded greatly in recent years. These treatments include resection, ablation or embolization of liver metastases and systemic therapy with everolimus or sunitinib and cytotoxic agents. New investigational approaches include the use of inhibitors of multiple downstream effectors in the PI3K/Akt/mTOR pathway, novel antiangiogenics, somatostatin analogues, new tyrosine kinase inhibitors and peptide receptor radionuclide therapy. The treatment horizon for pNET patients may offer improved duration of tumor control and survival and more effective symptom control.
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31
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Igaz P. Efficacy of somatostatin analogues in the treatment of neuroendocrine tumours based on the results of recent clinical trials. Orv Hetil 2014; 155:1908-12. [DOI: 10.1556/oh.2014.30048] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Due to their inhibitory effects on hormone secretion, somatostatin analogues are of pivotal importance in the symptomatic treatment of hormone-secreting neuroendocrine tumours. Although several earlier clinical observations supported the view that these biological agents are capable of inhibiting the growth of neuroendocrine tumours, the PROMID study published in 2009 was the first to confirm the inhibitory effect of octreotide on tumour growth and demonstrated the prolongation of progression free survival. These findings have been confirmed and extended by the most recent CLARINET trial with lanreotide published in 2014. Somatostatin analogues are capable of inhibiting tumour growth and stabilizing disease irrespective of the hormonal activity of the tumour and, therefore, their applicability is expected to be extended to the treatment of hormonally inactive neuroendocrine tumours, as well. Orv. Hetil., 2014, 155(48), 1908–1912.
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Affiliation(s)
- Péter Igaz
- Semmelweis Egyetem, Általános Orvostudományi Kar II. Belgyógyászati Klinika Budapest Szentkirályi u. 46. 1088
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Rossi RE, Massironi S, Conte D, Peracchi M. Therapy for metastatic pancreatic neuroendocrine tumors. ANNALS OF TRANSLATIONAL MEDICINE 2014; 2:8. [PMID: 25332984 DOI: 10.3978/j.issn.2305-5839.2013.03.01] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 02/18/2013] [Accepted: 03/19/2013] [Indexed: 02/05/2023]
Abstract
BACKGROUND Pancreatic neuroendocrine tumors (pNETs) are frequently malignant (50-80%, except for insulinoma) and may show an aggressive course with metastases to the liver as well as more distant sites. These heterogeneous neoplasms include functioning tumors, which secrete a variety of peptide hormones, and non-functioning tumors (up to 90% of pNETs), which often show metastases at the time of diagnosis. METHODS A PubMed search was performed for English-language publications from 1995 through December 2012. Reference lists from studies selected were manually searched to identify further relevant reports. Manuscripts comparing different therapeutic options and advances for metastatic pNETs were selected. RESULTS The therapeutic options for metastatic pNETs are expanding and include surgery, which remains the only curative approach, liver-directed therapies, and medical therapy. In selected cases also liver transplantation (OLT) may be considered. The option of OLT for metastatic disease is unique to neuroendocrine tumors. Recently, novel promising targeted therapies have been proposed for progressive well-differentiated pNETs. CONCLUSIONS The best therapeutic approach for pNETs is still matter of debating. However, since pNETs often show a more indolent behavior compared to other malignancies, the preservation of the quality of life of the patient and the personalization of the therapy according to tumor's and patient's features are mandatory.
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Affiliation(s)
- Roberta Elisa Rossi
- 1 Gastroenterology Unit II, Fondazione IRCCS Ca' Granda- Ospedale Maggiore Policlinico, Milan, Italy ; 2 Department of Pathophysiology and Transplant, Università degli Studi di Milano, Milan, Italy
| | - Sara Massironi
- 1 Gastroenterology Unit II, Fondazione IRCCS Ca' Granda- Ospedale Maggiore Policlinico, Milan, Italy ; 2 Department of Pathophysiology and Transplant, Università degli Studi di Milano, Milan, Italy
| | - Dario Conte
- 1 Gastroenterology Unit II, Fondazione IRCCS Ca' Granda- Ospedale Maggiore Policlinico, Milan, Italy ; 2 Department of Pathophysiology and Transplant, Università degli Studi di Milano, Milan, Italy
| | - Maddalena Peracchi
- 1 Gastroenterology Unit II, Fondazione IRCCS Ca' Granda- Ospedale Maggiore Policlinico, Milan, Italy ; 2 Department of Pathophysiology and Transplant, Università degli Studi di Milano, Milan, Italy
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Ryan J, Akhurst T, Lynch AC, Michael M, Heriot AG. Neoadjuvant 90 Yttrium peptide receptor radionuclide therapy for advanced rectal neuroendocrine tumour: a case report. ANZ J Surg 2014; 87:92-93. [PMID: 25307828 DOI: 10.1111/ans.12854] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Jennifer Ryan
- Department of Cancer Surgery, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.,Department of Surgery, Epworth Healthcare, Melbourne, Victoria, Australia
| | - Timothy Akhurst
- Department of Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
| | - A Craig Lynch
- Department of Cancer Surgery, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
| | - Michael Michael
- Department of Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
| | - Alexander G Heriot
- Department of Cancer Surgery, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
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Wagner T, Zeglis BM, Groveman S, Hille C, Pöthig A, Francesconi LC, Herrmann WA, Kühn FE, Reiner T. Synthesis of the first radiolabeled 188Re N-heterocyclic carbene complex and initial studies on its potential use in radiopharmaceutical applications. J Labelled Comp Radiopharm 2014; 57:441-7. [PMID: 24889257 PMCID: PMC4381871 DOI: 10.1002/jlcr.3203] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Revised: 03/27/2014] [Accepted: 04/01/2014] [Indexed: 11/08/2022]
Abstract
A novel approach towards the synthesis of radiolabeled organometallic rhenium complexes is presented. We successfully synthesized and analyzed the first (188)Re-labeled N-heterocyclic biscarbene complex, trans-dioxobis(1,1'-methylene-bis(3,3'-diisopropylimidazolium-2-ylidene))(188)rhenium(V) hexafluorophosphate ((188)Re-4) via transmetalation using an air-stable and moisture-stable silver(I) biscarbene complex. In order to assess the viability of this complex as a potential lead structure for in vivo applications, the stability of the (188)Re-NHC complex was tested in physiologically relevant media. Ultimately, our studies illustrate that the complex we synthesized dissociates rapidly and is therefore unsuitable for use in radiopharmaceuticals. However, it is clear that the transmetalation approach we have developed is a rapid, robust, and mild method for the synthesis of new (188)Re-labeled carbene complexes.
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Affiliation(s)
- Thomas Wagner
- Chair of Inorganic Chemistry/Molecular Catalysis, Department of Chemistry and Catalysis Research Center, Technische Universität München, Garching b. München, Germany
| | - Brian M. Zeglis
- Radiochemistry and Imaging Sciences Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Claudia Hille
- Chair of Inorganic Chemistry/Molecular Catalysis, Department of Chemistry and Catalysis Research Center, Technische Universität München, Garching b. München, Germany
| | - Alexander Pöthig
- Chair of Inorganic Chemistry/Molecular Catalysis, Department of Chemistry and Catalysis Research Center, Technische Universität München, Garching b. München, Germany
| | | | - Wolfgang A. Herrmann
- Chair of Inorganic Chemistry/Molecular Catalysis, Department of Chemistry and Catalysis Research Center, Technische Universität München, Garching b. München, Germany
| | - Fritz E. Kühn
- Chair of Inorganic Chemistry/Molecular Catalysis, Department of Chemistry and Catalysis Research Center, Technische Universität München, Garching b. München, Germany
| | - Thomas Reiner
- Radiochemistry and Imaging Sciences Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Center for Molecular Imaging and Nanotechnology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Delpassand ES, Samarghandi A, Zamanian S, Wolin EM, Hamiditabar M, Espenan GD, Erion JL, O'Dorisio TM, Kvols LK, Simon J, Wolfangel R, Camp A, Krenning EP, Mojtahedi A. Peptide receptor radionuclide therapy with 177Lu-DOTATATE for patients with somatostatin receptor-expressing neuroendocrine tumors: the first US phase 2 experience. Pancreas 2014; 43:518-25. [PMID: 24632546 DOI: 10.1097/mpa.0000000000000113] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Peptide receptor radionuclide therapy with radiolabeled somatostatin analogs is a novel method of treatment in patients with metastatic neuroendocrine tumors (NETs). For the first time in the United States, we present preliminary results of the treatment with Lutetium (177)(Lu) DOTATATE in patients with progressive NETs. METHODS Thirty-seven patients with grade 1 and grade 2 disseminated and progressive gastroenteropancreatic NET were enrolled in a nonrandomized, phase 2 clinical trial. Repeated cycles of 200 mCi (7.4 GBq; ±10%) were administered up to the cumulative dose of 800 mCi (29.6 GBq; ±10%). RESULTS Among 32 evaluable patients, partial response and minimal response to treatment were seen in 28% and 3%, respectively, and stable disease was seen in 41% of patients. A total of 28% had progressive disease. A response to treatment was significantly associated with lower burden of disease in the liver. No significant acute or delayed hematologic or kidney toxicity was observed. An impressive improvement of performance status and quality of life were seen after Lu-DOTATATE therapy. CONCLUSIONS Treatment with multiple cycles of (177)Lu-DOTATATE peptide receptor radionuclide therapy is well tolerated. This treatment results in control of the disease in most patients, whereas systemic toxicities are limited and reversible. Quality of life is also improved.
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Affiliation(s)
- Ebrahim S Delpassand
- From the *Excel Diagnostics and Nuclear Oncology Center, Houston, TX; †RadioMedix, Inc, Houston, TX; ‡Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA; §Physics Services Inc, Metairie, LA; ∥BioSynthema Inc, St Louis, MO; ¶Department of Internal Medicine, Holden Comprehensive Cancer Center, University of Iowa Health Care, Iowa City, IA; #Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL; **IsoTherapeutics Group, Angleton, TX; ††Certus International, Inc, St Louis, MO; ‡‡Iso-Tex Diagnostics, Inc, Friendswood, TX; and §§Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
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Abstract
PURPOSE OF REVIEW To review the recent advances and current controversies in patients with Zollinger-Ellison syndrome (ZES). RECENT FINDINGS Recent advances in the management of ZES include: improved understanding of the pathogenesis of gastrinoma and pancreatic neuroendocrine tumors, new prognostic classification systems, new diagnostic algorithms, more sensitive localization studies, new treatment strategies including improved control of gastric acid secretion and role for surgery, and new approaches to patients with advanced disease. Controversies include: the best approach to a patient with hypergastrinemia suspected of possibly having ZES, the appropriate gastrin assay to use, the role of surgery in patients with ZES, especially those with multiple endocrine neoplasia type 1, and the precise order of therapeutic modalities in the treatment of patients with advanced disease. SUMMARY This review updates clinicians regarding important advances and controversies required to optimally diagnose and manage patients with ZES.
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Affiliation(s)
- Tetsuhide Ito
- aDepartment of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan bDigestive Diseases Branch, NIDDK, NIH, Bethesda, Maryland, USA
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Veenstra MJ, de Herder WW, Feelders RA, Hofland LJ. Targeting the somatostatin receptor in pituitary and neuroendocrine tumors. Expert Opin Ther Targets 2013; 17:1329-43. [DOI: 10.1517/14728222.2013.830711] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Walker RC, Smith GT, Liu E, Moore B, Clanton J, Stabin M. Measured human dosimetry of 68Ga-DOTATATE. J Nucl Med 2013; 54:855-60. [PMID: 23516312 DOI: 10.2967/jnumed.112.114165] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
UNLABELLED Measured human dosimetry of the (68)Ga-labeled synthetic somatostatin analog (68)Ga-DOTATATE has not been reported in the peer-reviewed literature. (68)Ga-DOTATATE is an investigational PET/CT imaging agent that binds with high affinity to somatostatin receptor subtype 2, found on many human cancers, most classically neuroendocrine tumors but also others. Reporting of measured dosimetry of (68)Ga-DOTATATE could be useful for investigations for diagnosis, staging, and restaging of somatostatin receptor-expressing tumors. METHODS We performed measured dosimetry with (68)Ga-DOTATATE PET/CT scanning in 6 volunteer human subjects as part of an Institutional Review Board-approved biodistribution investigation of the use of this radiopharmaceutical for possible future use in the diagnosis of indeterminate lung nodules or lung cancer. Five subjects were imaged at 3 time points, and 1 subject was imaged at 2 time points. Dosimetry was then measured for the whole body and for specific organs. RESULTS There were no observed adverse events to the radiopharmaceutical in the immediate or delayed time frames, with a follow-up of 1 y. One patient had stage IV non-small cell lung cancer and remains alive but with disease progressing on treatment. For the other 5 patients, it was ultimately proven that they had benign nodules. The measured dosimetry shows that the critical organ with (68)Ga-DOTATATE is the spleen, followed by the uroepithelium of the bladder, the kidneys, and the liver, in that order. Organ-specific and whole-body dosimetries for (68)Ga-DOTATATE were similar to but often slightly greater than those for (68)Ga-DOTATOC or (68)Ga-DOTANOC but less than those for (111)In-diethylenetriaminepentaacetic acid-octreotide. CONCLUSION No toxicity was observed in our 6 patients, and no adverse events occurred. The measured human dosimetry of (68)Ga-DOTATATE is similar to that of other (68)Ga-labeled somatostatin receptor analogs.
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Affiliation(s)
- Ronald C Walker
- Medical Imaging Service, Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee 37232-2675, USA.
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Abstract
INTRODUCTION The role of pharmacotherapy in the management of patients with Zollinger-Ellison syndrome (ZES) is often equated with the medical management of acid hypersecretion. However, pharmacotherapy is also increasingly involved in the other management areas of these patients. AREAS COVERED This paper reviews the role of pharmacotherapy in all aspects of the management of patients with ZES. Newer aspects are emphasized. This includes the difficulty of diagnosing ZES in patients taking proton pump inhibitors. Also covered is the role of pharmacotherapy in controlling acid hypersecretion and other hormonal hypersecretory states these patients may develop, including hyperparathyroidism in patients with multiple endocrine neoplasia type 1 and ZES; tumor localization; and the treatment of advanced metastatic disease. The last includes chemotherapy, liver-directed therapies, biotherapy (somatostatin/interferon), peptide radio-receptor therapy and molecular-targeted therapies including the use of mTor inhibitors (everolimus) and tyrosine kinase inhibitors (sunitinib). EXPERT OPINION Pharmacotherapy is now involved in all aspects of the management of patients with ZES, with the result that ZES has progressed from being considered an entirely surgical disease initially to the present where medical treatment plays a major role in almost all aspects of the management of these patients.
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Affiliation(s)
- Tetsuhide Ito
- Kyushu University, Graduate School of Medical Sciences, Department of Medicine and Bioregulatory Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
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Ito T, Igarashi H, Jensen RT. Therapy of metastatic pancreatic neuroendocrine tumors (pNETs): recent insights and advances. J Gastroenterol 2012; 47:941-60. [PMID: 22886480 PMCID: PMC3754804 DOI: 10.1007/s00535-012-0642-8] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2012] [Accepted: 06/23/2012] [Indexed: 02/08/2023]
Abstract
Neuroendocrine tumors (NETs) [carcinoids, pancreatic neuroendocrine tumors (pNETs)] are becoming an increasing clinical problem because not only are they increasing in frequency, but they can frequently present with advanced disease that requires diagnostic and treatment approaches different from those used in the neoplasms that most physicians are used to seeing and treating. In the past few years there have been numerous advances in all aspects of NETs including: an understanding of their unique pathogenesis; specific classification systems developed which have prognostic value; novel methods of tumor localization developed; and novel treatment approaches described. In patients with advanced metastatic disease these include the use of newer chemotherapeutic approaches, an increased understanding of the role of surgery and cytoreductive methods, the development of methods for targeted delivery of cytotoxic agents, and the development of targeted medical therapies (everolimus, sunitinib) based on an increased understanding of the disease biology. Although pNETs and gastrointestinal NETs share many features, recent studies show they differ in pathogenesis and in many aspects of diagnosis and treatment, including their responsiveness to different therapies. Because of limited space, this review will be limited to the advances made in the management and treatment of patients with advanced metastatic pNETs over the past 5 years.
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Affiliation(s)
- Tetsuhide Ito
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Hisato Igarashi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Robert T. Jensen
- Digestive Diseases Branch, NIDDK, NIH, Building 10, Room 9C-103, Bethesda, MD 20892, USA
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Tatsi A, Maina T, Cescato R, Waser B, Krenning EP, de Jong M, Cordopatis P, Reubi JC, Nock BA. [111In-DOTA]Somatostatin-14 analogs as potential pansomatostatin-like radiotracers - first results of a preclinical study. EJNMMI Res 2012; 2:25. [PMID: 22682002 PMCID: PMC3407795 DOI: 10.1186/2191-219x-2-25] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2012] [Accepted: 06/09/2012] [Indexed: 02/04/2023] Open
Abstract
Background In this study, we report on the synthesis, radiolabeling, and biological evaluation of two new somatostatin-14 (SS14) analogs, modified with the universal chelator DOTA. We were interested to investigate if and to what extent such radiotracer prototypes may be useful for targeting sst1-5-expressing tumors in man but, most importantly, to outline potential drawbacks and benefits associated with their use. Methods AT1S and AT2S (DOTA-Ala1-Gly2-c[Cys3-Lys4-Asn5-Phe6-Phe7-Trp8/DTrp8-Lys9-Thr10-Phe11-Thr12-Ser13-Cys14-OH], respectively) were synthesized on the solid support and labeled with 111In. The sst1-5 affinity profile of AT1S/AT2S was determined by receptor autoradiography using [Leu8,dTrp22,125I-Tyr25]SS28 as radioligand. The ability of AT2S to stimulate sst2 or sst3 internalization was qualitatively analyzed by an immunofluorescence-based internalization assay using hsst2- or hsst3-expressing HEK293 cells. Furthermore, the internalization of the radioligands [111In]AT1S and [111In]AT2S was studied at 37 °C in AR4-2J cells endogenously expressing sst2. The in vivo stability of [111In]AT1S and [111In]AT2S was tested by high-performance liquid chromatography analysis of mouse blood collected 5 min after radioligand injection, and biodistribution was studied in normal mice. Selectively for [111In]AT2S, biodistribution was further studied in SCID mice bearing AR4-2J, HEK293-hsst2A+, -hsst3+ or -hsst5+ tumors. Results The new SS14-derived analogs were obtained by solid phase peptide synthesis and were easily labeled with 111In. Both SS14 conjugates, AT1S, and its DTrp8 counterpart, AT2S, showed a pansomatostatin affinity profile with the respective hsst1-5 IC50 values in the lower nanomolar range. In addition, AT2S behaved as an agonist for sst2 and sst3 since it stimulated receptor internalization. The 111In radioligands effectively and specifically internalized into rsst2A-expressing AR4-2J cells with [111In]AT2S internalizing faster than [111In]AT1S. Ex vivo mouse blood analysis revealed a rapid degradation of both radiopeptides in the bloodstream with the DTrp8 analog showing higher stability. Biodistribution results in healthy mice were consistent with these findings with only [111In]AT2S showing specific uptake in the sst2-rich pancreas. Biodistribution of [111In]AT2S in tumor-bearing mice revealed receptor-mediated uptake in the AR4-2J (1.82 ± 0.36 %ID/g - block 0.21 ± 0.17 %ID/g at 4 h post injection (pi)), the HEK293-hsst2A+ (1.49 ± 0.2 %ID/g - block 0.27 ± 0.20 %ID/g at 4 h pi), the HEK293-hsst3+ (1.24 ± 0.27 %ID/g - block 0.32 ± 0.06 %ID/g at 4 h pi), and the HEK293-hsst5+ tumors (0.41 ± 0.12 %ID/g - block 0.22 ± 0.006 %ID/g at 4 h pi). Radioactivity washed out from blood and background tissues via the kidneys. Conclusions This study has revealed that the native SS14 structure can indeed serve as a motif for the development of promising pansomatostatin-like radiotracers. Further peptide stabilization is required to increase in vivo stability and, consequently, to enhance in vivo delivery and tumor targeting.
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Affiliation(s)
- Aikaterini Tatsi
- Molecular Radiopharmacy, Institute of Radioisotopes - Radiodiagnostic Products, National Center for Scientific Research "Demokritos", 153 10 Ag, Paraskevi Attikis, Athens, GR-153 10, Greece.
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Kunz PL. A renaissance in therapeutic options for pancreatic neuroendocrine tumors. Am Soc Clin Oncol Educ Book 2012:271-274. [PMID: 24451747 DOI: 10.14694/edbook_am.2012.32.136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
The field of pancreatic neuroendocrine tumors (NETs) has seen a remarkable renaissance in recent years with exponential increases in published research, clinical trials, and U.S. Food and Drug Administration (FDA)-approved treatments. Surgical resection remains the foundation for management of locoregional disease. However, for patients with advanced disease, novel therapeutic options have emerged. Two separate randomized placebo-controlled studies have shown prolonged progression-free survival (PFS) with everolimus or sunitinib. Future studies are designed to answer questions about the role of somatostatin analogs as antiproliferative agents, combinations of biologic therapies, and new cytotoxic chemotherapy backbones.
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Affiliation(s)
- Pamela L Kunz
- From the Stanford University School of Medicine, Stanford Cancer Institute, Stanford, CA
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