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1
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Matsumoto K, Kato H, Tsutsumi K, Otsuka M. Current status of endoscopic ultrasound-guided antitumor treatment for pancreatic cancer. Dig Endosc 2025; 37:18-28. [PMID: 38752622 PMCID: PMC11718125 DOI: 10.1111/den.14815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 04/15/2024] [Indexed: 01/11/2025]
Abstract
Endoscopic ultrasound (EUS) was developed in the 1990s and has significantly transformed pancreatic tumor diagnosis. Subsequently, EUS has rapidly shifted from being a purely diagnostic procedure to being used in a wide range of interventional procedures. Recently, new therapeutic techniques, such as EUS-guided fine needle injection (EUS-FNI) or radiofrequency ablation (RFA), have been developed to deliver various antitumor agents. Despite technological advancements, pancreatic cancer (PC) has a poor prognosis and improvements in treatment outcomes are urgently required. One of the reasons for the limited response to antitumor agents in PC is the abundant desmoplasia and hypovascular nature of the tumor, complicating drug delivery into the tumor. Thus, changing the tumor microenvironment may be important to enhance the effectiveness of chemotherapy, and direct injection of antitumor agents into the tumor under EUS guidance can help overcome treatment challenges in PC. Treatment approaches using the EUS-FNI or RFA technique are expected to further improve the prognosis of PC. Therefore, this study reviewed the existing literature on EUS-guided antitumor therapy, specifically highlighting its application in PC to address the current challenges and to identify potential advancements in the field.
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Affiliation(s)
- Kazuyuki Matsumoto
- Department of Gastroenterology and HepatologyOkayama University HospitalOkayamaJapan
| | - Hironari Kato
- Department of Gastroenterology and HepatologyOkayama University HospitalOkayamaJapan
| | - Koichiro Tsutsumi
- Department of Gastroenterology and HepatologyOkayama University HospitalOkayamaJapan
| | - Motoyuki Otsuka
- Department of Gastroenterology and HepatologyOkayama University HospitalOkayamaJapan
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2
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Ye J, Suizu F, Yamakawa K, Mukai Y, Yoneyama H, Kondo J, Kato M, Nishiyama A, Yahagi N, Kadota K. Intra-tumoral administration of CHST15 siRNA remodels tumor microenvironment and augments tumor-infiltrating T cells in pancreatic cancer. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200812. [PMID: 38799652 PMCID: PMC11127163 DOI: 10.1016/j.omton.2024.200812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 03/24/2024] [Accepted: 04/30/2024] [Indexed: 05/29/2024]
Abstract
The dense stroma is one cause of poor efficacy of T cell-mediated immunotherapy in pancreatic ductal adenocarcinoma (PDAC). Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan-synthetic enzyme responsible for remodeling tumor stroma. Intra-tumoral injection of CHST15 small interfering RNA (siRNA) has been shown to increase the tumor-infiltrating T cells (TILs) in patients with unresectable PDAC. However, the mechanism underlying the enhanced accumulation of TILs is not fully explored. Here, we demonstrate that intra-tumoral injection of CHST15 siRNA locally and remotely diminishes myeloid-derived suppressor cells (MDSCs) and enhances TILs in mice. CHST15 was expressed by tumor cells and MDSCs in both tumor and tumor-draining lymph nodes (TDLNs), and CHST15 siRNA repressed stromal density, neutrophil extracellular traps, and Ly6C/G+ MDSCs in vivo. Remarkably, tumor growth inhibition was only observed in the immunocompetent KPC model, which is associated with enhanced TILs. In vitro, CHST15 siRNA significantly downregulated the levels of CHST15 and indoleamine 2,3-dioxygenase mRNA in CD33+ MDSCs derived from human peripheral blood mononuclear cells. These results suggest a dual role for intra-tumorally injected CHST15 siRNA on modulating the tumor immune microenvironment for T cell entry and remotely diminishing CHST15+ MDSCs, decreasing T cell suppression and expanding T cells in the TDLN, ultimately leading to an enhanced accumulation of TILs.
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Affiliation(s)
- Juanjuan Ye
- Molecular Oncologic Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kita-gun 761-0793, Kagawa, Japan
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa 761-0793, Japan
| | - Futoshi Suizu
- Molecular Oncologic Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kita-gun 761-0793, Kagawa, Japan
| | - Keiko Yamakawa
- Molecular Oncologic Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kita-gun 761-0793, Kagawa, Japan
| | - Yuri Mukai
- Molecular Oncologic Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kita-gun 761-0793, Kagawa, Japan
| | | | - Jiro Kondo
- Department of Materials and Life Sciences, Sophia University, Chiyoda-ku, Tokyo 102-8554, Japan
| | - Motohiko Kato
- Center for Diagnostic and Therapeutic Endoscopy, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Akira Nishiyama
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa 761-0793, Japan
| | - Naohisa Yahagi
- Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Kyuichi Kadota
- Molecular Oncologic Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kita-gun 761-0793, Kagawa, Japan
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3
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Xu R, Zhang K, Ge N, Sun S. EUS-guided interventional therapies for pancreatic diseases. Front Med (Lausanne) 2024; 10:1329676. [PMID: 38259846 PMCID: PMC10801084 DOI: 10.3389/fmed.2023.1329676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Accepted: 12/26/2023] [Indexed: 01/24/2024] Open
Abstract
Endoscopic ultrasound (EUS) is an integrated diagnostic technique merging endoscope and ultrasound to examine the digestive system. EUS has emerged as a primary diagnostic method for pancreatic diseases due to its distinctive benefits. Over the past four decades, EUS has undergone a transformation, shifting its role from primarily diagnostic to increasingly therapeutic. Additionally, in recent years, EUS has emerged as an increasingly prominent adjunctive or alternative approach to conventional surgical interventions. This review provides a comprehensive analysis of current technological approaches in the treatment of pancreatic diseases. The dynamic interplay with diverse therapeutic approaches has reinvigorated EUS and shaped its trajectory in the management of pancreatic diseases.
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Affiliation(s)
| | | | | | - Siyu Sun
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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Nakai Y. Endoscopic Ultrasound-Guided Antitumor Therapy. Gastrointest Endosc Clin N Am 2024; 34:79-89. [PMID: 37973232 DOI: 10.1016/j.giec.2023.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2023]
Abstract
Endoscopic ultrasound (EUS) has been used for various interventions to manage intra-abdominal lesions. EUS-guided antitumor therapy via delivery of chemotherapeutic agents, energy, and radioactive seeds has advantages of less invasiveness than surgical approaches, and the anatomic proximity allows easy and accurate access to the pancreas. The feasibility of EUS-guided antitumor therapy has been reported both in pancreatic solid and cystic neoplasms, with promising preliminary results. Randomized controlled trials are mandatory to further confirm its role.
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Affiliation(s)
- Yousuke Nakai
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Endoscopy and Endoscopic Surgery, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
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5
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Ye J, Suizu F, Yamakawa K, Mukai Y, Kato M, Yoneyama H, Yahagi N, Matsuda Y. Silencing of tumoral carbohydrate sulfotransferase 15 reactivates lymph node pancreatic cancer T cells in mice. Eur J Immunol 2023; 53:e2250160. [PMID: 37248998 DOI: 10.1002/eji.202250160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 05/16/2023] [Accepted: 05/17/2023] [Indexed: 05/31/2023]
Abstract
Limited intratumoral T-cell infiltration in pancreatic ductal adenocarcinoma (PDAC) is an obstacle to immunotherapy, yet the efficient approach to enhance tumor-infiltrating T cells is not fully established. Here, we show that tumor-specific knockdown of carbohydrate sulfotransferase 15 (CHST15), a tumor stromal proteoglycan-synthetic enzyme, suppresses tumor growth in a T-cell-dependent manner in a murine model of PDAC. Silencing of tumoral CHST15 unexpectedly expanded CD4+ and CD8+ T cells in tumor draining LN (TDLN), leading to accelerated accumulation of EdU+ proliferating CD4+ and CD8+ T cells and granzyme B+ CD8+ T cells in the tumor. RNA expression analysis indicated that tumoral CHST15 knockdown (KD) downregulated matrix remodeling-related genes, while upregulated anti-tumor T-cell activity-related genes in both tumor and TDLN. CHST15 KD significantly diminished intratumoral and TDLN Ly6C/G+ myeloid-derived suppressor cells prior to TDLN T-cell expansion, suggesting that tumoral CHST15 remotely regulated myeloid-derived suppressor cell mediated T-cell suppression in the TDLN. Our findings illustrate a novel immunotherapeutic potential of tumoral CHST15 blockage by reactivating T cells in immune suppressive TDLN of PDAC.
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Affiliation(s)
- Juanjuan Ye
- Oncology Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Futoshi Suizu
- Oncology Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Keiko Yamakawa
- Oncology Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Yuri Mukai
- Oncology Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Motohiko Kato
- Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Tokyo, Japan
| | | | - Naohisa Yahagi
- Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Tokyo, Japan
| | - Yoko Matsuda
- Oncology Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kagawa, Japan
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Schepis T, De Lucia SS, Pellegrino A, del Gaudio A, Maresca R, Coppola G, Chiappetta MF, Gasbarrini A, Franceschi F, Candelli M, Nista EC. State-of-the-Art and Upcoming Innovations in Pancreatic Cancer Care: A Step Forward to Precision Medicine. Cancers (Basel) 2023; 15:3423. [PMID: 37444534 PMCID: PMC10341055 DOI: 10.3390/cancers15133423] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 06/20/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
Pancreatic cancer remains a social and medical burden despite the tremendous advances that medicine has made in the last two decades. The incidence of pancreatic cancer is increasing, and it continues to be associated with high mortality and morbidity rates. The difficulty of early diagnosis (the lack of specific symptoms and biomarkers at early stages), the aggressiveness of the disease, and its resistance to systemic therapies are the main factors for the poor prognosis of pancreatic cancer. The only curative treatment for pancreatic cancer is surgery, but the vast majority of patients with pancreatic cancer have advanced disease at the time of diagnosis. Pancreatic surgery is among the most challenging surgical procedures, but recent improvements in surgical techniques, careful patient selection, and the availability of minimally invasive techniques (e.g., robotic surgery) have dramatically reduced the morbidity and mortality associated with pancreatic surgery. Patients who are not candidates for surgery may benefit from locoregional and systemic therapy. In some cases (e.g., patients for whom marginal resection is feasible), systemic therapy may be considered a bridge to surgery to allow downstaging of the cancer; in other cases (e.g., metastatic disease), systemic therapy is considered the standard approach with the goal of prolonging patient survival. The complexity of patients with pancreatic cancer requires a personalized and multidisciplinary approach to choose the best treatment for each clinical situation. The aim of this article is to provide a literature review of the available treatments for the different stages of pancreatic cancer.
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Affiliation(s)
- Tommaso Schepis
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy; (T.S.); (S.S.D.L.); (A.P.); (A.d.G.); (R.M.); (G.C.); (A.G.)
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
| | - Sara Sofia De Lucia
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy; (T.S.); (S.S.D.L.); (A.P.); (A.d.G.); (R.M.); (G.C.); (A.G.)
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
| | - Antonio Pellegrino
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy; (T.S.); (S.S.D.L.); (A.P.); (A.d.G.); (R.M.); (G.C.); (A.G.)
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
| | - Angelo del Gaudio
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy; (T.S.); (S.S.D.L.); (A.P.); (A.d.G.); (R.M.); (G.C.); (A.G.)
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
| | - Rossella Maresca
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy; (T.S.); (S.S.D.L.); (A.P.); (A.d.G.); (R.M.); (G.C.); (A.G.)
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
| | - Gaetano Coppola
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy; (T.S.); (S.S.D.L.); (A.P.); (A.d.G.); (R.M.); (G.C.); (A.G.)
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
| | - Michele Francesco Chiappetta
- Section of Gastroenterology and Hepatology, Promise, Policlinico Universitario Paolo Giaccone, 90127 Palermo, Italy;
- IBD-Unit, Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy
| | - Antonio Gasbarrini
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy; (T.S.); (S.S.D.L.); (A.P.); (A.d.G.); (R.M.); (G.C.); (A.G.)
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
| | - Francesco Franceschi
- Department of Emergency Anesthesiological and Reanimation Sciences, Fondazione Universitaria Policlinico Agostino Gemelli di Roma, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy; (F.F.); (M.C.)
| | - Marcello Candelli
- Department of Emergency Anesthesiological and Reanimation Sciences, Fondazione Universitaria Policlinico Agostino Gemelli di Roma, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy; (F.F.); (M.C.)
| | - Enrico Celestino Nista
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy; (T.S.); (S.S.D.L.); (A.P.); (A.d.G.); (R.M.); (G.C.); (A.G.)
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
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7
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Willink CY, Jenniskens SFM, Klaassen NJM, Stommel MWJ, Nijsen JFW. Intratumoral injection therapies for locally advanced pancreatic cancer: systematic review. BJS Open 2023; 7:zrad052. [PMID: 37254902 PMCID: PMC10230443 DOI: 10.1093/bjsopen/zrad052] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 03/03/2023] [Accepted: 04/05/2023] [Indexed: 06/01/2023] Open
Abstract
INTRODUCTION Pancreatic cancer has one of the worst prognoses of all cancers. Patients with locally advanced pancreatic cancer have a 12.7-20.2 per cent chance of receiving curative surgery after induction systemic chemotherapy. Intratumoral injection therapies have been studied as complementary treatment options for improved local tumour control. The aim of this systematic review was to provide an overview of intratumoral injection therapies, their safety, and oncological outcome in patients with locally advanced pancreatic cancer. METHODS A literature search was conducted in PubMed, Embase and the Cochrane Library for articles written in English up to 28 November 2022. All study designs involving at least five patients with locally advanced pancreatic cancer who were treated with an intratumoral injection therapy were included. Critical appraisal of the included studies was performed using the Newcastle-Ottawa scale. RESULTS After evaluation of the 1680 articles yielded by the systematic search, 52 studies treating 1843 patients were included. Included intratumoral injection treatment modalities comprised iodine-125 (125I) seed brachytherapy (32 studies, 1283 patients), phosphorus-32 (32P) microbrachytherapy (5 studies, 133 patients), palladium-103 (103Pd) seed brachytherapy (2 studies, 26 patients), immunotherapy (9 studies, 330 patients), and chemotherapy (4 studies, 71 patients). Overall survival ranged between 7.0 and 16.0 months for 125I, 5.2 and 15.5 months for 32P, 6.9 and 10.0 months for 103Pd, 5.8 and 13.8 months for immunotherapy, and 9.0 and 16.2 months for chemotherapy. Severe complication (greater than or equal to grade III complications using Clavien-Dindo classification) rates were 6.2 per cent for 125I, 49.2 per cent for 32P, 15 per cent for 103Pd, 57.9 per cent for immunotherapy, and 0 per cent for chemotherapy. CONCLUSION Five intratumoral injection therapies are described and an overview is reported. Some intratumoral injection therapies for patients with locally advanced pancreatic cancer seem safe, although 32P microbrachytherapy and immunotherapy require additional evidence. Currently available data are insufficient to provide firm conclusions regarding the added value to survival. The potential advantage of intratumoral injection therapies complementary to conventional care should be studied in well designed RCTs.
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Affiliation(s)
- Coen Ysbrand Willink
- Department of Medical Imaging, Radboud Institute for Health Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands
| | | | - Nienke Johanna Maria Klaassen
- Department of Medical Imaging, Radboud Institute for Health Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Martijn Willem Jan Stommel
- Department of Surgery, Radboud Institute for Health Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Johannes Frank Wilhelmus Nijsen
- Department of Medical Imaging, Radboud Institute for Health Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands
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Wang T, Zhang Y, Wu J, Feng H, Wang R, Yuan H. Association of genetic variants of CircCHST15 with oral squamous cell carcinoma in the Chinese Han population. Head Neck 2023; 45:806-815. [PMID: 36608057 DOI: 10.1002/hed.27293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 11/22/2022] [Accepted: 12/21/2022] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Oral squamous cell carcinoma (OSCC) is the most common cancer in the oral cavity. The relationship between the genetic susceptibility of circCHST15 and OSCC remains unclear. METHODS Genetic variants of circCHST15 were screened using a genotyping analysis from 1044 patients with OSCC and 3199 healthy participants. The circCHST15 expression was detected in 32 pairs of OSCC tissues. The circular RNA quantitative trait locus analysis and the reporter gene assay were performed for verification. RESULTS The circCHST15 expression was upregulated in OSCC (Wilcoxon p < 1e-3). The genotyping analysis screened out 61 loci in circCHST15 associated with the risk of OSCC. After adjustment and annotation, rs28707473 (A > C, odds ratio = 1.21, 95% CI: 1.076-1.361, p = 1.453e-3) was selected. This genetic variation could elevate the circCHST15 expression level possibly by altering the structure of circular RNAs and affecting transcription factor binding. CONCLUSIONS The results of this study suggested that genetic variants of circCHST15 may contribute to OSCC susceptibility.
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Affiliation(s)
- Tianxiao Wang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China
| | - Yehao Zhang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China
| | - Jia Wu
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China
| | - Hongjie Feng
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China
| | - Ruixia Wang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China
| | - Hua Yuan
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
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Liu J, Mroczek M, Mach A, Stępień M, Aplas A, Pronobis-Szczylik B, Bukowski S, Mielczarek M, Gajewska E, Topolski P, Król ZJ, Szyda J, Dobosz P. Genetics, Genomics and Emerging Molecular Therapies of Pancreatic Cancer. Cancers (Basel) 2023; 15:779. [PMID: 36765737 PMCID: PMC9913594 DOI: 10.3390/cancers15030779] [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: 11/22/2022] [Revised: 01/14/2023] [Accepted: 01/18/2023] [Indexed: 02/01/2023] Open
Abstract
The number of cases of pancreatic cancers in 2019 in Poland was 3852 (approx. 2% of all cancers). The course of the disease is very fast, and the average survival time from the diagnosis is 6 months. Only <2% of patients live for 5 years from the diagnosis, 8% live for 2 years, and almost half live for only about 3 months. A family predisposition to pancreatic cancer occurs in about 10% of cases. Several oncogenes in which somatic changes lead to the development of tumours, including genes BRCA1/2 and PALB2, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1, are involved in pancreatic cancer. Between 4% and 10% of individuals with pancreatic cancer will have a mutation in one of these genes. Six percent of patients with pancreatic cancer have NTRK pathogenic fusion. The pathogenesis of pancreatic cancer can in many cases be characterised by homologous recombination deficiency (HRD)-cell inability to effectively repair DNA. It is estimated that from 24% to as many as 44% of pancreatic cancers show HRD. The most common cause of HRD are inactivating mutations in the genes regulating this DNA repair system, mainly BRCA1 and BRCA2, but also PALB2, RAD51C and several dozen others.
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Affiliation(s)
- Jakub Liu
- Biostatistics Group, Wroclaw University of Environmental and Life Sciences, 51-631 Wroclaw, Poland
| | - Magdalena Mroczek
- Centre for Cardiovascular Genetics and Gene Diagnostics, Foundation for People with Rare Diseases, Wagistrasse 25, 8952 Schlieren, Switzerland
| | - Anna Mach
- Department of Psychiatry, Medical University of Warsaw, 00-665 Warsaw, Poland
- Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw, 02-507 Warsaw, Poland
| | - Maria Stępień
- Department of Infectious Diseases, Doctoral School, Medical University of Lublin, 20-059 Lublin, Poland
| | - Angelika Aplas
- Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw, 02-507 Warsaw, Poland
| | - Bartosz Pronobis-Szczylik
- Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw, 02-507 Warsaw, Poland
| | - Szymon Bukowski
- Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw, 02-507 Warsaw, Poland
| | - Magda Mielczarek
- Biostatistics Group, Wroclaw University of Environmental and Life Sciences, 51-631 Wroclaw, Poland
- National Research Institute of Animal Production, Krakowska 1, 32-083 Balice, Poland
| | - Ewelina Gajewska
- Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw, 02-507 Warsaw, Poland
| | - Piotr Topolski
- Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw, 02-507 Warsaw, Poland
| | - Zbigniew J. Król
- Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw, 02-507 Warsaw, Poland
| | - Joanna Szyda
- Biostatistics Group, Wroclaw University of Environmental and Life Sciences, 51-631 Wroclaw, Poland
- National Research Institute of Animal Production, Krakowska 1, 32-083 Balice, Poland
| | - Paula Dobosz
- Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw, 02-507 Warsaw, Poland
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10
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Fujisawa T, Tsuchiya T, Kato M, Mizuide M, Takakura K, Nishimura M, Kutsumi H, Matsuda Y, Arai T, Ryozawa S, Itoi T, Isayama H, Saya H, Yahagi N. STNM01, the RNA oligonucleotide targeting carbohydrate sulfotransferase 15, as second-line therapy for chemotherapy-refractory patients with unresectable pancreatic cancer: An open label, phase I/IIa trial. EClinicalMedicine 2023; 55:101731. [PMID: 36425867 PMCID: PMC9678806 DOI: 10.1016/j.eclinm.2022.101731] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 10/16/2022] [Accepted: 10/18/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND The impact of stroma-targeting therapy on tumor immune suppression is largely unexplored. An RNA oligonucleotide, STNM01, has been shown to repress carbohydrate sulfotransferase 15 (CHST15) responsible for tumor proteoglycan synthesis and matrix remodeling. This phase I/IIa study aimed to evaluate the safety and efficacy of STNM01 in patients with unresectable pancreatic ductal adenocarcinoma (PDAC). METHODS This was an open-label, dose-escalation study of STNM01 as second-line therapy in gemcitabine plus nab-paclitaxel-refractory PDAC. A cycle comprised three 2-weekly endoscopic ultrasound-guided locoregional injections of STNM01 at doses of 250, 1,000, 2,500, or 10,000 nM in combination with S-1 (80-120 mg twice a day for 14 days every 3 weeks). The primary outcome was the incidence of dose-liming toxicity (DLT). The secondary outcomes included overall survival (OS), tumor response, changes in tumor microenvironment on immunohistopathology, and safety (jRCT2031190055). FINDINGS A total of 22 patients were enrolled, and 3 cycles were repeated at maximum; no DLT was observed. The median OS was 7.8 months. The disease control rate was 77.3%; 1 patient showed complete disappearance of visible lesions in the pancreas and tumor-draining lymph nodes. Higher tumoral CHST15 expression was associated with poor CD3+ and CD8+ T cell infiltration at baseline. STNM01 led to a significant reduction in CHST15, and increased tumor-infiltrating CD3+ and CD8+ T cells in combination with S-1 at the end of cycle 1. Higher fold increase in CD3+ T cells correlated with longer OS. There were 8 grade 3 adverse events. INTERPRETATION Locoregional injection of STNM01 was well tolerated in patients with unresectable PDAC as combined second-line therapy. It prolonged survival by enhancing T cell infiltration in tumor microenvironment. FUNDING The present study was supported by the Japan Agency for Medical Research and Development (AMED).
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Key Words
- 5-FU, fluorouracil
- AMED, Japan Agency for Medical Research and Development
- CHST15, carbohydrate sulfotransferase 15
- CI, confidence interval
- CS-E, chondroitin sulfate E
- CTCAE, Common Terminology Criteria for Adverse Events
- Carbohydrate sulfotransferase 15 (CHST15)
- DCR, disease control rate
- DLT, dose-liming toxicity
- ECM, extracellular matrix
- EMT, epithelial mesenchymal transition
- EUS-FNI, endoscopic ultrasound-guided fine needle injection
- Endoscopic ultrasound-guided fine needle injection
- FAS, full analysis set
- GM-CSF, Granulocyte-macrophage colony-stimulating factor
- IQR, interquartile range
- IRB, Institutional Review Board
- LV, leucovorin
- MTD, maximum tolerated dose
- OS, overall survival
- PDAC, pancreatic ductal adenocarcinoma
- PFS, progression free survival
- STNM01
- TEAE, treatment emergent adverse event
- TGF, transforming growth factor
- Tumor-infiltrating CD3+ and CD8+ T cells
- Unresectable pancreatic cancer
- nal-IRI, nanoliposomal irinotecan
- sCD44v6, soluble CD44 variant 6
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Affiliation(s)
- Toshio Fujisawa
- Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo, Japan
| | - Takayoshi Tsuchiya
- Department of Gastroenterology and Hepatology, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan
| | - Motohiko Kato
- Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Masafumi Mizuide
- Department of Gastroenterology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan
| | - Kazuki Takakura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan
| | - Makoto Nishimura
- Department of Gastroenterology, Hepatology and Nutrition, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Hiromu Kutsumi
- Center for Clinical Research and Advanced Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Yoko Matsuda
- Oncology Pathology, Department of Pathology and Host-Defense, Kagawa University, Takamastu, Kagawa, Japan
| | - Tomio Arai
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi-ku, Tokyo, Japan
| | - Shomei Ryozawa
- Department of Gastroenterology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan
| | - Takao Itoi
- Department of Gastroenterology and Hepatology, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan
| | - Hiroyuki Isayama
- Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo, Japan
| | - Hideyuki Saya
- Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Naohisa Yahagi
- Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
- Corresponding author. Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Shinjuku-ku, Tokyo, 160-8542, Japan.
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11
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Taniguchi H, Suzuki Y, Imai K, Adachi Y. Antitumoral RNA-targeted oligonucleotide therapeutics: The third pillar after small molecule inhibitors and antibodies. Cancer Sci 2022; 113:2952-2961. [PMID: 35701833 PMCID: PMC9459246 DOI: 10.1111/cas.15461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 05/17/2022] [Accepted: 06/07/2022] [Indexed: 12/01/2022] Open
Abstract
Oligonucleotide therapeutics, drugs consisting of 10-50 nucleotide-long single- or double-stranded DNA or RNA molecules that can bind to specific DNA or RNA sequences or proteins, include antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNAs (miRNAs), aptamers, and decoys. These oligonucleotide therapeutics could potentially become the third pillar of drug development. In particular, ASOs and siRNAs are advanced tools that are widely used to silence gene expression. They are used in clinical trials, as they have high specificity for target mRNAs and non-coding RNAs and limited toxicity. However, their clinical application remains challenging. Although chemotherapy has benefits, it has severe adverse effects in many patients. Therefore, new modalities for targeted molecular therapy against tumors, including oligonucleotide therapeutics, are required, and they should be compatible with diagnosis using next-generation sequencing. This review provides an overview of the therapeutic uses of ASOs, siRNAs, and miRNAs in clinical studies on malignant tumors. Understanding previous research and development will help in developing novel oligonucleotide therapeutics against malignant tumors.
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Affiliation(s)
- Hiroaki Taniguchi
- Keio Cancer CenterKeio University School of MedicineTokyoJapan
- Innovation Center of NanoMedicineKawasaki Institute of Industrial PromotionKawasakiJapan
| | - Yasunori Suzuki
- Keio Cancer CenterKeio University School of MedicineTokyoJapan
| | - Kohzoh Imai
- Institute for Genetic MedicineHokkaido UniversitySapporoJapan
| | - Yasushi Adachi
- Department of Gastroenterology and HepatologySapporo Medical University School of MedicineSapporoJapan
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12
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Kaur J, Jaruvongvanich V, Chandrasekhara V. Endoscopic ultrasound-guided injectable therapy for pancreatic cancer: A systematic review. World J Gastroenterol 2022; 28:2383-2395. [PMID: 35800184 PMCID: PMC9185216 DOI: 10.3748/wjg.v28.i21.2383] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/18/2022] [Accepted: 04/22/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Given the low survival rate in pancreatic cancer, new therapeutic techniques have been explored, especially for unresectable or borderline resectable disease. Endoscopic ultrasound (EUS) provides real-time imaging and minimally invasive access for local and targeted injection of anti-tumor agents directly into the pancreatic tumor. Limited studies have been reported using this technique for the treatment of pancreatic ductal adenocarcinoma (PDAC). AIM To evaluate the progress made with EUS-guided injectable therapies in the treatment of PDAC. METHODS All original articles published in English until July 15, 2021, were retrieved via a library-assisted literature search from Ovid Evidence-Based Medicine Reviews and Scopus databases. Reference lists were reviewed to identify additional relevant articles. Prospective clinical studies evaluating the use of EUS-guided injectable therapies in PDAC were included. Studies primarily directed at non-EUS injectable therapies and other malignancies were excluded. Retrieved manuscripts were reviewed descriptively with on critical appraisal of published studies based on their methods and outcome measures such as safety, feasibility, and effectiveness in terms of tumor response and survival. Heterogeneity in data outcomes and therapeutic techniques limited the ability to perform comparative statistical analysis. RESULTS A total of thirteen articles (503 patients) were found eligible for inclusion. The EUS-injectable therapies used were heterogeneous among the studies consisting of immunotherapy (n = 5) in 59 patients, chemotherapy (n = 1) in 36 patients, and viral and other biological therapies (n = 7) in 408 patients. Eleven of the studies reviewed were single armed while two were double armed with one randomized trial and one non-randomized comparative study. Overall, the included studies demonstrated EUS-guided injectable therapies to be safe and feasible with different agents as monotherapy or in conjunction with other modalities. Promising results were also observed regarding their efficacy and survival parameters in patients with PDAC. CONCLUSION EUS-guided injectable therapies, including immunotherapy, chemotherapy, and viral or other biological therapies have shown minimal adverse events and potential efficacy in the treatment of PDAC. Comparative studies, including controlled trials, are required to confirm these results in order to offer novel EUS-based treatment options for patients with PDAC.
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Affiliation(s)
- Jyotroop Kaur
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States
| | | | - Vinay Chandrasekhara
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States
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13
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Wu K, Liu Y, Liu L, Peng Y, Pang H, Sun X, Xia D. Emerging Trends and Research Foci in Tumor Microenvironment of Pancreatic Cancer: A Bibliometric and Visualized Study. Front Oncol 2022; 12:810774. [PMID: 35515122 PMCID: PMC9063039 DOI: 10.3389/fonc.2022.810774] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Accepted: 03/21/2022] [Indexed: 01/07/2023] Open
Abstract
Background Pancreatic cancer (PC) is a serious disease with high mortality. The tumor microenvironment plays a key role in the occurrence and development of PC. The purpose of this study is to analyze trends by year, country, institution, journal, reference and keyword in publications on the PC microenvironment and to predict future research hotspots. Methods The Web of Science Core Collection was used to search for publications. We analyzed the contributions of various countries/regions, institutes, and authors and identified research hotspots and promising future trends using the CiteSpace and VOSviewer programs. We also summarized relevant completed clinical trials. Results A total of 2,155 papers on the PC microenvironment published between 2011 and 2021 were included in the study. The number of publications has increased every year. The average number of citations per article was 32.69. The USA had the most publications, followed by China, and a total of 50 influential articles were identified through co-citation analysis. Clustering analysis revealed two clusters of keywords: basic research and clinical application. The co-occurrence cluster analysis showed glutamine metabolism, carcinoma-associated fibroblasts, oxidative phosphorylation as the highly concerned research topics of basic research in recently. The three latest hot topics in clinical application are liposomes, endoscopic ultrasound and photodynamic therapy. Conclusion The number of publications and research interest have generally increased, and the USA has made prominent contributions to the study of the tumor microenvironment of PC. The current research hotspots mainly focus on energy metabolism in the hypoxic tumor microenvironment, cancer associated fibroblasts in regulating the tumor microenvironment, accurate diagnosis, drug delivery and new treatments.
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Affiliation(s)
- Kaiwen Wu
- Department of Gastroenterology, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, China.,Southwest Jiaotong University College of Medicine, Southwest Jiaotong University Affiliated Chengdu Third People's Hospital, Chengdu, China
| | - Ye Liu
- Naval Medical University, Shanghai, China
| | - Lei Liu
- Medical Research Center, Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, China
| | - Yunlan Peng
- Southwest Jiaotong University College of Medicine, Southwest Jiaotong University Affiliated Chengdu Third People's Hospital, Chengdu, China
| | - Honglin Pang
- Southwest Jiaotong University College of Medicine, Southwest Jiaotong University Affiliated Chengdu Third People's Hospital, Chengdu, China
| | - Xiaobin Sun
- Department of Gastroenterology, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, China
| | - Demeng Xia
- Luodian Clinical Drug Research Center, Shanghai Baoshan Luodian Hospital, Shanghai University, Shanghai, China
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14
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Affiliation(s)
- Atsushi Irisawa
- Department of Gastroenterology, Dokkyo Medical University School of Medicine, Tochigi, Japan
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15
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Watanabe I. Properties of Monoclonal Antibodies Recognizing Chondroitin Sulfate E. TRENDS GLYCOSCI GLYC 2022. [DOI: 10.4052/tigg.2120.1j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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16
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Watanabe I. Properties of Monoclonal Antibodies Recognizing Chondroitin Sulfate E. TRENDS GLYCOSCI GLYC 2022. [DOI: 10.4052/tigg.2120.1e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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17
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Dhar J, Samanta J. Role of therapeutic endoscopic ultrasound in gastrointestinal malignancy- current evidence and future directions. Clin J Gastroenterol 2022; 15:11-29. [PMID: 35028906 DOI: 10.1007/s12328-021-01559-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 11/11/2021] [Indexed: 12/31/2022]
Abstract
Endoscopic ultrasound (EUS) has come a long way from a mere diagnostic tool to an advanced therapeutic modality. With the advent of better technologies and accessories, EUS has found ground in the management of gastrointestinal (GI) malignancies, not only for diagnosis but also for therapeutic purposes. EUS can tackle a host of conditions, including hepato-pancreatico-biliary malignancies. Advances and experience in various EUS-guided biliary drainage techniques have enabled the endosonologist to tackle biliary obstruction when conventional techniques of endoscopic retrograde cholangiopancreatography (ERCP) and/or percutaneous transhepatic biliary drainage (PTBD) fails. More and more emerging data not only establishes the safety of EUS-BD but also demonstrates superior efficacy over PTBD and sometimes even ERCP. Malignant gastric outlet obstruction can now be safely managed with EUS-guided gastroenterostomy. Starting from pain management in malignant tumors through celiac plexus neurolysis to various tumor ablative therapies, EUS has forged ahead over percutaneous treatment or surgical options in the management of GI malignancies. Additional data is now coming up on the prospects of EUS-guided immunotherapy and biological therapy for tumor management. The future of EUS therapeutics in the field of GI malignancies is bright. With increasing evidence, this modality becoming a key player in management of a host of complex clinical conditions arising out of GI malignancies is in the offing. This review focuses on elucidating the role of therapeutic EUS in the management of GI malignancies, a synopsis of various techniques, data on its safety and efficacy as well as future advancements in this domain.
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Affiliation(s)
- Jahnvi Dhar
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Jayanta Samanta
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.
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18
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Sbeit W, Napoléon B, Khoury T. Endoscopic ultrasound role in pancreatic adenocarcinoma treatment: A review focusing on technical success, safety and efficacy. World J Gastroenterol 2022; 28:332-347. [PMID: 35110953 PMCID: PMC8771609 DOI: 10.3748/wjg.v28.i3.332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 11/22/2021] [Accepted: 01/06/2022] [Indexed: 02/06/2023] Open
Abstract
The impressive technological advances in recent years have rapidly translated into the shift of endoscopic ultrasound (EUS) from diagnostic modality into an interventional and therapeutic tool. Despite the great advance in its diagnosis, the majority of pancreatic adenocarcinoma cases are inoperable when diagnosed, thus demanding alternative optional therapies. EUS has emerged as an easy, minimally invasive modality targeting this carcinoma with different interventions that have been reported recently. In this review we summarize the evolving role of interventional therapeutic EUS in pancreatic adenocarcinoma management.
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Affiliation(s)
- Wisam Sbeit
- Department of Gastroenterology, Galilee Medical Center, Faculty of Medicine in the Galilee, Bar-Ilan University, Nahariya 2221006, Israel
| | - Bertrand Napoléon
- Department of Endoscopy Unit, Private Hospital Jean Mermoz, Ramsay Generale de Sante, Lyon 69008, France
| | - Tawfik Khoury
- Department of Gastroenterology, Galilee Medical Center, Faculty of Medicine in the Galilee, Bar-Ilan University, Nahariya 2221006, Israel
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19
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Gui CP, Liao B, Luo CG, Chen YH, Tan L, Tang YM, Li JY, Hou Y, Song HD, Lin HS, Xu QH, Yao GS, Yao HH, Xi-Liu, Luo JH, Cao JZ, Wei JH. circCHST15 is a novel prognostic biomarker that promotes clear cell renal cell carcinoma cell proliferation and metastasis through the miR-125a-5p/EIF4EBP1 axis. Mol Cancer 2021; 20:169. [PMID: 34922539 PMCID: PMC8684108 DOI: 10.1186/s12943-021-01449-w] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 09/14/2021] [Indexed: 12/22/2022] Open
Abstract
Background Circular RNAs (circRNAs) have been indicated as potentially critical mediators in various types of tumor progression, generally acting as microRNA (miRNA) sponges to regulate downstream gene expression. However, the aberrant expression profile and dysfunction of circRNAs in human clear cell renal cell carcinoma (ccRCC) need to be further investigated. This study mined key prognostic circRNAs and elucidates the potential role and molecular mechanism of circRNAs in regulating the proliferation and metastasis of ccRCC. Methods circCHST15 (hsa_circ_0020303) was identified by mining two circRNA microarrays from the Gene Expression Omnibus database and comparing matched tumor versus adjacent normal epithelial tissue pairs or matched primary versus metastatic tumor tissue pairs. These results were validated by quantitative real-time polymerase chain reaction and agarose gel electrophoresis. We demonstrated the biological effect of circCHST15 in ccRCC both in vitro and in vivo. To test the interaction between circCHST15 and miRNAs, we conducted a number of experiments, including RNA pull down assay, dual-luciferase reporter assay and fluorescence in situ hybridization. Results The expression of circCHST15 was higher in ccRCC tissues compared to healthy adjacent kidney tissue and higher in RCC cell lines compared to normal kidney cell lines. The level of circCHST15 was positively correlated with aggressive clinicopathological characteristics, and circCHST15 served as an independent prognostic indicator for overall survival and progression-free survival in patients with ccRCC after surgical resection. Our in vivo and in vitro data indicate that circCHST15 promotes the proliferation, migration, and invasion of ccRCC cells. Mechanistically, we found that circCHST15 directly interacts with miR-125a-5p and acts as a microRNA sponge to regulate EIF4EBP1 expression. Conclusions We found that sponging of miR-125a-5p to promote EIF4EBP1 expression is the underlying mechanism of hsa_circ_0020303-induced ccRCC progression. This prompts further investigation of circCHST15 as a potential prognostic biomarker and therapeutic target for ccRCC. Supplementary Information The online version contains supplementary material available at 10.1186/s12943-021-01449-w.
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20
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Bratanic A, Bozic D, Mestrovic A, Martinovic D, Kumric M, Ticinovic Kurir T, Bozic J. Role of endoscopic ultrasound in anticancer therapy: Current evidence and future perspectives. World J Gastrointest Oncol 2021; 13:1863-1879. [PMID: 35070030 PMCID: PMC8713319 DOI: 10.4251/wjgo.v13.i12.1863] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/17/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023] Open
Abstract
The digestive system is one of the most common sites of malignancies in humans. Since gastrointestinal tumors represent a massive global health burden both in terms of morbidity and health care expenditures, scientists continuously develop novel diagnostic and therapeutic methods to ameliorate the detrimental effects of this group of diseases. Apart from the well-established role of the endoscopic ultrasound (EUS) in the diagnostic course of gastrointestinal and hepatobiliary malignancies, we have recently become acquainted with a vast array of its therapeutic possibilities. A multitude of previously established, evidence-based methods that might now be guided by the EUS emerged: Radiofrequency ablation, brachytherapy, fine needle injection, celiac plexus neurolysis, and endoscopic submucosal dissection. In this review we endeavored to provide a comprehensive overview of the role of these methods in different malignancies of the digestive system, primarily in the treatment and symptom control in pancreatic cancer, and additionally in the management of hepatic, gastrointestinal tumors, and pancreatic cysts.
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Affiliation(s)
- Andre Bratanic
- Department of Gastroenterology and Hepatology, University Hospital of Split, Split 21000, Croatia
| | - Dorotea Bozic
- Department of Gastroenterology and Hepatology, University Hospital of Split, Split 21000, Croatia
| | - Antonio Mestrovic
- Department of Gastroenterology and Hepatology, University Hospital of Split, Split 21000, Croatia
| | - Dinko Martinovic
- Department of Pathophysiology, University of Split School of Medicine, Split 21000, Croatia
| | - Marko Kumric
- Department of Pathophysiology, University of Split School of Medicine, Split 21000, Croatia
| | - Tina Ticinovic Kurir
- Department of Pathophysiology, University of Split School of Medicine, Split 21000, Croatia
- Department of Endocrinology, University Hospital of Split, Split 21000, Croatia
| | - Josko Bozic
- Department of Pathophysiology, University of Split School of Medicine, Split 21000, Croatia
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21
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Larghi A, Rimbaș M, Rizzatti G, Carbone C, Gasbarrini A, Costamagna G, Alfieri S, Tortora G. Endoscopic ultrasound-guided therapies for pancreatic solid tumors: An overview. Semin Oncol 2021; 48:95-105. [PMID: 33608132 DOI: 10.1053/j.seminoncol.2021.01.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 01/16/2021] [Indexed: 12/14/2022]
Abstract
The close proximity of the endoscopic ultrasound (EUS) probe to the pancreas, coupled with the ease with which a needle can be inserted into a pancreatic lesion, have contributed to the development of EUS-guided therapies for both adenocarcinoma and neuroendocrine pancreatic neoplasms. EUS-guided fine needle injection of different types of drugs, implantation of fiducial markers to facilitate stereotactic body radiation therapy or of radioactive seeds to perform brachytherapy, and the use of different thermal and nonthermal ablation devices and techniques have all been tested in preliminary human studies. This manuscript will present the available evidence accumulated thus far in the field of EUS-guided oncological treatment of pancreatic solid tumors, along with a look into possible future applications.
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Affiliation(s)
- Alberto Larghi
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy.
| | - Mihai Rimbaș
- Gastroenterology Department, Colentina Clinical Hospital, Carol Davila University of Medicine, Bucharest, Romania
| | - Gianenrico Rizzatti
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy; Gastroenterology Division, Fondazione Policlinico Universitario A. Gemelli, Catholic University, IRCCS, Rome, Italy
| | - Carmine Carbone
- Oncological Division, Fondazione Policlinico Universitario A. Gemelli, Catholic University, IRCCS, Rome, Italy
| | - Antonio Gasbarrini
- Gastroenterology Division, Fondazione Policlinico Universitario A. Gemelli, Catholic University, IRCCS, Rome, Italy
| | - Guido Costamagna
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Catholic University, Rome, Italy; IHU-USIAS, University of Strasbourg, Strasbourg, France
| | - Sergio Alfieri
- Digestive Surgery, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Catholic University, Rome, Italy
| | - Giampaolo Tortora
- Oncological Division, Fondazione Policlinico Universitario A. Gemelli, Catholic University, IRCCS, Rome, Italy
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22
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Nakai Y, Chang KJ. EUS-guided fine-needle injection for pancreatic cancer: back to the future. Gastrointest Endosc 2020; 92:1053-1054. [PMID: 33160487 DOI: 10.1016/j.gie.2020.06.025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 06/05/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Yousuke Nakai
- Department of Endoscopy and Endoscopic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kenneth J Chang
- Division of Gastroenterology and Hepatology, H. H. Chao Comprehensive Digestive Disease Center, University of California, Irvine Medical Center, Orange, California, USA
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23
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Wang X, Cheng G, Zhang T, Deng L, Xu K, Xu X, Wang W, Zhou Z, Feng Q, Chen D, Bi N, Wang L. CHST15 promotes the proliferation of TE‑1 cells via multiple pathways in esophageal cancer. Oncol Rep 2019; 43:75-86. [PMID: 31746400 PMCID: PMC6908928 DOI: 10.3892/or.2019.7395] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 10/04/2019] [Indexed: 02/06/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a common type of esophageal cancer and is prevalent worldwide. Understanding the mechanisms underlying its formation and the search for more effective therapeutic strategies are critical due to the occurrence of chemotherapeutic drug resistance. The aim of the present study was to determine the functional relevance and therapeutic potential of carbohydrate sulfotransferase 15 (CHST15) in ESCC. CHST15 levels were measured in different ESCC cell lines and evaluated in ESCC tissues using tissue chip immunohistochemistry. Cell growth and apoptosis assays, 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide assays, and clonogenic assays were conducted using TE‑1 cells and lenti‑shCHST15 virus constructs were used to investigate the function of CHST15 in cell proliferation and apoptosis. mRNA microarray analysis was performed to determine the underlying mechanism of CHST15 regulation in TE‑1 cell proliferation and apoptosis. The results showed that knockdown of CHST15 inhibited TE‑1 cell growth and proliferation, but induced cell apoptosis. CHST15 was more frequently detected in ESCC tissue compared with that in normal esophageal tissue. Microarray data analysis indicated that the inhibition of cell proliferation and activation of cell apoptosis in CHST15‑knockdown cells may be caused by altered CHST15/ILKAP/CCND1 and CHST15/RABL6/PMAIP1 signaling axes, respectively.
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Affiliation(s)
- Xin Wang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Guowei Cheng
- Department of Radiotherapy, Huanxing Tumor Hospital, Beijing 100023, P.R. China
| | - Tao Zhang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Lei Deng
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Kunpeng Xu
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Xin Xu
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Wenqing Wang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Zongmei Zhou
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Qinfu Feng
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Dongfu Chen
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Nan Bi
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Luhua Wang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, Guangdong 518116, P.R. China
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Yamakawa K, Nakano-Narusawa Y, Hashimoto N, Yokohira M, Matsuda Y. Development and Clinical Trials of Nucleic Acid Medicines for Pancreatic Cancer Treatment. Int J Mol Sci 2019; 20:ijms20174224. [PMID: 31470511 PMCID: PMC6747711 DOI: 10.3390/ijms20174224] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 08/24/2019] [Accepted: 08/27/2019] [Indexed: 12/22/2022] Open
Abstract
Approximately 30% of pancreatic cancer patients harbor targetable mutations. However, there has been no therapy targeting these molecules clinically. Nucleic acid medicines show high specificity and can target RNAs. Nucleic acid medicine is expected to be the next-generation treatment next to small molecules and antibodies. There are several kinds of nucleic acid drugs, including antisense oligonucleotides, small interfering RNAs, microRNAs, aptamers, decoys, and CpG oligodeoxynucleotides. In this review, we provide an update on current research of nucleic acid-based therapies. Despite the challenging obstacles, we hope that nucleic acid drugs will have a significant impact on the treatment of pancreatic cancer. The combination of genetic diagnosis using next generation sequencing and targeted therapy may provide effective precision medicine for pancreatic cancer patients.
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Affiliation(s)
- Keiko Yamakawa
- Oncology Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Yuko Nakano-Narusawa
- Oncology Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Nozomi Hashimoto
- Oncology Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Masanao Yokohira
- Oncology Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Yoko Matsuda
- Oncology Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
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25
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Matsuda Y, Fujii Y, Matsukawa M, Ishiwata T, Nishimura M, Arai T. Overexpression of carbohydrate sulfotransferase 15 in pancreatic cancer stroma is associated with worse prognosis. Oncol Lett 2019; 18:4100-4105. [PMID: 31516610 PMCID: PMC6732957 DOI: 10.3892/ol.2019.10764] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 07/11/2019] [Indexed: 12/17/2022] Open
Abstract
Carbohydrate sulfotransferase 15 (CHST15) synthesizes matrix proteoglycan that regulates various pathogenic mediators and contributes to tissue remodeling and fibrosis during injury. CHST15 has been reported to promote tumor growth and invasion in various types of cancer. Our previous study reported the safety and efficacy of EUS-guided fine-needle injection (EUS-FNI) of STNM01, a double-stranded RNA oligonucleotide that specifically represses CHST15, for use in patients with pancreatic cancer. The present study aimed to determine the expression and clinicopathological characteristics of CHST15 in pancreatic cancer. Immunohistochemical staining was performed for CHST15 using pancreatic tissues from 64 patients (28 males and 36 females; age, 69.0±9.6 years) with pancreatic cancer who underwent surgery. For the evaluation of fibrosis, two categories were defined (mature and immature), based on the existence of collagen, myxoid stroma and fibroblasts, using hematoxylin and eosin specimens. The positive percentage of CHST15 was quantified, patients were divided into two groups according to high and low CHST15 expression in both the cancer and stroma tissues, and the association between CHST15 expression in cancer cells and the stroma was analyzed. Additionally, the present study analyzed the association between CHST15 expression and clinicopathological information, including overall and disease-free survival. The expression levels of CHST15 were detected in the cytoplasm of pancreatic cancer cells and fibroblasts in the cancer stroma. CHST15 expression in cancer cells was not identified to be associated with overall survival (P=0.52). However, patients with high CHST15 expression in the stroma exhibited worse overall survival compared with patients with low CHST15 expression (P=0.02). CHST15 expression in the stroma exhibited a positive association with that in cancer cells (P=0.01). High CHST15 expression in the stroma group was associated with a higher incidence of immature fibrosis (P=0.02) compared with mature fibrosis. CHST15 expression in cancer cells was associated with Union for International Cancer Control stage (P=0.02) and invasive front. Age and sex were not associated with CHST15 expression. The present study revealed that overexpression of CHST15 in stroma was associated with worse overall survival and immature fibrosis. Overexpression of CHST15 in cancer cells was associated with tumor stage. These results suggested that targeting therapy for CHST15 may be useful for stroma fibroblasts and cancer cells.
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Affiliation(s)
- Yoko Matsuda
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Itabashi, Tokyo 173-0015, Japan.,Oncology Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kita, Kagawa 761-0793, Japan
| | - Yuko Fujii
- Department of Endoscopy, Tokyo Metropolitan Geriatric Hospital, Itabashi, Tokyo 173-0015, Japan
| | - Miho Matsukawa
- Department of Endoscopy, Tokyo Metropolitan Geriatric Hospital, Itabashi, Tokyo 173-0015, Japan
| | - Toshiyuki Ishiwata
- Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi, Tokyo 173-0015, Japan
| | - Makoto Nishimura
- Department of Endoscopy, Tokyo Metropolitan Geriatric Hospital, Itabashi, Tokyo 173-0015, Japan
| | - Tomio Arai
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Itabashi, Tokyo 173-0015, Japan
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26
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Nakai Y, Takahara N, Mizuno S, Kogure H, Koike K. Current Status of Endoscopic Ultrasound Techniques for Pancreatic Neoplasms. Clin Endosc 2019; 52:527-532. [PMID: 31337194 PMCID: PMC6900295 DOI: 10.5946/ce.2019.025] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 02/13/2019] [Indexed: 12/15/2022] Open
Abstract
Endoscopic ultrasound (EUS) now plays an important role in the management of pancreatic neoplasms. There are various types of pancreatic neoplasms, from benign to malignant lesions, and the role of EUS ranges from the imaging diagnosis to treatment. EUS is useful for the detection, characterization, and tissue acquisition of pancreatic lesions. Recent advancement of contrast-enhanced harmonic EUS and elastography enables better characterization of pancreatic lesions. In addition to these enhanced EUS imaging techniques, EUS-guided tissue acquisition is now the standard procedure to establish the pathological diagnosis of pancreatic neoplasms. While these diagnostic roles of EUS have been established, EUS-guided interventions such as ablation and drainage are also increasingly utilized in the management of pancreatic neoplasms. However, most of these EUS-guided interventions are not yet standardized in terms of techniques and devices and thus need further investigations.
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Affiliation(s)
- Yousuke Nakai
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Naminatsu Takahara
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Suguru Mizuno
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hirofumi Kogure
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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27
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Takakura K, Kawamura A, Torisu Y, Koido S, Yahagi N, Saruta M. The Clinical Potential of Oligonucleotide Therapeutics against Pancreatic Cancer. Int J Mol Sci 2019; 20:ijms20133331. [PMID: 31284594 PMCID: PMC6651255 DOI: 10.3390/ijms20133331] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Revised: 07/03/2019] [Accepted: 07/03/2019] [Indexed: 02/07/2023] Open
Abstract
Although many diagnostic and therapeutic modalities for pancreatic cancer have been proposed, an urgent need for improved therapeutic strategies remains. Oligonucleotide therapeutics, such as those based on antisense RNAs, small interfering RNA (siRNA), microRNA (miRNA), aptamers, and decoys, are promising agents against pancreatic cancer, because they can identify a specific mRNA fragment of a given sequence or protein, and interfere with gene expression as molecular-targeted agents. Within the past 25 years, the diversity and feasibility of these drugs as diagnostic or therapeutic tools have dramatically increased. Several clinical and preclinical studies of oligonucleotides have been conducted for patients with pancreatic cancer. To support the discovery of effective diagnostic or therapeutic options using oligonucleotide-based strategies, in the absence of satisfactory therapies for long-term survival and the increasing trend of diseases, we summarize the current clinical trials of oligonucleotide therapeutics for pancreatic cancer patients, with underlying preclinical and scientific data, and focus on the possibility of oligonucleotides for targeting pancreatic cancer in clinical implications.
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Affiliation(s)
- Kazuki Takakura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan.
| | - Atsushi Kawamura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan
| | - Yuichi Torisu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan
| | - Shigeo Koido
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan
| | - Naohisa Yahagi
- Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan
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28
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Nabi Z, Reddy DN. Endoscopic Palliation for Biliary and Pancreatic Malignancies: Recent Advances. Clin Endosc 2019; 52:226-234. [PMID: 30665289 PMCID: PMC6547342 DOI: 10.5946/ce.2019.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Revised: 12/17/2018] [Accepted: 12/17/2018] [Indexed: 02/06/2023] Open
Abstract
Malignancies of the pancreatobiliary system are usually unresectable at the time of diagnosis. As a consequence, a majority of these cases are candidates for palliative care. With advances in chemotherapeutic agents and multidisciplinary care, the survival rate in pancreatobiliary malignancies has improved. Therefore, there is a need to provide an effective and long-lasting palliative care for these patients. Endoscopic palliation is preferred to surgery as the former is associated with equal efficacy and reduced morbidity. The main role of endoscopic palliation in the vast majority of pancreatobiliary malignancies includes biliary and enteral stenting for malignant obstructive jaundice and gastric outlet obstruction, respectively. Recent advances in endoscopic palliation appear promising in imparting long-lasting relief of symptoms. Use of radiofrequency ablation and photodynamic therapy in malignant biliary obstruction has been shown to improve the survival rates as well as the patency of biliary stents. The emergence of endoscopic ultrasound (EUS) as a therapeutic tool has enhanced the capability of minimally invasive palliation in pancreatobiliary cancers. EUS is a valuable alternative to endoscopic retrograde cholangiopancreatography for the palliation of obstructive jaundice. More recently, EUS is emerging as an effective primary modality for biliary and gastric bypass.
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Affiliation(s)
- Zaheer Nabi
- Asian Institute of Gastroenterology, Hyderabad, India
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29
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DeWitt JM, Sandrasegaran K, O'Neil B, House MG, Zyromski NJ, Sehdev A, Perkins SM, Flynn J, McCranor L, Shahda S. Phase 1 study of EUS-guided photodynamic therapy for locally advanced pancreatic cancer. Gastrointest Endosc 2019; 89:390-398. [PMID: 30222972 DOI: 10.1016/j.gie.2018.09.007] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 09/07/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Locally advanced pancreatic cancer (LAPC) has a poor prognosis. There are limited data describing the use of photodynamic therapy (PDT) for pancreatic cancer in humans. We hypothesized that EUS-guided PDT for LAPC is safe, technically feasible, and produces a dose- and time-dependent increasing degree of image-defined tumor necrosis. METHODS In a single-center, prospective, dose-escalation phase 1 study, patients with treatment-naïve LAPC received intravenous porfimer sodium (Concordia Laboratories Inc, St Michael, Barbados) followed 2 days later by EUS-PDT. EUS-PDT was performed by puncture with a 19-gauge needle and insertion of a 1.0-cm light diffuser (Pioneer Optics, Bloomfield, Conn) and illumination with a 630-nm light (Diomed Inc, Andover, Mass). A CT scan 18 days after PDT was done to assess for change in pancreatic necrosis. Nab-paclitaxel (125 mg/ m2 intravenously) and gemcitabine (1000 mg /m2 intravenously) were initiated 7 days after CT and given weekly for 3 of 4 weeks (1 cycle) until disease progression or unacceptable toxicity. RESULTS Twelve patients (mean age, 67 ± 6 years; 8 male) with tumors (mean diameter, 45.2 ± 12.9 mm) in the head and/or neck (8) or body and/or tail (4) underwent EUS-PDT. Compared with baseline imaging, increased volume and percentage of tumor necrosis were observed in 6 of 12 patients (50%) after EUS-PDT. The mean overall increases in volume and percentage necrosis were 10 ± 26 cm3 (P = .20) and 18% ± 22% (P = .016), respectively. After a median follow-up of 10.5 months (range, 1.0-37.4 months), median progression-free (PFS) and overall survival (OS) were 2.6 months (95% confidence interval, 0.7, not estimable) and 11.5 months (95% confidence interval, 1.1, 16.9), respectively. Surgical resection was attempted in 2 patients, and pathology showed a complete response (n = 1) and residual 2-mm tumor (n = 1). There were 8 serious adverse events and none related to EUS or EUS-PDT. CONCLUSION EUS-PDT for LAPC appears to be safe and produces measurable imaged-defined tumor necrosis. Phase 2 studies are warranted. (Clinical trial registration number: NCT01770132.).
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Affiliation(s)
- John M DeWitt
- Department of Gastroenterology, Indiana University Health Medical Center, Indianapolis, Indiana, USA
| | - Kumar Sandrasegaran
- Department of Radiology, Indiana University Health Medical Center, Indianapolis, Indiana, USA
| | - Bert O'Neil
- Department of Oncology, Indiana University Health Medical Center, Indianapolis, Indiana, USA
| | - Michael G House
- Department of Surgery, Indiana University Health Medical Center, Indianapolis, Indiana, USA
| | - Nicholas J Zyromski
- Department of Surgery, Indiana University Health Medical Center, Indianapolis, Indiana, USA
| | - Amikar Sehdev
- Department of Oncology, Indiana University Health Medical Center, Indianapolis, Indiana, USA
| | - Susan M Perkins
- Department of Statistics, Indiana University Health Medical Center, Indianapolis, Indiana, USA
| | - Janet Flynn
- Department of Oncology, Indiana University Health Medical Center, Indianapolis, Indiana, USA
| | - Lynne McCranor
- Department of Oncology, Indiana University Health Medical Center, Indianapolis, Indiana, USA
| | - Safi Shahda
- Department of Oncology, Indiana University Health Medical Center, Indianapolis, Indiana, USA
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