|
1
|
Mavroeidis L, Kalofonou F, Casey R, Napolitano A, Bulusu R, Jones RL. Identifying and managing rare subtypes of gastrointestinal stromal tumors. Expert Rev Gastroenterol Hepatol 2025; 19:549-561. [PMID: 40156874 DOI: 10.1080/17474124.2025.2486304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 02/23/2025] [Accepted: 03/26/2025] [Indexed: 04/01/2025]
Abstract
INTRODUCTION A subset of gastrointestinal stromal tumors (GISTs) lacks the common mutations in KIT/PDGFRa genes. This is a rare and heterogeneous group of challenging GISTs due to their diversity and absence of sensitivity to the tyrosine kinase inhibitor (TKI) imatinib. AREAS COVERED In this manscript, we review the pathogenesis, natural history, diagnostic features and management of KIT/PDGFRa wild-type (WT) GISTs, including SDH-deficient GISTs, GISTs with mutations in the RAS/RAF pathway, and quadruple WT GISTs which lack mutations in either KIT/PDGFRa and SDH genes or components of the RAS/RAF pathway, and syndromic GISTs as well as GISTs with rare KIT/PDGFRa mutations. EXPERT OPINION Patients should be managed in reference centers. There has been progress in the understanding of the biology of these GISTs, and promising therapeutic targets have been identified. In SDH-deficient GISTs, the TKI olverembatinib has shown encouraging clinical activity but requires further clinical validation, while the HIF2a inhibitor bezultifan and temozolomide alone or in combination with the death receptor agonist 5 are under clinical investigation. Targeting the RAS/RAF pathway in RAS/RAF-mutated GISTs warrants evaluation in clinical trials. Rare molecular alterations in quadruple WT GISTs require investigation for their oncogenic potential. Collaborative research and patient advocacy is critical for these extremely rare tumors.
Collapse
Affiliation(s)
- Leonidas Mavroeidis
- Sarcoma Unit, The Royal Marsden Hospital and Institute of Cancer Research, London, UK
- Department of Oncology, Oxford University Hospitals, Oxford, UK
| | - Foteini Kalofonou
- Sarcoma Unit, The Royal Marsden Hospital and Institute of Cancer Research, London, UK
| | - Ruth Casey
- Department of Endocrinology for Ruth Casey and Department of Oncology for Ramesh Bulusu, Cambridge University Hospitals, Cambridge, UK
| | - Andrea Napolitano
- Sarcoma Unit, The Royal Marsden Hospital and Institute of Cancer Research, London, UK
| | - Ramesh Bulusu
- Department of Endocrinology for Ruth Casey and Department of Oncology for Ramesh Bulusu, Cambridge University Hospitals, Cambridge, UK
| | - Robin L Jones
- Sarcoma Unit, The Royal Marsden Hospital and Institute of Cancer Research, London, UK
| |
Collapse
|
|
2
|
Munter S, Sharma A, Antkowiak M, Ranjbarian T, Hosseini M, Sicklick JK. Gastrointestinal Stromal Tumor (GIST) Quiz: Test your knowledge. J Gastrointest Surg 2024:101859. [PMID: 39455050 DOI: 10.1016/j.gassur.2024.10.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 09/29/2024] [Accepted: 10/12/2024] [Indexed: 10/28/2024]
Abstract
Having a strong understanding of the epidemiology, pathophysiology, and clinical management of gastrointestinal stromal tumors (GISTs) is crucial for clinicians who may encounter this cancer. The quiz below is designed for medical students, residents, fellows, and practicing physicians to test their knowledge and review key concepts for understanding GIST.
Collapse
Affiliation(s)
- Sadie Munter
- Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA, United States
| | - Ashwyn Sharma
- Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA, United States
| | - Mark Antkowiak
- Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA, United States
| | - Tannaz Ranjbarian
- Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA, United States
| | - Mojgan Hosseini
- Department of Pathology, University of California San Diego School of Medicine, La Jolla, CA, United States
| | - Jason K Sicklick
- Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA, United States.
| |
Collapse
|
|
3
|
Pereira MM, Couto E, Shamseddine A, Macedo T. Two Decades of Gastrointestinal Stromal Tumor Management With First-Line Treatment: A Case Report. Cureus 2024; 16:e71299. [PMID: 39529789 PMCID: PMC11552204 DOI: 10.7759/cureus.71299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/12/2024] [Indexed: 11/16/2024] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are rare malignant tumors that arise from the connective tissues of the gastrointestinal tract. Reports about GISTs treated with imatinib for over five years are exceedingly rare. In this case report, we present a patient with GIST who remained alive for two decades after undergoing imatinib treatment. We describe a man in his forties with no significant prior medical issues, who presented in 2004 to the emergency department with severe abdominal pain. A computed tomography scan revealed a ruptured intra-abdominal mass. He underwent surgical resection, leading to the diagnosis of jejunal GIST. Following this, he underwent active surveillance until 2007, when the disease recurred. After completing a two-year course of imatinib, no signs of disease were detected, and medical therapy was stopped. However, in 2011, a pelvic recurrence was observed, leading to the re-introduction of imatinib therapy, which was maintained until 2018. A year later, disease progression was noted, prompting the re-initiation of imatinib. Since then, the patient was receiving imatinib therapy with good tolerance, until March of 2024. This case highlights the potential sensitivity of imatinib for a long duration.
Collapse
Affiliation(s)
- Maria M Pereira
- Medical Oncology, Unidade Local de Saúde de Braga, Braga, PRT
- School of Medicine, Universidade do Minho, Braga, PRT
| | - Elisabete Couto
- Medical Oncology, Unidade Local de Saúde de Braga, Braga, PRT
| | - Ali Shamseddine
- Hematology/Oncology Division, American University of Beirut Medical Center, Beirut, LBN
| | - Teresa Macedo
- Paliative Care, Unidade Local de Saúde de Braga, Braga, PRT
| |
Collapse
|
|
4
|
Beecroft JR, Brar S, Feng X, Hamilton T, Han-Lee C, Henning JW, Josephy PD, Khalili K, Ko YJ, Lemieux C, Liu DM, MacDonald DB, Noujaim J, Pollett A, Salawu A, Saleh R, Smrke A, Warren BE, Zbuk K, Razak AA. Pan-Canadian consensus recommendations for GIST management in high- and low-throughput centres across Canada. Ther Adv Med Oncol 2024; 16:17588359241266179. [PMID: 39386314 PMCID: PMC11461906 DOI: 10.1177/17588359241266179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 06/18/2024] [Indexed: 10/12/2024] Open
Abstract
Gastrointestinal stromal tumours (GISTs) are mesenchymal tumours that originate from the interstitial cells of Cajal. GISTs are mainly driven by gain-of-function mutations in receptor tyrosine kinase or platelet-derived growth factor receptor alpha. Surgical resection is the only curative treatment for localized tumours and all currently approved medical GIST treatments are based on orally available tyrosine kinase inhibitors. Recent discoveries in the molecular and clinical features of GISTs have greatly impacted GIST management. Due to the provincially rather than nationally administered Canadian healthcare system, there have been inconsistencies in the treatment of GISTs across the country. Therefore, guidance on the latest knowledge, clinical management and treatment of GIST is needed to standardize the approach to GIST management nationwide. To establish pan-Canadian guidance, provide up-to-date data and harmonize the clinical practice of GIST management in high- and low-throughput centres across Canada; a panel of 20 physicians with extensive clinical experience in GIST management reviewed relevant literature. This included radiologists, pathologists, interventional radiologists, surgeons and medical oncologists across Canada. The structured literature focused on seven key domains: molecular profiling, radiological techniques/reporting, targeted localized therapy, intricacies of systemic treatments, emerging tests, multidisciplinary care and patient advocacy. This literature review, along with clinical expertise and opinion, was used to develop this concise and clinically relevant consensus paper to harmonize the knowledge and clinical practice on GIST management across Canada. The content presented here will help guide healthcare providers, especially in Canada, in terms of approaching and managing GIST.
Collapse
Affiliation(s)
- J. Robert Beecroft
- Division of Interventional Radiology, Joint Department of Medical Imaging, University Health Network, Mount Sinai Hospital, Toronto, ON, Canada
| | - Savtaj Brar
- Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - Xiaolan Feng
- Division of Medical Oncology, Tom Baker Cancer Center, Calgary, AB, Canada
| | - Trevor Hamilton
- Department of Surgery, BC Cancer, Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Cheng Han-Lee
- Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, AB, Canada
| | - Jan-Willem Henning
- Department of Oncology, Tom Baker Cancer Centre, Cuming School of Medicine, University of Calgary, Calgary, AB, Canada
| | | | - Korosh Khalili
- Department of Medical Imaging, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Yoo-Joung Ko
- Department of Medicine, St. Michael’s Hospital, Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Christopher Lemieux
- Division of Hematology and Medical Oncology, Centre Hospitalier Universitaire de Québec, Université Laval, Quebec City, QC, Canada
| | - David M. Liu
- Department of Radiology, University of British Columbia, School of Biomedical Engineering, Vancouver, BC, Canada
- Department of Interventional Radiology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - D. Blair MacDonald
- Department of Medical Radiology, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada
| | - Jonathan Noujaim
- Division of Medical Oncology, Hôpital Maisonneuve-Rosemont, University of Montreal, Montreal, QC, Canada
| | - Aaron Pollett
- Pathology and Laboratory Medicine, Division of Diagnostic Medical Genetics, Mount Sinai Hospital, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Abdulazeez Salawu
- Division of Medical Oncology, Princess Margaret Cancer Centre, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - Ramy Saleh
- Division of Medical Oncology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Alannah Smrke
- Division of Medical Oncology, BC Cancer, University of British Columbia, Vancouver, BC, Canada
| | - Blair E. Warren
- Department of Medical Imaging, University of Toronto, Toronto, ON, Canada
| | - Kevin Zbuk
- Department of Oncology, McMaster University, Hamilton, ON, Canada
| | - Albiruni Abdul Razak
- Division of Medical Oncology, Princess Margaret Cancer Centre, Mount Sinai Hospital, University of Toronto, 610 University Ave., Toronto, ON M2G 2M9, Canada
| |
Collapse
|
|
5
|
Ali MS, Cheleng A, Behera P, Sahoo MR. A Gastrointestinal Stromal Tumor (GIST) and a Pseudocyst of the Pancreas: A Peculiar Case of Both Co-existing in the Same Patient. Cureus 2024; 16:e61642. [PMID: 38966474 PMCID: PMC11223449 DOI: 10.7759/cureus.61642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/04/2024] [Indexed: 07/06/2024] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal (GI) tract, typically originating from the interstitial cells of Cajal. The clinical presentations are variable according to their size and shape but rarely present as a palpable abdominal mass. Pancreatic pseudocysts are common complications of chronic pancreatitis characterized by fluid collections surrounded by a non-epithelialized wall of fibrous and granulation tissue. Patients may present with non-specific symptoms like abdominal pain, nausea, and vomiting and they generally have a history of acute pancreatitis. Small pseudocysts often resolve spontaneously, but larger ones often become symptomatic and may lead to complications. It is rare to find both a GIST of the stomach and a pseudocyst of the pancreas in the same patient. We present a unique case of a giant GIST and a pancreatic pseudocyst in a 72-year-old male who was experiencing abdominal pain and distension. Imaging revealed a massive lesion originating from the posterior gastric wall, which resembled a pseudocyst, along with a distinct cystic lesion adjacent to the pancreatic body. During surgical exploration, a complex interplay of both pathologies was discovered, requiring a comprehensive resection approach. The successful outcome highlights the importance of careful evaluation and personalized management in such rare cases.
Collapse
Affiliation(s)
- Manwar S Ali
- Surgery, All India Institute of Medical Sciences, Bhubaneswar, Bhubaneswar, IND
| | - Ankur Cheleng
- General Surgery, All India Institute of Medical Sciences, Bhubaneswar, Bhubaneswar, IND
| | - Pravanjan Behera
- General Surgery, All India Institute of Medical Sciences, Bhubaneswar, Bhubaneswar, IND
| | - Manash R Sahoo
- General Surgery, All India Institute of Medical Sciences, Bhubaneswar, Bhubaneswar, IND
| |
Collapse
|
|
6
|
Ben Yehuda A, Hammerschlag J, Jeroukhimov I, Markman O, Lavy R, Hershkovitz Y. Should Advanced Age Preclude Surgical Treatment of Gastrointestinal Stromal Tumor? J Laparoendosc Adv Surg Tech A 2024; 34:461-463. [PMID: 38354293 DOI: 10.1089/lap.2023.0503] [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: 02/16/2024] Open
Abstract
Introduction: Surgical resection is a gold standard treatment for gastrointestinal stromal tumors (GISTs). It can be performed by minimally invasive surgery approach in most of the patients. It has been shown that advanced age is not a clear poor prognostic factor in patients who underwent surgery for GIST. We hypothesized that elderly patients undergo elective surgery less often compared to younger population. We aim to evaluate the safety, efficacy and oncological results of GIST treatment in the elderly population in our Medical Center. Materials and Methods: All patients who underwent surgery for GIST in Shamir Medical Center from January 1, 2016, to July 31, 2023, were included in the study. The patients were divided into 2 groups. Group 1 included patients younger than 75 years, while patients older than 75 years were included in Group 2. The groups were compared according to demographics, clinical and surgical parameters, complications, and pathology results. Results: Overall, 49 patients were included in the study. Group 1 included 28 patients and Group 2 included 21 patients. Group 2 patients more often underwent emergency surgery (52.4% versus 14.3%, P < .05) and had increased open surgery rate (19% versus 0%, P < .05). No difference between the groups was noted in surgical parameters, complications, and length of hospital stay. Tumor size, number of mitoses, level of ki67%, and involvement of surgical margins were not significantly different. However, in Group 2 patients, tumor size was larger and there was a trend toward higher rate of ki67 > 5%. Conclusion: Elderly patients with GIST are less frequently undergoing electively surgery and relatively often undergo open surgery. Frequency of complications is similar in elderly patients compares to younger patients group.
Collapse
Affiliation(s)
- Amir Ben Yehuda
- Division of Surgery, Shamir Medical Center Affiliated with University Tel Aviv, Zerifin, Israel
| | - Jonathan Hammerschlag
- Division of Surgery, Shamir Medical Center Affiliated with University Tel Aviv, Zerifin, Israel
| | - Igor Jeroukhimov
- Trauma Unit, Shamir Medical Center Affiliated with University Tel Aviv, Zerifin, Israel
| | - Olena Markman
- Department of Surgery, Barzilai Medical Center, Ashkelon, Israel
| | - Ron Lavy
- Division of Surgery, Shamir Medical Center Affiliated with University Tel Aviv, Zerifin, Israel
| | - Yehuda Hershkovitz
- Trauma Unit, Shamir Medical Center Affiliated with University Tel Aviv, Zerifin, Israel
| |
Collapse
|
|
7
|
Al Saleem MA, Khan NM, ElSharkawy TM. Multifocal gastrointestinal stromal tumor with osseous metaplasia: a case report. J Med Case Rep 2023; 17:546. [PMID: 38098096 PMCID: PMC10722813 DOI: 10.1186/s13256-023-04262-9] [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: 04/04/2022] [Accepted: 11/13/2023] [Indexed: 12/17/2023] Open
Abstract
BACKGROUND Gastrointestinal stromal tumor is considered the most common mesenchymal neoplasm of the gastrointestinal tract. The majority of gastrointestinal stromal tumor cases are located in the stomach and usually affects older adults. Most of gastrointestinal stromal tumor cases are sporadic; however, few have a syndromic association, including Carney triad, Carney-Stratakis syndrome, familial gastrointestinal stromal tumor syndrome, and neurofibromatosis type 1. CASE PRESENTATION Herein, we report a rare case of a 54-year-old Middle-Eastern female with multifocal gastrointestinal stromal tumor mixed type (epithelioid and spindle cell type) with osseous metaplasia. Fluoresce in situ hybridization analysis of platelet-derived growth factor receptor alpha revealed deletion in 42% of the tumor cells studied. Interestingly, next generation sequencing revealed platelet-derived growth factor receptor alpha exon 12 mutation (p.Y555C) and exon 14 mutation (p.N659Y). CONCLUSIONS In conclusion, osseous metaplasia in GIST is a very rare event and only few cases are reported in the literature. The number of reported cases is inadequate to confirm the pathogenesis and the prognosis.
Collapse
Affiliation(s)
- Maryam Abdullah Al Saleem
- Department of Pathology, King Fahd Hospital of University, College of Medicine, Imam Abdulrahman Bin Faisal University, Khobar, Saudi Arabia.
| | - Nida Mirzaman Khan
- Department of Pathology, King Fahd Hospital of University, College of Medicine, Imam Abdulrahman Bin Faisal University, Khobar, Saudi Arabia
| | - Tarek Mohammad ElSharkawy
- Department of Pathology, King Fahd Hospital of University, College of Medicine, Imam Abdulrahman Bin Faisal University, Khobar, Saudi Arabia
| |
Collapse
|
|
8
|
Trotter N, White J. Gastrointestinal stromal tumour-induced hypercalcaemia. BMJ Case Rep 2023; 16:e243613. [PMID: 37967927 PMCID: PMC10660897 DOI: 10.1136/bcr-2021-243613] [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: 11/17/2023] Open
Abstract
Hypercalcaemia is recognised as the most common oncological metabolic emergency, with several proposed underlying mechanisms. Nevertheless, hypercalcaemia has been rarely reported as a complication in patients with gastrointestinal stromal tumours (GISTs). GISTs are uncommon mesenchymal tumours of the gastrointestinal tract. There are only nine previous cases of hypercalcaemia occurring in patients with GIST reported in the literature. We report a case of a man in his 70s with a background of metastatic GIST on fourth-line treatment. The patient presented with new hypercalcaemia and acute kidney injury. Despite medical management, his calcium remained elevated and he deteriorated secondary to significant disease progression.
Collapse
Affiliation(s)
- Nicola Trotter
- Internal Medicine, NHS Greater Glasgow and Clyde, Glasgow, UK
| | - Jeff White
- Medical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, UK
| |
Collapse
|
|
9
|
Erhan SS, Kulduk G, Dobral A, Bugra A. An entity that should be kept in mind: Synchronous gastrointestinal stromal tumor encountered in resection materials obtained for the detection of intra-abdominal malignancies. North Clin Istanb 2023; 10:797-802. [PMID: 38328725 PMCID: PMC10846574 DOI: 10.14744/nci.2022.98623] [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: 07/06/2022] [Revised: 08/31/2022] [Accepted: 11/27/2022] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Gastrointestinal stromal tumors (GISTs), often sporadic, arise from interstitial Cajal cells of the gastrointestinal tract or their stem cell-like precursors. Apart from tumor-associated syndromes, it has been reported that GISTs are also associated with other tumors. There is no clear information about the etiology of these synchronous tumors. In this study, we wanted to present the clinicopathological features of 13 cases diagnosed as synchronous GIST with other tumors. METHODS Demographic characteristics of the cases, risk of progressive disease score, tumor localization, size, and the mitotic activity of tumors along with survival status were evaluated. RESULTS Thirteen of 101 cases diagnosed with GIST had a primary tumor synchronous with GIST. Synchronous GISTs were located in the stomach and small intestine. Most of the cases were detected incidentally in the intraoperative and post-operative periods. Risk scores for progressive disease were categorized as low (n=1), very low (n=1), and no risk (n=11). Non-GIST tumors were located in the stomach, transverse colon, left colon, rectum, gallbladder, kidney, and retroperitoneal space. Histological tumor types were adenocarcinoma, diffuse large B-cell lymphoma, mesothelioma, and neuroendocrine tumor. Life expectancy was found to be significantly lower in synchronous GISTs. CONCLUSION In cases operated for non-GIST tumors, the possibility of incidental detection of GIST should always be kept in mind.
Collapse
Affiliation(s)
- Selma Sengiz Erhan
- Department of Pathology, Prof. Dr. Cemil Tascioglu City Hospital, Istanbul, Turkiye
| | - Gamze Kulduk
- Department of Pathology, Prof. Dr. Cemil Tascioglu City Hospital, Istanbul, Turkiye
| | - Arzu Dobral
- Department of Pathology, Prof. Dr. Cemil Tascioglu City Hospital, Istanbul, Turkiye
| | - Aytul Bugra
- Division of Histopathology, Department of Morgue, Council of Forensic Medicine, Istanbul, Turkiye
| |
Collapse
|
|
10
|
Mudavath S, Ashok D. Effect of Verapamil, a P-glycoprotein-1 and Cytochrome P450 3A4 Inhibitor, on Pharmacokinetics and Metabolic Stability of Ripretinib: A Drug-Drug Interaction Study in Rats. Eur J Drug Metab Pharmacokinet 2023; 48:733-746. [PMID: 37831396 DOI: 10.1007/s13318-023-00860-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/26/2023] [Indexed: 10/14/2023]
Abstract
BACKGROUND AND OBJECTIVES Ripretinib was developed to target a whole range of KIT proto-oncogene mutations and platelet-derived growth factor receptor A (PDGFR-A) kinases found in certain cancers and myeloproliferative neoplasms, particularly gastrointestinal stromal tumours (GISTs). This study investigated the effect of verapamil, a potential inhibitor of P-glycoprotein-1 (P-gp1) and cytochrome P450 3A4 (CYP3A4), on the pharmacokinetics of ripretinib in rats when administered orally together. This study also assessed the metabolic stability and in vitro cellular absorption of ripretinib in the presence of verapamil. METHODS A novel sensitive time-saving liquid chromatography tandem mass spectometry (LC-MS/MS) technique for determining ripretinib in rat plasma was developed and validated. A Zorbax SB C18 column was used for the separation and analysis of ripretinib with a mobile phase consisting of 50:50 (%v/v) acetonitrile and 10 mM ammonium formate buffer at a flow rate of 0.4 mL/min. Imatinib was used as an internal standard (IS) in the method. The pharmacokinetic characteristics of ripretinib were evaluated in Wistar rats by successfully administering an oral dosage of 5 mg/kg body weight of ripretinib in the presence of verapamil (10 mg/kg body weight). Subsequently, rat liver microsomes were used to assess the effect of verapamil on ripretinib metabolic stability, and absorption was tested using a Caco-2 cell transwell model. RESULTS Ripretinib and IS were identified using multiple reaction monitoring (MRM) modes by mass spectrometry and showed ion transitions of 510.09→94.06 m/z and 494.26→ 394.16 m/z, respectively. The high-performance liquid chromatography (HPLC) method successfully eluted ripretinib and IS at retention times of 0.91 and 0.68 min, respectively, and the method was validated for all parameters and met the criteria for acceptance. Co-administration of verapamil increased the maximum concentration (Cmax) of ripretinib from 437 ± 84 ng/mL to 492 ± 50 ng/mL (12%), and the area under the concentration-time curve from 0 to the last sampling time t (AUC0-t) increased by approximately 40.6%. Verapamil significantly reduced the basolateral-to-apical transfer of ripretinib through Caco-2 cells. Findings also showed that verapamil increased the metabolic stability of ripretinib. CONCLUSION The study results indicate that the co-administration of ripretinib with CYP3A4 and/or P-gp1 inhibitors is associated with significant drug-drug interactions that affect the pharmacokinetics of ripretinib. Further research in human subjects is suggested to confirm dosage adjustment and therapeutic drug monitoring of ripretinib when administered along with P-gp1/CYP3A4 inhibitors ensuring patient safety and optimizing the therapeutic benefits of ripretinib.
Collapse
Affiliation(s)
- Shyamala Mudavath
- Department of Pharmaceutical Analysis, Joginpally B R Pharmacy College, Hyderabad, Telangana, 500075, India.
| | - Dongamanti Ashok
- Department of Green Chemistry and Medicinal Chemistry Laboratory, Osmania University, Hyderabad, Telangana, 500007, India
| |
Collapse
|
|
11
|
Patil A, Haval S, Nichkaode P, Dwivedi D. Gastrointestinal Stromal Tumor: A Clinicopathological Study and Management. Cureus 2023; 15:e49469. [PMID: 38024086 PMCID: PMC10679960 DOI: 10.7759/cureus.49469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/26/2023] [Indexed: 12/01/2023] Open
Abstract
Background and aim Gastrointestinal stromal tumors (GISTs) account for a major portion of gastrointestinal mesenchymal tumors. The purpose of the current study is to examine the clinicopathological features, management, and therapeutic outcomes of primary GIST in a tertiary care hospital. Materials and methods This is a prospective observational analysis. Seventeen patients with GIST have been detected and treated in the Department of Surgery of a tertiary care hospital with an attached medical institution over the last seven years. The clinical presentation, diagnosis method, tumor locations, histopathological results, surgical treatment, and postoperative results were analyzed. Results There were six females and 11 males with ages ranging between 35 to 72 years. All the patients had symptoms, with abdominal pain the most prevalent. The most frequent primary site for GIST was the stomach (60-70%), followed by the small intestine (25-30%), the rectum, the esophagus, and the colon (2%). Preoperative diagnosis was made through endoscopy and a contrast-enhanced CT scan. Ninety-two percent of the cases tested positive for CD117. Surgery has been conducted for all 17 patients, with the liver being the most common site of metastasis. Imatinib and sunitinib increased the survival as well as postoperative recurrence rate while decreasing metastasis. Conclusions The most general symptom of GIST was abdominal pain. In most instances, it was treated with surgery as well as adjuvant imatinib and sunitinib, and had a favorable prognosis. With increasing size and mitotic activity, the five-year survival rate falls, and the prognosis worsens.
Collapse
Affiliation(s)
- Aditya Patil
- General Surgery, Dr. DY Patil Vidyapeeth, Pune, IND
| | - Shriya Haval
- General Surgery, Dr. DY Patil Vidyapeeth, Pune, IND
| | | | | |
Collapse
|
|
12
|
Campanella NC, Gomes INF, Alves ALV, Leal LF, Evangelista AF, Rosa MN, Melendez ME, Silva VAO, Dias RLK, Abrahão-Machado LF, Santana I, Martinho O, Guimarães DP, Faça VM, Reis RM. Biological and therapeutic implications of RKIP in Gastrointestinal Stromal Tumor (GIST): an integrated transcriptomic and proteomic analysis. Cancer Cell Int 2023; 23:256. [PMID: 37907993 PMCID: PMC10619323 DOI: 10.1186/s12935-023-03102-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 10/16/2023] [Indexed: 11/02/2023] Open
Abstract
BACKGROUND Gastrointestinal stromal tumors (GIST) represent a significant clinical challenge due to their metastatic potential and limited treatment options. Raf kinase inhibitor protein (RKIP), a suppressor of the MAPK signaling pathway, is downregulated in various cancers and acts as a metastasis suppressor. Our previous studies demonstrated low RKIP expression in GIST and its association with poor outcomes. This study aimed to expand on the previous findings and investigate the biological and therapeutic implications of RKIP loss on GIST. METHODS To validate the RKIP prognostic significance, its expression was evaluated by immunohistochemistry in 142 bona fide GIST cases. The functional role of RKIP was evaluated in vitro, using the GIST-T1 cell line, which was knocked out for RKIP. The biological and therapeutic implications of RKIP were evaluated by invasion, migration, apoptosis, and 2D / 3D viability assays. Additionally, the transcriptome and proteome of RKIP knockout cells were determined by NanoString and mass spectrometry, respectively. RESULTS Immunohistochemical analysis revealed the absence of RKIP in 25.3% of GIST cases, correlating with a tendency toward poor prognosis. Functional assays demonstrated that RKIP knockout increased GIST cells' invasion and migration potential by nearly 60%. Moreover, we found that RKIP knockout cells exhibited reduced responsiveness to Imatinib treatment and higher cellular viability in 2D and 3D in vitro models, as assessed by apoptosis-related protein expression. Through comprehensive genetic and proteomic profiling of RKIP knockout cells, we identified several putative RKIP-regulated proteins in GIST, such as COL3A1. CONCLUSIONS Using a multidimensional integrative analysis, we identified, for the first time in GIST, molecules and pathways modulated by RKIP that may potentially drive metastasis and, consequently, poor prognosis in this disease.
Collapse
Affiliation(s)
- Nathália Cristina Campanella
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, S. Paulo, 14784-400, Brazil
| | - Izabela Natalia Faria Gomes
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, S. Paulo, 14784-400, Brazil
| | - Ana Laura Vieira Alves
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, S. Paulo, 14784-400, Brazil
| | - Leticia Ferro Leal
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, S. Paulo, 14784-400, Brazil
- School of Health Sciences Dr. Paulo Prata (FACISB), Barretos, 14785-002, Brazil
| | - Adriane Feijó Evangelista
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, S. Paulo, 14784-400, Brazil
| | - Marcela Nunes Rosa
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, S. Paulo, 14784-400, Brazil
| | - Matias Eliseo Melendez
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, S. Paulo, 14784-400, Brazil
- Molecular Carcinogenesis Program, National Cancer Institute, Rio de Janeiro, 20231-050, Brazil
| | - Viviane Aline Oliveira Silva
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, S. Paulo, 14784-400, Brazil
- Department of Pathology, School of Medicine, Federal University of Bahia, Salvador, 40110-909, Brazil
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, 40296-710, Brazil
| | - Richard Lucas Konichi Dias
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, S. Paulo, 14784-400, Brazil
- School of Health Sciences Dr. Paulo Prata (FACISB), Barretos, 14785-002, Brazil
| | | | - Iara Santana
- Department of Pathology, Barretos Cancer Hospital, Barretos, 14784-400, Brazil
| | - Olga Martinho
- ICVS/3B's - PT Government Associate Laboratory, Braga, 4806-909, Portugal
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, 4710-057, Portugal
| | - Denise Peixoto Guimarães
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, S. Paulo, 14784-400, Brazil
- Department of Endoscopy, Barretos Cancer Hospital, Barretos, 14784-400, Brazil
| | - Vitor Marcel Faça
- Department of Biochemistry and Immunology, Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Ribeirão Preto, 14049-900, Brazil
| | - Rui Manuel Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, S. Paulo, 14784-400, Brazil.
- ICVS/3B's - PT Government Associate Laboratory, Braga, 4806-909, Portugal.
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, 4710-057, Portugal.
| |
Collapse
|
|
13
|
Zhang QW, Zhang RY, Yan ZB, Zhao YX, Wang XY, Jin JZ, Qiu QX, Chen JJ, Xie ZH, Lin J, Cao H, Zhou Y, Chen HM, Li XB. Personalized radiomics signature to screen for KIT-11 mutation genotypes among patients with gastrointestinal stromal tumors: a retrospective multicenter study. J Transl Med 2023; 21:726. [PMID: 37845765 PMCID: PMC10577986 DOI: 10.1186/s12967-023-04520-w] [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: 06/30/2023] [Accepted: 09/11/2023] [Indexed: 10/18/2023] Open
Abstract
OBJECTIVES Gastrointestinal stromal tumors (GISTs) carrying different KIT exon 11 (KIT-11) mutations exhibit varying prognoses and responses to Imatinib. Herein, we aimed to determine whether computed tomography (CT) radiomics can accurately stratify KIT-11 mutation genotypes to benefit Imatinib therapy and GISTs monitoring. METHODS Overall, 1143 GISTs from 3 independent centers were separated into a training cohort (TC) or validation cohort (VC). In addition, the KIT-11 mutation genotype was classified into 4 categories: no KIT-11 mutation (K11-NM), point mutations or duplications (K11-PM/D), KIT-11 557/558 deletions (K11-557/558D), and KIT-11 deletion without codons 557/558 involvement (K11-D). Subsequently, radiomic signatures (RS) were generated based on the arterial phase of contrast CT, which were then developed as KIT-11 mutation predictors using 1408 quantitative image features and LASSO regression analysis, with further evaluation of its predictive capability. RESULTS The TC AUCs for K11-NM, K11-PM/D, K11-557/558D, and K11-D ranged from 0.848 (95% CI 0.812-0.884), 0.759 (95% CI 0.722-0.797), 0.956 (95% CI 0.938-0.974), and 0.876 (95% CI 0.844-0.908), whereas the VC AUCs ranged from 0.723 (95% CI 0.660-0.786), 0.688 (95% CI 0.643-0.732), 0.870 (95% CI 0.824-0.918), and 0.830 (95% CI 0.780-0.878). Macro-weighted AUCs for the KIT-11 mutant genotype ranged from 0.838 (95% CI 0.820-0.855) in the TC to 0.758 (95% CI 0.758-0.784) in VC. TC had an overall accuracy of 0.694 (95%CI 0.660-0.729) for RS-based predictions of the KIT-11 mutant genotype, whereas VC had an accuracy of 0.637 (95%CI 0.595-0.679). CONCLUSIONS CT radiomics signature exhibited good predictive performance in estimating the KIT-11 mutation genotype, especially in prediction of K11-557/558D genotype. RS-based classification of K11-NM, K11-557/558D, and K11-D patients may be an indication for choice of Imatinib therapy.
Collapse
Affiliation(s)
- Qing-Wei Zhang
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ran-Ying Zhang
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Zhi-Bo Yan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Yu-Xuan Zhao
- Department of Radiology, Qilu Hospital of Shandong University, Jinan, China
| | - Xin-Yuan Wang
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jing-Zheng Jin
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qi-Xuan Qiu
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jie-Jun Chen
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Zhen-Hui Xie
- Department of Radiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160, Pujian Rd., Shanghai, 200127, China
| | - Jiang Lin
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Hui Cao
- Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, No. 160 Pujian Road, Shanghai, 200127, China.
| | - Yan Zhou
- Department of Radiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160, Pujian Rd., Shanghai, 200127, China.
| | - Hui-Min Chen
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Xiao-Bo Li
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| |
Collapse
|
|
14
|
Goetsch Weisman A, Weiss McQuaid S, Radtke HB, Stoll J, Brown B, Gomes A. Neurofibromatosis- and schwannomatosis-associated tumors: Approaches to genetic testing and counseling considerations. Am J Med Genet A 2023; 191:2467-2481. [PMID: 37485904 DOI: 10.1002/ajmg.a.63346] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 05/26/2023] [Accepted: 06/24/2023] [Indexed: 07/25/2023]
Abstract
Neurofibromatosis (NF) and schwannomatosis (SWN) are genetic conditions characterized by the risk of developing nervous system tumors. Recently revised diagnostic criteria include the addition of genetic testing to confirm a pathogenic variant, as well as to detect the presence of mosaicism. Therefore, the use and interpretation of both germline and tumor-based testing have increasing importance in the diagnostic approach, treatment decisions, and risk stratification of these conditions. This focused review discusses approaches to genetic testing of NF- and SWN-related tumor types, which are somewhat rare and perhaps lesser known to non-specialized clinicians. These include gastrointestinal stromal tumors, breast cancer, plexiform neurofibromas with or without transformation to malignant peripheral nerve sheath tumors, gliomas, and schwannomas, and emphasizes the need for inclusion of genetic providers in patient care and appropriate pre- and post-test education, genetic counseling, and focused evaluation by a medical geneticist or other healthcare provider familiar with clinical manifestations of these disorders.
Collapse
Affiliation(s)
- Allison Goetsch Weisman
- Division of Genetics, Genomics and Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Shelly Weiss McQuaid
- Division of Genetics, Genomics and Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
- Division of Oncology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
| | - Heather B Radtke
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Children's Tumor Foundation, New York, New York, USA
| | | | - Bryce Brown
- Medical Genomics Laboratory, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Alicia Gomes
- Medical Genomics Laboratory, University of Alabama at Birmingham, Birmingham, Alabama, USA
| |
Collapse
|
|
15
|
Rahimi-Ardabily A, Murdande S, Dong M, Gu KW, Zhang B, Miller K, Aploks K, Da Dong X. Liver resection for metastatic GIST tumor improves survival in the era of tyrosine kinase inhibitors: a systematic review and meta-analysis. Langenbecks Arch Surg 2023; 408:373. [PMID: 37740754 DOI: 10.1007/s00423-023-03052-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 08/08/2023] [Indexed: 09/25/2023]
Abstract
INTRODUCTION Survival for gastrointestinal stromal tumor (GIST) has been increasing over the years after the introduction of tyrosine kinase inhibitors. However, the role of metastasectomy for GIST is still controversial. Patients are currently treated with imatinib or sunitinib in case of imatinib failures as optimal medical therapy for metastatic GIST. METHODS The Pubmed, EMBASE, and Cochrane Library were systematically searched. Overall survival following liver resection ± tyrosine kinase inhibitor treatment for metastatic GIST was compared to treatment with tyrosine kinase inhibitors alone. RESULTS Eleven studies including both randomized control trials and retrospective cohort studies were included in the final analysis with a total of 988 patients. Seven studies encompassed data on 556 patients with isolated liver metastases (219 surgery ± drug groups and 337 drug-only groups) were included. Overall survival was significantly improved in patients undergoing liver resection ± drug therapy in comparison to drug therapy alone. [HR (95%CI) = 2.10 (1.58, 2.79); p<0.00001]. Subgroup analysis showed that patients also had improved progression free survival based on 4 studies. [HR (95%CI) = 1.92 (1.43, 2.56); p<0.00001]. In case of concurrent liver and peritoneal metastases, patients showed improved overall survival with aggressive surgical approaches based on 10 studies. [HR (95%CI) = 1.90 (1.56, 2.31); p<0.00001]. CONCLUSION This meta-analysis found that liver resection for patients with metastatic GIST regardless of peritoneal metastases improved progression free and overall survival in conjunction with tyrosine kinase inhibitors as compared with medical therapy alone. Furthermore, liver resections did not have any immediate detrimental impact on survival in the group of patients selected.
Collapse
Affiliation(s)
- Arash Rahimi-Ardabily
- Division of Surgical Oncology, Department of Surgery, Nuvance Health, Whittingham Cancer Center, 34 Maple Street, Norwalk, CT, 06856, USA
| | - Sanjana Murdande
- Division of Surgical Oncology, Department of Surgery, Nuvance Health, Whittingham Cancer Center, 34 Maple Street, Norwalk, CT, 06856, USA
| | - Michael Dong
- Division of Surgical Oncology, Department of Surgery, Nuvance Health, Whittingham Cancer Center, 34 Maple Street, Norwalk, CT, 06856, USA
| | - Katie W Gu
- Division of Surgical Oncology, Department of Surgery, Nuvance Health, Whittingham Cancer Center, 34 Maple Street, Norwalk, CT, 06856, USA
| | - Brianna Zhang
- Division of Surgical Oncology, Department of Surgery, Nuvance Health, Whittingham Cancer Center, 34 Maple Street, Norwalk, CT, 06856, USA
| | - Kendall Miller
- Division of Surgical Oncology, Department of Surgery, Nuvance Health, Whittingham Cancer Center, 34 Maple Street, Norwalk, CT, 06856, USA
| | - Krist Aploks
- Division of Surgical Oncology, Department of Surgery, Nuvance Health, Whittingham Cancer Center, 34 Maple Street, Norwalk, CT, 06856, USA
| | - Xiang Da Dong
- Division of Surgical Oncology, Department of Surgery, Nuvance Health, Whittingham Cancer Center, 34 Maple Street, Norwalk, CT, 06856, USA.
| |
Collapse
|
|
16
|
Guo S, Qian H, Zhu H, Yang Y, Yang X, Sun H. Metanephric stromal tumor in an adult with PDGFRA mutation: a case report. Diagn Pathol 2023; 18:83. [PMID: 37454137 DOI: 10.1186/s13000-023-01372-2] [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: 05/09/2023] [Accepted: 07/08/2023] [Indexed: 07/18/2023] Open
Abstract
BACKGROUND Metanephric stromal tumors (MST) are rare benign renal tumors that mainly occur in infants and children. Approximately 72% of MST in children have the B-Raf proto-oncogene serine/threonine kinase (BRAF) V600E mutation. To date, only five cases of adult MSTs have been reported and no clear genetic alterations have been found. CASE PRESENTATION We report a case of MST in a 45-year-old woman who complained of left lower back pain for a week, accompanied by hypertension (150/79 mmHg). Magnetic resonance imaging (MRI) showed an abnormally enhanced nodule (1.1 cm in the middle of the left kidney), which was histopathologically consistent with an MST. The BRAF V600E mutation was not detected in tumor cells using PCR and next-generation sequencing (NGS). However, a platelet-derived growth factor receptor alpha (PDGFRA) mutation was detected in this case using NGS. The patient showed no recurrence or metastasis nine months after partial nephrectomy, and her blood pressure was consistently normal. CONCLUSION This is the first report of alterations in PDGFRA in MSTs. This result advances our knowledge of genetic variations in adult MSTs, which may have different gene alterations from MSTs in children.
Collapse
Affiliation(s)
- Sanjun Guo
- Department of Pathology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, 610072, China
| | - Huan Qian
- Department of Pathology, The First People's Hospital of Guangyuan, Guangyuan, Sichuan, 628017, China
| | - Hong Zhu
- Department of Pathology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, 610072, China
| | - Yue Yang
- Department of Pathology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, 610072, China
| | - Xudan Yang
- Department of Pathology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, 610072, China
- Department of Pathology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Huajun Sun
- Department of Pathology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, 610072, China.
- Department of Pathology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China.
| |
Collapse
|
|
17
|
Pandey P, Khan F, Upadhyay TK, Seungjoon M, Park MN, Kim B. New insights about the PDGF/PDGFR signaling pathway as a promising target to develop cancer therapeutic strategies. Biomed Pharmacother 2023; 161:114491. [PMID: 37002577 DOI: 10.1016/j.biopha.2023.114491] [Citation(s) in RCA: 52] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 02/20/2023] [Accepted: 03/07/2023] [Indexed: 03/14/2023] Open
Abstract
Numerous cancers express platelet-derived growth factors (PDGFs) and PDGF receptors (PDGFRs). By directly stimulating tumour cells in an autocrine manner or by stimulating tumour stromal cells in a paracrine manner, the platelet-derived growth factor (PDGF)/platelet-derived growth factor receptor (PDGFR) pathway is crucial in the growth and spread of several cancers. To combat hypoxia in the tumour microenvironment, it encourages angiogenesis. A growing body of experimental data shows that PDGFs target malignant cells, vascular cells, and stromal cells to modulate tumour growth, metastasis, and the tumour microenvironment. To combat medication resistance and enhance patient outcomes in cancers, targeting the PDGF/PDGFR pathway is a viable therapeutic approach. There have been reports of anomalies in the PDGF pathway, including the gain of function point mutations, activating chromosomal translocations, or overexpression or amplification of PDGF receptors (PDGFRs). As a result, it has been shown that targeting the PDGF/PDGFR signaling pathway is an effective method for treating cancer. As a result, this study will concentrate on the regulation of the PDGF/PDGFR signaling system, in particular the current methods and inhibitors used in cancer treatment, as well as the associated therapeutic advantages and side effects.
Collapse
Affiliation(s)
- Pratibha Pandey
- Department of Biotechnology, Noida Institute of Engineering and Technology, Greater Noida, UP, India
| | - Fahad Khan
- Department of Biotechnology, Noida Institute of Engineering and Technology, Greater Noida, UP, India.
| | - Tarun Kumar Upadhyay
- Department of Biotechnology, Parul Institute of Applied Sciences and Centre of Research for Development, Parul University, Vadodara 391760, India
| | - Moon Seungjoon
- Chansol Hospital of Korean Medicine, 290, Buheung-ro, Bupyeong-gu, Incheon 21390, Republic of Korea; Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - Moon Nyeo Park
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemun-gu, Seoul 02447, Republic of Korea; Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Bonglee Kim
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemun-gu, Seoul 02447, Republic of Korea; Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
| |
Collapse
|
|
18
|
Sun Y, Yue L, Xu P, Hu W. An overview of agents and treatments for PDGFRA-mutated gastrointestinal stromal tumors. Front Oncol 2022; 12:927587. [PMID: 36119525 PMCID: PMC9471148 DOI: 10.3389/fonc.2022.927587] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 08/15/2022] [Indexed: 11/25/2022] Open
Abstract
Platelet-derived growth factor receptor A (PDGFRA) mutations occur in approximately 10-15% of gastrointestinal stromal tumors (GISTs). These tumors with PDGFRA mutations have a different pathogenesis, clinical characteristics, and treatment response compared to tumors with receptor tyrosine kinase protein (KIT) mutations (60-70%). Many clinical studies have investigated the use of tyrosine kinase inhibitors mainly in patients with KIT mutations; however, there is a lack of attention to the PDGFRA-mutated molecular subtype. The main effective inhibitors of PDGFRA are ripretinib, avapritinib, and crenolanib, and their mechanisms and efficacy in GIST (as confirmed in clinical trials) are described in this review. Some multi-targeted tyrosine kinase inhibitors with inhibitory effects on this molecular subtype are also introduced and summarized in this paper. This review focuses on PDGFRA-mutated GISTs, introduces their clinical characteristics, downstream molecular signaling pathways, and existing resistance mechanisms. We focus on the most recent literature that describes the development of PDGFRA inhibitors and their use in clinical trials, as well as the potential benefits from different combination therapy strategies.
Collapse
Affiliation(s)
- Yingchao Sun
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou, China
| | - Lei Yue
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou, China
| | - Pengfu Xu
- Department of Gastrointestinal Surgery, Taizhou Hospital, Zhejiang University, Taizhou, China
| | - Weiling Hu
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou, China
- Institute of Gastroenterology, Zhejiang University (IGZJU), Hangzhou, China
- Zhejiang University Cancer Center, Hangzhou, China
| |
Collapse
|
|
19
|
Tropomyosin-Related Kinase Fusions in Gastrointestinal Stromal Tumors. Cancers (Basel) 2022; 14:cancers14112659. [PMID: 35681640 PMCID: PMC9179593 DOI: 10.3390/cancers14112659] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary The canonical mutations in gastrointestinal stromal tumors (GISTs) are typically activating mutations in KIT and platelet-derived growth factor receptor alpha (PDGFRA). Imatinib, the treatment of choice for GISTs, shows a lower response in KIT/PDGFRA wild-type GISTs. Neurotrophic tyrosine receptor kinase (NTRK) fusion, which can be treated with an NTRK target agent, has been reported in KIT/PDGFRA wild-type GISTs, and, therefore, the Yonsei Cancer Center analyzed NTRK fusion incidence in KIT/PDGFRA wild-type GISTs. At the Yonsei Cancer Center, NTRK fusion was confirmed in 16% of cases. Confirmation of NTRK fusion in KIT/PDGFRA wild-type GISTs provides important information for improving therapeutic outcomes. NTRK fusion was confirmed in 16% of KIT/PDGFRA wild-type GIST cases at the Yonsei Cancer Center. Confirmation of NTRK fusion in KIT/PDGFRA wild-type GISTs will improve therapeutic outcomes. Abstract The canonical mutations in gastrointestinal stromal tumors (GISTs) are typically activating mutations in KIT and platelet-derived growth factor receptor alpha (PDGFRA). GISTs with non-canonical mutations are a heterogeneous group. Here, we examined tropomyosin-related kinase (TRK) fusion in GIST cases without KIT/PDGFRA mutations (KIT/PDGFRA wild-type (WT) GISTs). We retrospectively analyzed patients who were diagnosed with GISTs at the Yonsei Cancer Center, Severance Hospital, between January 1998 and December 2016. Thirty-one patients with KIT/PDGFRA WT GISTs were included in the analysis. TRK expression in tumor samples was assessed by pan-TRK immunohistochemistry (IHC), and the neurotrophic tyrosine receptor kinase (NTRK: the gene encoding TRK) rearrangement was analyzed by fluorescence in situ hybridization (FISH). IHC analyses revealed that five cases in this cohort exhibited a weak to moderate TRK expression. NTRK1 fusions were detected in three tumor samples, and two samples harbored NTRK3 fusions. The remaining 26 samples did not harbor NTRK fusions. Two types of NTRK fusions were detected, and the overall NTRK fusion frequency in KIT/PDGFRA WT GIST cases was 16% (5/31). Our data provide insights into the molecular alterations underpinning KIT/PDGFRA WT GISTs. More effort should be devoted to improve methods to identify this distinct disease subtype within the KIT/PDGFRA WT GIST group.
Collapse
|
|
20
|
Baranov E, Winsnes K, O'Brien M, Voss SD, Church AJ, Janeway KA, DuBois SG, Davis JL, Al-Ibraheemi A. Histologic characterization of pediatric mesenchymal neoplasms treated with kinase-targeted therapy. Histopathology 2022; 81:215-227. [PMID: 35543076 DOI: 10.1111/his.14680] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 05/05/2022] [Accepted: 05/09/2022] [Indexed: 11/28/2022]
Abstract
AIMS Recurrent alterations involving receptor tyrosine or cytoplasmic kinase genes have been described in soft tissue neoplasms such as infantile fibrosarcoma (IFS) and inflammatory myofibroblastic tumor (IMT). Recent trials and regulatory approvals for targeted inhibitors against the kinase domains of these oncoproteins have allowed for increased use of targeted therapies. We aimed to characterize the histologic features of pediatric mesenchymal neoplasms with kinase alterations treated with targeted inhibitors. METHODS AND RESULTS Eight patients with tyrosine kinase-altered mesenchymal neoplasms with pre- and post-treatment samples were identified. Tumors occurred in 5 females and 3 males with a median age at presentation of 6.5 years. Tumor sites were bone/somatic soft tissue (n=5) and viscera (n=3). Pre-treatment diagnoses were: IMT (n=3), epithelioid inflammatory myofibroblastic sarcoma (n=1), and descriptive diagnoses (n=4) such as "kinase-driven spindle cell tumor". Fusions identified were ETV6::NTRK3 (n=2), TPM3::NTRK1, SEPT7::BRAF, TFG::ROS1, KLC1::ALK, RANBP2::ALK, and MAP4::RAF1. Patients were treated with larotrectinib (n=3), ALK or ALK/ROS1 inhibitors (n=3), and MEK inhibitors (n=2). Post-treatment tumors exhibited a striking decrease in cellularity (7/8) and the presence of collagenous stroma (7/8) with extensive glassy hyalinization (5/8). In two cases, abundant coarse or psammomatous calcifications were seen and in one case prominent perivascular hyalinization was noted. Residual viable tumor was seen in 3/8 cases (<5% in one case, and >75% in 2/8 cases). CONCLUSIONS Mesenchymal neoplasms with tyrosine kinase alterations treated with targeted inhibitors show pathologic response, which includes decreased cellularity and stromal hyalinization. The presence of these features may be helpful in assessing tumor response after targeted therapy.
Collapse
Affiliation(s)
- Esther Baranov
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Katrina Winsnes
- Division of Pediatric Hematology and Oncology, Oregon Health & Science University/Doernbecher Children's Hospital, Portland, OR, United States
| | - Matthew O'Brien
- Department of Radiology, Oregon Health & Science University, Portland, OR, United States
| | - Stephan D Voss
- Department of Radiology, Boston Children's Hospital, Boston, MA, United States
| | - Alanna J Church
- Department of Pathology, Boston Children's Hospital, Boston, MA, United States
| | - Katherine A Janeway
- Department of Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, United States
| | - Steven G DuBois
- Department of Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, United States
| | - Jessica L Davis
- Department of Pathology, Oregon Health & Science University, Portland, OR, United States
| | - Alyaa Al-Ibraheemi
- Department of Pathology, Boston Children's Hospital, Boston, MA, United States
| |
Collapse
|
|
21
|
Feng M, Yang Y, Liao W, Li Q. Cost-Effectiveness Analysis of Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumor: A Systematic Review. Front Public Health 2022; 9:768765. [PMID: 35083189 PMCID: PMC8784780 DOI: 10.3389/fpubh.2021.768765] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 12/13/2021] [Indexed: 02/05/2023] Open
Abstract
Background: The introduction of tyrosine kinase inhibitor (TKI) therapy has dramatically improved the clinical effectiveness of patients with locally advanced and/or metastatic gastrointestinal stromal tumors (GIST), and this systematic review was conducted aiming at the cost-effectiveness analysis of TKIs in GIST. Methods: A thorough literature search of online databases was performed, using appropriate terms such as “gastrointestinal stromal tumor or GIST,” “cost-effectiveness,” and “economic evaluation.” Data extraction was conducted independently by two authors, and completeness of reporting and quality of the evaluation were assessed. The systematic review was conducted following the PRISMA statement. Results: Published between 2005 and 2020, 15 articles were incorporated into the systematic review. For advanced GIST, imatinib followed by sunitinib was considered cost-effective, and regorafenib was cost-effective compared with imatinib re-challenge therapy in the third-line treatment. For resectable GIST, 3-year adjuvant imatinib therapy represented a cost-effective treatment option. The precision medicine-assisted imatinib treatment was cost-effective compared with empirical treatment. Conclusion: Although identified studies varied in predicted costs and quality-adjusted life years, there was general agreement in study conclusions. More cost-effectiveness analysis should be conducted regarding more TKIs that have been approved for the treatment of GIST. Systematic Review Registration:https://www.crd.york.ac.uk/, PROSPERO: CRD42021225253.
Collapse
Affiliation(s)
- Mingyang Feng
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.,West China Biomedical Big Data Center, Sichuan University, Chengdu, China
| | - Yang Yang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.,West China Biomedical Big Data Center, Sichuan University, Chengdu, China
| | - Weiting Liao
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.,West China Biomedical Big Data Center, Sichuan University, Chengdu, China
| | - Qiu Li
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.,West China Biomedical Big Data Center, Sichuan University, Chengdu, China
| |
Collapse
|
|
22
|
George S, von Mehren M, Fletcher JA, Sun J, Zhang S, Pritchard JR, Hodgson JG, Kerstein D, Rivera VM, Haluska FG, Heinrich MC. PHASE 2 STUDY OF PONATINIB IN ADVANCED GASTROINTESTINAL STROMAL TUMORS: EFFICACY, SAFETY, AND IMPACT OF LIQUID BIOPSY AND OTHER BIOMARKERS. Clin Cancer Res 2022; 28:1268-1276. [PMID: 35091442 DOI: 10.1158/1078-0432.ccr-21-2037] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 12/15/2021] [Accepted: 01/25/2022] [Indexed: 11/16/2022]
Abstract
PURPOSE Evaluate ponatinib for advanced gastrointestinal stromal tumors (GIST). PATIENTS AND METHODS This single-arm phase 2 trial enrolled patients with metastatic and/or unresectable GIST with failure of prior tyrosine kinase inhibitor (TKI) treatment into two cohorts based on presence or absence of KIT exon 11 (ex11) primary mutations. Patients initially received ponatinib 45 mg once daily. Following a temporary clinical hold in October 2013, dose reductions were implemented to reduce risk of arterial occlusive events (AOEs). Primary endpoint was 16-week clinical benefit rate (CBR) in KIT ex11-positive cohort. KIT mutations in circulating tumor DNA (ctDNA) were assessed. RESULTS Forty-five patients enrolled (30 KIT ex11-positive and 15 KIT ex11-negative); median follow-up was 14.7 and 13.6 months, respectively, as of August 1, 2016. Sixteen-week CBR was 36% (KIT ex11-positive; primary endpoint) and 20% (KIT ex11-negative). ctDNA analyses (n = 37) demonstrated strong concordance of primary KIT mutations between plasma and tumor. At least two secondary mutations were detected in 35% of patients overall and 54% of KIT ex11-positive patients. Changes from baseline in mutated ctDNA levels were consistent with clinical activity. Ponatinib was ineffective in patients with KIT exon 9 primary mutations. Resistance was associated with emergence of V654A. AOEs and venous thromboembolic events occurred in three and two patients, respectively. Six patients died; two deaths (pneumonia and pulmonary embolism) were considered possibly ponatinib-related. CONCLUSION Ponatinib demonstrated activity in advanced GIST, particularly in KIT ex11-positive disease. ctDNA analysis confirmed heterogeneous resistance mutations in TKI-pretreated advanced GIST. Safety was consistent with previous studies.
Collapse
Affiliation(s)
| | | | - Jonathan A Fletcher
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School
| | - Jichao Sun
- Clinical Research, ARIAD Pharmaceuticals, Inc
| | - Sen Zhang
- ARIAD Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited
| | | | | | - David Kerstein
- Clinical Research and Development, Theseus Pharmaceuticals
| | | | | | - Michael C Heinrich
- Knight Cancer Institute, Portland VA Health Care System and Oregon Health & Science University
| |
Collapse
|
|
23
|
Khoo CH, Raimes S, Griffith D. Colonic gastro-intestinal stromal tumours: a rare cause of gastro-intestinal bleeding. ANZ J Surg 2022; 92:2371-2372. [PMID: 35076158 DOI: 10.1111/ans.17487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/05/2022] [Accepted: 01/08/2022] [Indexed: 11/30/2022]
Affiliation(s)
- Choo Hang Khoo
- General Surgery Rotorua, Lakes DHB, Rotorua, New Zealand
| | - Simon Raimes
- General Surgery Rotorua, Lakes DHB, Rotorua, New Zealand
| | - David Griffith
- General Surgery Rotorua, Lakes DHB, Rotorua, New Zealand
| |
Collapse
|
|
24
|
Uzunoglu H, Tosun Y, Akinci O, Baris B. Gastrointestinal stromal tumors of the stomach: A 10-year experience of a single-center. Niger J Clin Pract 2021; 24:1785-1792. [PMID: 34889786 DOI: 10.4103/njcp.njcp_558_20] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Background Gastrointestinal tract stromal tumors (GIST) are the most common mesenchymal tumors in the gastrointestinal tract (GIS). GISTs may cause significant morbidity and mortality rates. Aim In this study, it was aimed to evaluate 10 years of gastric GIST cases followed in our hospital, and to analyze the prognostic factors. Subjects and Methods In this single-center retrospective study, a total of 64 patients who were operated between May 2010 and May 2020 due to gastric GIST tumor were reviewed. Clinical and pathological features, risk classifications, overall survival (OS) and disease-free survival (DFS) were evaluated. Results According to the risk classification, 18.8% of the patients were in the high-risk group. The overall 5-year OS and DFS rates were 85.7%. The mean OS of the patients was 47.9 SD36.2 months, and the duration of DFS was 45.5 months. Patients with a 5-year OS rate above 5 cm in diameter (P = 0.024), with a mitotic index above 5/50 high power field (HPF) (P = 0.038), and those with a high-risk group (P = 0.011) were significantly lower than the other group. In the correlation analysis, it was found that tumor diameter correlated significantly with OS (P = 0.034; r = -0.317). Tumor diameter and mitotic index were found to be inversely correlated with DFS duration (P = 0.004; r = -0.425 and P = 0.035; r = -0.316, respectively). Conclusion Our findings showed that in gastric GIST cases, as the primary tumor diameter and mitotic index increase, correlate with survival rates and the mean overall and disease-free survival times decrease.
Collapse
Affiliation(s)
- H Uzunoglu
- Department of General Surgery, Kartal Dr Lütfi Kırdar City Hospital, Istanbul, Turkey
| | - Y Tosun
- Department of General Surgery, Kartal Dr Lütfi Kırdar City Hospital, Istanbul, Turkey
| | - O Akinci
- Department of General Surgery, Kartal Dr Lütfi Kırdar City Hospital, Istanbul, Turkey
| | - B Baris
- Department of General Surgery, Kartal Dr Lütfi Kırdar City Hospital, Istanbul, Turkey
| |
Collapse
|
|
25
|
Fujii Y, Iwasaki R, Ikeda S, Chimura S, Goto M, Yoshizaki K, Sakai H, Ito N, Mori T. Gastrointestinal stromal tumour lacking mutations in the KIT and PDGFRA genes in a cat. J Small Anim Pract 2021; 63:239-243. [PMID: 34409605 DOI: 10.1111/jsap.13416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 07/05/2021] [Accepted: 08/06/2021] [Indexed: 11/28/2022]
Abstract
Molecular subtyping in gastrointestinal stromal tumours is a useful method for predicting the efficacy of treatment using tyrosine kinase inhibitors in humans. However, owing to the paucity of reports on mutational analyses, the association between genetic mutations and the therapeutic response to tyrosine kinase inhibitors remains unclear in feline gastrointestinal stromal tumours. In this report, we describe the case of a cat with a gastrointestinal stromal tumour which was unresponsive to tyrosine kinase inhibitors. A mutational analysis revealed that the cat lacked mutations in both the KIT and platelet-derived growth factor receptor-alpha (PDGFRA) genes. Our findings are consistent with the fact that KIT/PDGFRA wild-type gastrointestinal stromal tumours are less responsive to tyrosine kinase inhibitors in humans. This signifies the need for further evaluation and possibly individualised treatment for gastrointestinal stromal tumours in cats on the basis of mutational analyses.
Collapse
Affiliation(s)
- Y Fujii
- Joint Graduate School of Veterinary Sciences, Gifu University, Gifu, Gifu, Japan.,Animal Medical Centre, Gifu University, Gifu, Gifu, Japan
| | - R Iwasaki
- Animal Medical Centre, Gifu University, Gifu, Gifu, Japan
| | - S Ikeda
- Chimura Animal Hospital, Iwakura, Aichi, Japan
| | - S Chimura
- Chimura Animal Hospital, Iwakura, Aichi, Japan
| | - M Goto
- Laboratory of Veterinary Pathology, Faculty of Applied Biological Sciences, Gifu University, Gifu, Gifu, Japan
| | - K Yoshizaki
- Laboratory of Veterinary Pathology, Faculty of Applied Biological Sciences, Gifu University, Gifu, Gifu, Japan
| | - H Sakai
- Joint Graduate School of Veterinary Sciences, Gifu University, Gifu, Gifu, Japan.,Laboratory of Veterinary Pathology, Faculty of Applied Biological Sciences, Gifu University, Gifu, Gifu, Japan
| | - N Ito
- Joint Graduate School of Veterinary Sciences, Gifu University, Gifu, Gifu, Japan
| | - T Mori
- Joint Graduate School of Veterinary Sciences, Gifu University, Gifu, Gifu, Japan.,Animal Medical Centre, Gifu University, Gifu, Gifu, Japan
| |
Collapse
|
|
26
|
Bauer S, George S, von Mehren M, Heinrich MC. Early and Next-Generation KIT/PDGFRA Kinase Inhibitors and the Future of Treatment for Advanced Gastrointestinal Stromal Tumor. Front Oncol 2021; 11:672500. [PMID: 34322383 PMCID: PMC8313277 DOI: 10.3389/fonc.2021.672500] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 06/22/2021] [Indexed: 12/21/2022] Open
Abstract
The majority of gastrointestinal stromal tumors (GIST) harbor an activating mutation in either the KIT or PDGFRA receptor tyrosine kinases. Approval of imatinib, a KIT/PDGFRA tyrosine kinase inhibitor (TKI), meaningfully improved the treatment of advanced GIST. Other TKIs subsequently gained approval: sunitinib as a second-line therapy and regorafenib as a third-line therapy. However, resistance to each agent occurs in almost all patients over time, typically due to secondary kinase mutations. A major limitation of these 3 approved therapies is that they target the inactive conformation of KIT/PDGFRA; thus, their efficacy is blunted against secondary mutations in the kinase activation loop. Neither sunitinib nor regorafenib inhibit the full spectrum of KIT resistance mutations, and resistance is further complicated by extensive clonal heterogeneity, even within single patients. To combat these limitations, next-generation TKIs were developed and clinically tested, leading to 2 new USA FDA drug approvals in 2020. Ripretinib, a broad-spectrum KIT/PDGFRA inhibitor, was recently approved for the treatment of adult patients with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib. Avapritinib, a type I kinase inhibitor that targets active conformation, was approved for the treatment of adults with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. In this review, we will discuss how resistance mutations have driven the need for newer treatment options for GIST and compare the original GIST TKIs with the next-generation KIT/PDGFRA kinase inhibitors, ripretinib and avapritinib, with a focus on their mechanisms of action.
Collapse
Affiliation(s)
- Sebastian Bauer
- Department of Medical Oncology, West German Cancer Center, Essen University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Suzanne George
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Margaret von Mehren
- Department of Hematology and Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, United States
| | - Michael C. Heinrich
- Department of Medicine, Portland VA Health Care System and OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR, United States
| |
Collapse
|
|
27
|
Yin X, Yin Y, Dai L, Shen C, Chen N, Li J, Cai Z, Jiang Z, Wang J, Zhao Z, Chen X, Deng H, Zhang B. Integrated analysis of long non-coding RNAs and mRNAs associated with malignant transformation of gastrointestinal stromal tumors. Cell Death Dis 2021; 12:669. [PMID: 34218261 PMCID: PMC8254811 DOI: 10.1038/s41419-021-03942-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 04/25/2021] [Accepted: 04/26/2021] [Indexed: 02/07/2023]
Abstract
Malignant transformation of gastrointestinal stromal tumors (GISTs) is correlated with poor prognosis; however, the underlying biological mechanism is not well understood. In the present study, low-risk (LR) GISTs, GISTs categorized as high-risk based on tumor size (HBS), and on mitotic rate (HBM) were collected for RNA sequencing. Candidate hub lncRNAs were selected by Oncomine analysis. Expression of a selected hub lncRNA, DNM3OS, and its correlation with patients' prognosis were analyzed using FISH staining, followed with the determination of function and underlying mechanism. Our results revealed a series of key pathways and hub lncRNAs involved in the malignant transformation of GISTs. Oncomine analysis revealed a tight association between clinical signatures and DNM3OS and suggested that DNM3OS is a hub lncRNA that is involved in the Hippo signaling pathway. In addition, DNM3OS was upregulated in HBS, HBM, and HBS/M GIST and correlated with worse prognosis in patients with GISTs. In addition, DNM3OS promoted GIST cell proliferation and mitosis by regulating the expression of GLUT4 and CD36. Collectively, these results improve our understanding of the malignant transformation of GISTs and unveil a series of hub lncRNAs in GISTs.
Collapse
MESH Headings
- CD36 Antigens/genetics
- CD36 Antigens/metabolism
- Cell Line, Tumor
- Cell Proliferation
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Databases, Genetic
- Gastrointestinal Neoplasms/genetics
- Gastrointestinal Neoplasms/metabolism
- Gastrointestinal Neoplasms/pathology
- Gastrointestinal Stromal Tumors/genetics
- Gastrointestinal Stromal Tumors/metabolism
- Gastrointestinal Stromal Tumors/pathology
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Gene Regulatory Networks
- Glucose Transporter Type 4/genetics
- Glucose Transporter Type 4/metabolism
- Humans
- Mitosis
- Protein Interaction Maps
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Signal Transduction
- Transcriptome
Collapse
Affiliation(s)
- Xiaonan Yin
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Yuan Yin
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Lei Dai
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, 610041, China.
| | - Chaoyong Shen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Na Chen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, 610041, China
| | - Junshu Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, 610041, China
| | - Zhaolun Cai
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Zhiyuan Jiang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Jian Wang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Zhou Zhao
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Xin Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Hongxin Deng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, 610041, China.
| | - Bo Zhang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
| |
Collapse
|
|
28
|
Recent Progress and Challenges in the Diagnosis and Treatment of Gastrointestinal Stromal Tumors. Cancers (Basel) 2021; 13:cancers13133158. [PMID: 34202544 PMCID: PMC8268322 DOI: 10.3390/cancers13133158] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/18/2021] [Accepted: 06/22/2021] [Indexed: 12/31/2022] Open
Abstract
Simple Summary Gastrointestinal stromal tumors (GIST) are potentially malignant tumors and require evidence-based surgical and/or medical treatment. Laparoscopy has similar safety and prognostic outcomes to those of laparotomy and is currently a standard procedure for localized GISTs. However, surgery for gastric GISTs less than 2 cm may be re-evaluated due to the indolent nature of the GIST and other competing risks among GIST patients. A work-up with endoscopy and endoscopic ultrasonography as well as endoscopic or percutaneous biopsy is important for the preoperative diagnosis of GISTs. Medical treatment with tyrosine kinase inhibitors is the mainstay for recurrent/metastatic GISTs. The activity of an individual drug is well correlated with gene alterations, and, in the era of precision medicine, cancer genome profiling should be considered before medical treatment. Abstract Gastrointestinal stromal tumors (GISTs) are the most frequent malignant mesenchymal tumors in the gastrointestinal tract. The clinical incidence of GISTs is estimated 10/million/year; however, the true incidence is complicated by frequent findings of tiny GISTs, of which the natural history is unknown. The initial work-up with endoscopy and endoscopic ultrasonography plays important roles in the differential diagnosis of GISTs. Surgery is the only modality for the permanent cure of localized GISTs. In terms of safety and prognostic outcomes, laparoscopy is similar to laparotomy for GIST treatment, including tumors larger than 5 cm. GIST progression is driven by mutations in KIT or PDGFRA or by other rare gene alterations, all of which are mutually exclusive. Tyrosine kinase inhibitors (TKIs) are the standard therapy for metastatic/recurrent GISTs. Molecular alterations are the most reliable biomarkers for TKIs and for other drugs, such as NTRK inhibitors. The pathological and genetic diagnosis prior to treatment has been challenging; however, a newly developed endoscopic device may be useful for diagnosis. In the era of precision medicine, cancer genome profiling by targeted gene panel analysis may enable potential targeted therapy even for GISTs without KIT or PDGFRA mutations.
Collapse
|
|
29
|
Song Q, Li G, Li Z, Ao S, Hou J, Lv G. Mutations in ALK and TSC1 in a gastrointestinal stromal tumor: a case report. BMC Surg 2021; 21:202. [PMID: 33879132 PMCID: PMC8059153 DOI: 10.1186/s12893-021-01208-0] [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: 09/29/2020] [Accepted: 04/14/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Gastrointestinal stromal tumors rarely occur in children, but when they do, their biological behavior and histopathological patterns differ from those of adults. CASE PRESENTATION A 13-year-old boy with a gastrointestinal stromal tumor was characterized by a rare genetic mutation. The patient complained of "fatigue with intermittent abdominal pain for 1 month". According to the preoperative imaging examination, gastroscopy, and gastroscopic biopsy, the patient was diagnosed with a gastric stromal tumor. Postoperative pathology showed that the tumor cells were fusiform and ovoid, and mitotic figures were easily seen. Immunohistochemistry revealed that the tumor was S-100(+), SOX10(-), CD34(+), SMA(partially+), DOG-1(+), CD117(+), KI-67 (positive for 20% + of the subjects and 40% + of the hotspots), and SDHB(-). Genetic tests showed missense mutations in ALK and TSC1. With surgical treatment, the tumor was completely removed. The patient recovered well and was discharged on the ninth day after the operation. He is currently under follow-up. CONCLUSIONS In this case involving a patient with a gastrointestinal stromal tumor, immunohistochemistry indicated that the tumor was an "SDH-deficient type", and gene detection showed no KIT or PDGFRA mutation but rare ALK and TSC1 mutations, which adds to the knowledge of the types of gene mutations in children with gastrointestinal stromal tumors.
Collapse
Affiliation(s)
- Qingzhi Song
- Peking University Shenzhen Hospital, Clinical College of Anhui Medical University, Shenzhen, 518036, Guangdong, People's Republic of China
| | - Guan Li
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong, People's Republic of China
| | - Zhuofei Li
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong, People's Republic of China
| | - Sheng Ao
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong, People's Republic of China
| | - Jianing Hou
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong, People's Republic of China
| | - Guoqing Lv
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong, People's Republic of China.
| |
Collapse
|
|
30
|
Wang Q, Huang ZP, Zhu Y, Fu F, Tian L. Contribution of Interstitial Cells of Cajal to Gastrointestinal Stromal Tumor Risk. Med Sci Monit 2021; 27:e929575. [PMID: 33760802 PMCID: PMC8006562 DOI: 10.12659/msm.929575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Accepted: 01/17/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Gastrointestinal stromal tumors (GISTs), which originate from interstitial cells of Cajal (ICCs), are one of most common mesenchymal tumors of the gastrointestinal tract. This study explored the impact of ICCs and immunological markers on GIST risk. MATERIAL AND METHODS A total of 122 patients diagnosed with GISTs who underwent surgery were recruited for the study. Demographic and clinical information, including modified NIH criteria, sex, age, tumor site, and tumor size, of all patients were collected. GIST risk was assessed using the modified NIH risk classification for primary GISTs. Paraffin-embedded GIST specimens were evaluated by hematoxylin-eosin staining and ICCs immunohistochemistry. RESULTS According to the modified NIH criteria, most GIST cases (44 cases, 36.07%) were at very low risk. Females had greater incidence of high-risk GISTs (P<0.05). The mean age at GIST diagnosis was 58.69±9.90 years and had no impact on GIST risk (P>0.05). Most GISTs were located in the stomach (87 cases, 71.73%), and the size of the tumors varied (0.5-20 cm). CD117/c-kit and CD34 were specific immuno-markers for ICCs and GIST. Most patients with GIST were CD117-positive (115 cases, 94.26%), 111 cases (90.98%) were CD34-positive, and 109 cases (89.34%) were positive for both CD117/c-kit and CD34. With increasing GIST risk, CD117 (also named c-k0it) and CD34 expression levels increased, as well as the number of ICCs (all P<0.05). CONCLUSIONS ICCs have a great impact on GISTs incidence. CD117/c-kit and CD34 expression, as well ICCs levels, appear to affect GIST risk.
Collapse
Affiliation(s)
- Qi Wang
- Department of Pathology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, P.R. China
| | - Zhen-peng Huang
- Guangzhou Institute of Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, Guangdong, P.R. China
| | - Yu Zhu
- Department of Science and Education, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, P.R. China
| | - Fei Fu
- Department of Pathology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, P.R. China
| | - Lin Tian
- Department of Pathology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, P.R. China
| |
Collapse
|
|
31
|
Yonkus JA, Alva-Ruiz R, Grotz TE. Surgical Management of Metastatic Gastrointestinal Stromal Tumors. Curr Treat Options Oncol 2021; 22:37. [PMID: 33743084 DOI: 10.1007/s11864-021-00837-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/18/2021] [Indexed: 02/08/2023]
Abstract
Treatment with the tyrosine kinase inhibitor (TKI), imatinib is the standard first-line treatment for metastatic gastrointestinal stromal tumors (GISTs). Unfortunately, acquired c-kit mutations cause secondary resistance to imatinib in a median of 18-24 months. Sunitinib and regorafenib are multi-kinase inhibitors that can be used as second-line or third-line therapy in imatinib-resistant or -intolerant GISTs, respectively. Ripretinib (a switch-control tyrosine kinase inhibitor) has recently been approved for fourth-line treatment in metastatic GIST. The TKI avapritinib has been approved for metastatic GIST harboring the imatinib-resistant PDGFRA exon 18 mutation. Although TKI therapies have revolutionized the treatment of metastatic GISTs, they cannot cure metastatic GISTs. Therefore, cytoreductive surgery is of considerable interest and has been accordingly investigated. Retrospective non-randomized studies demonstrated the feasibility and safety of continuous TKI therapy and surgical resection. Most studies demonstrate response to TKI therapy, completeness of resection, extent of disease, and surgical complexity as predictors of outcomes. Most TKIs can be stopped shortly before surgery and restarted shortly after. There is no known survival benefit from debulking operations or R2 resections and this should not be considered. However, debulking/palliative surgery may be necessary for patients with complications of hemorrhage, pain, or intestinal obstruction. SDH-deficient GISTs have an indolent natural history despite metastatic disease and may be another uncommon subgroup that would benefit from surgical debulking (R2 resection). At the time of operation, care should be taken to avoid tumor rupture. After surgical resection, patients should resume tyrosine kinase inhibitor (TKI) therapy as soon as possible and be monitored for disease progression. In all patients with metastatic GIST, the decision to pursue metastasectomy for GIST should be made in a multidisciplinary setting and be individualized according to patient age, comorbidities, functional status, symptoms, mutation status, extent of disease, completeness of resection, TKI response, and goals of the patient.
Collapse
Affiliation(s)
- Jennifer A Yonkus
- Department of Surgery, Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, 200 First Street S.W, Rochester, MN, 55905, USA
| | - Roberto Alva-Ruiz
- Department of Surgery, Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, 200 First Street S.W, Rochester, MN, 55905, USA
| | - Travis E Grotz
- Department of Surgery, Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, 200 First Street S.W, Rochester, MN, 55905, USA.
| |
Collapse
|
|
32
|
Huang C, Li CG, Zhang P, Yang WC, Lin Y, Shuai XM, Gao JB, Cai M, Tao KX. Duodenal gastrointestinal stromal tumors: A retrospective study based on a 13 years experience of a single center in China. Asia Pac J Clin Oncol 2021; 17:506-512. [PMID: 33567161 DOI: 10.1111/ajco.13509] [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: 12/04/2019] [Accepted: 10/03/2020] [Indexed: 01/10/2023]
Abstract
AIM Duodenal gastrointestinal stromal tumors (GISTs) constitute a small rare subset. This study aims to analyze the prognostic differences between duodenal and jejunoileal GISTs and evaluate the clinical treatment and prognostic characteristics of patients with duodenal GISTs. METHODS Data of patients with primary duodenal or jejunoileal GISTs were collected. Patients were matched through propensity score matching (PSM). Perioperative and long-term outcomes of patients with duodenal GISTs were compared based on surgical approach. RESULTS Altogether, 101 duodenal and 219 jejunoileal GISTs were identified. In patients with duodenal GISTs, 79 (78%) underwent local resection (LR) and 22 (22%) underwent pancreaticoduodenectomy (PD). Patients undergoing PD had a longer postoperation stay (18.5 vs 13 days, P = 0.001) and more complications (Clavien-Dindo I-II complications for PD vs LR, 31.8 vs 15.2%; Clavien-Dindo III-V complications for PD vs LR, 22.7 vs. 2.5%; P < 0.001). There was no difference in recurrence-free survival (RFS) (P = 0.8) or overall survival (OS) (P = 0.9) when comparing patients who underwent LR versus PD. Multivariable analysis showed that tumor size >5 cm was the only independent predictor of shorter RFS (P = 0.004) and OS (P = 0.012). After matching, there was no significant difference in RFS and OS between patients with duodenal versus jejunoileal GISTs (both P > 0.05). CONCLUSION The prognosis of duodenal and jejunoileal GISTs are similar. Recurrence and OS of duodenal GISTs primarily depend on tumor size. For duodenal GISTs, LR is associated with comparable long-term survival when compared to PD, but with superior short-term outcomes.
Collapse
Affiliation(s)
- Cheng Huang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
| | - Cheng-Guo Li
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
| | - Peng Zhang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
| | - Wen-Chang Yang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
| | - Yao Lin
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
| | - Xiao-Ming Shuai
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
| | - Jin-Bo Gao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
| | - Ming Cai
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
| | - Kai-Xiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
| |
Collapse
|
|
33
|
Vallilas C, Sarantis P, Kyriazoglou A, Koustas E, Theocharis S, Papavassiliou AG, Karamouzis MV. Gastrointestinal Stromal Tumors (GISTs): Novel Therapeutic Strategies with Immunotherapy and Small Molecules. Int J Mol Sci 2021; 22:493. [PMID: 33419029 PMCID: PMC7825300 DOI: 10.3390/ijms22020493] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/03/2021] [Accepted: 01/04/2021] [Indexed: 02/08/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common types of malignant mesenchymal tumors in the gastrointestinal tract, with an estimated incidence of 1.5/100.000 per year and 1-2% of gastrointestinal neoplasms. About 75-80% of patients have mutations in the KIT gene in exons 9, 11, 13, 14, 17, and 5-10% of patients have mutations in the platelet-derived growth factor receptor a (PDGFRA) gene in exons 12, 14, 18. Moreover, 10-15% of patients have no mutations and are classified as wild type GIST. The treatment for metastatic or unresectable GISTs includes imatinib, sunitinib, and regorafenib. So far, GIST therapies have raised great expectations and offered patients a better quality of life, but increased pharmacological resistance to tyrosine kinase inhibitors is often observed. New treatment options have emerged, with ripretinib, avapritinib, and cabozantinib getting approvals for these tumors. Nowadays, immune checkpoint inhibitors form a new landscape in cancer therapeutics and have already shown remarkable responses in various tumors. Studies in melanoma, non-small-cell lung cancer, and renal cell carcinoma are very encouraging as these inhibitors have increased survival rates. The purpose of this review is to present alternative approaches for the treatment of the GIST patients, such as combinations of immunotherapy and novel inhibitors with traditional therapies (tyrosine kinase inhibitors).
Collapse
Affiliation(s)
- Christos Vallilas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.V.); (P.S.); (E.K.); (A.G.P.)
| | - Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.V.); (P.S.); (E.K.); (A.G.P.)
| | - Anastasios Kyriazoglou
- 2nd Propaedeutic Department of Medicine, ATTIKON University Hospital, 12462 Athens, Greece;
| | - Evangelos Koustas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.V.); (P.S.); (E.K.); (A.G.P.)
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Athanasios G. Papavassiliou
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.V.); (P.S.); (E.K.); (A.G.P.)
| | - Michalis V. Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.V.); (P.S.); (E.K.); (A.G.P.)
| |
Collapse
|
|
34
|
Rai N, Singh AK, Keshri PK, Barik S, Kamble SC, Singh SK, Kumar R, Mishra P, Kotiya D, Gautam V. Probiotics for Management of Gastrointestinal Cancers. PROBIOTIC RESEARCH IN THERAPEUTICS 2021:191-209. [DOI: 10.1007/978-981-15-8214-1_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
35
|
Vanden Bempt I, Vander Borght S, Sciot R, Spans L, Claerhout S, Brems H, Lehnert S, Dehaspe L, Fransis S, Neuville B, Topal B, Schöffski P, Legius E, Debiec-Rychter M. Comprehensive targeted next-generation sequencing approach in the molecular diagnosis of gastrointestinal stromal tumor. Genes Chromosomes Cancer 2020; 60:239-249. [PMID: 33258138 DOI: 10.1002/gcc.22923] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/25/2020] [Accepted: 11/28/2020] [Indexed: 12/26/2022] Open
Abstract
Mutational analysis guides therapeutic decision making in patients with advanced-stage gastrointestinal stromal tumors (GISTs). We evaluated three targeted next-generation sequencing (NGS) assays, consecutively used over 4 years in our laboratory for mutational analysis of 162 primary GISTs: Agilent GIST MASTR, Illumina TruSight 26 and an in-house developed 96 gene panels. In addition, we investigated the feasibility of a more comprehensive approach by adding targeted RNA sequencing (Archer FusionPlex, 11 genes) in an attempt to reduce the number of Wild Type GISTs. We found KIT or PDGFRA mutations in 149 out of 162 GISTs (92.0%). Challenging KIT exon 11 alterations were initially missed by different assays in seven GISTs and typically represented deletions at the KIT intron 10-exon 11 boundary or large insertions/deletions (>24 base pairs). Comprehensive analysis led to the additional identification of driver alterations in 8/162 GISTs (4.9%): apart from BRAF and SDHA mutations (one case each), we found five GISTs harboring somatic neurofibromatosis type 1 (NF1) alterations (3.1%) and one case with an in-frame TRIM4-BRAF fusion not reported in GIST before. Eventually, no driver alteration was found in two out of 162 GISTs (1.2%) and three samples (1.9%) failed analysis. Our study shows that a comprehensive targeted NGS approach is feasible for routine mutational analysis of GIST, thereby substantially reducing the number of Wild Type GISTs, and highlights the need to optimize assays for challenging KIT exon 11 alterations.
Collapse
Affiliation(s)
- Isabelle Vanden Bempt
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Sara Vander Borght
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.,Department of Pathology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Raf Sciot
- Department of Pathology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Lien Spans
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Sofie Claerhout
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Hilde Brems
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Stefan Lehnert
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Luc Dehaspe
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Sabine Fransis
- Department of Pathology, Ziekenhuis Oost Limburg, Genk, Belgium
| | - Bart Neuville
- Department of Gastroenterology and Hepatology, Ziekenhuis Oost-Limburg, Genk, Belgium
| | - Baki Topal
- Department of Abdominal Surgery, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Patrick Schöffski
- Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, and Department of Oncology, KU Leuven, Laboratory of Experimental Oncology, Leuven, Belgium.,Department of Oncology, KU Leuven, Laboratory of Experimental Oncology, Leuven, Belgium
| | - Eric Legius
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Maria Debiec-Rychter
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| |
Collapse
|
|
36
|
Fornasarig M, Gasparotto D, Foltran L, Campigotto M, Lombardi S, Del Savio E, Buonadonna A, Puglisi F, Sulfaro S, Canzonieri V, Cannizzaro R, Maestro R. A Novel Kindred with Familial Gastrointestinal Stromal Tumors Caused by a Rare KIT Germline Mutation (N655K): Clinico-Pathological Presentation and TKI Sensitivity. J Pers Med 2020; 10:jpm10040234. [PMID: 33212994 PMCID: PMC7711910 DOI: 10.3390/jpm10040234] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 11/09/2020] [Accepted: 11/14/2020] [Indexed: 02/07/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, are characterized by activating mutations in KIT or PDGFRA genes. The vast majority of GISTs are sporadic, but rare hereditary forms have been reported, often featuring multifocality and younger age of onset. We here report the identification of a novel kindred affected by familial GIST caused by a KIT germline mutation in exon 13 (N655K). No family affected by hereditary GIST due to this KIT variant has been reported in literature so far. We were able to track the mutation in three members of the family (proband, mother, and second-degree cousin), all affected by multiple GISTs. Due to its rarity, the N655K variant is poorly characterized. We conducted in vitro drug sensitivity assays that indicated that most tyrosine kinase inhibitors (TKIs) currently included in the therapeutic armamentarium for GISTs have a limited inhibitory activity toward this mutation. However, when compared to a classical imatinib-resistant KIT mutation (T670I), N655K was slightly more sensitive to imatinib, and encouraging responses were observed with last-generation TKIs.
Collapse
Affiliation(s)
- Mara Fornasarig
- Unit of Oncological Gastroenterology, Centro di Riferimento Oncologico di Aviano (CRO Aviano), IRCCS, 33081 Aviano, Italy; (M.F.); (R.C.)
| | - Daniela Gasparotto
- Unit of Oncogenetics and Functional Oncogenomics, Centro di Riferimento Oncologico di Aviano (CRO Aviano), IRCCS, 33081 Aviano, Italy; (D.G.); (S.L.); (E.D.S.)
| | - Luisa Foltran
- Unit of Medical Oncology and Cancer Prevention, Centro di Riferimento Oncologico di Aviano (CRO Aviano), IRCCS, 33081 Aviano, Italy; (L.F.); (A.B.); (F.P.)
| | - Michele Campigotto
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (M.C.); (V.C.)
| | - Sara Lombardi
- Unit of Oncogenetics and Functional Oncogenomics, Centro di Riferimento Oncologico di Aviano (CRO Aviano), IRCCS, 33081 Aviano, Italy; (D.G.); (S.L.); (E.D.S.)
| | - Elisa Del Savio
- Unit of Oncogenetics and Functional Oncogenomics, Centro di Riferimento Oncologico di Aviano (CRO Aviano), IRCCS, 33081 Aviano, Italy; (D.G.); (S.L.); (E.D.S.)
| | - Angela Buonadonna
- Unit of Medical Oncology and Cancer Prevention, Centro di Riferimento Oncologico di Aviano (CRO Aviano), IRCCS, 33081 Aviano, Italy; (L.F.); (A.B.); (F.P.)
| | - Fabio Puglisi
- Unit of Medical Oncology and Cancer Prevention, Centro di Riferimento Oncologico di Aviano (CRO Aviano), IRCCS, 33081 Aviano, Italy; (L.F.); (A.B.); (F.P.)
- Department of Medicine, University of Udine, 3310 Udine, Italy
| | - Sandro Sulfaro
- Unit of Pathology, Santa Maria Degli Angeli General Hospital, 33170 Pordenone, Italy;
| | - Vincenzo Canzonieri
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (M.C.); (V.C.)
- Unit of Pathology, Centro di Riferimento Oncologico di Aviano (CRO Aviano), IRCCS, 33081 Aviano, Italy
| | - Renato Cannizzaro
- Unit of Oncological Gastroenterology, Centro di Riferimento Oncologico di Aviano (CRO Aviano), IRCCS, 33081 Aviano, Italy; (M.F.); (R.C.)
| | - Roberta Maestro
- Unit of Oncogenetics and Functional Oncogenomics, Centro di Riferimento Oncologico di Aviano (CRO Aviano), IRCCS, 33081 Aviano, Italy; (D.G.); (S.L.); (E.D.S.)
- Correspondence:
| |
Collapse
|
|
37
|
Fassan M, Scarpa A, Remo A, De Maglio G, Troncone G, Marchetti A, Doglioni C, Ingravallo G, Perrone G, Parente P, Luchini C, Mastracci L. Current prognostic and predictive biomarkers for gastrointestinal tumors in clinical practice. Pathologica 2020; 112:248-259. [PMID: 33179625 PMCID: PMC7931577 DOI: 10.32074/1591-951x-158] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 06/24/2020] [Indexed: 12/12/2022] Open
Abstract
The pathologist emerged in the personalized medicine era as a central actor in the definition of the most adequate diagnostic and therapeutic algorithms. In the last decade, gastrointestinal oncology has seen a significantly increased clinical request for the integration of novel prognostic and predictive biomarkers in histopathological reports. This request couples with the significant contraction of invasive sampling of the disease, thus conferring to the pathologist the role of governor for both proper pathologic characterization and customized processing of the biospecimens. This overview will focus on the most commonly adopted immunohistochemical and molecular biomarkers in the routine clinical characterization of gastrointestinal neoplasms referring to the most recent published recommendations, guidelines and expert opinions.
Collapse
Affiliation(s)
- Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Italy
| | - Aldo Scarpa
- ARC-NET Research Centre, University of Verona, Italy
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Andrea Remo
- Pathology Unit, Service Department, ULSS9 “Scaligera”, Verona, Italy
| | | | - Giancarlo Troncone
- Department of Public Health, Federico II University Medical School Naples, Italy
| | - Antonio Marchetti
- Center of Predictive Molecular Medicine, Center for Excellence on Aging and Translational Medicine, University of Chieti-Pescara, Italy
| | - Claudio Doglioni
- Vita e Salute University, Milan, Italy
- Pathology Unit, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giuseppe Ingravallo
- Department of Emergency and Organ Transplantation, Section of Pathological Anatomy, University of Bari Aldo Moro, Bari, Italy
| | - Giuseppe Perrone
- Department of Pathology, Campus Bio-Medico University, Rome, Italy
| | - Paola Parente
- Pathology Unit, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Luca Mastracci
- Anatomic Pathology, San Martino IRCCS Hospital,, Genova, Italy
- Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Genova, Italy
| |
Collapse
|
|
38
|
Ahmed M. Recent advances in the management of gastrointestinal stromal tumor. World J Clin Cases 2020; 8:3142-3155. [PMID: 32874969 PMCID: PMC7441252 DOI: 10.12998/wjcc.v8.i15.3142] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 05/26/2020] [Accepted: 07/14/2020] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal stromal tumor (GIST) is a rare but an important clinical entity seen in our clinical practice. It is the most common mesenchymal tumor of the gastrointestinal tract and most common malignancy of the small intestine. Although the exact prevalence of GIST is not known, the incidence of GIST has been increasing. GISTs arise from interstitial cells of Cajal. Most of the GISTs occur due to mutation in c-kit gene or platelet derived growth factor receptor alpha gene. 15% of GISTs do not have these mutations and they are called wild-type GISTs. Almost all GISTs express KIT receptor tyrosine kinase. Histologically, GISTs look like spindle cell tumors most of the time but they can be epitheloid or mixed type. The median size of GISTs varies from 2.7 cm to 8.9 cm. Clinically, patients with small GISTs remain asymptomatic but as the GIST size increases, patients present with various symptoms depending on the location of the GIST. Most of GISTs are located in the stomach or small bowel. Diagnosis is suspected on imaging and endoscopic studies, and confirmed by tissue acquisition with immunohistochemical staining. The aggressiveness of GISTs depends on the size, mitotic index and location. Surgical resection is the treatment of choice. But various endoscopic modalities of resection are increasingly being tried. Tyrosine kinase inhibitors are extremely useful in the management of large GISTs, unresectable GISTs and metastatic GISTs. Treatment options for metastatic GISTs also include radiotherapy, chemotherapy, hepatic artery embolization, chemoembolization and radiofrequency ablation.
Collapse
Affiliation(s)
- Monjur Ahmed
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Thomas Jefferson University, Philadelphia, PA 19107, United States
| |
Collapse
|
|
39
|
Zhang H, Liu Q. Prognostic Indicators for Gastrointestinal Stromal Tumors: A Review. Transl Oncol 2020; 13:100812. [PMID: 32619820 PMCID: PMC7327422 DOI: 10.1016/j.tranon.2020.100812] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/25/2020] [Accepted: 05/27/2020] [Indexed: 02/08/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are potentially malignancies that can occur anywhere in the digestive tract. Tyrosine kinase inhibitors (TKIs) such as imatinib have proven effective since the discovery of KIT and PDGFRA. The current version of NCNN, ESMO and EURACAN guidelines recognized that the three main prognostic factors are the mitotic rate, tumor size and tumor site. In addition, tumor rupture is also recognized as an independent risk factor. However, recent evidence shows that various types of gene mutations are associated with prognosis, and influencing factors such as gastrointestinal bleeding and high Ki67 index have been associated with poor prognosis. It shows that the current risk classification is still insufficient and controversial. With the emergence of more and more lack mutation in KIT/PDGFRA GISTs (KIT/PDGFRA wild-type GISTs) or drug resistance genes, primary and secondary drug resistance problems are caused, which makes the treatment of late or metastatic GIST face challenges. Therefore, this article will review the clinicopathological characteristics of GIST, the special molecular subtypes and other factors that may affect prognosis. We will also explore reliable prognostic markers for better postoperative management and improve the prognosis of patients with GIST.
Collapse
Affiliation(s)
- Haixin Zhang
- Department of Trauma center, The First Hospital of China Medical University, Shenyang, China
| | - Qi Liu
- Department of Trauma center, The First Hospital of China Medical University, Shenyang, China.
| |
Collapse
|
|
40
|
Mootz A, Nguyen T, Poddar K, Goel A. Primary Gastrointestinal Stromal Tumor Presenting as an Isolated Lung Mass. Cureus 2020; 12:e8343. [PMID: 32617217 PMCID: PMC7325361 DOI: 10.7759/cureus.8343] [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] [Indexed: 11/07/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are rare gastrointestinal (GI) tumors, representing a small portion of soft tissue tumors of the abdominal cavity. Extraintestinal gastrointestinal stromal tumors (EGISTs) are uncommon forms of GISTs that present outside the GI tract. There have only been a rare number of reported cases of EGIST presenting above the diaphragm. We present the case of a 50-year-old female with shortness of breath, and found to have bilateral pleural effusions and left-sided lung mass. The initial lung mass aspiration was negative for malignancy; yet, pleural fluid was suggestive of malignancy, and repeat biopsy and immunohistochemical stain were diagnostic for GIST. Ultimately, the patient underwent video-assisted thoracoscopic surgery, pleurodesis with doxycycline, and adjuvant therapy with imatinib. This is a report of primary EGIST presenting as an isolated lung lesion with no involvement of the GI tract. In patients with suspected malignancy, it is of paramount importance to obtain a detailed history, including remote signs and symptoms, while performing a thorough work-up. Especially in the lung where initial biopsies can be skewed due to inflammation and atelectasis, repeat biopsies may be necessary to obtain an accurate diagnosis.
Collapse
Affiliation(s)
- Allison Mootz
- Anesthesiology, University of Texas Southwestern Medical Center, Dallas, USA
| | - Thuy Nguyen
- Internal Medicine, Texas College of Osteopathic Medicine, Fort Worth, USA
| | - Keshav Poddar
- Internal Medicine, Methodist Health System, Dallas, USA
| | - Anuj Goel
- Internal Medicine, Methodist Health System, Dallas, USA
| |
Collapse
|
|
41
|
Abstract
OPINION STATEMENT The treatment of advanced GIST is rapidly evolving with the development of novel molecular compounds such as avapritinib and ripretinib, but also promising results have been achieved with cabozantinib in a phase II trial. The availability of over five lines of treatment for patients with advanced GIST is likely to completely shift the current second-line and third-line treatment options, and will also potentially enable a personalised approach to treatment. Imatinib will most likely remain as the first-line treatment of choice for the vast majority of GIST patients. However, for GIST patients with tumours harbouring a D842V mutation in PDGFRA exon 18, avapritinib has shown efficacy and will become first-line therapy for this molecular subgroup. For second- and third-line treatment, results are awaited of a number of clinical trials. However, second-line and further treatment could potentially be tailored depending on secondary mutations found in imatinib-resistant GISTs. As secondary resistance to TKIs remains the biggest challenge in the treatment of GIST and despite negative results with alternating regimens in phase II, combination treatments should be further evaluated to tackle this issue. Moreover, the favourable safety profiles observed with avapritinib and ripretinib suggest that combination treatments are feasible, for instance, combining two TKIs or a TKI with drugs targeting downstream signalling pathways, such as PI3K inhibitors or MEK inhibitors. Finally, in line with further personalisation of treatment in GIST, a multidisciplinary approach is essential, and local treatment options, such as RFA, resection in case of unifocal progression, and radiotherapy, should be considered.
Collapse
|
|
42
|
Xu D, Lin X, Qiu X. The epithelioid gastrointestinal stromal tumor with pulmonary metastasis: A rare case report and literature review. Medicine (Baltimore) 2020; 99:e19346. [PMID: 32118771 PMCID: PMC7478712 DOI: 10.1097/md.0000000000019346] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
RATIONALE Available literature states that the histological subtype of the gastrointestinal stromal tumor (GIST) with pulmonary metastasis is often spindle cell type. To our knowledge, this is the first report of the GIST with pulmonary metastasis of very uncommon epithelioid subtype. PATIENT CONCERNS We report a 63-year-old male presenting with the symptom of bloodstained sputum without obvious inducement. The patient had no chest pain, low back pain, fatigue, fever or night sweats symptoms. DIAGNOSES Combined chest digital radiography and the history of the patient who presented with the colon GIST of the epithelioid subtype two years ago that the mass may be a metastasis tumor. Combined with morphological and immunohistochemical staining results, a pathological diagnosis of the GIST with pulmonary metastasis was considered. INTERVENTIONS Right lobectomy and partial upper lobectomy were performed. OUTCOMES The patient had not experienced any noticeable symptom and recurrent tumors at 6 months follow-up. LESSONS We report a rare case of the GIST with pulmonary metastasis of epithelioid subtype. This case is of great significance to the pathologist's clinical work. For pathologists, if an epithelioid tumor in the lung is found, it is necessary to check whether the gastrointestinal tract also has the tumor, which may be an epithelioid GIST with pulmonary metastasis.
Collapse
|
|
43
|
Kalfusova A, Linke Z, Kalinova M, Krskova L, Hilska I, Szabova J, Vicha A, Kodet R. Gastrointestinal stromal tumors – Summary of mutational status of the primary/secondary KIT/PDGFRA mutations, BRAF mutations and SDH defects. Pathol Res Pract 2019; 215:152708. [DOI: 10.1016/j.prp.2019.152708] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 10/18/2019] [Accepted: 10/19/2019] [Indexed: 02/08/2023]
|
|
44
|
Burns J, Wilding CP, L Jones R, H Huang P. Proteomic research in sarcomas - current status and future opportunities. Semin Cancer Biol 2019; 61:56-70. [PMID: 31722230 PMCID: PMC7083238 DOI: 10.1016/j.semcancer.2019.11.003] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 11/04/2019] [Indexed: 02/07/2023]
Abstract
Sarcomas are a rare group of mesenchymal cancers comprising over 70 different histological subtypes. For the majority of these diseases, the molecular understanding of the basis of their initiation and progression remains unclear. As such, limited clinical progress in prognosis or therapeutic regimens have been made over the past few decades. Proteomics techniques are being increasingly utilised in the field of sarcoma research. Proteomic research efforts have thus far focused on histological subtype characterisation for the improvement of biological understanding, as well as for the identification of candidate diagnostic, predictive, and prognostic biomarkers for use in clinic. However, the field itself is in its infancy, and none of these proteomic research findings have been translated into the clinic. In this review, we provide a brief overview of the proteomic strategies that have been employed in sarcoma research. We evaluate key proteomic studies concerning several rare and ultra-rare sarcoma subtypes including, gastrointestinal stromal tumours, osteosarcoma, liposarcoma, leiomyosarcoma, malignant rhabdoid tumours, Ewing sarcoma, myxofibrosarcoma, and alveolar soft part sarcoma. Consequently, we illustrate how routine implementation of proteomics within sarcoma research, integration of proteomics with other molecular profiling data, and incorporation of proteomics into clinical trial studies has the potential to propel the biological and clinical understanding of this group of complex rare cancers moving forward.
Collapse
Affiliation(s)
- Jessica Burns
- Division of Molecular Pathology, The Institute of Cancer Research, London, SW3 6JB, UK
| | - Christopher P Wilding
- Division of Molecular Pathology, The Institute of Cancer Research, London, SW3 6JB, UK
| | - Robin L Jones
- Division of Clinical Studies, The Institute of Cancer Research, London SW3 6JB, UK; Sarcoma Unit, The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK
| | - Paul H Huang
- Division of Molecular Pathology, The Institute of Cancer Research, London, SW3 6JB, UK.
| |
Collapse
|
|
45
|
Orbital metastasis from a gastrointestinal stromal tumor: A case report. Am J Ophthalmol Case Rep 2019; 16:100528. [PMID: 31440692 PMCID: PMC6699248 DOI: 10.1016/j.ajoc.2019.100528] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Revised: 01/27/2019] [Accepted: 07/29/2019] [Indexed: 12/25/2022] Open
Abstract
Background Gastrointestinal stromal tumor (GIST) is the most common primary mesenchymal tumor. The most common metastasis sites are the liver and the surface of the peritoneum. In this study, we present a case of orbital GIST metastasis. Case presentation A 43-year-old woman who had a history of small intestinal stromal tumor 4 years ago suffered GIST metastasis to the left orbit. MRI confirmed the presence of a lacrimal gland lesion with isointense on T1 and hyperintense on T2 weighted images. Histopathology analysis of the tumor showed predominantly spindle or oval cells with nuclear pleomorphism and increased mitoses. The tumor also stained positive for c-KIT (CD117) upon immunochemistry, confirming the diagnosis. Conclusions GISTs typically occur as sporadic solitary tumors, and their common metastasis sites are the liver and the surface of the peritoneum. Orbital involvement is extremely rare. The orbital GIST metastatic tumor has special imaging properties, as evidenced by histopathology, immunochemistry, and magnetic resonance imaging (MRI).
Collapse
|
|
46
|
Fujimi A, Nagamachi Y, Yamauchi N, Tamura F, Kimura T, Miyajima N, Inomata H, Nishisato T, Yoshida M, Takada K, Kobayashi K, Kato J. Gastrointestinal Stromal Tumor in a Patient with Neurofibromatosis Type 1 That Was Successfully Treated with Regorafenib. Intern Med 2019; 58:1865-1870. [PMID: 30918185 PMCID: PMC6663552 DOI: 10.2169/internalmedicine.2321-18] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 01/07/2019] [Indexed: 12/29/2022] Open
Abstract
An unconscious 55-year-old man with a history of neurofibromatosis type 1 (NF1) was transported to the emergency department and was diagnosed with acute renal failure owing to a large bladder tumor. A submucosal tumor was also identified in the duodenum. The patient was diagnosed with a primary gastrointestinal stromal tumor (GIST) of the bladder and duodenum. After six cycles of regorafenib therapy, 18F-fluorodeoxyglucose accumulation in the duodenal GIST on positron emission tomography-computed tomography (PET-CT) showed a partial metabolic response. Currently, no standard drug therapy for unresectable or relapsed NF1-associated GIST has been established. Regorafenib may thus be considered as and appropriate initial therapy.
Collapse
Affiliation(s)
- Akihito Fujimi
- Department of Hematology, Sapporo Kiyota Hospital, Japan
| | | | | | - Fumito Tamura
- Department of Internal Medicine, Sapporo Kiyota Hospital, Japan
| | - Tomohiro Kimura
- Department of Internal Medicine, Sapporo Kiyota Hospital, Japan
| | - Naoya Miyajima
- Department of Internal Medicine, Sapporo Kiyota Hospital, Japan
| | | | | | - Makoto Yoshida
- Department of Medical Oncology, Sapporo Medical University, Japan
| | - Kohichi Takada
- Department of Medical Oncology, Sapporo Medical University, Japan
| | - Ko Kobayashi
- Department of Urology, Sapporo Medical University, Japan
| | - Junji Kato
- Department of Medical Oncology, Sapporo Medical University, Japan
| |
Collapse
|
|
47
|
Ibrahim A, Chopra S. Succinate Dehydrogenase–Deficient Gastrointestinal Stromal Tumors. Arch Pathol Lab Med 2019; 144:655-660. [DOI: 10.5858/arpa.2018-0370-rs] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Succinate dehydrogenase (SDH)–deficient gastrointestinal stromal tumor (GIST) is a subset of wild-type GIST that constitutes approximately 10% of gastric GISTs. SDH-mutated GISTs lack mutations in the proto-oncogene receptor tyrosine kinase (also known as KIT, c-KIT, or CD117) or platelet-derived growth factor receptor α (PDGFR-α). These tumors have female predilection, affect children and young adults, and have a spectrum of behavior from indolent to progressive. These tumors have characteristic morphologic features including multinodular architecture, multiple tumors, lymphovascular involvement, and occasional lymph node metastasis. They can be seen in patients with Carney triad or Carney-Stratakis syndrome. Although a mutation in any one of the SDH subunits can be pathogenic, deficiency of a single subunit leads to loss of detectable SDH subunit B by immunohistochemistry, enabling a convenient, tissue-based screening method. The prognosis and the clinical course of these tumors is different from that of KIT- or PDGFR-α–mutated GISTs. Surgical management is considered the main line of treatment. SDH-mutated GISTs do not respond well to the common targeted therapy, with no objective tumor response to imatinib. The role of the pathologist in diagnosing these cases is imperative in management and subsequent follow-up.
Collapse
Affiliation(s)
- Ahmad Ibrahim
- From the Department of Pathology, LAC + USC Medical Center, University of Southern California, Keck School of Medicine, Los Angeles (Dr Ibrahim); and the Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles (Dr Chopra)
| | - Shefali Chopra
- From the Department of Pathology, LAC + USC Medical Center, University of Southern California, Keck School of Medicine, Los Angeles (Dr Ibrahim); and the Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles (Dr Chopra)
| |
Collapse
|
|
48
|
Yan J, Chen D, Chen X, Sun X, Dong Q, Hu C, Zhou F, Chen W. Downregulation of lncRNA CCDC26 contributes to imatinib resistance in human gastrointestinal stromal tumors through IGF-1R upregulation. ACTA ACUST UNITED AC 2019; 52:e8399. [PMID: 31166382 PMCID: PMC6556970 DOI: 10.1590/1414-431x20198399] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 02/21/2019] [Indexed: 12/11/2022]
Abstract
Imatinib is the first line of therapy for patients with metastatic or gastrointestinal stromal tumors (GIST). However, drug resistance limits the long-term effect of imatinib. Long non-coding RNAs (lncRNAs) are emerging as key players in regulating drug resistance in cancer. In this study, we investigated the association between lncRNA CCDC26 and IGF-1R in GIST and their involvement in drug resistance. Considering the key role of lncRNAs in drug resistance in cancer, we hypothesized that IGF-1R is regulated by lncRNAs. The expression of a series of reported drug resistance-related lncRNAs, including CCDC26, ARF, H19, NBR2, NEAT1, and HOTAIR, in GIST cells treated with imatinib H19 was examined at various time-points by qRT-PCR. Based on our results and published literature, CCDC26, a strongly down-regulated lncRNA following imatinib treatment, was chosen as our research target. GIST cells with high expression of CCDC26 were sensitive to imatinib treatment while knockdown of CCDC26 significantly increased the resistance to imatinib. Furthermore, we found that CCDC26 interacted with c-KIT by RNA pull down, and that CCDC26 knockdown up-regulated the expression of IGF-1R. Moreover, IGF-1R inhibition reversed CCDC26 knockdown-mediated imatinib resistance in GIST. These results indicated that treatments targeting CCDC26-IGF-1R axis would be useful in increasing sensitivity to imatinib in GIST.
Collapse
Affiliation(s)
- Jingyi Yan
- Department of Gastroenterology and General Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Didi Chen
- Department of Radiotherapy and Medical Oncology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Xiaolei Chen
- Department of Gastroenterology and General Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Xuecheng Sun
- Department of Gastroenterology and Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Qiantong Dong
- Department of Gastroenterology and General Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Changyuan Hu
- Department of Gastroenterology and General Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Feng Zhou
- Department of Gastroenterology and General Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Wei Chen
- Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, China
| |
Collapse
|
|
49
|
Wu CE, Tzen CY, Wang SY, Yeh CN. Clinical Diagnosis of Gastrointestinal Stromal Tumor (GIST): From the Molecular Genetic Point of View. Cancers (Basel) 2019; 11:cancers11050679. [PMID: 31100836 PMCID: PMC6563074 DOI: 10.3390/cancers11050679] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 05/13/2019] [Accepted: 05/15/2019] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) originating from the interstitial cells of Cajal are mesenchymal tumors of the gastrointestinal tract and have been found to harbor c-KIT mutations and KIT (CD117) expression since 1998. Later, PDGFRA mutations, SDH alterations, and other drive mutations were identified in GISTs. In addition, more and more protein markers such as DOG1, PKCθ were found to be expressed in GISTs which might help clinicians diagnose CD117-negative GISTs. Therefore, we plan to comprehensively review the molecular markers and genetics of GISTs and provide clinicians useful information in diagnostic and therapeutic strategies of GISTs. Twenty years after the discovery of KIT in GISTs, the diagnosis of GISTs became much more accurate by using immunohistochemical (IHC) panel (CD117/DOG1) and molecular analysis (KIT/PDGFRA), both of which constitute the gold standard of diagnosis in GISTs. The accurately molecular diagnosis of GISTs guides clinicians to precision medicine and provides optimal treatment for the patients with GISTs. Successful treatment in GISTs prolongs the survival of GIST patients and causes GISTs to become a chronic disease. In the future, the development of effective treatment for GISTs resistant to imatinib/sunitinib/regorafenib and KIT/PDGFRA-WT GISTs will be the challenge for GISTs.
Collapse
Affiliation(s)
- Chiao-En Wu
- GIST Team, Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou branch, Chang Gung University, Taoyuan 333, Taiwan.
| | - Chin-Yuan Tzen
- Forlab Clinic, F2, No 14, Sec 2, Zhongxiao East Rd, Taipei 100, Taiwan.
| | - Shang-Yu Wang
- GIST Team, Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan.
| | - Chun-Nan Yeh
- GIST Team, Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan.
| |
Collapse
|
|
50
|
Janardhan KS, Venkannagari P, Jensen H, Hoenerhoff MJ, Herbert RA, Malarkey DE, Sills RC, Pandiri AR. Do GISTs Occur in Rats and Mice? Immunohistochemical Characterization of Gastrointestinal Tumors Diagnosed as Smooth Muscle Tumors in The National Toxicology Program. Toxicol Pathol 2019; 47:577-584. [PMID: 31064278 DOI: 10.1177/0192623319845838] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The majority of the tumors in the gastrointestinal (GI) tract of rats and mice, with spindle cell morphology, are diagnosed as smooth muscle tumors (SMTs). Similarly, several decades ago human GI tumors with spindle cell morphology were also diagnosed as SMTs. However, later investigations identified most of these tumors in humans as gastrointestinal stromal tumors (GISTs). The GISTs are considered to arise from the interstitial cells of Cajal located throughout the GI tract. Positive immunohistochemical staining with CKIT antibody is a well-accepted diagnostic marker for GISTs in humans. Since there is a considerable overlap between the histomorphology of SMTs and GISTs, it is not possible to distinguish them on hematoxylin and eosin stained sections. As a result, GISTs are not routinely diagnosed in toxicological studies. The current study was designed to evaluate the tumors diagnosed as leiomyoma or leiomyosarcoma in the National Toxicology Program's 2-year bioassays using CKIT, smooth muscle actin, and desmin immunohistochemistry. The results demonstrate that most of the mouse SMTs diagnosed as leiomyoma or leiomyosarcoma are likely GISTs, whereas in rats the tumors are likely SMTs and not GISTs.
Collapse
Affiliation(s)
| | - Priyanka Venkannagari
- 2 Division of National Toxicology Program, Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Venkannagari is now with the Bain and Company Inc, Boston, MA, USA. Mark is now with the Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Heather Jensen
- 2 Division of National Toxicology Program, Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Venkannagari is now with the Bain and Company Inc, Boston, MA, USA. Mark is now with the Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Mark J Hoenerhoff
- 2 Division of National Toxicology Program, Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Venkannagari is now with the Bain and Company Inc, Boston, MA, USA. Mark is now with the Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Ronald A Herbert
- 2 Division of National Toxicology Program, Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Venkannagari is now with the Bain and Company Inc, Boston, MA, USA. Mark is now with the Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - David E Malarkey
- 2 Division of National Toxicology Program, Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Venkannagari is now with the Bain and Company Inc, Boston, MA, USA. Mark is now with the Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Robert C Sills
- 2 Division of National Toxicology Program, Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Venkannagari is now with the Bain and Company Inc, Boston, MA, USA. Mark is now with the Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Arun R Pandiri
- 2 Division of National Toxicology Program, Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Venkannagari is now with the Bain and Company Inc, Boston, MA, USA. Mark is now with the Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA
| |
Collapse
|