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Qin H, Yan H, Zhang X, Huang Z, Chen Y, Zhang Y, Xiang S, Zhang Y, Yang N, Zeng L. Octreotide plus IBI-318 plus anlotinib in the treatment of multiple neuroendocrine metastases of unknown primary lesions: a case report. Front Oncol 2024; 14:1390299. [PMID: 39723389 PMCID: PMC11668696 DOI: 10.3389/fonc.2024.1390299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 11/04/2024] [Indexed: 12/28/2024] Open
Abstract
Background The second-line treatment of neuroendocrine tumors (NETs) of unknown primary origin remains uncertain. This report presented a patient who received octreotide plus IBI-318 plus anlotinib as a second-line treatment for multiple metastatic NETs of unknown primary lesions after the failure of octreotide plus everolimus. Case presentation A 32-year-old male patient presented with elevated CEA (197.83 ng/ml) without specific symptoms. A contrast-enhanced computed tomography (CT) scan showed multiple metastatic lymph nodes and multiple low-density nodules in the liver of undetermined nature. A right supraclavicular lymph node biopsy indicated NET, but the primary tumor origin remained unknown. PD-L1 expression was negative in tumor tissue according to immunohistochemistry. Immunofluorescence indicated the CD4+ T cells, CD8+ T cells, and Treg cells were gathered around blood vessels, with only a few infiltrating lymphocytes in the tumor tissue. Treatment with octreotide (30 mg/28 d) plus everolimus (5 mg qd) led to disease progression after three cycles. Treatment was changed to octreotide (30 mg/28 d) plus IBI318 (400 mg/28 d) plus anlotinib (10 mg/1-14 d/q3w), leading to partial remission, which was sustained up to the last follow-up (June 20, 2023), with a PFS of 11 months. The patient experienced no treatment-related adverse reactions. Conclusions Octreotide plus IBI318 plus anlotinib achieved benefits in a patient with advanced NETs of unknown primary lesions after first-line treatment failure, even though with low PD-L1 expression. This case suggests that combining SSAs, TKIs and PD-1/PD-L1 inhibitors could be an alternative second-line treatment for patients with advanced, well-differentiated NETs.
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Affiliation(s)
- Haoyue Qin
- Graduate Collaborative Training Base of Hunan Cancer Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Huan Yan
- Graduate Collaborative Training Base of Hunan Cancer Hospital, Hengyang Medical School, University of South China, Hengyang, China
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Xing Zhang
- Graduate Collaborative Training Base of Hunan Cancer Hospital, Hengyang Medical School, University of South China, Hengyang, China
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Zhe Huang
- Graduate Collaborative Training Base of Hunan Cancer Hospital, Hengyang Medical School, University of South China, Hengyang, China
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Yangqian Chen
- Graduate Collaborative Training Base of Hunan Cancer Hospital, Hengyang Medical School, University of South China, Hengyang, China
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Yuda Zhang
- Graduate Collaborative Training Base of Hunan Cancer Hospital, Hengyang Medical School, University of South China, Hengyang, China
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Siqi Xiang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Yongchang Zhang
- Graduate Collaborative Training Base of Hunan Cancer Hospital, Hengyang Medical School, University of South China, Hengyang, China
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Nong Yang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- The Cancer Center, The Second People's Hospital of Hunan Province/The School of Clinical Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Liang Zeng
- Graduate Collaborative Training Base of Hunan Cancer Hospital, Hengyang Medical School, University of South China, Hengyang, China
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
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Candeli N, Dayton T. Investigating pulmonary neuroendocrine cells in human respiratory diseases with airway models. Dis Model Mech 2024; 17:dmm050620. [PMID: 38813849 DOI: 10.1242/dmm.050620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2024] Open
Abstract
Despite accounting for only ∼0.5% of the lung epithelium, pulmonary neuroendocrine cells (PNECs) appear to play an outsized role in respiratory health and disease. Increased PNEC numbers have been reported in a variety of respiratory diseases, including chronic obstructive pulmonary disease and asthma. Moreover, PNECs are the primary cell of origin for lung neuroendocrine cancers, which account for 25% of aggressive lung cancers. Recent research has highlighted the crucial roles of PNECs in lung physiology, including in chemosensing, regeneration and immune regulation. Yet, little is known about the direct impact of PNECs on respiratory diseases. In this Review, we summarise the current associations of PNECs with lung pathologies, focusing on how new experimental disease models, such as organoids derived from human pluripotent stem cells or tissue stem cells, can help us to better understand the contribution of PNECs to respiratory diseases.
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Affiliation(s)
- Noah Candeli
- European Molecular Biology Laboratory (EMBL) Barcelona, Tissue Biology and Disease Modelling, 08003, Barcelona, Spain
| | - Talya Dayton
- European Molecular Biology Laboratory (EMBL) Barcelona, Tissue Biology and Disease Modelling, 08003, Barcelona, Spain
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Milewska-Kranc A, Ćwikła JB, Kolasinska-Ćwikła A. The Role of Receptor-Ligand Interaction in Somatostatin Signaling Pathways: Implications for Neuroendocrine Tumors. Cancers (Basel) 2023; 16:116. [PMID: 38201544 PMCID: PMC10778465 DOI: 10.3390/cancers16010116] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 12/19/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
Neuroendocrine tumors (NETs) arise from neuroendocrine cells and manifest in diverse organs. Key players in their regulation are somatostatin and its receptors (SSTR1-SSTR5). Understanding receptor-ligand interactions and signaling pathways is vital for elucidating their role in tumor development and therapeutic potential. This review highlights SSTR characteristics, localization, and expression in tissues, impacting physiological functions. Mechanisms of somatostatin and synthetic analogue binding to SSTRs, their selectivity, and their affinity were analyzed. Upon activation, somatostatin initiates intricate intracellular signaling, involving cAMP, PLC, and MAP kinases and influencing growth, differentiation, survival, and hormone secretion in NETs. This review explores SSTR expression in different tumor types, examining receptor activation effects on cancer cells. SSTRs' significance as therapeutic targets is discussed. Additionally, somatostatin and analogues' role in hormone secretion regulation, tumor growth, and survival is emphasized, presenting relevant therapeutic examples. In conclusion, this review advances the knowledge of receptor-ligand interactions and signaling pathways in somatostatin receptors, with potential for improved neuroendocrine tumor treatments.
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Affiliation(s)
| | - Jarosław B. Ćwikła
- School of Medicine, University of Warmia and Mazury, Aleja Warszawska 30, 10-082 Olsztyn, Poland
- Diagnostic Therapeutic Center–Gammed, Lelechowska 5, 02-351 Warsaw, Poland
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Oron-Herman M, Kirmayer D, Lupp A, Schulz S, Kostenich G, Afargan M. Expression prevalence and dynamics of GPCR somatostatin receptors 2 and 3 as cancer biomarkers beyond NET: a paired immunohistochemistry approach. Sci Rep 2023; 13:20857. [PMID: 38012197 PMCID: PMC10682014 DOI: 10.1038/s41598-023-47877-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 11/16/2023] [Indexed: 11/29/2023] Open
Abstract
Somatostatin receptors are clinically validated GPCR biomarkers for diagnosis and treatment of various neuroendocrine tumors (NET). Among the five somatostatin receptors, SST2 and SST3 are associated with apoptosis and cell cycle arrest, making these receptor subtypes better differentiated targets in precision oncology. In this study we performed immunohistochemistry of paired tissue microarrays containing 1125 cores, representing 43 tumor types, each stained for SST2 and SST3. A 12-point immunoreactive scoring (IRS) range was used for interpretation of the staining results. We analyzed the results twice, using the conventional positivity IRS cutoffs ≥ 3 and more stringent ≥ 6. Evaluation of receptors expression dynamics was performed for tumor-nodes-metastases (TNM) defined subgroups (ovarian and hepatocellular adenocarcinomas) as a function of their tumor stage. Our results indicate that two-thirds of tested cores exhibit clinically significant expression of at least SST2 or SST3 (IRS ≥ 6). The expression prevalence of both receptors tends to decline with tumor progression. However, an unexpected upregulation of both SST2 and SST3 reemerged in metastases suggesting conserved receptors genetic potential during tumor life cycle. We suggest that SST2 and SST3 should be further explored as potential biomarkers and therapeutic tools for maximizing the efficiency of somatostatin-based precision oncology of solid tumors beyond NET.
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Affiliation(s)
- Mor Oron-Herman
- Starget Pharma, 26 Snir st., 4704086, Ramat Hasharon, Israel.
| | - David Kirmayer
- Starget Pharma, 26 Snir st., 4704086, Ramat Hasharon, Israel
| | - Amelie Lupp
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Drackendorfer Str. 1, 07747, Jena, Germany
| | - Stefan Schulz
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Drackendorfer Str. 1, 07747, Jena, Germany
| | - Genady Kostenich
- Starget Pharma, 26 Snir st., 4704086, Ramat Hasharon, Israel
- The Advanced Technology Center, Sheba Medical Center, Tel Hashomer, 5262000, Ramat Gan, Israel
| | - Michel Afargan
- Starget Pharma, 26 Snir st., 4704086, Ramat Hasharon, Israel
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Modena D, Moras ML, Sandrone G, Stevenazzi A, Vergani B, Dasgupta P, Kliever A, Gulde S, Marangelo A, Schillmaier M, Luque RM, Bäuerle S, Pellegata NS, Schulz S, Steinkühler C. Identification of a Novel SSTR3 Full Agonist for the Treatment of Nonfunctioning Pituitary Adenomas. Cancers (Basel) 2023; 15:3453. [PMID: 37444563 DOI: 10.3390/cancers15133453] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/21/2023] [Accepted: 06/22/2023] [Indexed: 07/15/2023] Open
Abstract
Somatostatin receptor (SSTR) agonists have been extensively used for treating neuroendocrine tumors. Synthetic therapeutic agonists showing selectivity for SSTR2 (Octreotide) or for SSTR2 and SSTR5 (Pasireotide) have been approved for the treatment of patients with acromegaly and Cushing's syndrome, as their pituitary tumors highly express SSTR2 or SSTR2/SSTR5, respectively. Nonfunctioning pituitary adenomas (NFPAs), which express high levels of SSTR3 and show only modest response to currently available SSTR agonists, are often invasive and cannot be completely resected, and therefore easily recur. The aim of the present study was the evaluation of ITF2984, a somatostatin analog and full SSTR3 agonist, as a new potential treatment for NFPAs. ITF2984 shows a 10-fold improved affinity for SSTR3 compared to Octreotide or Pasireotide. Molecular modeling and NMR studies indicated that the higher affinity for SSTR3 correlates with a higher stability of a distorted β-I turn in the cyclic peptide backbone. ITF2984 induces receptor internalization and phosphorylation, and triggers G-protein signaling at pharmacologically relevant concentrations. Furthermore, ITF2984 displays antitumor activity that is dependent on SSTR3 expression levels in the MENX (homozygous mutant) NFPA rat model, which closely recapitulates human disease. Therefore, ITF2984 may represent a novel therapeutic option for patients affected by NFPA.
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Affiliation(s)
- Daniela Modena
- Preclinical R&D, Italfarmaco Group, 20092 Cinisello Balsamo, Milan, Italy
| | - Maria Luisa Moras
- Preclinical R&D, Italfarmaco Group, 20092 Cinisello Balsamo, Milan, Italy
| | - Giovanni Sandrone
- Preclinical R&D, Italfarmaco Group, 20092 Cinisello Balsamo, Milan, Italy
| | - Andrea Stevenazzi
- Preclinical R&D, Italfarmaco Group, 20092 Cinisello Balsamo, Milan, Italy
| | - Barbara Vergani
- Preclinical R&D, Italfarmaco Group, 20092 Cinisello Balsamo, Milan, Italy
| | - Pooja Dasgupta
- Institute of Pharmacology and Toxicology, Universitätsklinikum Jena, Friedrich-Schiller-Universität, 07747 Jena, Germany
| | - Andrea Kliever
- Institute of Pharmacology and Toxicology, Universitätsklinikum Jena, Friedrich-Schiller-Universität, 07747 Jena, Germany
| | - Sebastian Gulde
- Institute for Diabetes and Cancer, Helmholtz Zentrum München, 85764 Neuherberg, Germany
- Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Alessandro Marangelo
- Institute for Diabetes and Cancer, Helmholtz Zentrum München, 85764 Neuherberg, Germany
- Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, 69120 Heidelberg, Germany
- Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, 27100 Pavia, Italy
| | - Mathias Schillmaier
- Department of Nuclear Medicine, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, 80333 Munich, Germany
- Department of Diagnostic and Interventional Radiology, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, 80333 Munich, Germany
| | - Raul M Luque
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain
- Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain
| | - Stephen Bäuerle
- Department of Mathematics, Technical University Munich, 85748 Garching, Germany
| | - Natalia S Pellegata
- Institute for Diabetes and Cancer, Helmholtz Zentrum München, 85764 Neuherberg, Germany
- Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, 69120 Heidelberg, Germany
- Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, 27100 Pavia, Italy
| | - Stefan Schulz
- Institute of Pharmacology and Toxicology, Universitätsklinikum Jena, Friedrich-Schiller-Universität, 07747 Jena, Germany
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6
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Zaki U, Shakeel AS, Rauf Y, Raza M. Pituicytoma: A rare tumor of the sella. A case report and review of literature for diagnosis and management. Surg Neurol Int 2023; 14:220. [PMID: 37404513 PMCID: PMC10316132 DOI: 10.25259/sni_248_2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 06/13/2023] [Indexed: 07/06/2023] Open
Abstract
Background Pituicytomas are rare tumors of the pituitary gland derived from the ependymal cells and line the pituitary stalk and posterior lobe. These tumors are located in the vulnerable regions of the brain: Either in the sellar or suprasellar area. The location marks the difference in the clinical features of the tumor. Here, we report a case of histopathologically diagnosed pituicytoma of the sellar region. Literature is also reviewed and discussed to gain a better understanding of this rare disease. Case Description A 24-year-old female presented to the outpatient department with complaints of headache, diplopia, dizziness, and decreased vision in the right eye for 6 months. Computed tomography scan brain without contrast showed a well-defined hyperdense lesion in the sella without associated bony erosion. Her magnetic resonance imaging showed well defined rounded lesion in the pituitary fossa which was isointense on T1-weighted image and hyperintense on T2-weighted images. A presumptive diagnosis of pituitary adenoma was made. She underwent endoscopic endonasal transsphenoidal resection of pituitary mass. Intraoperatively, normal pituitary gland was visualized and there was a grayish-green-colored, jelly like tumor which was pulled gently. On 9th postoperative day, she presented with cerebrospinal fluid (CSF) rhinorrhea. She underwent endoscopic CSF leak repair. Her histopathology was concluded to be Pituicytoma. Conclusion Pituicytoma is an uncommon diagnosis. The surgical aim is to completely excise the tumor which results in complete cure, but incomplete resection may be performed due to high vascularity of this tumor. In case of incomplete excision, recurrence is common and adjuvant radiotherapy may be administered.
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Affiliation(s)
- Umaima Zaki
- Department of Neurosurgery, Patel Hospital, Karachi, Pakistan
| | | | - Yaseen Rauf
- Department of Neurosurgery, Patel Hospital, Karachi, Pakistan
| | - Muhammad Raza
- Department of Histopathology, Aga Khan University Hospital, Karachi, Pakistan
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7
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Ruggeri RM, Benevento E, De Cicco F, Fazzalari B, Guadagno E, Hasballa I, Tarsitano MG, Isidori AM, Colao A, Faggiano A. Neuroendocrine neoplasms in the context of inherited tumor syndromes: a reappraisal focused on targeted therapies. J Endocrinol Invest 2023; 46:213-234. [PMID: 36038743 DOI: 10.1007/s40618-022-01905-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 08/16/2022] [Indexed: 01/25/2023]
Abstract
PURPOSE Neuroendocrine neoplasms can occur as part of inherited disorders, usually in the form of well-differentiated, slow-growing tumors (NET). The main predisposing syndromes include: multiple endocrine neoplasias type 1 (MEN1), associated with a large spectrum of gastroenteropancreatic and thoracic NETs, and type 4 (MEN4), associated with a wide tumour spectrum similar to that of MEN1; von Hippel-Lindau syndrome (VHL), tuberous sclerosis (TSC), and neurofibromatosis 1 (NF-1), associated with pancreatic NETs. In the present review, we propose a reappraisal of the genetic basis and clinical features of gastroenteropancreatic and thoracic NETs in the setting of inherited syndromes with a special focus on molecularly targeted therapies for these lesions. METHODS Literature search was systematically performed through online databases, including MEDLINE (via PubMed), and Scopus using multiple keywords' combinations up to June 2022. RESULTS Somatostatin analogues (SSAs) remain the mainstay of systemic treatment for NETs, and radiolabelled SSAs can be used for peptide-receptor radionuclide therapy for somatostatin receptor (SSTR)-positive NETs. Apart of these SSTR-targeted therapies, other targeted agents have been approved for NETs: the mTOR inhibitor everolimus for lung, gastroenteropatic and unknown origin NET, and sunitinib, an antiangiogenic tyrosine kinase inhibitor, for pancreatic NET. Novel targeted therapies with other antiangiogenic agents and immunotherapies have been also under evaluation. CONCLUSIONS Major advances in the understanding of genetic and epigenetic mechanisms of NET development in the context of inherited endocrine disorders have led to the recognition of molecular targetable alterations, providing a rationale for the implementation of treatments and development of novel targeted therapies.
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Affiliation(s)
- R M Ruggeri
- Unit of Endocrinology, Department of Clinical and Experimental Medicine, University of Messina, AOU Policlinico "Gaetano Martino" University Hospital, 98125, Messina, Italy.
| | - E Benevento
- Department of Clinical Medicine and Surgery, Endocrinology Unit, University Federico II, Naples, Italy
| | - F De Cicco
- SSD Endocrine Disease and Diabetology, ASL TO3, Pinerolo, TO, Italy
| | - B Fazzalari
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy
| | - E Guadagno
- Department of Clinical Medicine and Surgery, Endocrinology Unit, University Federico II, Naples, Italy
| | - I Hasballa
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - M G Tarsitano
- Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - A M Isidori
- Gruppo NETTARE, Policlinico Umberto I, Università Sapienza, Rome, Italy
| | - A Colao
- Department of Clinical Medicine and Surgery, Endocrinology Unit, University Federico II, Naples, Italy
- UNESCO Chair "Education for Health and Sustainable Development", Federico II University, Naples, Italy
| | - A Faggiano
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy
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8
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Chiloiro S, Costa D, Lauretta R, Mercuri V, Sbardella E, Samperi I, Appetecchia M, Bianchi A, Giampietro A, Gargiulo P, Isidori AM, Poggi M, Pontecorvi A, De Marinis L. Partial response to first generation SSA guides the choice and predict the outcome of second line therapy in acromegaly. Endocrine 2022; 78:343-353. [PMID: 35986839 PMCID: PMC9584996 DOI: 10.1007/s12020-022-03158-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Accepted: 07/27/2022] [Indexed: 11/17/2022]
Abstract
INTRODUCTION Treatment of acromegaly resistant to first generation somatostatin analogues (first gen-SSA) is often difficult. We aimed to investigate the role of partial response and resistance to first gen-SSA in the choice of second line treatments and their outcomes. PATIENTS AND METHODS A retrospective and multicenter study was conducted on 100 SSA-resistant acromegaly patients and treated with Pasireotide Lar (Pasi-Lar), Peg-V in monotherapy (m-Peg-V) or in combination with first gen-SSA (c-Peg-V). RESULTS Thirty-three patients (33%) were treated with m-Peg-V, 36 (36%) with c-Peg-V and 31 with Pasi-Lar (31%). According to logistic regression, m-Peg-V was chosen in older patients (p = 0.01) and with not-invasive adenomas (p = 0.009), c-Peg-V therapy in younger patients (p = 0.001), with invasive adenomas (p = 0.02), Pasi-Lar was in invasive adenomas (p = 0.01) and in patients partially responsive to first-gen SSA (p = 0.01). At the last follow-up, 68 patients (68%) reached the acromegaly control: 22 with m-Peg-V (32.4%), 23 with c-Peg-V (33.8%) and 23 with Pasi-Lar (33.8%). Patients non-responsive to c-Peg-V had higher IGF-I levels (median 3.2 x ULN, IQR: 1.6, p < 0.001) and required higher Peg-V dosage (median 30 mg/daily IQR: 10, p = 0.002) as compared to responsive patients (median IGF-I x ULN: 2.1 IQR: 1.4; median Peg-V dosage 20 mg/daily IQR: 10). All patients responsive to Pasi-Lar were partially responsive to first gen-SSAs (p = 0.02). CONCLUSION Our data showed that c-Peg-V and Pasi-Lar are chosen for the treatment of invasive tumors. The partial response to first gen-SSA seems to be the main determinant for the choice of Pasi-Lar and positively predicts the treatment outcome.
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Affiliation(s)
- Sabrina Chiloiro
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168, Roma, Italy
- UOC Endocrinology and Diabetology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168, Roma, Italy
| | - Denise Costa
- Department of Experimental Medicine, Endocrinology-Pituitary Disease, "Sapienza" University of Rome, Roma, Italy
| | - Rosa Lauretta
- Oncological Endocrinology Unit, IRCCS Regina Elena National Cancer Institute, Roma, Italy
| | - Valeria Mercuri
- Department of Experimental Medicine, Endocrinology-Pituitary Disease, "Sapienza" University of Rome, Roma, Italy
| | - Emilia Sbardella
- Department of Experimental Medicine, Endocrinology-Pituitary Disease, "Sapienza" University of Rome, Roma, Italy
| | - Irene Samperi
- Endocrine-Metabolic Unit, Sant'Andrea University Hospital, Rome, Italy
| | - Marialuisa Appetecchia
- Oncological Endocrinology Unit, IRCCS Regina Elena National Cancer Institute, Roma, Italy
| | - Antonio Bianchi
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168, Roma, Italy
- UOC Endocrinology and Diabetology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168, Roma, Italy
| | - Antonella Giampietro
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168, Roma, Italy
- UOC Endocrinology and Diabetology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168, Roma, Italy
| | - Patrizia Gargiulo
- Department of Experimental Medicine, Endocrinology-Pituitary Disease, "Sapienza" University of Rome, Roma, Italy
| | - Andrea M Isidori
- Department of Experimental Medicine, Endocrinology-Pituitary Disease, "Sapienza" University of Rome, Roma, Italy
| | - Maurizio Poggi
- Endocrine-Metabolic Unit, Sant'Andrea University Hospital, Rome, Italy
| | - Alfredo Pontecorvi
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168, Roma, Italy
- UOC Endocrinology and Diabetology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168, Roma, Italy
| | - Laura De Marinis
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168, Roma, Italy.
- UOC Endocrinology and Diabetology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168, Roma, Italy.
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9
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Shen X, Wang X, Lu X, Zhao Y, Guan W. Molecular biology of pancreatic neuroendocrine tumors: From mechanism to translation. Front Oncol 2022; 12:967071. [PMID: 36248960 PMCID: PMC9554633 DOI: 10.3389/fonc.2022.967071] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 09/12/2022] [Indexed: 11/13/2022] Open
Abstract
Pancreatic neuroendocrine tumors (pNETs) are a group of heterogeneous tumors originated from progenitor cells. As these tumors are predominantly non-functional, most of them display asymptomatic characteristics, making it difficult to be realized from early onset. Therefore, patients with pNETs are usually diagnosed with metastatic disease or at a late disease stage. The relatively low incidence also limits our understanding of the biological background of pNETs, which largely impair the development of new effective drugs. The fact that up to 10% of pNETs develop in patients with genetic syndromes have promoted researchers to focus on the gene mutations and driver mutations in MEN1, DAXX/ATRX and mTOR signaling pathway genes have been implicated in disease development and progression. Recent advances in sequencing technologies have further enriched our knowledge of the complex molecular landscape of pNETs, pointing out crucial roles of genes in DNA damage pathways, chromosomal and telomere alterations and epigenetic dysregulation. These novel findings may not only benefit early diagnosis of pNETs, but also help to uncover tumor heterogeneity and shape the future of translational medical treatment. In this review, we focus on the current molecular biology of pNETs and decipher how these findings may translate into future development of targeted therapy.
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Affiliation(s)
- Xiaofei Shen
- Department of General Surgery, Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
| | - Xingzhou Wang
- Department of General Surgery, Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
| | - Xiaofeng Lu
- Department of General Surgery, Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
| | - Yang Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- *Correspondence: Wenxian Guan, ; Yang Zhao,
| | - Wenxian Guan
- Department of General Surgery, Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
- *Correspondence: Wenxian Guan, ; Yang Zhao,
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10
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Mohindroo C, McAllister F, De Jesus-Acosta A. Genetics of Pancreatic Neuroendocrine Tumors. Hematol Oncol Clin North Am 2022; 36:1033-1051. [PMID: 36154786 DOI: 10.1016/j.hoc.2022.07.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Pancreatic neuroendocrine tumors (pNETs) represent a relatively rare disease; however, the incidence has been increasing during the last 2 decades. Next generation sequencing has greatly increased our understanding of driver mutations in pNETs. Sporadic pNETs have consistently presented with mutations in MEN1, DAXX/ATRX, and genes related to the mammalian target of rapamycin pathway. Inherited pNETs have traditionally been associated with multiple endocrine neoplasia type 1, von Hippel-Lindau syndrome, neurofibromatosis type 1, and tuberous sclerosis complex. The current review expands on the existing knowledge and the relevant updates on the genetics of pNETs.
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Affiliation(s)
- Chirayu Mohindroo
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Unit 1360, Houston, TX 77030, USA; Department of Internal Medicine, Sinai Hospital of Baltimore, 2435 W. Belvedere Ave, Ste 56, Baltimore, MD 21215, USA
| | - Florencia McAllister
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Unit 1360, Houston, TX 77030, USA; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ana De Jesus-Acosta
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, CRB1, 1650 Orleans Street, CRB1 Rm 409, Baltimore, MD 21287.
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11
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Modica R, Liccardi A, Minotta R, Cannavale G, Benevento E, Colao A. Therapeutic strategies for patients with neuroendocrine neoplasms: current perspectives. Expert Rev Endocrinol Metab 2022; 17:389-403. [PMID: 35822906 DOI: 10.1080/17446651.2022.2099840] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 07/06/2022] [Indexed: 10/17/2022]
Abstract
INTRODUCTION Neuroendocrine neoplasms (NENs) are a heterogeneous group of malignancies mainly arising in the gastroenteropancreatic (GEP) and bronchopulmonary systems, with steadily increasing incidence. The therapeutic landscape has widened and the therapeutic strategy should be based on new sequences and combinations, still debated. AREAS COVERED Herein, we provide an overview of current approved pharmacological treatments in patients with NENs, with the aim to summarize evidence of efficacy of the main different options in GEP and pulmonary NENs, principally focusing on somatostatin analogs (SSAs), targeted therapy with everolimus and sunitinib, peptide receptor radionuclide therapy (PRRT) and chemotherapy. We discuss biological rationale and toxicities, including current indications according to differentiation and placement in the therapeutic algorithm, clinical trials, and combinations. Furthermore, we recommend areas for further research. EXPERT OPINION Therapeutic management of patients with NENs represents a challenge for clinicians and the identification of effective sequences and combinations is of utmost importance. Major efforts should be directed to early identify and overcome resistance and to limit toxicity. The progress in the therapeutic management of NENs grows faster and the choice of the best approach should be based on randomized clinical trials, as well as on long-term, real-world data.
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Affiliation(s)
- Roberta Modica
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Alessia Liccardi
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Roberto Minotta
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Giuseppe Cannavale
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Elio Benevento
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Annamaria Colao
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
- UNESCO Chair, Education for Health and Sustainable Development, Federico II University, Naples, Italy
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12
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Martinovich VP, Baradzina KU. Peptide Hormones in Medicine: A 100-Year History. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2022. [DOI: 10.1134/s1068162022020157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Abstract
This review is devoted to the 100-year history of the investigation of peptide hormones and the creation of drugs on their basis, starting from the insulin discovery and its introduction into a medical practice in 1921. The basic groups of the peptide hormones are discussed: neurohypophyseal hormones, hypothalamic releasing hormones, incretins, insulin, adrenocorticotropic hormone (ACTH), and calcitonin. The first therapeutic agents based on the peptide hormones were created by a traditional approach that involved the isolation of peptides from animal tissues, their purification to individual compounds, determination of their primary structure, their chemical synthesis or their deep purification, and the creation of a pharmaceutical substance. A modern approach to creation of peptide hormone drugs is based on their consideration as ligands of the corresponding cellular receptors and the use of computer modeling, efficient synthesis methods, and high-throughput screening. The combination of these methods enabled the development of analogs which would be more active than the corresponding natural compounds, exhibit other activities in addition to the hormonal regulation, and be resistant to biodegradation. Such therapeutic agents have been designed on the basis of agonistic and antagonistic analogs of somatostatin and luliberin, and have found wide application in hormonal regulation and cancer treatment. Over the past two decades, the glucagon-like peptide (GLP-1) has been intensively investigated as a potential therapeutic agent. In our review, we describe modifications which resulted in the most highly effective long-acting drugs. Now, natural hormones and their analogs are widely present in the pharmaceutical market.
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13
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Bo Q, Yang F, Li Y, Meng X, Zhang H, Zhou Y, Ling S, Sun D, Lv P, Liu L, Shi P, Tian C. Structural insights into the activation of somatostatin receptor 2 by cyclic SST analogues. Cell Discov 2022; 8:47. [PMID: 35595746 PMCID: PMC9122944 DOI: 10.1038/s41421-022-00405-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 03/23/2022] [Indexed: 11/09/2022] Open
Abstract
The endogenous cyclic tetradecapeptide SST14 was reported to stimulate all five somatostatin receptors (SSTR1-5) for hormone release, neurotransmission, cell growth arrest and cancer suppression. Two SST14-derived short cyclic SST analogues (lanreotide or octreotide) with improved stability and longer lifetime were developed as drugs to preferentially activate SSTR2 and treat acromegalia and neuroendocrine tumors. Here, cryo-EM structures of the human SSTR2-Gi complex bound with SST14, octreotide or lanreotide were determined at resolutions of 2.85 Å, 2.97 Å, and 2.87 Å, respectively. Structural and functional analysis revealed that interactions between β-turn residues in SST analogues and transmembrane SSTR2 residues in the ligand-binding pocket are crucial for receptor binding and functional stimulation of the two SST14-derived cyclic octapeptides. Additionally, Q1022.63, N2766.55, and F2947.35 could be responsible for the selectivity of lanreotide or octreotide for SSTR2 over SSTR1 or SSTR4. These results provide valuable insights into further rational development of SST analogue drugs targeting SSTR2.
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Affiliation(s)
- Qing Bo
- Department of Chemistry and the First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of China, Hefei, Anhui, China
| | - Fan Yang
- Department of Chemistry and the First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of China, Hefei, Anhui, China
| | - Yingge Li
- Department of Chemistry and the First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of China, Hefei, Anhui, China
| | - Xianyu Meng
- Department of Chemistry and the First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of China, Hefei, Anhui, China
| | - Huanhuan Zhang
- Department of Chemistry and the First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of China, Hefei, Anhui, China
| | - Yingxin Zhou
- Department of Chemistry and the First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of China, Hefei, Anhui, China
| | - Shenglong Ling
- Department of Chemistry and the First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of China, Hefei, Anhui, China
| | - Demeng Sun
- Department of Chemistry and the First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of China, Hefei, Anhui, China
| | - Pei Lv
- Department of Chemistry and the First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of China, Hefei, Anhui, China
| | - Lei Liu
- Tsinghua-Peking Joint Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, China.
| | - Pan Shi
- Department of Chemistry and the First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of China, Hefei, Anhui, China.
| | - Changlin Tian
- Department of Chemistry and the First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of China, Hefei, Anhui, China.
- High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui, China.
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Valente M, Covre A, Giacomo AMD, Maio M. Personalized Medicine for Patients with Liver, Biliary Tract, and Pancreatic Cancer. HEPATO-PANCREATO-BILIARY MALIGNANCIES 2022:761-776. [DOI: 10.1007/978-3-030-41683-6_50] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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15
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Malviya R, Verma S, Sundram S. Advancement and Strategies for the Development of Peptide-Drug Conjugates: Pharmacokinetic Modulation, Role and Clinical Evidence Against Cancer Management. Curr Cancer Drug Targets 2021; 22:286-311. [PMID: 34792003 DOI: 10.2174/1568009621666211118111506] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 07/29/2021] [Accepted: 09/09/2021] [Indexed: 12/24/2022]
Abstract
Currently, many new treatment strategies are being used for the management of cancer. Among them, chemotherapy based on peptides has been of great interest due to the unique features of peptides. This review discusses the role of peptide and peptides analogues in the treatment of cancer, with special emphasis on their pharmacokinetic modulation and research progress. Low molecular weight, targeted drug delivery, enhanced permeability, etc., of the peptide-linked drug conjugates, lead to an increase in the effectiveness of cancer therapy. Various peptides have recently been developed as drugs and vaccines with an altered pharmacokinetic parameter which has subsequently been assessed in different phases of the clinical study. Peptides have made a great impact in the area of cancer therapy and diagnosis. Targeted chemotherapy and drug delivery techniques using peptides are emerging as excellent tools in minimizing problems with conventional chemotherapy. It can be concluded that new advances in using peptides to treat different types of cancer have been shown by different clinical studies indicating that peptides could be used as an ideal therapeutic method in treating cancer due to the novel advantages of peptides. The development of identifying and synthesizing novel peptides could provide a promising choice to patients with cancer.
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Affiliation(s)
- Rishabha Malviya
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida. India
| | - Swati Verma
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida. India
| | - Sonali Sundram
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida. India
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16
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Combination Therapies with PRRT. Pharmaceuticals (Basel) 2021; 14:ph14101005. [PMID: 34681229 PMCID: PMC8538931 DOI: 10.3390/ph14101005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 09/26/2021] [Accepted: 09/27/2021] [Indexed: 02/06/2023] Open
Abstract
Peptide receptor radionuclide therapy (PRRT) is a successful targeted radionuclide therapy in neuroendocrine tumors (NETs). However, complete responses remain elusive. Combined treatments anticipate synergistic effects and thus better responses by combining ionizing radiation with other anti-tumor treatments. Furthermore, multimodal therapies often have a balanced toxicity profile. To date, few studies have evaluated the effect of combination therapies with PRRT, some of them phase I/II trials. This review will focus on several clinically tested, tailored approaches to improving the effects of PRRT. The aim is to help clinicians in the treatment planning of NETs to choose the most effective and safe treatment for each patient in the sense of personalized medicine. Current promising combination partners of PRRT are somatostatin analogues (SSAs), chemotherapy, molecular targeted treatment, liver radioembolization, and dual radionuclide PRRT (Lutetium-177-PRRT combined with Yttrium-90-PRRT).
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17
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Massironi S, Cavalcoli F, Artoni A, Sciola V, Zilli A, Ciafardini C, Rossi RE. Thrombotic risk in gastroenteropancreatic neuroendocrine tumor patients: a single-center experience. Ann Gastroenterol 2021; 34:588-593. [PMID: 34276200 PMCID: PMC8276356 DOI: 10.20524/aog.2021.0613] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 12/28/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Only scanty specific studies are available on venous thromboembolism (VTE) in neuroendocrine neoplasms (NEN). We retrospectively assessed the incidence of VTE in gastroenteropancreatic (GEP) NEN patients. METHODS Between 2000 and 2016, GEP-NEN patients were retrospectively evaluated for VTE. Major thrombotic events included deep venous thrombosis (DVT) and pulmonary embolism (PE). 160 patients were included. The primary tumor site was: the gut in 99, pancreas in 54, and unknown in 7. A total of 93 patients had grade (G) 1 tumor, 36 G2, 4 G3; G was not available in 27 patients. TNM stage was I in 76 patients, II in 17, III in 23, and IV in 44. RESULTS Twelve patients developed VTE: 9 had DVT and 3 PE. The primary site of the tumor was located in the pancreas in 9 patients, in the gut in 2, and it was unknown in one patient. Two patients had a functioning tumor. Grading was G1 in 3 patients, G2 in 6, G3 in 2 cases, and not available in one. The TNM stage was IV in 5 patients, III in 2, II in 3, and I in 2. Two patients died during the study period, one of whom died from PE. CONCLUSION GEP-NEN patients harbor a considerable risk of VTE, particularly high for pancreatic NEN patients, for patients with moderate-poorly differentiated neoplasms, and at an advanced tumor stage.
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Affiliation(s)
- Sara Massironi
- Division of Gastroenterology - European Reference Network on Hepatological Diseases (ERN RARE-LIVER) San Gerardo Hospital (Sara Massironi)
- University of Milano-Bicocca, Monza (Sara Massironi)
| | - Federica Cavalcoli
- Gastroenterology and Endoscopy Unit, Istituti Clinici Zucchi, Monza (Federica Cavalcoli)
| | - Andrea Artoni
- ”Bianchi Bonomi Hemophilia and Thrombosis Center”, Fondazione IRCCS Ca’ Granda – Ospedale Policlinico di Milano (Andrea Artoni)
| | - Valentina Sciola
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano (Valentina Sciola, Alessandra Zilli, Clorinda Ciafardini)
| | - Alessandra Zilli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano (Valentina Sciola, Alessandra Zilli, Clorinda Ciafardini)
| | - Clorinda Ciafardini
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano (Valentina Sciola, Alessandra Zilli, Clorinda Ciafardini)
| | - Roberta Elisa Rossi
- HPB Surgery, Hepatology and Liver Transplantation Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (Roberta Elisa Rossi)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy (Roberta Elisa Rossi)
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18
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Chen KS, Lawhn-Heath C, Behr S, Juarez R, Whitman J, Paciorek A, Nakakura EK, Fidelman N, Feng MUS, Bergsland EK, Anwar M. Outcomes after high-dose radiation in the management of neuroendocrine neoplasms. PLoS One 2021; 16:e0252574. [PMID: 34077464 PMCID: PMC8171937 DOI: 10.1371/journal.pone.0252574] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 05/18/2021] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Neuroendocrine neoplasms (NENs) comprise a rare and heterogenous group of cancers, for which the role of radiation therapy continues to evolve. The purpose of this study is to analyze oncologic outcomes after the use of high-dose radiation in management of NENs at a tertiary hospital. MATERIALS AND METHODS We performed a retrospective review of patients who received high-dose radiation with intent to cure or provide durable local control (defined as biologically effective dose (BED) ≥40, α/β = 10) for a localized or metastatic NEN from 2006 to 2019. Evaluation of disease status after radiation was performed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria when possible. Patients were grouped by differentiation (well-differentiated (WD) or poorly-differentiated (PD)) and stage (localized/locally advanced disease (L) or metastatic (M)) in analysis of probabilities of progression after radiation. RESULTS 45 patients completed a radiation course with BED ≥40 for a NEN (median BED 72). With a median follow-up of 24 months after radiation, the 2-year actuarial rates of local relapse-free survival, new metastasis-free survival, progression-free survival, and overall survival after radiation were 98%, 45%, 41%, and 69%, respectively. 25 patients (56%) developed new metastases after completion of radiation, including 33% (n = 3) of patients with WD-L disease, 44% (n = 8) of WD-M, 77% (n = 10) of PD-L, and 80% (n = 4) of PD-M, with progressively shorter median times to progression (26, 9, 8, and 3 months, respectively; p = 0.093). Of the 25 patients evaluable by RECIST, 68% (n = 17) achieved either a complete or partial best response in the irradiated lesion. CONCLUSIONS These data suggest that focal, high-dose radiation has a role in the management of selected patients with NENs. Local failure is rare in patients with both well-differentiated and poorly-differentiated disease, although the predominant pattern of failure remains development of new metastases.
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Affiliation(s)
- Katherine S. Chen
- Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, United States of America
| | - Courtney Lawhn-Heath
- Department of Radiology, University of California San Francisco, San Francisco, CA, United States of America
| | - Spencer Behr
- Department of Radiology, University of California San Francisco, San Francisco, CA, United States of America
| | - Roxanna Juarez
- Department of Radiology, University of California San Francisco, San Francisco, CA, United States of America
| | - Julia Whitman
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, United States of America
| | - Alan Paciorek
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, United States of America
| | - Eric K. Nakakura
- Department of Surgery, Division of Surgical Oncology, University of California San Francisco, San Francisco, CA, United States of America
| | - Nicholas Fidelman
- Department of Radiology, University of California San Francisco, San Francisco, CA, United States of America
| | - Mary Uan-Sian Feng
- Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, United States of America
| | - Emily K. Bergsland
- Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, CA, United States of America
| | - Mekhail Anwar
- Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, United States of America
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Undesirable Status of Prostate Cancer Cells after Intensive Inhibition of AR Signaling: Post-AR Era of CRPC Treatment. Biomedicines 2021; 9:biomedicines9040414. [PMID: 33921329 PMCID: PMC8069212 DOI: 10.3390/biomedicines9040414] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 04/07/2021] [Accepted: 04/09/2021] [Indexed: 12/19/2022] Open
Abstract
Recent advances in prostate cancer (PC) research unveiled real androgen receptor (AR) functions in castration-resistant PC (CRPC). Moreover, AR still accelerates PC cell proliferation via the activation of several mechanisms (e.g., mutation, variants, and amplifications in CRPC). New-generation AR signaling-targeted agents, inhibiting extremely the activity of AR, were developed based on these incontrovertible mechanisms of AR-induced CRPC progression. However, long-term administration of AR signaling-targeted agents subsequently induces the major problem that AR (complete)-independent CRPC cells present neither AR nor prostate-specific antigen, including neuroendocrine differentiation as a subtype of AR-independent CRPC. Moreover, there are few treatments effective for AR-independent CRPC with solid evidence. This study focuses on the transformation mechanisms of AR-independent from AR-dependent CRPC cells and potential treatment strategy for AR-independent CRPC and discusses them based on a review of basic and clinical literature.
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20
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Brandi ML, Agarwal SK, Perrier ND, Lines KE, Valk GD, Thakker RV. Multiple Endocrine Neoplasia Type 1: Latest Insights. Endocr Rev 2021; 42:133-170. [PMID: 33249439 PMCID: PMC7958143 DOI: 10.1210/endrev/bnaa031] [Citation(s) in RCA: 121] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Indexed: 02/06/2023]
Abstract
Multiple endocrine neoplasia type 1 (MEN1), a rare tumor syndrome that is inherited in an autosomal dominant pattern, is continuing to raise great interest for endocrinology, gastroenterology, surgery, radiology, genetics, and molecular biology specialists. There have been 2 major clinical practice guidance papers published in the past 2 decades, with the most recent published 8 years ago. Since then, several new insights on the basic biology and clinical features of MEN1 have appeared in the literature, and those data are discussed in this review. The genetic and molecular interactions of the MEN1-encoded protein menin with transcription factors and chromatin-modifying proteins in cell signaling pathways mediated by transforming growth factor β/bone morphogenetic protein, a few nuclear receptors, Wnt/β-catenin, and Hedgehog, and preclinical studies in mouse models have facilitated the understanding of the pathogenesis of MEN1-associated tumors and potential pharmacological interventions. The advancements in genetic diagnosis have offered a chance to recognize MEN1-related conditions in germline MEN1 mutation-negative patients. There is rapidly accumulating knowledge about clinical presentation in children, adolescents, and pregnancy that is translatable into the management of these very fragile patients. The discoveries about the genetic and molecular signatures of sporadic neuroendocrine tumors support the development of clinical trials with novel targeted therapies, along with advancements in diagnostic tools and surgical approaches. Finally, quality of life studies in patients affected by MEN1 and related conditions represent an effort necessary to develop a pharmacoeconomic interpretation of the problem. Because advances are being made both broadly and in focused areas, this timely review presents and discusses those studies collectively.
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Affiliation(s)
| | | | - Nancy D Perrier
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Gerlof D Valk
- University Medical Center Utrecht, CX Utrecht, the Netherlands
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Störmann S, Schopohl J, Bullmann C, Terkamp C, Christ-Crain M, Finke R, Flitsch J, Kreitschmann-Andermahr I, Luger A, Stalla G, Houchard A, Helbig D, Petersenn S. Multicenter, Observational Study of Lanreotide Autogel for the Treatment of Patients with Acromegaly in Routine Clinical Practice in Germany, Austria and Switzerland. Exp Clin Endocrinol Diabetes 2020; 129:224-233. [PMID: 33285601 DOI: 10.1055/a-1247-4713] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Evidence from controlled trials has shown that lanreotide autogel is effective in achieving biochemical and symptom control in patients with acromegaly. However, it is important to better understand the real-world patient population receiving lanreotide autogel treatment. METHODS In this non-interventional study the long-term treatment response to lanreotide autogel in adult patients with acromegaly from office-based centers or clinics in Germany, Austria and Switzerland was studied. Assessments included growth hormone and insulin-like growth factor-I levels, symptoms, quality of life, lanreotide plasma levels and tumor somatostatin receptor subtype expression. The primary endpoint was achievement of full biochemical control, defined as growth hormone ≤2.5 µg/L and insulin-like growth factor I normalization at month 12. RESULTS 76 patients were enrolled from 21 sites. 7/51 (13.7%) patients of the efficacy population had full biochemical control at baseline, 15/33 (45.5%) at month 12 and 10/26 (38.5%) at month 24 of treatment. At 12 months of treatment higher rates of biochemical control were observed in the following subgroups: older patients (>53 years [median]), females, treatment-naïve patients, and patients with a time since diagnosis of longer than 1.4 years (median). No clinically relevant differences in acromegaly symptoms or quality of life scores were observed. Median fasting blood glucose and glycated hemoglobin levels remained unchanged throughout the study. No new safety signals were observed. Overall tolerability of treatment with lanreotide autogel was judged by 80.8% of the enrolled patients at month 12 as 'very good' or 'good'. CONCLUSION Treatment with lanreotide autogel in a real-world setting showed long-term effectiveness and good tolerability in patients with acromegaly.
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Affiliation(s)
- Sylvère Störmann
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, München, Germany
| | - Jochen Schopohl
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, München, Germany
| | | | - Christoph Terkamp
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover
| | - Mirjam Christ-Crain
- Clinic of Endocrinology, Diabetology and Metabolism, University Hospital Basel, Basel
| | | | - Jörg Flitsch
- Department of Neurosurgery, University Hospital Hamburg-Eppendorf, Hamburg
| | - Ilonka Kreitschmann-Andermahr
- Department of Neurosurgery and Spine Surgery, University Medicine Essen, University of Duisburg-Essen, Essen, Germany
| | - Anton Luger
- Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna
| | - Günter Stalla
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, München, Germany.,MEDICOVER Neuroendocrinology MVZ, Munich
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22
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Bell J, Alhudairy M, Kazakova V, Johnstone M, Tsao L. Right and Left-Sided Carcinoid Heart Disease in the Setting of Selective Serotonin Reuptake Inhibitor Use. JACC Case Rep 2020; 2:1841-1844. [PMID: 33106792 PMCID: PMC7577728 DOI: 10.1016/j.jaccas.2020.07.060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 05/29/2020] [Accepted: 07/07/2020] [Indexed: 12/30/2022]
Abstract
Carcinoid heart disease is a complication of carcinoid syndrome. The role of selective serotonin reuptake inhibitors in carcinoid heart disease is unclear. We present a case of refractory heart failure due to right- and left-sided carcinoid heart disease in the setting of selective serotonin reuptake inhibitor use despite remission of carcinoid syndrome. (Level of Difficulty: Beginner.)
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Affiliation(s)
- Jennifer Bell
- Division of Cardiovascular Medicine, St. Elizabeth's Medical Center, Brighton, Massachusetts
| | - Maad Alhudairy
- Department of Medicine, St. Elizabeth's Medical Center, Brighton, Massachusetts
| | - Vera Kazakova
- Department of Medicine, St. Elizabeth's Medical Center, Brighton, Massachusetts
| | - Michael Johnstone
- Division of Cardiovascular Medicine, St. Elizabeth's Medical Center, Brighton, Massachusetts
| | - Lana Tsao
- Division of Cardiovascular Medicine, St. Elizabeth's Medical Center, Brighton, Massachusetts
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Wu W, Zhou Y, Wang Y, Liu L, Lou J, Deng Y, Zhao P, Shao A. Clinical Significance of Somatostatin Receptor (SSTR) 2 in Meningioma. Front Oncol 2020; 10:1633. [PMID: 33014821 PMCID: PMC7494964 DOI: 10.3389/fonc.2020.01633] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 07/27/2020] [Indexed: 12/30/2022] Open
Abstract
Somatostatin receptor (SSTR) 2, widely expressed in meningioma, is a G-protein-coupled receptor and can be activated by somatostatin or its synthetic analogs. SSTR2 is therefore extensively studied as a marker and target for the diagnosis and treatment of meningioma. Accumulating studies have revealed the crucial clinical significance of SSTR2 in meningioma. Summarizing the progress of these studies is urgently needed as it may not only provide novel and better management for patients with meningioma but also indicate the direction of future research. Pertinent literature is reviewed to summarize the recent collective knowledge and understanding of SSTR2’s clinical significance in meningioma in this review. SSTR2 offers novel ideas and approaches in the diagnosis, treatment, and prognostic prediction for meningioma, but more and further studies are required.
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Affiliation(s)
- Wei Wu
- Department of Medical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yunxiang Zhou
- Department of Surgical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yali Wang
- Department of Surgical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lihong Liu
- Department of Radiation Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jianyao Lou
- Department of General Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yongchuan Deng
- Department of Surgical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Peng Zhao
- Department of Medical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Anwen Shao
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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24
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von Arx C, Rea G, Napolitano M, Ottaiano A, Tatangelo F, Izzo F, Petrillo A, Clemente O, Di Sarno A, Botti G, Scala S, Tafuto S. Effect of Octreotide Long-Acting Release on Tregs and MDSC Cells in Neuroendocrine Tumour Patients: A Pivotal Prospective Study. Cancers (Basel) 2020; 12:E2422. [PMID: 32859050 PMCID: PMC7563951 DOI: 10.3390/cancers12092422] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 08/14/2020] [Accepted: 08/19/2020] [Indexed: 02/08/2023] Open
Abstract
Octreotide long-acting repeatable (LAR) is largely used to treat functional and/or metastatic neuroendocrine neoplasms (NENs). Its effect in controlling carcinoid syndrome and partially reduce tumour burden is attributable to the ability of octreotide to bind somatostatin receptors (SSTRs) on the tumour and metastasis, regulating growth hormone secretion and cell growth. Notably, SSTRs are also expressed, at different levels, on Tregs. Tregs, together with myeloid-derived suppressor cells (MDSCs), are key components in the anti-tumour immunoregulation. This is the first prospective study aimed to explore the impact of Octreotide (OCT) LAR on the immune system, with a particular focus on Tregs and MDSC cells. Here, we show that circulating Tregs are elevated in NENs patients compared to healthy donors and that treatment with OCT LAR significantly decrease the level of total Tregs and of the three functional Tregs populations: nTregs, eTregs and non-Tregs. Furthermore, OCT LAR treatment induces a functional impairment of the remaining circulating Tregs, significantly decreasing the expression of PD1, CTLA4 and ENTPD1. A trend in circulating MDSC cells is reported in patients treated with OCT LAR. The results reported here suggest that the effect of OCT LAR on Tregs could tip the balance of the patients' immune-system towards a durable anti-tumour immunosurveillance with consequent long-term control of the NENs disease.
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Affiliation(s)
- Claudia von Arx
- Department of Clinical and Experimental Thoracic oncology Istituto Nazionale Tumori, IRCCS Fondazione G.Pascale, 80131 Naples, Italy;
| | - Giuseppina Rea
- UOC Bersagli Molecolari del Microambiente, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy; (G.R.); (M.N.); (S.S.)
| | - Maria Napolitano
- UOC Bersagli Molecolari del Microambiente, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy; (G.R.); (M.N.); (S.S.)
| | - Alessandro Ottaiano
- Department of Abdominal Oncology, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy; (A.O.); (F.I.); (O.C.)
| | - Fabiana Tatangelo
- Department of Pathology, Istituto Nazionale Tumori, IRCCS-Fondazione G. Pascale, 80131 Naples, Italy;
| | - Francesco Izzo
- Department of Abdominal Oncology, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy; (A.O.); (F.I.); (O.C.)
| | - Antonella Petrillo
- Department of Diagnostic Imaging, Radiant and Metabolic Therapy, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy;
| | - Ottavia Clemente
- Department of Abdominal Oncology, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy; (A.O.); (F.I.); (O.C.)
| | - Antonella Di Sarno
- Department of Internal Medicine, AORN dei Colli, Ospedale “A. Monaldi”, 80131 Naples, Italy;
| | - Gerardo Botti
- Scientific Directorate, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy;
| | - Stefania Scala
- UOC Bersagli Molecolari del Microambiente, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy; (G.R.); (M.N.); (S.S.)
| | - Salvatore Tafuto
- Sarcomas and Rare Tumours Unit, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy
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25
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Kashyap S, Zeidler JD, Chini CCS, Chini EN. Implications of the PAPP-A-IGFBP-IGF-1 pathway in the pathogenesis and treatment of polycystic kidney disease. Cell Signal 2020; 73:109698. [PMID: 32569826 DOI: 10.1016/j.cellsig.2020.109698] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 06/17/2020] [Accepted: 06/18/2020] [Indexed: 12/19/2022]
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic diseases implicated in the development of end stage renal disease (ESRD). Although FDA has recently approved a drug against ADPKD, there is still a great need for development of alternative management strategies for ADPKD. Understanding the different mechanisms that lead to cystogenesis and cyst expansion in ADPKD is imperative to develop new therapies against ADPKD. Recently, we demonstrated that caloric restriction can prevent the development of cystic disease in animal models of ADPKD and through these studies identified a new role for pregnancy associated plasma protein-A (PAPP-A), a component of the insulin-like growth factors (IGF) pathway, in the pathogenesis of this disease. The PAPP-A-IGF pathway plays an important role in regulation of cell growth, differentiation, and transformation and dysregulation of this pathway has been implicated in many diseases. Several indirect studies support the involvement of IGF-1 in the pathogenesis of ADPKD. However, it was only recently that we described a direct role for a component of this pathway in pathogenesis of ADPKD, opening a new avenue for the therapeutic approaches for this cystic disease. The present literature review will critically discuss the evidence that supports the role of components of IGF pathway in the pathogenesis of ADPKD and discuss the pharmacological implications of PAPP-A-IGF axis in this disease.
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Affiliation(s)
- Sonu Kashyap
- Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
| | - Julianna D Zeidler
- Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
| | - Claudia C S Chini
- Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
| | - Eduardo Nunes Chini
- Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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26
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Barrett JR, Rendell V, Pokrzywa C, Lopez-Aguiar AG, Cannon J, Poultsides GA, Rocha F, Crown A, Beal E, Pawlik TM, Fields R, Panni RZ, Smith P, Idrees K, Cho C, Beems M, Maithel S, Weber S, Abbott DE. Adjuvant therapy following resection of gastroenteropancreatic neuroendocrine tumors provides no recurrence or survival benefit. J Surg Oncol 2020; 121:1067-1073. [PMID: 32153032 PMCID: PMC7279693 DOI: 10.1002/jso.25896] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 02/16/2020] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND OBJECTIVES Lack of high-level evidence supporting adjuvant therapy for patients with resected gastroenteropancreatic neuroendocrine tumors (GEP NETs) warrants an evaluation of its non-standard of care use. METHODS Patients with primary GEP NETs who underwent curative-intent resection at eight institutions between 2000 and 2016 were identified; 91 patients received adjuvant therapy. Recurrence-free survival (RFS) and overall survival (OS) were compared between adjuvant cytotoxic chemotherapy and somatostatin analog cohorts. RESULTS In resected patients, 33 received cytotoxic chemotherapy, and 58 received somatostatin analogs. Five-year RFS/OS was 49% and 83%, respectively. Cytotoxic chemotherapy RFS/OS was 36% and 61%, respectively, lower than the no therapy cohort (P < .01). RFS with somatostatin analog therapy (compared to none) was lower (P < .01), as was OS (P = .01). On multivariable analysis, adjuvant cytotoxic therapy was negatively associated with RFS but not OS controlling for patient/tumor-specific characteristics (RFS P < .01). CONCLUSIONS Our data, reflecting the largest reported experience to date, demonstrate that adjuvant therapy for resected GEP NETs is negatively associated with RFS and confers no OS benefit. Selection bias enriching our treatment cohort for individuals with unmeasured high-risk characteristics likely explains some of these results; future studies should focus on patient subsets who may benefit from adjuvant therapy.
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Affiliation(s)
- James R Barrett
- University of Wisconsin-Madison, Department of Surgery, Madison, WI
| | - Victoria Rendell
- University of Wisconsin-Madison, Department of Surgery, Madison, WI
| | | | | | - John Cannon
- Stanford University, Department of Surgery, Stanford, CA
| | | | - Flavio Rocha
- Virginia Mason Medical Center, Department of Surgery, Seattle, WA
| | - Angelena Crown
- Virginia Mason Medical Center, Department of Surgery, Seattle, WA
| | - Eliza Beal
- The Ohio State University Wexner Medical Center, Department of Surgery, Columbus, OH
| | | | - Ryan Fields
- Washington University in St. Louis, Department of Surgery, St Louis, MO
| | - Roheena Z Panni
- Washington University in St. Louis, Department of Surgery, St Louis, MO
| | - Paula Smith
- Vanderbilt University Medical Center, Department of Surgery, Nashville, TN
| | - Kamran Idrees
- Vanderbilt University Medical Center, Department of Surgery, Nashville, TN
| | - Clifford Cho
- University of Michigan, Department of Surgery, Ann Arbor, MI
| | - Megan Beems
- University of Michigan, Department of Surgery, Ann Arbor, MI
| | - Shishir Maithel
- Emory University, Department of Surgery, Winship Cancer Institute, Atlanta, GA
| | - Sharon Weber
- University of Wisconsin-Madison, Department of Surgery, Madison, WI
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27
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Kaposi's Sarcoma-Associated Herpesvirus Infection Induces the Expression of Neuroendocrine Genes in Endothelial Cells. J Virol 2020; 94:JVI.01692-19. [PMID: 31969437 DOI: 10.1128/jvi.01692-19] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 01/14/2020] [Indexed: 12/30/2022] Open
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated with endothelial Kaposi's sarcoma (KS) in immunocompromised individuals. KS lesion cells exhibit many similarities to neuroendocrine (NE) cancers, such as highly vascular and red/purple tumor lesions, spindle-shaped cells, an insignificant role for classic oncogenes in tumor development, the release of bioactive amines, and indolent growth of the tumors. However, the mechanistic basis for the similarity of KS lesion endothelial cells to neuroendocrine tumors remains unknown. Next-generation sequencing and bioinformatics analysis in the present study demonstrate that endothelial cells latently infected with KSHV express several neuronal and NE genes. De novo infection of primary dermal endothelial cells with live and UV-inactivated KSHV demonstrated that viral gene expression is responsible for the upregulation of five selected NE genes (adrenomedullin 2 [ADM2], histamine receptor H1 [HRH1], neuron-specific enolase [NSE] [ENO2], neuronal protein gene product 9.5 [PGP9.5], and somatostatin receptor 1 [SSTR1]). Immunofluorescence and immunohistochemistry examinations demonstrated the robust expression of the NE genes HRH1 and NSE/ENO2 in KSHV-infected KS tissue samples and KS visceral tissue microarrays. Further analysis demonstrated that KSHV latent open reading frame K12 (ORFK12) gene (kaposin A)-mediated decreased host REST/NRSF (RE1-silencing transcription factor/neuron-restrictive silencer factor) protein, a neuronal gene transcription repressor protein, is responsible for NE gene expression in infected endothelial cells. The NE gene expression observed in KSHV-infected cells was recapitulated in uninfected endothelial cells by the exogenous expression of ORFK12 and by the treatment of cells with the REST inhibitor X5050. When the neuroactive ligand-activating receptor HRH1 and inhibitory SSTR1 were knocked out by CRISPR, HRH1 knockout (KO) significantly inhibited cell proliferation, while SSTR1 KO induced cell proliferation, thus suggesting that HRH1 and SSTR1 probably counteract each other in regulating KSHV-infected endothelial cell proliferation. These results demonstrate that the similarity of KS lesion cells to neuroendocrine tumors is probably a result of KSHV infection-induced transformation of nonneuronal endothelial cells into cells with neuroendocrine features. These studies suggest a potential role of neuroendocrine pathway genes in the pathobiological characteristics of KSHV-infected endothelial cells, including a potential mechanism of escape from the host immune system by the expression of immunologically privileged neuronal-site NE genes, and NE genes could potentially serve as markers for KSHV-infected KS lesion endothelial cells as well as novel therapeutic targets to control KS lesions.IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) manipulates several cellular pathways for its survival advantage during its latency in the infected human host. Here, we demonstrate that KSHV infection upregulates the expression of genes related to neuronal and neuroendocrine (NE) functions that are characteristic of NE tumors, both in vitro and in KS patient tissues and the heterogeneity of neuroendocrine receptors having opposing roles in KSHV-infected cell proliferation. Induction of NE genes by KSHV could also provide a potential survival advantage, as the expression of proteins at immunologically privileged sites such as neurons on endothelial cells may be an avenue to escape host immune surveillance functions. The NE gene products identified here could serve as markers for KSHV-infected cells and could potentially serve as therapeutic targets to combat KSHV-associated KS.
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28
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Lines KE, Filippakopoulos P, Stevenson M, Müller S, Lockstone HE, Wright B, Knapp S, Buck D, Bountra C, Thakker RV. Effects of epigenetic pathway inhibitors on corticotroph tumour AtT20 cells. Endocr Relat Cancer 2020; 27:163-174. [PMID: 31935194 PMCID: PMC7040567 DOI: 10.1530/erc-19-0448] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 01/13/2020] [Indexed: 12/13/2022]
Abstract
Medical treatments for corticotrophinomas are limited, and we therefore investigated the effects of epigenetic modulators, a new class of anti-tumour drugs, on the murine adrenocorticotropic hormone (ACTH)-secreting corticotrophinoma cell line AtT20. We found that AtT20 cells express members of the bromo and extra-terminal (BET) protein family, which bind acetylated histones, and therefore, studied the anti-proliferative and pro-apoptotic effects of two BET inhibitors, referred to as (+)-JQ1 (JQ1) and PFI-1, using CellTiter Blue and Caspase Glo assays, respectively. JQ1 and PFI-1 significantly decreased proliferation by 95% (P < 0.0005) and 43% (P < 0.0005), respectively, but only JQ1 significantly increased apoptosis by >50-fold (P < 0.0005), when compared to untreated control cells. The anti-proliferative effects of JQ1 and PFI-1 remained for 96 h after removal of the respective compound. JQ1, but not PFI-1, affected the cell cycle, as assessed by propidium iodide staining and flow cytometry, and resulted in a higher number of AtT20 cells in the sub G1 phase. RNA-sequence analysis, which was confirmed by qRT-PCR and Western blot analyses, revealed that JQ1 treatment significantly altered expression of genes involved in apoptosis, such as NFκB, and the somatostatin receptor 2 (SSTR2) anti-proliferative signalling pathway, including SSTR2. JQ1 treatment also significantly reduced transcription and protein expression of the ACTH precursor pro-opiomelanocortin (POMC) and ACTH secretion by AtT20 cells. Thus, JQ1 treatment has anti-proliferative and pro-apoptotic effects on AtT20 cells and reduces ACTH secretion, thereby indicating that BET inhibition may provide a novel approach for treatment of corticotrophinomas.
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Affiliation(s)
- K E Lines
- OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK
| | | | - M Stevenson
- OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK
| | - S Müller
- Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, Frankfurt, Germany
| | - H E Lockstone
- Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - B Wright
- Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - S Knapp
- Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, Frankfurt, Germany
- Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Frankfurt, Germany
| | - D Buck
- Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - C Bountra
- Structural Genomics Consortium, University of Oxford, Oxford, UK
| | - R V Thakker
- OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK
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29
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Gomes-Porras M, Cárdenas-Salas J, Álvarez-Escolá C. Somatostatin Analogs in Clinical Practice: a Review. Int J Mol Sci 2020; 21:ijms21051682. [PMID: 32121432 PMCID: PMC7084228 DOI: 10.3390/ijms21051682] [Citation(s) in RCA: 138] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 02/22/2020] [Accepted: 02/25/2020] [Indexed: 12/14/2022] Open
Abstract
Somatostatin analogs are an invaluable therapeutic option in the diagnosis and treatment of somatotropinomas, thyrotropinomas, and functioning and non-functioning gastroenteropancreatic neuroendocrine tumors. They should also be considered an effective and safe therapeutic alternative to corticotropinomas, gonadotropinomas, and prolactinomas resistant to dopamine agonists. Somatostatin analogs have also shown to be useful in the treatment of other endocrine diseases (congenital hyperinsulinism, Graves’ orbitopathy, diabetic retinopathy, diabetic macular edema), non-endocrine tumors (breast, colon, prostate, lung, and hepatocellular), and digestive diseases (chronic refractory diarrhea, hepatorenal polycystosis, gastrointestinal hemorrhage, dumping syndrome, and intestinal fistula).
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Affiliation(s)
- Mariana Gomes-Porras
- Department of Endocrinology, “La Paz” University Hospital. Paseo de la Castellana, 261, 28046 Madrid, Spain;
| | - Jersy Cárdenas-Salas
- Department of Endocrinology, “Fundación Jiménez-Diaz” University Hospital. Av. de los Reyes Católicos, 2, 28040 Madrid, Spain;
| | - Cristina Álvarez-Escolá
- Department of Endocrinology, “La Paz” University Hospital. Paseo de la Castellana, 261, 28046 Madrid, Spain;
- Correspondence: ; Tel.: +34-917-277-209
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30
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Lessons from a multicentre retrospective study of peptide receptor radionuclide therapy combined with lanreotide for neuroendocrine tumours: a need for standardised practice. Eur J Nucl Med Mol Imaging 2020; 47:2358-2371. [PMID: 32062681 PMCID: PMC7396404 DOI: 10.1007/s00259-020-04712-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 02/03/2020] [Indexed: 02/07/2023]
Abstract
Purpose PRELUDE aimed to assess use and effectiveness/safety of lanreotide autogel/depot (LAN) combined with 177Lu-DOTATOC or 177Lu-DOTATATE (LAN–peptide receptor radionuclide therapy [PRRT]) in patients with progressive neuroendocrine tumours (NETs). Methods International, non-interventional, retrospective, non-comparative analysis of medical records from patients with progressive metastatic or locally advanced grade 1 or 2 gastroenteropancreatic (GEP)- or lung-NETs. The primary endpoint was progression-free survival (PFS) at end of last LAN–PRRT cycle. Secondary endpoints included PFS at last available follow-up, best overall response, objective response rate (ORR), presence and severity of diarrhoea and flushing, and safety. Post-hoc analyses were conducted to determine pre-treatment tumour growth rate (TGR) cutoffs that best predicted the ORR during treatment. Results Forty patients were enrolled (GEP-NETs, n = 39; lung-NETs, n = 1). PFS rates were 91.7% at end of last LAN–PRRT cycle and 95.0% at last available follow-up. In the full analysis set, best overall response among patients with GEP-NETs (n = 23) was stable disease (n = 14, 60.9%), partial response (n = 8, 34.8%) and progressive disease (n = 1, 4.3%). The ORR was 27.3% at end of last LAN–PRRT cycle and 36.8% at last available follow-up. Optimal baseline TGR cutoffs for predicting ORR at these time points were 1.18% and 0.33%, respectively. At baseline, 81.0% of patients had diarrhoea or flushing; both remained stable or improved in most cases. No increased adverse drug reactions were reported. Conclusion Despite the major recruitment shortfall for the PRELUDE study, effectiveness data were encouraging in this selected population, highlighting the potential usefulness and feasibility of LAN combined with and after PRRT in patients with GEP-NETs. The study also identified challenges associated with evaluating clinical practice in a rare-disease setting and highlighted the need for standardisation of PRRT procedures. Trial registration Trial number: NCT02788578; URL: https://clinicaltrials.gov/ct2/show/NCT02788578
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31
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Al-Toubah T, Strosberg J, Halfdanarson TR, Oleinikov K, Gross DJ, Haider M, Sonbol MB, Almquist D, Grozinsky-Glasberg S. Somatostatin Analogs Improve Respiratory Symptoms in Patients With Diffuse Idiopathic Neuroendocrine Cell Hyperplasia. Chest 2020; 158:401-405. [PMID: 32059961 DOI: 10.1016/j.chest.2020.01.031] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 12/30/2019] [Accepted: 01/26/2020] [Indexed: 10/25/2022] Open
Abstract
BACKGROUND Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare lung disease associated with proliferation of neuroendocrine cells in the lung and multifocal neuroendocrine tumorlets/tumors. Although usually considered an indolent condition, DIPNECH causes chronic, progressive cough and dyspnea which can adversely impact quality of life. There is very limited information on the treatment of this condition. The objective of this study was to assess changes in symptoms and pulmonary function tests (PFTs) in response to somatostatin analog (SSA) treatment. METHODS Patients with clinical and/or pathologic diagnosis of DIPNECH and chronic respiratory symptoms were treated with SSAs at the H. Lee Moffitt Cancer Center and Research Institute, Hadassah-Hebrew University Medical Center, and Mayo Clinic Cancer Center. Their charts were reviewed to assess changes in symptoms and PFTs. RESULTS Forty-two patients were identified who had either chronic cough or dyspnea because of proven or suspected DIPNECH and who had received treatment with an SSA. Thirty-three patients experienced symptomatic improvement. Additionally, 14 of 15 patients in whom PFTs were checked were noted to have an improvement in FEV1 after treatment. CONCLUSIONS SSA treatment can improve chronic respiratory symptoms and PFTs in patients with DIPNECH.
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Affiliation(s)
- Taymeyah Al-Toubah
- Department of GI Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Jonathan Strosberg
- Department of GI Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
| | | | - Kira Oleinikov
- Neuroendocrine Tumor Unit, ENETS Center of Excellence, Endocrinology & Metabolism Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - David J Gross
- Neuroendocrine Tumor Unit, ENETS Center of Excellence, Endocrinology & Metabolism Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Mintallah Haider
- Department of GI Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | | | - Daniel Almquist
- Department of Hematology and Oncology, Mayo Clinic Cancer Center, Phoenix, AZ
| | - Simona Grozinsky-Glasberg
- Neuroendocrine Tumor Unit, ENETS Center of Excellence, Endocrinology & Metabolism Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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Clift AK, Kidd M, Bodei L, Toumpanakis C, Baum RP, Oberg K, Modlin IM, Frilling A. Neuroendocrine Neoplasms of the Small Bowel and Pancreas. Neuroendocrinology 2020; 110:444-476. [PMID: 31557758 PMCID: PMC9175236 DOI: 10.1159/000503721] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 09/24/2019] [Indexed: 12/12/2022]
Abstract
The traditionally promulgated perspectives of neuroendocrine neoplasms (NEN) as rare, indolent tumours are blunt and have been outdated for the last 2 decades. Clear increments in their incidence over the past decades render them increasingly clinically relevant, and at initial diagnosis many present with nodal and/or distant metastases (notably hepatic). The molecular pathogenesis of these tumours is increasingly yet incompletely understood. Those arising from the small bowel (SB) or pancreas typically occur sporadically; the latter may occur within the context of hereditary tumour predisposition syndromes. NENs can also be associated with endocrinopathy of hormonal hypersecretion. Tangible advances in the development of novel biomarkers, functional imaging modalities and therapy are especially applicable to this sub-set of tumours. The management of SB and pancreatic neuroendocrine tumours (NET) may be challenging, and often comprises a multidisciplinary approach wherein surgical, medical, interventional radiological and radiotherapeutic modalities are implemented. This review provides a comprehensive overview of the epidemiology, pathophysiology, diagnosis and treatment of SB and pancreatic NETs. Moreover, we provide an outlook of the future in these tumour types which will include the development of precision oncology frameworks for individualised therapy, multi-analyte predictive biomarkers, artificial intelligence-derived clinical decision support tools and elucidation of the role of the microbiome in NEN development and clinical behaviour.
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Affiliation(s)
- Ashley Kieran Clift
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Mark Kidd
- Wren Laboratories, Branford, Connecticut, USA
| | - Lisa Bodei
- Department of Nuclear Medicine, Memorial Sloan Kettering Cancer Centre, New York, New York, USA
| | - Christos Toumpanakis
- Centre for Gastroenterology/Neuroendocrine Tumour Unit, Royal Free Hospital, London, United Kingdom
| | - Richard P Baum
- Theranostics Centre for Molecular Radiotherapy and Precision Oncology, Zentralklinik, Bad Berka, Germany
| | - Kjell Oberg
- Department of Endocrine Oncology, Uppsala University, Uppsala, Sweden
| | - Irvin M Modlin
- Yale University School of Medicine, New Haven, Connecticut, USA
| | - Andrea Frilling
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom,
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Ren B, Rose JB, Liu Y, Jaskular-Sztul R, Contreras C, Beck A, Chen H. Heterogeneity of Vascular Endothelial Cells, De Novo Arteriogenesis and Therapeutic Implications in Pancreatic Neuroendocrine Tumors. J Clin Med 2019; 8:jcm8111980. [PMID: 31739580 PMCID: PMC6912347 DOI: 10.3390/jcm8111980] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 11/08/2019] [Accepted: 11/12/2019] [Indexed: 02/07/2023] Open
Abstract
Arteriogenesis supplies oxygen and nutrients in the tumor microenvironment (TME), which may play an important role in tumor growth and metastasis. Pancreatic neuroendocrine tumors (pNETs) are the second most common pancreatic malignancy and are frequently metastatic on presentation. Nearly a third of pNETs secrete bioactive substances causing debilitating symptoms. Current treatment options for metastatic pNETs are limited. Importantly, these tumors are highly vascularized and heterogeneous neoplasms, in which the heterogeneity of vascular endothelial cells (ECs) and de novo arteriogenesis may be critical for their progression. Current anti-angiogenetic targeted treatments have not shown substantial clinical benefits, and they are poorly tolerated. This review article describes EC heterogeneity and heterogeneous tumor-associated ECs (TAECs) in the TME and emphasizes the concept of de novo arteriogenesis in the TME. The authors also emphasize the challenges of current antiangiogenic therapy in pNETs and discuss the potential of tumor arteriogenesis as a novel therapeutic target. Finally, the authors prospect the clinical potential of targeting the FoxO1-CD36-Notch pathway that is associated with both pNET progression and arteriogenesis and provide insights into the clinical implications of targeting plasticity of cancer stem cells (CSCs) and vascular niche, particularly the arteriolar niche within the TME in pNETs, which will also provide insights into other types of cancer, including breast cancer, lung cancer, and malignant melanoma.
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Affiliation(s)
- Bin Ren
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (J.B.R.); (R.J.-S.); (C.C.); (A.B.); (H.C.)
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Nutrition & Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Diabetes Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Graduate Biomedical Science Program of the Graduate School, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Correspondence:
| | - J. Bart Rose
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (J.B.R.); (R.J.-S.); (C.C.); (A.B.); (H.C.)
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Yehe Liu
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA;
| | - Renata Jaskular-Sztul
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (J.B.R.); (R.J.-S.); (C.C.); (A.B.); (H.C.)
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Carlo Contreras
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (J.B.R.); (R.J.-S.); (C.C.); (A.B.); (H.C.)
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Adam Beck
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (J.B.R.); (R.J.-S.); (C.C.); (A.B.); (H.C.)
| | - Herbert Chen
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (J.B.R.); (R.J.-S.); (C.C.); (A.B.); (H.C.)
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Graduate Biomedical Science Program of the Graduate School, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Torniai M, Scortichini L, Tronconi F, Rubini C, Morgese F, Rinaldi S, Mazzanti P, Berardi R. Systemic treatment for lung carcinoids: from bench to bedside. Clin Transl Med 2019; 8:22. [PMID: 31273555 PMCID: PMC6609661 DOI: 10.1186/s40169-019-0238-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Accepted: 06/21/2019] [Indexed: 12/13/2022] Open
Abstract
In the huge spectrum of lung neuroendocrine neoplasms, typical and atypical carcinoids should be considered as a separate biological entity from poorly differentiated forms, harboring peculiar molecular alterations. Despite their indolent behavior, lung carcinoids correlate with a worse survival. To date, only limited therapeutic options are available and novel drugs are strongly needed. In this work, we extensively reviewed scientific literature exploring available therapeutic options, new molecular targets and future perspectives in the management of well differentiated neoplasms of bronchopulmonary tree. Systemic therapy represents the main option in advanced and unresectable disease; accepted choices are somatostatin analogs, peptide receptor radionuclide therapy, everolimus and chemotherapy. To date, an univocal treatment strategy has not been identified yet, thus tailored therapeutic algorithms should consider treatment efficacy as well as safety profiles. Several molecular alterations found in carcinoid tumors might act as molecular targets leading to development of new therapeutic options. Further studies are necessary to identify new potential "druggable" molecular targets in the selected subset of low-grade lung carcinoids. Furthermore, evaluating the available therapies in more homogeneous population might improve their efficacy through a perfect tailoring of treatment options.
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Affiliation(s)
- Mariangela Torniai
- Clinica Oncologica, Università Politecnica delle Marche, AOU Ospedali Riuniti di Ancona, Via Conca 71, 60126 Ancona, Italy
| | - Laura Scortichini
- Clinica Oncologica, Università Politecnica delle Marche, AOU Ospedali Riuniti di Ancona, Via Conca 71, 60126 Ancona, Italy
| | - Francesca Tronconi
- Clinica Oncologica, Università Politecnica delle Marche, AOU Ospedali Riuniti di Ancona, Via Conca 71, 60126 Ancona, Italy
| | - Corrado Rubini
- Section of Pathological Anatomy and Histopathology, Department of Neuroscience, Università Politecnica delle Marche, AOU Ospedali Riuniti di Ancona, Ancona, Italy
| | - Francesca Morgese
- Clinica Oncologica, Università Politecnica delle Marche, AOU Ospedali Riuniti di Ancona, Via Conca 71, 60126 Ancona, Italy
| | - Silvia Rinaldi
- Clinica Oncologica, Università Politecnica delle Marche, AOU Ospedali Riuniti di Ancona, Via Conca 71, 60126 Ancona, Italy
| | - Paola Mazzanti
- Clinica Oncologica, Università Politecnica delle Marche, AOU Ospedali Riuniti di Ancona, Via Conca 71, 60126 Ancona, Italy
| | - Rossana Berardi
- Clinica Oncologica, Università Politecnica delle Marche, AOU Ospedali Riuniti di Ancona, Via Conca 71, 60126 Ancona, Italy
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Lopez CL, Joos B, Bartsch DK, Manoharan J, Albers M, Slater EP, Bollmann C, Roth S, Bayer A, Fendrich V. Chemoprevention with Somatuline© Delays the Progression of Pancreatic Neuroendocrine Neoplasms in a Mouse Model of Multiple Endocrine Neoplasia Type 1 (MEN1). World J Surg 2019; 43:831-838. [PMID: 30600364 DOI: 10.1007/s00268-018-4839-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Long-acting synthetic somatostatin analogues (SSA) are an essential part of the treatment of neuroendocrine neoplasms. We evaluated the chemopreventive effects of a long-acting somatostatin analogue on the development of pancreatic neuroendocrine neoplasms (pNENs) in a genetically engineered MEN1 knockout mouse model. MATERIALS AND METHODS Heterozygote MEN1 knockout mice were injected every 28 days subcutaneously with the somatostatin analogue lanreotide (Somatuline Autogel©; Ipsen Pharma) or a placebo starting at day 35 after birth. Mice were euthanized after 6, 9, 12, 15 and 18 months, and the size and number of pNENs were measured due histological analysis and compared to the placebo group. RESULTS The median tumor size of pNENs was statistically significantly smaller after 9 (control group vs. SSA group; 706.476 µm2 vs. 195.271 µm2; p = 0.0012), 12 (placebo group vs. SSA group 822.022 vs. 255.482; p ≤ 0.001), 15 (placebo group vs. SSA group 1192.568 vs. 273.533; p ≤ 0.001) and after 18 months (placebo group vs. SSA group 1328.299 vs. 864.587; p ≤ 0.001) in the SSA group. Comparing the amount of tumors in both groups, a significant reduction was achieved in treated Men1(+/-) mice (41%, p = 0.002). Immunostaining showed, however, no significant difference in the expression of the apoptosis marker caspase-3, but a significant difference in Ki67 index as a marker for tumor cell proliferation (p ≤ 0.005). CONCLUSION Long-acting somatostatin analogues may be an effective chemopreventive approach to delay the progression of MEN1-associated pNENs. After our preclinical results, we would recommend to evaluate the effects of long-acting SSA in a prospective clinical trial.
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Affiliation(s)
- Caroline L Lopez
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35041, Marburg, Germany
| | - Barbara Joos
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35041, Marburg, Germany
| | - Detlef K Bartsch
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35041, Marburg, Germany
| | - Jerena Manoharan
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35041, Marburg, Germany
| | - Max Albers
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35041, Marburg, Germany
| | - Emily P Slater
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35041, Marburg, Germany
| | - Carmen Bollmann
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35041, Marburg, Germany
| | - Sylvia Roth
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35041, Marburg, Germany
| | - Aninja Bayer
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35041, Marburg, Germany
| | - Volker Fendrich
- Department of Endocrine Surgery, Schön Klinik Hamburg Eilbek, Dehnhaide 120, 22081, Hamburg, Germany.
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Stueven AK, Kayser A, Wetz C, Amthauer H, Wree A, Tacke F, Wiedenmann B, Roderburg C, Jann H. Somatostatin Analogues in the Treatment of Neuroendocrine Tumors: Past, Present and Future. Int J Mol Sci 2019; 20:ijms20123049. [PMID: 31234481 PMCID: PMC6627451 DOI: 10.3390/ijms20123049] [Citation(s) in RCA: 129] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 06/06/2019] [Accepted: 06/19/2019] [Indexed: 12/14/2022] Open
Abstract
In recent decades, the incidence of neuroendocrine tumors (NETs) has steadily increased. Due to the slow-growing nature of these tumors and the lack of early symptoms, most cases are diagnosed at advanced stages, when curative treatment options are no longer available. Prognosis and survival of patients with NETs are determined by the location of the primary lesion, biochemical functional status, differentiation, initial staging, and response to treatment. Somatostatin analogue (SSA) therapy has been a mainstay of antisecretory therapy in functioning neuroendocrine tumors, which cause various clinical symptoms depending on hormonal hypersecretion. Beyond symptomatic management, recent research demonstrates that SSAs exert antiproliferative effects and inhibit tumor growth via the somatostatin receptor 2 (SSTR2). Both the PROMID (placebo-controlled, prospective, randomized study in patients with metastatic neuroendocrine midgut tumors) and the CLARINET (controlled study of lanreotide antiproliferative response in neuroendocrine tumors) trial showed a statistically significant prolongation of time to progression/progression-free survival (TTP/PFS) upon SSA treatment, compared to placebo. Moreover, the combination of SSA with peptide receptor radionuclide therapy (PRRT) in small intestinal NETs has proven efficacy in the phase 3 neuroendocrine tumours therapy (NETTER 1) trial. PRRT is currently being tested for enteropancreatic NETs versus everolimus in the COMPETE trial, and the potential of SSTR-antagonists in PRRT is now being evaluated in early phase I/II clinical trials. This review provides a synopsis on the pharmacological development of SSAs and their use as antisecretory drugs. Moreover, this review highlights the clinical evidence of SSAs in monotherapy, and in combination with other treatment modalities, as applied to the antiproliferative management of neuroendocrine tumors with special attention to recent high-quality phase III trials.
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Affiliation(s)
- Anna Kathrin Stueven
- Charité, Campus Virchow Klinikum and Charité, Campus Mitte, Department of Hepatology and Gastroenterology, Universitätsmedizin Berlin, 10117 Berlin, Germany.
| | - Antonin Kayser
- Charité, Campus Virchow Klinikum and Charité, Campus Mitte, Department of Hepatology and Gastroenterology, Universitätsmedizin Berlin, 10117 Berlin, Germany.
| | - Christoph Wetz
- Charité, Campus Virchow Klinikum and Charité, Campus Mitte, Department of Nuclear Medicine, Universitätsmedizin Berlin, 10117 Berlin, Germany.
| | - Holger Amthauer
- Charité, Campus Virchow Klinikum and Charité, Campus Mitte, Department of Nuclear Medicine, Universitätsmedizin Berlin, 10117 Berlin, Germany.
| | - Alexander Wree
- Charité, Campus Virchow Klinikum and Charité, Campus Mitte, Department of Hepatology and Gastroenterology, Universitätsmedizin Berlin, 10117 Berlin, Germany.
| | - Frank Tacke
- Charité, Campus Virchow Klinikum and Charité, Campus Mitte, Department of Hepatology and Gastroenterology, Universitätsmedizin Berlin, 10117 Berlin, Germany.
| | - Bertram Wiedenmann
- Charité, Campus Virchow Klinikum and Charité, Campus Mitte, Department of Hepatology and Gastroenterology, Universitätsmedizin Berlin, 10117 Berlin, Germany.
| | - Christoph Roderburg
- Charité, Campus Virchow Klinikum and Charité, Campus Mitte, Department of Hepatology and Gastroenterology, Universitätsmedizin Berlin, 10117 Berlin, Germany.
| | - Henning Jann
- Charité, Campus Virchow Klinikum and Charité, Campus Mitte, Department of Hepatology and Gastroenterology, Universitätsmedizin Berlin, 10117 Berlin, Germany.
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Wang X, Zhou N, Xiao Y, Zhu W, Bai C, Zhao L. Metastatic Adrenal Cortical Carcinoma Responding to Octreotide: A Case Report. Oncologist 2019; 24:e793-e797. [PMID: 31073023 DOI: 10.1634/theoncologist.2018-0855] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 04/04/2019] [Accepted: 04/10/2019] [Indexed: 11/17/2022] Open
Abstract
Advanced adrenocortical carcinoma (ACC) is an aggressive disease with poor prognosis, and the current therapeutic options, such as mitotane or platinum-based chemotherapy regimens, often offer limited efficacy. Here, we present the first report, to the author's knowledge, of metastatic ACC with positive octreoscan scintigraphy that was successfully treated with octreotide long-acting release (LAR). A patient with metastatic ACC who showed poor tolerance to mitotane received octreotide LAR because of positive octreoscan scintigraphy. She obtained major partial response to the somatostatin analog. Interestingly, the expression of somatostatin receptor 2 from the previous local recurrence lesion was negative. The next-generation sequencing-based circulating tumor DNA analysis in the patient was performed and failed to identify any alterations. These findings suggest that octreotide LAR may be a good option for the treatment of metastatic ACC in selected patients.
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Affiliation(s)
- Xiang Wang
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Na Zhou
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Yu Xiao
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Wenjia Zhu
- Departments of Nuclear Medicine and Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Chunmei Bai
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Lin Zhao
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
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Chatzellis E, Kaltsas G. Somatostatin Receptor Expression in Gastrointestinal Tumors. ENCYCLOPEDIA OF ENDOCRINE DISEASES 2019:587-596. [DOI: 10.1016/b978-0-12-801238-3.64282-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Abstract
Neuroendocrine tumors, including carcinoids, are rare and insidiously growing tumors. Related to their site of origin, tumors can be functional, causing various forms of the carcinoid syndrome, owing to the overproduction of serotonin, histamine, or other bioactive substances. They often invade adjacent structures or metastasize to the liver and elsewhere. Treatment includes multimodal approaches, including cytoreductive surgery, locoregional embolization, cytotoxic therapy, peptide receptor radionuclide therapy, and various targeted therapies with goals of symptom relief and control of tumor growth. This article summarizes current and emerging approaches to management and reviews several promising future therapies.
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Affiliation(s)
- Paul Benjamin Loughrey
- Department of Ophthalmology, Royal Victoria Hospital, Belfast Trust, Grosvenor Road, Belfast, BT12 6BA, UK; Department of Endocrinology and Diabetes, Royal Victoria Hospital, Belfast Trust, Grosvenor Road, Belfast, BT12 6BA, UK
| | - Dongyun Zhang
- Department of Medicine, David Geffen School of Medicine, University of California, 700 Tiverton Avenue, Los Angeles, CA 90095, USA
| | - Anthony P Heaney
- Department of Medicine, David Geffen School of Medicine, University of California, 700 Tiverton Avenue, Los Angeles, CA 90095, USA; Department of Neurosurgery, David Geffen School of Medicine, University of California, 700 Tiverton Avenue, Los Angeles, CA 90095, USA.
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40
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Abstract
The concept of neuroendocrine tumors (NETs) began in the 1900s with Oberndorfer's description of carcinoid tumors, followed by specific cytotoxic agents and the identification of somatostatin. NETs diagnosis was confirmed by World Health Organization classification. Histopathology included immunohistochemistry with specific antibodies. Imaging was refined with molecular imaging. Somatostatin is the leading agent for controlling clinical symptoms related to hormone production. Increasing interest in these tumors, previously thought rare, led to increased incidence and prevalence. Between 1960 and 1970, the true NET-concept was established with development of radioimmunoassays for peptides and hormones, and imaging with computerized tomography.
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Affiliation(s)
- Kjell Öberg
- Department of Endocrine Oncology, Uppsala University Hospital, Entrance 40:5, SE-75185, Uppsala, Sweden.
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41
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Stevenson M, Lines KE, Thakker RV. Molecular Genetic Studies of Pancreatic Neuroendocrine Tumors: New Therapeutic Approaches. Endocrinol Metab Clin North Am 2018; 47:525-548. [PMID: 30098714 PMCID: PMC7614857 DOI: 10.1016/j.ecl.2018.04.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pancreatic neuroendocrine tumors (PNETs) arise sporadically or as part of familial syndromes. Genetic studies of hereditary syndromes and whole exome sequencing analysis of sporadic NETs have revealed the roles of some genes involved in PNET tumorigenesis. The multiple endocrine neoplasia type 1 (MEN1) gene is most commonly mutated. Its encoded protein, menin, has roles in transcriptional regulation, genome stability, DNA repair, protein degradation, cell motility and adhesion, microRNA biogenesis, cell division, cell cycle control, and epigenetic regulation. Therapies targeting epigenetic regulation and MEN1 gene replacement have been reported to be effective in preclinical models.
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Affiliation(s)
- Mark Stevenson
- Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LJ, UK
| | - Kate E Lines
- Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LJ, UK
| | - Rajesh V Thakker
- Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LJ, UK.
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Amair-Pinedo F, Matos I, Saurí T, Hernando J, Capdevila J. The Treatment Landscape and New Opportunities of Molecular Targeted Therapies in Gastroenteropancreatic Neuroendocrine Tumors. Target Oncol 2018; 12:757-774. [PMID: 29143176 DOI: 10.1007/s11523-017-0532-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms that originate from neuroendocrine stem cells and express both neural and endocrine markers. They are found in almost every organ, and while NENs are mostly associated with slow growth, complications due to the uncontrolled secretion of active peptides, and metastatic disease, may significantly impair the quality of life and can ultimately lead to the death of affected individuals. Expanding knowledge of the genetic, epigenetic, and proteomic landscapes of NENs has led to a better understanding of their molecular pathology and consequently increased treatment options for patients. Here, we review the principal breakthroughs in NEN treatment management, owing largely to omics technologies over the last few years, current recommendations of systemic treatment, and ongoing research into the identification of predictive and response biomarkers based on molecular targeted therapies.
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Affiliation(s)
| | - Ignacio Matos
- Vall d'Hebron University Hospital, Barcelona, Spain.,Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Tamara Saurí
- Vall d'Hebron University Hospital, Barcelona, Spain.,Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Jorge Hernando
- Vall d'Hebron University Hospital, Barcelona, Spain.,Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Jaume Capdevila
- Vall d'Hebron University Hospital, Barcelona, Spain. .,Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
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Chen X, Zhang XY, Shen Y, Fan LL, Ren ML, Wu YP. Synthetic paclitaxel-octreotide conjugate reversing the resistance of A2780/Taxol to paclitaxel in xenografted tumor in nude mice. Oncotarget 2018; 7:83451-83461. [PMID: 27825139 PMCID: PMC5347781 DOI: 10.18632/oncotarget.13120] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 10/12/2016] [Indexed: 12/11/2022] Open
Abstract
Peptide hormone-based targeted therapy to tumors has been studied extensively. Our previous study shows that somatostatin receptor expresses high level on drug-resistant human ovarian cancer. The paclitaxel-octreotide conjugate (POC) exhibits enhanced growth inhibition, as well as reduced toxicity, in paclitaxel-resistant human ovarian cancer cells. The aim of this study was to investigate the effect of targeted cytotoxicity and potential reversal mechanism of resistance in paclitaxel-resistant human ovarian cancer cells xenografted into nude mice. The SSTR2 shows higher expression levels in tumor tissue. Moreover, fluorescein-labeled POC displays favorable targeting in tumor cells. POC presents the perfect efficacy in inhibiting tumor growth and exerts lower or no toxic effects on normal tissues. Real-time PCR and Western Blotting has demonstrated that the mRNA and protein expressions of SSTR2 in POC group were significantly higher, while MDR1, α-tubulin, βIII-tubulin, VEGF and MMP-9 were significantly lower than in the other treatment groups and controls. Combined with the previous study in vitro, this study evaluates an effective approach on the treatment of paclitaxel-resistant ovarian cancer which expresses somatostatin receptor SSTR. Our investigation has also revealed the possible molecular mechanism of POC in treating the ovarian cancer, and therefore, provided a theoretical basis for the clinical application of this newly-invented compound.
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Affiliation(s)
- Xi Chen
- Department of Obstetrics and Gynaecology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Xiao-Yu Zhang
- Department of Obstetrics and Gynaecology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Yang Shen
- Department of Obstetrics and Gynaecology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Li-Li Fan
- Department of Obstetrics and Gynaecology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Mu-Lan Ren
- Department of Obstetrics and Gynaecology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Yong-Ping Wu
- Jiangsu Provincial Institute of Materia Medica, Nanjing 210009, China
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Abstract
Pancreatic neuroendocrine tumors (pNETs) constitute a heterogenous group of malignancies with varying clinical presentation, tumor biology and prognosis. The incidence of pNETs has steadily increased during the last decades with an estimated incidence 2012 of 4.8/100,000. Recent whole genome sequencing of pNETs has demonstrated mutations in the DNA repair genes MUTYH and point mutations and gene fusions in four main pathways from chromatin remodeling, DNA damage repair, activation of mechanistic target of rapamycin (mTOR) signaling and the telomere maintenance. This new information will be the foundation for new therapies in the near future for malignant pNETs. The functioning pNETs constitute about 30-40% of all pNETs displaying nine different clinical syndromes: insulinoma, Zollinger-Ellison, Verner-Morrison, glucagonoma, somatostatinomas, ectopic adrenocorticotropic hormone (ACTH) and parathyroid hormone related peptide (PTH-rP) syndromes. Single patients might also present carcinoid syndrome. The diagnostic work-up include histopathology with the new WHO 2017 Classification, biomarkers (CgA, NSE), radiology and molecular imaging including CT-scan, magnetic resonance imaging (MRI), ultrasound and PET-scan. A cornerstone in the treatment of pNETs is surgery which is rarely curative but can reduce the clinical symptoms by debulking which also include radiofrequency ablation, embolization of liver metastases. Medical treatment includes chemotherapy and the targeted agents such as everolimus, sunitinib and peptide receptor radiotherapy (PRRT). Somatostatin analogs has for the last decades been the main stay for management for clinical symptoms related to functioning pNETs and is often combined with new targeted agents as well as chemotherapy. Long-term management of functioning pNETs need a combination of different procedures, surgery, local ablation, targeted agents and somatostatin analogs. Future therapies might be based on the recent advances in molecular genetics and tumor biology.
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Affiliation(s)
- Kjell Öberg
- Department of Medical Sciences, Endocrine Oncology, Uppsala University Hospital, Uppsala, Sweden
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Oronsky B, Ma PC, Morgensztern D, Carter CA. Nothing But NET: A Review of Neuroendocrine Tumors and Carcinomas. Neoplasia 2017; 19:991-1002. [PMID: 29091800 PMCID: PMC5678742 DOI: 10.1016/j.neo.2017.09.002] [Citation(s) in RCA: 474] [Impact Index Per Article: 59.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 09/06/2017] [Accepted: 09/07/2017] [Indexed: 02/07/2023]
Abstract
This review covers the diverse topic of neuroendocrine neoplasms (NENs), a relatively rare and heterogeneous tumor type, comprising ~2% of all malignancies, with a prevalence of <200,000 in the United States, which makes it an orphan disease (Basu et al., 2010).1 For functional purposes, NENs are divided into two groups on the basis of clinical behavior, histology, and proliferation rate: well differentiated (low grade to intermediate grade) neuroendocrine tumors and poorly differentiated (high grade) neuroendocrine carcinoma (Bosman et al., 2010)2; this histological categorization/dichotomization is highly clinically relevant with respect to impact on treatment and prognosis even though it is not absolute since a subset of tumors with a low-grade appearance behaves similarly to high-grade lesions. Given the relative dearth of evidenced-based literature about this orphan disease as a whole (Modlin et al., 2008),3 since the focus of most articles is on particular anatomic subtypes of NENs (i.e., gastroenteropancreatic or pulmonary), the purpose of this review is to summarize the presentation, pathophysiology, staging, current standard of care treatments, and active areas of current research.
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Affiliation(s)
- Bryan Oronsky
- EpicentRx Inc, 4445 Eastgate Mall, Suite 200, San Diego, CA 92121, USA.
| | - Patrick C Ma
- West Virginia University, Mary Babb Randolph Cancer Center, 8901 Wisconsin Ave., PO Box 9162, Morgantown, WV 26506, USA
| | - Daniel Morgensztern
- Washington University School of Medicine, Division of Oncology, 660 S. Euclid, Box 8056, St. Louis, MO 63110, USA
| | - Corey A Carter
- Walter Reed National Military Medical Center, 8901 Wisconsin Ave., Bethesda, MD 20889, USA
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Khan M, Huang T, Lin CY, Wu J, Fan BM, Bian ZX. Exploiting cancer's phenotypic guise against itself: targeting ectopically expressed peptide G-protein coupled receptors for lung cancer therapy. Oncotarget 2017; 8:104615-104637. [PMID: 29262666 PMCID: PMC5732832 DOI: 10.18632/oncotarget.18403] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 05/23/2017] [Indexed: 02/07/2023] Open
Abstract
Lung cancer, claiming millions of lives annually, has the highest mortality rate worldwide. This advocates the development of novel cancer therapies that are highly toxic for cancer cells but negligibly toxic for healthy cells. One of the effective treatments is targeting overexpressed surface receptors of cancer cells with receptor-specific drugs. The receptors-in-focus in the current review are the G-protein coupled receptors (GPCRs), which are often overexpressed in various types of tumors. The peptide subfamily of GPCRs is the pivot of the current article owing to the high affinity and specificity to and of their cognate peptide ligands, and the proven efficacy of peptide-based therapeutics. The article summarizes various ectopically expressed peptide GPCRs in lung cancer, namely, Cholecystokinin-B/Gastrin receptor, the Bombesin receptor family, Bradykinin B1 and B2 receptors, Arginine vasopressin receptors 1a, 1b and 2, and the Somatostatin receptor type 2. The autocrine growth and pro-proliferative pathways they mediate, and the distinct tumor-inhibitory effects of somatostatin receptors are then discussed. The next section covers how these pathways may be influenced or 'corrected' through therapeutics (involving agonists and antagonists) targeting the overexpressed peptide GPCRs. The review proceeds on to Nano-scaled delivery platforms, which enclose chemotherapeutic agents and are decorated with peptide ligands on their external surface, as an effective means of targeting cancer cells. We conclude that targeting these overexpressed peptide GPCRs is potentially evolving as a highly promising form of lung cancer therapy.
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Affiliation(s)
- Mahjabin Khan
- Laboratory of Brain-Gut Research, School of Chinese Medicine, Hong Kong Baptist University, HKSAR, Kowloon Tong, P.R. China
| | - Tao Huang
- Laboratory of Brain-Gut Research, School of Chinese Medicine, Hong Kong Baptist University, HKSAR, Kowloon Tong, P.R. China
| | - Cheng-Yuan Lin
- Laboratory of Brain-Gut Research, School of Chinese Medicine, Hong Kong Baptist University, HKSAR, Kowloon Tong, P.R. China
- YMU-HKBU Joint Laboratory of Traditional Natural Medicine, Yunnan Minzu University, Kunming, P.R. China
| | - Jiang Wu
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, P. R. China
| | - Bao-Min Fan
- YMU-HKBU Joint Laboratory of Traditional Natural Medicine, Yunnan Minzu University, Kunming, P.R. China
| | - Zhao-Xiang Bian
- Laboratory of Brain-Gut Research, School of Chinese Medicine, Hong Kong Baptist University, HKSAR, Kowloon Tong, P.R. China
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Aerts M, Reynaert H. Disease Control on Lanreotide Autogel® 120 mg in a Patient with Metastatic Gastrinoma: A Case Report. Case Rep Gastroenterol 2017; 11:616-623. [PMID: 29430219 PMCID: PMC5803728 DOI: 10.1159/000485025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 11/03/2017] [Indexed: 11/19/2022] Open
Abstract
Gastrinomas are functionally active pancreatic neuroendocrine tumors (NETs) secreting gastrin and are associated with local or regional metastases in 60% of the cases. Somatostatin analogs (SSAs) are currently recommended as a first-line treatment for the symptomatic treatment of NETs. Although antiproliferative activity of SSAs has been demonstrated in various cancer types in several in vivo and in vitro studies, clinical benefits with SSAs have been only achieved in a small proportion of patients. We report a disease control on a long-acting SSA lanreotide in a patient with metastatic gastrinoma. A 60-year-old man, who had previously undergone a surgical resection of metastatic pancreatic gastrinoma, presented with abdominal bloating, edema in the lower limbs, fatigue, and weight loss. The gastrinoma relapse with additional metastases in the pancreas, duodenum, and liver was confirmed by positron emission tomography-computed tomography (PET-CT) scan; the patient's blood gastrin level was >5,000 ng/L. Treatment with the SSA octreotide long-acting release was initiated to treat the gastrinoma relapse. On the CT scan done in September 2011, the liver metastases were still identifiable. In December 2011, the treatment was switched to lanreotide Autogel® (120 mg every 2 weeks). Following the treatment, the gastrin levels were reduced to <1,200 ng/L in September 2013, and 812 ng/L in July 2016. Since November 2012, the gastrinoma lesions were no longer visible in abdominal CT. At the time of this report, the patient's gastrinoma was under control with lanreotide Autogel®. This case report supports the use of lanreotide Autogel® as effective treatment for metastatic gastrinoma.
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Affiliation(s)
- Maridi Aerts
- University Hospital, UZ Brussel, Department of Gastroenterology and Hepatology, Brussels, Belgium
| | - Hendrik Reynaert
- University Hospital, UZ Brussel, Department of Gastroenterology and Hepatology, Brussels, Belgium
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Enzler T, Fojo T. Long-acting somatostatin analogues in the treatment of unresectable/metastatic neuroendocrine tumors. Semin Oncol 2017; 44:141-156. [PMID: 28923213 DOI: 10.1053/j.seminoncol.2017.07.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Neuroendocrine tumors (NETs) are a relatively rare and heterogeneous group of neoplasms with an annual incidence of ~35 cases per 100,000 people in the United States. The updated World Health Organization (WHO) classification system of gastroenteropancreatic (GEP)-NETs categorizes these tumors according to site of origin, clinical syndrome, and degree of differentiation. Well-differentiated NETs arising from the gastrointestinal tract or lungs (formerly known as carcinoid tumors) are often indolent and slow-growing. In contrast, poorly differentiated neuroendocrine carcinomas (NECs) are aggressive and have a poor prognosis. Due to their insidious onset, most NETs are diagnosed at an advanced stage and a curative approach is not possible. In these patients, medical therapy is limited to disease control, including relief of symptoms that arise from overproduction of peptide hormones by the tumors. Somatostatin analogues (SSAs) have remained the mainstay of symptoms control. In addition to symptoms control, clinical data also support an anti-proliferative effect of SSAs in patients with well- to moderately differentiated NETs. Long-acting SSAs have greatly facilitated their use. This review will focus on two long-acting SSAs, octreotide LAR and lanreotide, and their use in the clinical setting. Information necessary to assess their relative merits is summarized. We conclude these two therapies are interchangeable making value a very important consideration in their use.
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Affiliation(s)
- Thomas Enzler
- Department of Medicine, Division of Hematology Oncology, Columbia University, New York, NY
| | - Tito Fojo
- Department of Medicine, Division of Hematology Oncology, Columbia University, New York, NY; James J. Peter VAMC, Bronx, NY.
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Mende KC, Matschke J, Burkhardt T, Saeger W, Buslei R, Buchfelder M, Fahlbusch R, Westphal M, Flitsch J. Pituicytoma-An outlook on possible targeted therapies. CNS Neurosci Ther 2017; 23:620-626. [PMID: 28556544 DOI: 10.1111/cns.12709] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Revised: 04/30/2017] [Accepted: 05/03/2017] [Indexed: 12/01/2022] Open
Abstract
INTRODUCTION Pituicytoma is a rare neoplasm of the sella region. Tumor resection is the primary treatment option, but remains subtotal due to excessive bleeding in many cases. The search for alternative or additional treatment regimens is necessary. AIMS We aimed to determine the receptor expression of pituicytoma to find alternatives or supplements to surgical therapy in the use of targeted therapies. METHODS Pituicytoma samples were collected from three institutions between 2006 and 2015 and were stained for vascular endothelial growth factors (VEGF), thyroid transcription factor (TTF1), and somatostatin receptors (SSTR 2/3/5). The stains were classified from 0=no staining to +++=strong staining. A complementary retrospective analysis of the patient charts regarding sex, age, and primary symptoms, pituitary function, and perioperative complications was performed. RESULTS Ten samples were analyzed; mean patient age was 57.8 years SD 16.3 years. Seven samples were acquired from male patients (one relapse) and three from female. All tumors stained strongly positive (+++) for VEGF-R. Six samples stained positive for TTF1. As for somatostatin receptors, three samples were slightly positive for SSTR 2; seven were negative. SSTR 3 was + in one, three were ++, three were +++, and three were 0. SSTR 5 stained +++ in 1, ++ in 5, + in 1, and 0 in three patients. CONCLUSIONS Pituicytomas were generally positive for VEGFR and showed regular expression of SSTR 3 and 5 indicating a possible treatment option through targeted therapies in cases where resection remains insufficient. Further research is necessary as to whether tumor growth can be inhibited using these pathways.
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Affiliation(s)
| | - Jakob Matschke
- Institute of Neuropathology, Hamburg University Medical Center, Hamburg, Germany
| | - Till Burkhardt
- Department of Neurosurgery, Hamburg University Medical Center, Hamburg, Germany
| | - Wolfgang Saeger
- Institute of Neuropathology, Hamburg University Medical Center, Hamburg, Germany
| | - Rolf Buslei
- Department of Neuropathology, University of Erlangen, Erlangen, Germany
| | | | - Rudolf Fahlbusch
- International Neuroscience Institute Hannover GmbH, Hannover, Germany
| | - Manfred Westphal
- Department of Neurosurgery, Hamburg University Medical Center, Hamburg, Germany
| | - Jörg Flitsch
- Department of Neurosurgery, Hamburg University Medical Center, Hamburg, Germany
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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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