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Tan S, Yang W, Yang G. Long-term outcomes of endoscopic treatment versus surgical resection for 0-2 cm gastrointestinal stromal tumor: A SEER database study. Surg Endosc 2025:10.1007/s00464-025-11720-6. [PMID: 40369280 DOI: 10.1007/s00464-025-11720-6] [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: 11/01/2024] [Accepted: 04/06/2025] [Indexed: 05/16/2025]
Abstract
BACKGROUND The optimal management of gastrointestinal stromal tumor (GIST) ≤ 2 cm in diameter remains debated. This study aimed to compare long-term survival outcomes between patients with small GIST undergoing endoscopic treatment (ET) and those treated with surgical resection (SR). METHODS Between 2000 and 2021, patients with small GIST were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was employed to minimize selection bias in the comparison process. Kaplan-Meier analysis and multivariate Cox proportional hazards models were applied to evaluate the effects of demographic and clinical characteristics on overall survival (OS) and cancer-specific survival (CSS). RESULTS A total of 1400 patients with small GIST were included, comprising 470 (33.57%) undergoing ET and 930 (66.43%) receiving SR. The 5-year OS and CSS rates were compared between the ET and SR groups both before and after PSM. Before PSM, the 5-year OS rates were 75.28% vs. 83.96% (P = 0.878), and CSS rates were 94.38% vs. 95.09% (P = 0.284). After PSM, the corresponding rates were 85.81% vs. 86.45% (P = 0.393) for OS and 96.77% vs. 95.48% (P = 0.075) for CSS. Multivariable analysis adjusting for covariates demonstrated comparable risks of OS (HR = 0.96, 95% CI 0.74-1.24, P = 0.737) and CSS (HR = 1.26, 95% CI 0.72-2.20, P = 0.426) between the two treatment groups. No significant differences were observed between the groups after PSM. CONCLUSIONS Our findings demonstrate comparable long-term OS and CSS outcomes between endoscopic and surgical treatment groups in patients with GIST ≤ 2 cm in diameter.
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Affiliation(s)
- Siyu Tan
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Wenjing Yang
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Guowang Yang
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China.
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Kleijn TG, Ameline B, Bleckman RF, Kooistra W, van den Broek E, Diercks GFH, van Hemel BM, Timmer B, Timens W, Kats‐Ugurlu G, van Kempen LC, van Etten B, Schuuring E, Suurmeijer AJH, de Haan JJ, Baumhoer D, Reyners AKL, Cleven AHG. Genome-Wide DNA Methylation and Copy Number Alterations in Gastrointestinal Stromal Tumors. Genes Chromosomes Cancer 2025; 64:e70046. [PMID: 40145859 PMCID: PMC11949093 DOI: 10.1002/gcc.70046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 03/12/2025] [Accepted: 03/18/2025] [Indexed: 03/28/2025] Open
Abstract
Gastrointestinal stromal tumors (GISTs) span a broad clinical spectrum, from indolent neoplasms to life-threatening metastatic tumors. A persistent limitation of current risk stratification systems is that a subset of GISTs is graded as low-risk but nevertheless metastasizes. Therefore, new predictive factors that improve risk stratification are needed. In this exploratory study, we investigated the potential of genome-wide DNA methylation profiling and copy number variation (CNV) analysis as additional prognostic tools for GISTs. We collected a cohort of 28 patients with GIST diagnosed between 2001 and 2022, with available follow-up and molecular data. This included 15 patients without progressive disease (seven low-risk and eight moderate- to high-risk GISTs) and 13 with progressive disease. Among those with progression, eight experienced recurrence or metastasis post-surgery (one low-risk, seven high-risk GISTs), while five had metastatic disease at initial diagnosis. Risk stratification was determined according to Miettinen's criteria. Genome-wide DNA methylation data and CNV plots were generated from imatinib-naïve primary GISTs using the Illumina Infinium MethylationEPIC BeadChip array. Unsupervised cluster analysis revealed distinct DNA methylation patterns predominantly associated with anatomical location and genotype. Differential DNA methylation analysis comparing primary gastric GISTs associated with and without progressive disease showed 8 differentially methylated regions spanning the coding and promoter areas of 6 genes. CNV analysis demonstrated that GISTs associated with progressive disease had the most CNVs, whereas low-risk, non-progressive GISTs had the fewest. Despite the limited sample size, this exploratory study indicates that genome-wide DNA methylation profiling and CNV analysis could enhance GIST risk stratification.
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Affiliation(s)
- Tony G. Kleijn
- Department of Pathology and Medical BiologyUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
| | - Baptiste Ameline
- Bone Tumor Reference Center at the Institute for Medical Genetics and Pathology, University Hospital Basel, University of BaselBaselSwitzerland
| | - Roos F. Bleckman
- Department of Medical OncologyUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
| | - Wierd Kooistra
- Department of Pathology and Medical BiologyUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
| | - Evert van den Broek
- Department of Pathology and Medical BiologyUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
| | - Gilles F. H. Diercks
- Department of Pathology and Medical BiologyUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
| | - Bettien M. van Hemel
- Department of Pathology and Medical BiologyUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
| | - Bert Timmer
- Department of Pathology and Medical BiologyUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
| | - Wim Timens
- Department of Pathology and Medical BiologyUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
| | - Gursah Kats‐Ugurlu
- Department of Pathology and Medical BiologyUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
| | - Léon C. van Kempen
- Department of Pathology and Medical BiologyUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
- Department of PathologyAntwerp University Hospital, University of AntwerpEdegemBelgium
| | - Boudewijn van Etten
- Department of SurgeryUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
| | - Ed Schuuring
- Department of Pathology and Medical BiologyUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
| | - Albert J. H. Suurmeijer
- Department of Pathology and Medical BiologyUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
| | - Jacco J. de Haan
- Department of Medical OncologyUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
| | - Daniel Baumhoer
- Bone Tumor Reference Center at the Institute for Medical Genetics and Pathology, University Hospital Basel, University of BaselBaselSwitzerland
| | - Anna K. L. Reyners
- Department of Medical OncologyUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
| | - Arjen H. G. Cleven
- Department of Pathology and Medical BiologyUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
- Department of PathologyAmsterdam University Medical CenterAmsterdamthe Netherlands
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Yoneyama F, Okamoto T, Hamaya T, Kodama H, Fujita N, Yamamoto H, Imai A, Hatakeyama S. Penile metastasis from a duodenal gastrointestinal stromal tumor: A rare case report. Urol Case Rep 2025; 59:102978. [PMID: 40034263 PMCID: PMC11872612 DOI: 10.1016/j.eucr.2025.102978] [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: 01/13/2025] [Accepted: 02/05/2025] [Indexed: 03/05/2025] Open
Abstract
Penile metastases are rare, and metastasis of a gastrointestinal stromal tumor (GIST) to the penis is exceedingly uncommon. An 81-year-old man with a history of duodenal GIST, initially treated with curative resection and tyrosine kinase inhibitor therapy for liver metastasis, presented with an enlarging penile mass. A biopsy confirmed penile metastasis from GIST. To relieve his symptoms, a total penectomy was performed. Molecular testing revealed a KIT exon 9 mutation and CDKN2A/B gene alterations, indicating aggressive tumor behavior and resistance to standard treatment. This case underscores the importance of recognizing atypical metastatic sites in GIST.
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Affiliation(s)
- Fumiya Yoneyama
- Department of Urology, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Teppei Okamoto
- Department of Urology, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Tomoko Hamaya
- Department of Urology, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Hirotake Kodama
- Department of Urology, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Naoki Fujita
- Department of Urology, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Hayato Yamamoto
- Department of Urology, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Atushi Imai
- Department of Urology, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Shingo Hatakeyama
- Department of Urology, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
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Menyailo ME, Kopantseva EE, Khozyainova AA, Korobeynikova AA, Denisov EV. Soft tissue sarcomas at the single-cell and spatial resolution: new markers and targets. Cancer Gene Ther 2025; 32:11-21. [PMID: 39582085 DOI: 10.1038/s41417-024-00856-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 11/12/2024] [Accepted: 11/12/2024] [Indexed: 11/26/2024]
Abstract
Soft tissue sarcomas (STS) are heterogeneous and aggressive tumors, originating in connective tissues embryologically derived from the mesenchyme. Due to their rarity, crucial information about their biology is still lacking. In recent years, single-cell and spatial analyses have opened up new horizons in oncology, leading to the possibility of characterizing the internal architecture of the tumor at the single-cell and spatial levels. This review summarizes the first results acquired through these revolutionary methods for different types of STS. We discuss tumor cell populations and their evolution, interactions between tumor cells and the microenvironment, new prognostic markers, and clinically important targets. Finally, we examine the challenges presented by the single-cell and spatial omics of STS and the future perspectives in this field.
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Affiliation(s)
- Maxim E Menyailo
- Single Cell Biology Laboratory, Research Institute of Molecular and Cellular Medicine, Peoples' Friendship University of Russia, 115093, Moscow, Russia
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009, Tomsk, Russia
| | - Elena E Kopantseva
- Single Cell Biology Laboratory, Research Institute of Molecular and Cellular Medicine, Peoples' Friendship University of Russia, 115093, Moscow, Russia
| | - Anna A Khozyainova
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009, Tomsk, Russia
| | - Anastasia A Korobeynikova
- Single Cell Biology Laboratory, Research Institute of Molecular and Cellular Medicine, Peoples' Friendship University of Russia, 115093, Moscow, Russia
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009, Tomsk, Russia
| | - Evgeny V Denisov
- Single Cell Biology Laboratory, Research Institute of Molecular and Cellular Medicine, Peoples' Friendship University of Russia, 115093, Moscow, Russia.
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009, Tomsk, Russia.
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Cao L, Tian W, Zhao Y, Song P, Zhao J, Wang C, Liu Y, Fang H, Liu X. Gene Mutations in Gastrointestinal Stromal Tumors: Advances in Treatment and Mechanism Research. Glob Med Genet 2024; 11:251-262. [PMID: 39176108 PMCID: PMC11341198 DOI: 10.1055/s-0044-1789204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/24/2024] Open
Abstract
Although gastrointestinal stromal tumors (GISTs) has been reported in patients of all ages, its diagnosis is more common in elders. The two most common types of mutation, receptor tyrosine kinase (KIT) and platelet-derived growth factor receptor a (PDGFRA) mutations, hold about 75 and 15% of GISTs cases, respectively. Tumors without KIT or PDGFRA mutations are known as wild type (WT)-GISTs, which takes up for 15% of all cases. WT-GISTs have other genetic alterations, including mutations of the succinate dehydrogenase and serine-threonine protein kinase BRAF and neurofibromatosis type 1. Other GISTs without any of the above genetic mutations are named "quadruple WT" GISTs. More types of rare mutations are being reported. These mutations or gene fusions were initially thought to be mutually exclusive in primary GISTs, but recently it has been reported that some of these rare mutations coexist with KIT or PDGFRA mutations. The treatment and management differ according to molecular subtypes of GISTs. Especially for patients with late-stage tumors, developing a personalized chemotherapy regimen based on mutation status is of great help to improve patient survival and quality of life. At present, imatinib mesylate is an effective first-line drug for the treatment of unresectable or metastatic recurrent GISTs, but how to overcome drug resistance is still an important clinical problem. The effectiveness of other drugs is being further evaluated. The progress in the study of relevant mechanisms also provides the possibility to develop new targets or new drugs.
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Affiliation(s)
- Lei Cao
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
- Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Wencong Tian
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Yongjie Zhao
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
- Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Peng Song
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Jia Zhao
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Chuntao Wang
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Yanhong Liu
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Hong Fang
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Xingqiang Liu
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
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Grabill N, Louis M, Cawthon M, Conway J, Chambers J. Managing locally advanced GIST complicated by perforation: A case report and comprehensive review. Radiol Case Rep 2024; 19:4824-4831. [PMID: 39228941 PMCID: PMC11367461 DOI: 10.1016/j.radcr.2024.07.105] [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: 06/25/2024] [Revised: 07/16/2024] [Accepted: 07/17/2024] [Indexed: 09/05/2024] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, frequently characterized by mutations in the KIT or PDGFRA genes. This case report details the complex clinical course of a 71-year-old female with a history of HIV and metastatic GIST presenting with acute abdominal symptoms indicative of perforated viscus. Initial imaging revealed a massive pneumoperitoneum and a large abdominal mass, necessitating immediate surgical intervention. The patient underwent multiple surgeries, including bowel resections and colostomy creation, to address the extensive tumor burden and complications. Postoperatively, she required intensive care management, including mechanical ventilation, vasopressor support, and hemodialysis for acute kidney injury. Pathological examination confirmed metastatic GIST with extensive mesenteric and omental involvement. Immunohistochemical staining was positive for CD117 (c-KIT) and DOG-1. Despite aggressive surgical and supportive measures, the patient's condition highlighted the significant challenges in managing advanced GIST with perforation. This case highlights the importance of a multidisciplinary approach, integrating surgical, medical, and intensive care to optimize outcomes. The prognosis of GIST varies widely, with localized tumors having favorable outcomes following resection, while metastatic cases often face a poorer prognosis despite advances in targeted therapies. This case exemplifies the critical need for personalized treatment plans and ongoing research to improve the management and prognosis of GIST patients.
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Affiliation(s)
- Nathaniel Grabill
- Northeast Georgia Medical Center, General Surgery Department. Gainesville, GA 30501, USA
| | - Mena Louis
- Northeast Georgia Medical Center, General Surgery Department. Gainesville, GA 30501, USA
| | - Mariah Cawthon
- Northeast Georgia Medical Center, General Surgery Department. Gainesville, GA 30501, USA
| | - Joseph Conway
- Northeast Georgia Medical Center, Pathology Department. Gainesville, GA 30501, USA
| | - James Chambers
- Northeast Georgia Medical Center, General Surgery Department, Braselton, GA 30517, USA
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7
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Refai F. Gastrointestinal Stromal Tumors: A Retrospective Study at a Tertiary Care Center in Saudi Arabia in the Last Decade. Cureus 2024; 16:e64560. [PMID: 39011316 PMCID: PMC11247948 DOI: 10.7759/cureus.64560] [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: 07/15/2024] [Indexed: 07/17/2024] Open
Abstract
INTRODUCTION Gastrointestinal stromal tumors (GISTs) are a significant subset of mesenchymal tumors primarily found in the gastrointestinal tract, impacting diagnostic and therapeutic approaches. Understanding their epidemiology is crucial for improving patient care and advancing treatment strategies. METHODOLOGY Our study at a Saudi tertiary hospital analyzed 50 patients with GIST, focusing on demographics, tumor locations, and risk assessments. We examined predictors of tumor size, including mitosis frequency, and assessed the impact of anatomical location and risk on clinical outcomes using RStudio software (Posit, Boston, MA). RESULTS Among 50 patients with GIST, 36 (72.0%) were male with a median age of 60.5 years, and most tumors (33, 66.0%) were in the stomach. Risk assessments categorized tumors as follows: 20 (40.0%) low risk, 12 (24.0%) high risk, 7 (14.0%) moderate risk, 7 (14.0%) very low risk, and 4 (8.0%) no risk. Most tumors were low-grade (41, 82.0%) and nonmetastatic (47, 94.0%), predominantly spindle cell type (37, 74.0%). Tumor size varied significantly across risk categories: high-risk tumors averaged 10.3 cm versus 0.5 cm for no risk and 3.5 cm for very low risk (P < 0.001). Mitosis frequency differed significantly by risk category and tumor grade (P < 0.001). Tumor grade varied notably with risk categories and morphologic types, especially high-grade tumors in high-risk groups (8, 66.7%) and epithelioid tumors (2, 100%). Multivariable analysis identified predictors of tumor size: anatomical location (extra-GI, intra-abdominal; beta = 7.08, P = 0.011) and risk assessment (low risk, beta = 6.91, P = 0.001; moderate risk, beta = 11.2, P < 0.001; high risk, beta = 8.93, P < 0.001). Liver metastasis did not differ significantly across gender, anatomical location, risk assessment, or tumor grade. CONCLUSIONS In Saudi Arabia, GISTs predominantly affect males and are primarily located in the stomach. Our findings highlight significant variations in tumor size and grade based on risk assessments and anatomical location. Most GISTs were low-grade, nonmetastatic, and spindle cell type, emphasizing the need for enhanced research to improve diagnostics, tailor treatments, and optimize outcomes in the region.
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Affiliation(s)
- Fahd Refai
- Department of Pathology, King Abdulaziz University Hospital, King Abdulaziz University, Jeddah, SAU
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Singh C, Gharde P, Nikhade PW, Morey MM, Sapkale B. Diagnostic Complexity and Long-Term Management of Gastrointestinal Stromal Tumor Mimicking Ovarian Origin: A Case Report. Cureus 2024; 16:e64523. [PMID: 39139344 PMCID: PMC11321471 DOI: 10.7759/cureus.64523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Accepted: 07/14/2024] [Indexed: 08/15/2024] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors occurring in the gastrointestinal tract particularly the stomach or small intestine originating from interstitial cells of Cajal. This case report describes a 50-year-old postmenopausal female presenting with a gradually increasing abdominal mass which clinically was thought to be a neoplasm originating in the ovaries. A clinical and imaging diagnosis of primary ovarian malignancy was made but during laparotomy, a mesenteric component to the malignancy as well as bilateral ovarian cysts were seen. The mass was removed with care and histopathological analysis confirmed it to be GIST. Follow-up of the patient was done for three years and there was no sign of any disease in the patient and she had an uncomplicated postoperative period. This case describes the intricacy of GISTs' diagnosis, the significance of detailed intraoperative analysis, and appropriate postoperative surveillance. Differences and similarities with other similar cases shed light on how such patients present themselves for treatment, thus encouraging differentiated care. Supervisory care is therefore vital in the monitoring of the patient for prolonged periods and to check for any relapse.
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Affiliation(s)
- Chahat Singh
- General Surgery, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Pankaj Gharde
- General Surgery, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Pravin W Nikhade
- General Surgery, Datta Meghe Medical College, Datta Meghe Institute of Higher Education and Research, Nagpur, IND
| | - Meen M Morey
- General Surgery, Datta Meghe Medical College, Datta Meghe Institute of Higher Education and Research, Nagpur, IND
| | - Bhagyesh Sapkale
- Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
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Valmary-Degano S. [Histoseminar tumoral peritoneal biopsies. Case No.1]. Ann Pathol 2024; 44:237-244. [PMID: 38782656 DOI: 10.1016/j.annpat.2024.04.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 03/28/2024] [Accepted: 04/14/2024] [Indexed: 05/25/2024]
Affiliation(s)
- Séverine Valmary-Degano
- Inserm U1209, CNRS UMR5309, Institut pour l'avancée des biosciences, service d'anatomie et cytologie pathologiques, CHU de Grenoble Alpes, University Grenoble Alpes, 38000 Grenoble, France.
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10
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Singh A, Chitti B, Aguiar C, Wernicke AG, Devoe CE, Rahman H, Sison C, Parashar B. Comparing gastrointestinal stromal tumor outcomes between geriatric and non-geriatric patients: A population-based analysis. World J Surg 2024; 48:1424-1432. [PMID: 38647223 DOI: 10.1002/wjs.12170] [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: 01/01/2024] [Accepted: 03/22/2024] [Indexed: 04/25/2024]
Abstract
BACKGROUND Gastrointestinal Stromal Tumors (GISTs) are the most common mesenchymal tumors of the GI tract. SEER is an extensive cancer database which proves useful in analyzing population trends. This analysis investigated GIST outcomes between geriatric & non-geriatric patients. METHODS SEER*STAT 8.4.0.1 was used to extract relevant GIST data from 2000 to 2019. Geriatric age was defined as ≥70 years. Variables included age, sex, surgery, cancer-specific death, and overall survival. Statistical tests included univariate analysis using KM survival estimate (95% confidence interval) to calculate 5-year survival (5YS). Log-Rank tests determined statistical significance. Multivariable Cox's PH regression estimated the geriatric hazard death ratio adjusted for sex, stage, and surgery. RESULTS The number of patients included was 13,579, yielding overall 5YS of 68.6% (95% CI 67.7-69.5). Cancer-specific death was 39.11% in 2000 & 3.33% in 2019. Non-geriatric & geriatric patient data yielded 5YS of 77.4% (76.4%-78.3%) and 53.3% (51.7%-54.8%) respectively (p < 0.0001). For no surgery/surgery, younger patient data yielded 5YS of 48.7% (45.8%-51.4%) and 83.7% (82.7%-84.7%) respectively (p < 0.0001); geriatric data yielded 5YS of 29.3% (26.5%-32.1%) and 62.8% (60.8%-64.6%) respectively (p < 0.0001). Multivariable analysis yielded a geriatric hazard death of 2.56 (2.42-2.70) (p < 0.0001). CONCLUSIONS Cancer-specific death decreased since 2000, indicating an improvement in survival & treatment methods. Observed lower survival rates overall in the geriatric group. Surgery appeared to enhance survival rates in both groups, suggesting that surgery is an important factor in GIST survival regardless of age. Large prospective studies will help define clinical management for geriatric patients.
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Affiliation(s)
- Abhiram Singh
- Department of Radiation Oncology, Northwell, New Hyde Park, New York, USA
- Department of Chemistry and Biochemistry, University of California-Los Angeles, Los Angeles, California, USA
| | - Bhargava Chitti
- Department of Radiation Oncology, Northwell, New Hyde Park, New York, USA
| | | | | | - Craig E Devoe
- Department of Medical Oncology, Northwell, New Hyde Park, New York, USA
| | - Husneara Rahman
- Biostatistics Unit, Office of Academic Affairs, Northwell Health, New Hyde Park, New York, USA
| | - Cristina Sison
- Biostatistics Unit, Office of Academic Affairs, Northwell Health, New Hyde Park, New York, USA
| | - Bhupesh Parashar
- Department of Radiation Oncology, Northwell, New Hyde Park, New York, USA
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Mochizuki K, Oishi N, Tahara I, Inoue T, Kondo T. Expression of TGF-β1 in Gastrointestinal Stromal Tumor (GIST) and the Occurrence of Frequent Desmoplasia. Appl Immunohistochem Mol Morphol 2024; 32:229-232. [PMID: 38584487 DOI: 10.1097/pai.0000000000001196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 03/11/2024] [Indexed: 04/09/2024]
Abstract
Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms with variable behavior characterized by differentiation toward the interstitial cells of Cajal occurring anywhere in the gastrointestinal stromal tract. Frequently, GISTs have fibrous stroma within tumor cell proliferation areas, which is unlike other types of malignant tumors. If this desmoplasia is active, there is a possibility that some sort of transmitter exists between GIST cells and cells related to fibrosis in the tumor cell proliferation areas. Transforming growth factor (TGF)-β isoforms, particularly TGF-β1, are critical for fibrosis pathogenesis. TGF-β1 regulation of myofibroblasts and fibroblasts during fibrosis is well described. The induced fibroblast activation resulting in myofibroblast differentiation has been reported as an important source of collagen, glycoproteins, proteoglycans, and matrix metallopeptidases in wound healing and fibrosis. However, there are a few reports on the relationship between TGF-β1 and GISTs. This study aims to clarify TGF-β1 expression in 30 gastric GISTs using immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). For comparison, we also enrolled 30 samples of gastric tubular adenocarcinoma (GTAC). We confirmed TGF-β1 expression (H-score ≥50 points) in 57% of GIST and 13% of GTAC samples, a significant difference between the 2 tumor types ( P =0.001). We examined the TGF-β1 mRNA expression of 3 representative GIST samples, each having their respective immunostained areas detected by RT-PCR. Finding TGF-β1 expression may indicate that this cytokine plays a part in the formation of desmoplasia within GIST cell proliferative areas.
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Affiliation(s)
- Kunio Mochizuki
- Department of Pathology, University of Yamanashi, Chuo, Yamanashi, Japan
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Tay WJ, Jeyasekharan A, Goh JY, Chang KTE, Kesavan A, Lee VK. Aggressive prostate myxoid mesenchymal neoplasm with novel CRTC1::NCOA2 fusion. Histopathology 2024; 84:909-912. [PMID: 38173295 DOI: 10.1111/his.15135] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 12/10/2023] [Accepted: 12/16/2023] [Indexed: 01/05/2024]
Affiliation(s)
- Wan Jing Tay
- Department of Pathology, National University Hospital (NUH) Singapore, Singapore, Singapore
| | - Anand Jeyasekharan
- National University Cancer Institute, Singapore (NCIS), National University Hospital (NUH), Singapore, Singapore
| | - Jian Yuan Goh
- Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore, Singapore
- Pathology Academic Clinical Programme, SingHealth Duke-NUS Medical School, Singapore, Singapore
| | - Kenneth Tou En Chang
- Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore, Singapore
| | - Arshvin Kesavan
- Department of Urology, National University Hospital (NUH) Singapore, Singapore, Singapore
| | - Victor K Lee
- Department of Pathology, National University Singapore, Singapore, Singapore
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13
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Zhou S, Abdihamid O, Tan F, Zhou H, Liu H, Li Z, Xiao S, Li B. KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST. Cell Commun Signal 2024; 22:153. [PMID: 38414063 PMCID: PMC10898159 DOI: 10.1186/s12964-023-01411-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 11/25/2023] [Indexed: 02/29/2024] Open
Abstract
Gastrointestinal stromal tumor (GIST) is the most common sarcoma located in gastrointestinal tract and derived from the interstitial cell of Cajal (ICC) lineage. Both ICC and GIST cells highly rely on KIT signal pathway. Clinically, about 80-90% of treatment-naive GIST patients harbor primary KIT mutations, and special KIT-targeted TKI, imatinib (IM) showing dramatic efficacy but resistance invariably occur, 90% of them was due to the second resistance mutations emerging within the KIT gene. Although there are multiple variants of KIT mutant which did not show complete uniform biologic characteristics, most of them have high KIT expression level. Notably, the high expression level of KIT gene is not correlated to its gene amplification. Recently, accumulating evidences strongly indicated that the gene coding, epigenetic regulation, and pre- or post- protein translation of KIT mutants in GIST were quite different from that of wild type (WT) KIT. In this review, we elucidate the biologic mechanism of KIT variants and update the underlying mechanism of the expression of KIT gene, which are exclusively regulated in GIST, providing a promising yet evidence-based therapeutic landscape and possible target for the conquer of IM resistance. Video Abstract.
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Affiliation(s)
- Shishan Zhou
- Division of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China, Xiangya road 87
| | - Omar Abdihamid
- Garissa Cancer Center, Garissa County Referral Hospital, Kismayu road, Garissa town, P.O BOX, 29-70100, Kenya
| | - Fengbo Tan
- Division of Surgery, Xiangya Hospital, Central South University, China, Hunan, Changsha
| | - Haiyan Zhou
- Division of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Heli Liu
- Division of Surgery, Xiangya Hospital, Central South University, China, Hunan, Changsha
| | - Zhi Li
- Center for Molecular Medicine of Xiangya Hospital, Collaborative Innovation Center for Cancer Medicine, Central South University, Changsha, Hunan, China, 410008
| | - Sheng Xiao
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, 410008, MA, USA
| | - Bin Li
- Division of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China, Xiangya road 87#.
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14
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Nieves Perez CA, Molina Obana MC, Uribe Torres R, Rivera Delgado S, Ceballos Vazquez Tagle B. Uncommon Association Between Gastrointestinal Stromal Tumors (GIST) and Pheochromocytoma With Abdominal Wall Relapse: Case Report and Literature Review. Cureus 2024; 16:e54532. [PMID: 38516470 PMCID: PMC10956479 DOI: 10.7759/cureus.54532] [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: 02/20/2024] [Indexed: 03/23/2024] Open
Abstract
Gastrointestinal stromal tumors (GISTs) represent a rare form of gastrointestinal neoplasm. This report details a medical case involving a 44-year-old woman who underwent bilateral pheochromocytoma resection, GIST gastrectomy, and laparoscopic adrenalectomy with intestinal resection. Despite an initially positive response to oral imatinib, treatment was delayed due to economic constraints. This delay resulted in a critical event marked by abdominal GIST metastasis to the abdominal wall, subsequent rupture leading to hemoperitoneum, and emergency surgery. Following an adequate postsurgical recovery, she was successfully discharged prior to medication adjustments.
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15
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Namløs HM, Khelik K, Nakken S, Vodák D, Hovig E, Myklebost O, Boye K, Meza‐Zepeda LA. Chromosomal instability and a deregulated cell cycle are intrinsic features of high-risk gastrointestinal stromal tumours with a metastatic potential. Mol Oncol 2023; 17:2432-2450. [PMID: 37622176 PMCID: PMC10620130 DOI: 10.1002/1878-0261.13514] [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: 02/28/2023] [Revised: 06/22/2023] [Accepted: 08/23/2023] [Indexed: 08/26/2023] Open
Abstract
Patients with localised, high-risk gastrointestinal stromal tumours (GIST) benefit from adjuvant imatinib treatment. Still, approximately 40% of patients relapse within 3 years after adjuvant therapy and the clinical and histopathological features currently used for risk classification cannot precisely predict poor outcomes after standard treatment. This study aimed to identify genomic and transcriptomic profiles that could be associated with disease relapse and thus a more aggressive phenotype. Using a multi-omics approach, we analysed a cohort of primary tumours from patients with untreated, resectable high-risk GISTs. We compared patients who developed metastatic disease within 3 years after finishing adjuvant imatinib treatment and patients without disease relapse after more than 5 years of follow-up. Combining genomics and transcriptomics data, we identified somatic mutations and deregulated mRNA and miRNA genes intrinsic to each group. Our study shows that increased chromosomal instability (CIN), including chromothripsis and deregulated kinetochore and cell cycle signalling, separates high-risk samples according to metastatic potential. The increased CIN seems to be an intrinsic feature for tumours that metastasise and should be further validated as a novel prognostic biomarker for high-risk GIST.
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Affiliation(s)
- Heidi Maria Namløs
- Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium HospitalOslo University HospitalOsloNorway
| | - Ksenia Khelik
- Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium HospitalOslo University HospitalOsloNorway
| | - Sigve Nakken
- Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium HospitalOslo University HospitalOsloNorway
- Centre for Cancer Cell Reprogramming, Faculty of Medicine, Institute of Clinical MedicineUniversity of OsloOsloNorway
- Department of InformaticsUniversity of OsloOsloNorway
| | - Daniel Vodák
- Bioinformatics Core Facility, Department of Core Facilities, Institute for Cancer ResearchOslo University HospitalOsloNorway
| | - Eivind Hovig
- Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium HospitalOslo University HospitalOsloNorway
- Department of InformaticsUniversity of OsloOsloNorway
| | - Ola Myklebost
- Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium HospitalOslo University HospitalOsloNorway
- Department for Clinical ScienceUniversity of BergenBergenNorway
| | - Kjetil Boye
- Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium HospitalOslo University HospitalOsloNorway
- Department of OncologyOslo University HospitalOsloNorway
| | - Leonardo A. Meza‐Zepeda
- Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium HospitalOslo University HospitalOsloNorway
- Genomics Core Facility, Department of Core Facilities, Institute for Cancer ResearchOslo University HospitalOsloNorway
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16
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Zhao C, Jin L, Tan Y, Chen Y, Su Z, Li W, Yang Q. Case Report: Multiple gastrointestinal stromal tumors along with numerous cutaneous neurofibromas: a case description and literature analysis. Front Oncol 2023; 13:1206991. [PMID: 37909015 PMCID: PMC10615565 DOI: 10.3389/fonc.2023.1206991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Accepted: 09/29/2023] [Indexed: 11/02/2023] Open
Abstract
Multiple gastrointestinal stromal tumors (GISTs) combined with cutaneous multiple neurofibromas are clinically rare. This paper presents a case of multiple gastrointestinal stromal tumors in the jejunum of a 68-year-old mother, along with her daughter who also had coexisting cutaneous multiple neurofibromas. The mother had been experiencing repeated melena for over 2 years and had previously been diagnosed with multiple small intestinal masses at other hospitals. Additionally, her 42-year-old daughter was admitted to our department due to recurrent abdominal pain caused by cholecystolithiasis. The mother and daughter both exhibited multiple nodular masses of varying sizes on their skin, including the truncus, limbs, and face, which were diagnosed as neurofibromas. The mother underwent a partial excision of the jejunum and a lateral jejunojejunal anastomosis side-to-side, as well as excision of skin lesions in our department. The final diagnosis of wild-type GISTs associated with neurofibromatosis type 1 (NF1) was confirmed through postoperative pathology, immunohistochemistry, and genetic testing results. During preoperative gastrointestinal endoscopy and intraoperative laparoscopic exploration of the gastrointestinal tract, no obvious tumors were found in her daughter. A combination of patient observations and a review of relevant literature in the field suggests that when patients present with gastrointestinal symptoms and multiple irregular painless swellings in the skin, it is important to consider the possibility of an association with NF1 and GIST. Additionally, obtaining a detailed family history can save time and improve the diagnosis of patients with both NF1 and GIST. We recommend that even if there are no gastrointestinal manifestations of GISTs in the offspring of newly mutated NF1 patients, regular review of gastroenteroscopy, imaging examination, and long-term follow-up after middle age are still crucial for the early diagnosis and treatment of NF1-related GISTs.
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Affiliation(s)
| | - Liquan Jin
- 1st Department of General Surgery, The First Affiliated Hospital of Dali University, Dali, Yunnan, China
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17
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Sacerdoţianu VM, Mirea CS, Popa P, Gheonea DI, Foarfă MC, Matei M, Săndulescu DL, Lungulescu CV, Ciurea T, Ungureanu BS. Giant exophytic gastrointestinal stromal tumor (GIST) causing gastric outlet obstruction: case report and review of literature. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY = REVUE ROUMAINE DE MORPHOLOGIE ET EMBRYOLOGIE 2023; 64:595-601. [PMID: 38184841 PMCID: PMC10863695 DOI: 10.47162/rjme.64.4.17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 12/08/2023] [Indexed: 01/09/2024]
Abstract
BACKGROUND Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors, mostly located within the stomach. About 30% of GISTs are incidentally diagnosed and as they become symptomatic may be associated with bleeding, bowel obstruction or spontaneous rupture. CASE PRESENTATION We present the case of a middle-aged patient diagnosed with a giant gastric GIST, which presented for intermittent gastric outlet obstruction symptoms, and emphasize the major imagistic, histopathological, and therapeutic challenges that may be encountered. There are only several cases of gastric exophytic gastric GIST provoking intermittent gastric outlet obstruction. Tumor resection should be adapted to every patient's status, focused on en bloc extraction, with preservation of invaded organs as much as possible.
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Affiliation(s)
- Victor-Mihai Sacerdoţianu
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, Romania
| | - Cecil Sorin Mirea
- Department of Surgery, University of Medicine and Pharmacy of Craiova, Romania
| | - Petrică Popa
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, Romania
| | - Dan Ionuţ Gheonea
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, Romania
| | - Maria Camelia Foarfă
- Department of Pathology, University of Medicine and Pharmacy of Craiova, Romania
| | - Marius Matei
- Department of Histology, University of Medicine and Pharmacy of Craiova, Romania
| | - Daniela Larisa Săndulescu
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, Romania
| | | | - Tudorel Ciurea
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, Romania
| | - Bogdan Silviu Ungureanu
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, Romania
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18
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Galluzzo A, Boccioli S, Danti G, De Muzio F, Gabelloni M, Fusco R, Borgheresi A, Granata V, Giovagnoni A, Gandolfo N, Miele V. Radiomics in gastrointestinal stromal tumours: an up-to-date review. Jpn J Radiol 2023; 41:1051-1061. [PMID: 37171755 DOI: 10.1007/s11604-023-01441-y] [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: 03/02/2023] [Accepted: 04/29/2023] [Indexed: 05/13/2023]
Abstract
Gastrointestinal stromal tumours are rare mesenchymal neoplasms originating from the Cajal cells and represent the most common sarcomas in the gastroenteric tract. Symptoms may be absent or non-specific, ranging from fatigue and weight loss to acute abdomen. Nowadays endoscopy, echoendoscopy, contrast-enhanced computed tomography, magnetic resonance imaging and positron emission tomography are the main methods for diagnosis. Because of their rarity, these neoplasms may not be included immediately in the differential diagnosis of a solitary abdominal mass. Radiomics is an emerging technique that can extract medical imaging information, not visible to the human eye, transforming it into quantitative data. The purpose of this review is to demonstrate how radiomics can improve the already known imaging techniques by providing useful tools for the diagnosis, treatment, and prognosis of these tumours.
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Affiliation(s)
- Antonio Galluzzo
- Department of Radiology, Careggi University Hospital, Largo Brambilla 3, 50134, Florence, Italy
| | - Sofia Boccioli
- Department of Radiology, Careggi University Hospital, Largo Brambilla 3, 50134, Florence, Italy
| | - Ginevra Danti
- Department of Radiology, Careggi University Hospital, Largo Brambilla 3, 50134, Florence, Italy.
| | - Federica De Muzio
- Department of Medicine and Health Sciences V. Tiberio, University of Molise, 86100, Campobasso, Italy
| | - Michela Gabelloni
- Department of Translational Research, Diagnostic and Interventional Radiology, University of Pisa, Pisa, Italy
| | - Roberta Fusco
- Medical Oncology Division, Igea SpA, 80013, Naples, Italy
| | - Alessandra Borgheresi
- Department of Clinical, Special and Dental Sciences, University Politecnica Delle Marche, Via Conca 71, 60126, Ancona, Italy
- Department of Radiology, University Hospital "Azienda Ospedaliera Universitaria Delle Marche", Via Conca 71, 60126, Ancona, Italy
| | - Vincenza Granata
- Department of Radiology, "Istituto Nazionale Tumori IRCCS Fondazione, Pascale-IRCCS di Napoli", 80131, Naples, Italy
| | - Andrea Giovagnoni
- Department of Clinical, Special and Dental Sciences, University Politecnica Delle Marche, Via Conca 71, 60126, Ancona, Italy
- Department of Radiology, University Hospital "Azienda Ospedaliera Universitaria Delle Marche", Via Conca 71, 60126, Ancona, Italy
| | - Nicoletta Gandolfo
- Diagnostic Imaging Department, Villa Scassi Hospital-ASL 3, Corso Scassi 1, 16149, Genoa, Italy
- Italian Society of Medical and Interventional Radiology (SIRM), SIRM Foundation, Via Della Signora 2, 20122, Milan, Italy
| | - Vittorio Miele
- Department of Radiology, Careggi University Hospital, Largo Brambilla 3, 50134, Florence, Italy
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19
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Žagar Ž, Schmidt JM. A Scoping Review on Tyrosine Kinase Inhibitors in Cats: Current Evidence and Future Directions. Animals (Basel) 2023; 13:3059. [PMID: 37835664 PMCID: PMC10572079 DOI: 10.3390/ani13193059] [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: 08/23/2023] [Revised: 09/19/2023] [Accepted: 09/27/2023] [Indexed: 10/15/2023] Open
Abstract
Tyrosine kinase inhibitors (TKIs) have become invaluable in the treatment of human and canine malignancies, but their role in feline oncology is less defined. While toceranib phosphate and masitinib mesylate are licensed for use in dogs, no TKI is yet approved for cats. This review systematically maps the research conducted on the expression of tyrosine kinases in neoplastic and non-neoplastic domestic feline tissues, as well as the in vitro/in vivo use of TKIs in domestic cats. We identify and discuss knowledge gaps and speculate on the further research and potential indications for TKI use in cats. A comprehensive search of three electronic databases and relevant paper reference lists identified 139 studies meeting the inclusion criteria. The most commonly identified tumors were mast cell tumors (MCTs), mammary and squamous cell carcinomas and injection-site sarcomas. Based on the current literature, toceranib phosphate appears to be the most efficacious TKI in cats, especially against MCTs. Exploring the clinical use of TKIs in mammary carcinomas holds promise. Despite the progress, currently, the evidence falls short, underscoring the need for further research to discover new indications in feline oncology and to bridge the knowledge gaps between human and feline medicine.
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Affiliation(s)
- Žiga Žagar
- IVC Evidensia Small Animal Clinic Hofheim, 65719 Hofheim am Taunus, Germany
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20
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Hu X, Su P, Liu B, Guo J, Wang Z, He C, Wang Z, Kou Y. Characterization of a Human Gastrointestinal Stromal Tumor Cell Line Established by SV40LT-Mediated Immortalization. Int J Mol Sci 2023; 24:13640. [PMID: 37686448 PMCID: PMC10487453 DOI: 10.3390/ijms241713640] [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: 07/24/2023] [Revised: 08/20/2023] [Accepted: 08/25/2023] [Indexed: 09/10/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the digestive tract and originate from the interstitial cells of Cajal (ICC), which is the pacemaker for peristaltic movement in the gastrointestinal tract. Existing GIST cell lines are widely used as cell models for in vitro experimental studies because the mutation sites are known. However, the immortalization methods of these cell lines are unknown, and no Chinese patient-derived GIST cell lines have been documented. Here, we transfected simian virus 40 large T antigen (SV40LT) into primary GIST cells to establish an immortalized human GIST cell line (ImGIST) for the first time. The ImGIST cells had neuronal cell-like irregular radioactive growth and retained the fusion growth characteristics of GIST cells. They stably expressed signature proteins, maintained the biological and genomic characteristics of normal primary GIST cells, and responded well to imatinib, suggesting that ImGIST could be a potential in vitro model for research in GIST to explore the molecular pathogenesis, drug resistance mechanisms, and the development of new adjuvant therapeutic options.
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Affiliation(s)
- Xiangchen Hu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; (X.H.)
| | - Peng Su
- Medical Research Center, Shengjing Hospital of China Medical University, Shenyang 117005, China
| | - Bo Liu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; (X.H.)
| | - Jingwei Guo
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Zitong Wang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Cai He
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Zhe Wang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Youwei Kou
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; (X.H.)
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21
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Godesi S, Lee J, Nada H, Quan G, Elkamhawy A, Choi Y, Lee K. Small Molecule c-KIT Inhibitors for the Treatment of Gastrointestinal Stromal Tumors: A Review on Synthesis, Design Strategies, and Structure-Activity Relationship (SAR). Int J Mol Sci 2023; 24:ijms24119450. [PMID: 37298401 DOI: 10.3390/ijms24119450] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/17/2023] [Accepted: 05/24/2023] [Indexed: 06/12/2023] Open
Abstract
The proto-oncogenic protein, c-KIT, plays a crucial role in regulating cellular transformation and differentiation processes, such as proliferation, survival, adhesion, and chemotaxis. The overexpression of, and mutations, in c-KIT can lead to its dysregulation and promote various human cancers, particularly gastrointestinal stromal tumors (GISTs); approximately 80-85% of cases are associated with oncogenic mutations in the KIT gene. Inhibition of c-KIT has emerged as a promising therapeutic target for GISTs. However, the currently approved drugs are associated with resistance and significant side effects, highlighting the urgent need to develop highly selective c-KIT inhibitors that are not affected by these mutations for GISTs. Herein, the recent research efforts in medicinal chemistry aimed at developing potent small-molecule c-KIT inhibitors with high kinase selectivity for GISTs are discussed from a structure-activity relationship perspective. Moreover, the synthetic pathways, pharmacokinetic properties, and binding patterns of the inhibitors are also discussed to facilitate future development of more potent and pharmacokinetically stable small-molecule c-KIT inhibitors.
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Affiliation(s)
- Sreenivasulu Godesi
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea
| | - Joohan Lee
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea
| | - Hossam Nada
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea
| | - Guofeng Quan
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea
| | - Ahmed Elkamhawy
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Yongseok Choi
- College of Biosciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea
| | - Kyeong Lee
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea
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22
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Unk M, Jezeršek Novaković B, Novaković S. Molecular Mechanisms of Gastrointestinal Stromal Tumors and Their Impact on Systemic Therapy Decision. Cancers (Basel) 2023; 15:1498. [PMID: 36900287 PMCID: PMC10001062 DOI: 10.3390/cancers15051498] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 02/23/2023] [Accepted: 02/24/2023] [Indexed: 03/08/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are soft tissue sarcomas that mostly derive from Cajal cell precursors. They are by far the most common soft tissue sarcomas. Clinically, they present as gastrointestinal malignancies, most often with bleeding, pain, or intestinal obstruction. They are identified using characteristic immunohistochemical staining for CD117 and DOG1. Improved understanding of the molecular biology of these tumors and identification of oncogenic drivers have altered the systemic treatment of primarily disseminated disease, which is becoming increasingly complex. Gain-of-function mutations in KIT or PDGFRA genes represent the driving mutations in more than 90% of all GISTs. These patients exhibit good responses to targeted therapy with tyrosine kinase inhibitors (TKIs). Gastrointestinal stromal tumors lacking the KIT/PDGFRA mutations, however, represent distinct clinico-pathological entities with diverse molecular mechanisms of oncogenesis. In these patients, therapy with TKIs is hardly ever as effective as for KIT/PDGFRA-mutated GISTs. This review provides an outline of current diagnostics aimed at identifying clinically relevant driver alterations and a comprehensive summary of current treatments with targeted therapies for patients with GISTs in both adjuvant and metastatic settings. The role of molecular testing and the selection of the optimal targeted therapy according to the identified oncogenic driver are reviewed and some future directions are proposed.
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Affiliation(s)
- Mojca Unk
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia
- Division of Medical Oncology, Institute of Oncology Ljubljana, Zaloška 2, 1000 Ljubljana, Slovenia
| | - Barbara Jezeršek Novaković
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia
- Division of Medical Oncology, Institute of Oncology Ljubljana, Zaloška 2, 1000 Ljubljana, Slovenia
| | - Srdjan Novaković
- Department of Molecular Diagnostics, Institute of Oncology Ljubljana, 1000 Ljubljana, Slovenia
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23
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Boye K, Gorunova L, Gunawan B, Hompland I, Sander B, Panagopoulos I, Langer C, Golas M, Heim S, Füzesi L, Hølmebakk T, Micci F. Genomic Complexity as a Biomarker to De-Escalate Adjuvant Imatinib Treatment in High-Risk Gastrointestinal Stromal Tumor. JCO Precis Oncol 2023; 7:e2200351. [PMID: 36724411 DOI: 10.1200/po.22.00351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
PURPOSE Adjuvant imatinib treatment is recommended for patients with localized gastrointestinal stromal tumor (GIST) at high risk of recurrence. Almost half of high-risk patients are cured by surgery alone, indicating a need for improved selection of patients for adjuvant therapy. The aim of this study was to investigate if genomic tumor complexity could be used as a prognostic biomarker. METHODS The discovery cohort consisted of patients who underwent resection of primary GIST at Oslo University Hospital between 1998 and 2020. Karyotypes were categorized as simple if they had ≤ 5 chromosomal changes and complex if there were > 5 chromosomal aberrations. Validation was performed in an independent patient cohort where chromosomal imbalances were mapped using comparative genomic hybridization. RESULTS Chromosomal aberrations were detected in 206 tumors, of which 76 had a complex karyotype. The most frequently observed changes were losses at 14q, 22q, 1p, and 15q. The 5-year recurrence-free survival (RFS) in patients classified as very low, low, or intermediate risk was 99%. High-risk patients with a simple tumor karyotype had an estimated 5-year RFS of 94%, and patients with a complex karyotype had an estimated 5-year RFS of 51%. A complex karyotype was associated with poor RFS in patients with and without adjuvant imatinib treatment and in multivariable analysis adjusted for tumor site, size, mitotic count, and rupture. The prognostic impact of genomic complexity was confirmed in the validation cohort. In both cohorts, the 5-year disease-specific survival was > 90% for high-risk patients with genomically simple tumors. CONCLUSION Genomic tumor complexity is an independent prognostic biomarker in localized, high-risk GIST. Recurrences were infrequent for tumors with simple karyotypes. De-escalation of adjuvant imatinib treatment should be explored in patients with cytogenetically simple GISTs.
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Affiliation(s)
- Kjetil Boye
- Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Ludmila Gorunova
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway
| | - Bastian Gunawan
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany
| | - Ivar Hompland
- Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Bjoern Sander
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.,Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Ioannis Panagopoulos
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway
| | - Claus Langer
- Clinic for General, Visceral, Thoracic and Minimally Invasive Surgery, Evangelical Hospital Göttingen-Weende, Göttingen, Germany
| | - Monika Golas
- Human Genetics, Faculty of Medicine, University of Augsburg, Augsburg, Germany.,Comprehensive Cancer Center Augsburg, University Medical Center Augsburg, Augsburg, Germany
| | - Sverre Heim
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - László Füzesi
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.,Pathology, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | - Toto Hølmebakk
- Department of Abdominal and Pediatric Surgery, Oslo University Hospital, Oslo, Norway
| | - Francesca Micci
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway
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24
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Li L, Huang X, Zhang S, Zhan Z, Kang D, Guan G, Xu S, Zhou Y, Chen J. Rapid and label-free detection of gastrointestinal stromal tumor via a combination of two-photon microscopy and imaging analysis. BMC Cancer 2023; 23:38. [PMID: 36627575 PMCID: PMC9830707 DOI: 10.1186/s12885-023-10520-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 01/06/2023] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Gastrointestinal stromal tumor (GIST) is currently regarded as a potentially malignant tumor, and early diagnosis is the best way to improve its prognosis. Therefore, it will be meaningful to develop a new method for auxiliary diagnosis of this disease. METHODS Here we try out a new means to detect GIST by combining two-photon imaging with automatic image processing strategy. RESULTS Experimental results show that two-photon microscopy has the ability to label-freely identify the structural characteristics of GIST such as tumor cells, desmoplastic reaction, which are entirely different from those from gastric adenocarcinoma. Moreover, an image processing approach is used to extract eight collagen morphological features from tumor microenvironment and normal muscularis, and statistical analysis demonstrates that there are significant differences in three features-fiber area, density and cross-link density. The three morphological characteristics may be considered as optical imaging biomarkers to differentiate between normal and abnormal tissues. CONCLUSION With continued improvement and refinement of this technology, we believe that two-photon microscopy will be an efficient surveillance tool for GIST and lead to better management of this disease.
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Affiliation(s)
- Lianhuang Li
- grid.411503.20000 0000 9271 2478Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory for Photonics Technology, Fujian Normal University, 350007 Fuzhou, P. R. China
| | - Xingxin Huang
- grid.411503.20000 0000 9271 2478Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory for Photonics Technology, Fujian Normal University, 350007 Fuzhou, P. R. China
| | - Shichao Zhang
- grid.411503.20000 0000 9271 2478Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory for Photonics Technology, Fujian Normal University, 350007 Fuzhou, P. R. China
| | - Zhenlin Zhan
- grid.411503.20000 0000 9271 2478Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory for Photonics Technology, Fujian Normal University, 350007 Fuzhou, P. R. China
| | - Deyong Kang
- grid.411176.40000 0004 1758 0478Department of Pathology, Fujian Medical University Union Hospital, 350001 Fuzhou, P. R. China
| | - Guoxian Guan
- grid.412683.a0000 0004 1758 0400Department of Colorectal Surgery, the First Affiliated Hospital of Fujian Medical University, 350001 Fuzhou, P. R. China
| | - Shuoyu Xu
- grid.416466.70000 0004 1757 959XDepartment of General Surgery, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, P. R. China
| | - Yongjian Zhou
- grid.411176.40000 0004 1758 0478Department of Gastric Surgery, Fujian Medical University Union Hospital, 350001 Fuzhou, P. R. China
| | - Jianxin Chen
- grid.411503.20000 0000 9271 2478Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory for Photonics Technology, Fujian Normal University, 350007 Fuzhou, P. R. China
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25
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Moga D, Department of Surgery, Military Emergency Hospital Sibiu and Lucian Blaga University Sibiu, Romania, Popențiu A, Popa D, Department of Surgery, Military Emergency Hospital Sibiu and Lucian Blaga University Sibiu, Romania, Department of Gastroenterology, Military Emergency Hospital Sibiu and Lucian Blaga University Sibiu, Romania. Laparoscopic Wedge Resection for Gastric Mesenchymal Tumor – Small Case Series. ROMANIAN JOURNAL OF MILITARY MEDICINE 2023. [DOI: 10.55453/rjmm.2023.126.3.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/06/2023]
Abstract
" Introduction: Gastric mesenchymal tumors are a pathology that is increasing in incidence in recent years but the treatment is not yet standardized. The laparoscopic approach to these lesions is a modern option, with the patient benefiting from the advantages of minimally invasive surgery. Methods: We included in the study 4 patients operated laparoscopically for suspicion of gastric GISTs between Mars 2019 and May 2022. From a prospectively kept database, we extracted the following characteristics: age, sex, length of postoperative hospital admission, operation time, tumor location, tumor size, histopathological assessment of resection margins, intraoperative blood loss, and incidence of postoperative complications. Results: Average tumor size was 4.3 cm, ranging from 4 to 6 cm. Laparoscopic wedge resection was possible in all cases. There was no conversion, no episode of tumor rupture or spillage, and no major intraoperative complications. Histology confirmed a GIST in 3 of 4 cases. In one case histological workup showed gastric schwannoma. Conclusion: Laparoscopic wedge resection for gastric stromal tumors, even larger than 5 cm, appears to be safe and feasible in selected patients, with acceptable operative time and oncological outcome after an intermediate follow-up. More important than the size of tumors that are approached laparoscopically is their location and the possibility of a stenosis-free resection."
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26
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Radu P, Zurzu M, Paic V, Bratucu M, Garofil D, Tigora A, Georgescu V, Prunoiu V, Popa F, Surlin V, Strambu V. Interstitial Cells of Cajal-Origin, Distribution and Relationship with Gastrointestinal Tumors. MEDICINA (KAUNAS, LITHUANIA) 2022; 59:63. [PMID: 36676686 PMCID: PMC9865743 DOI: 10.3390/medicina59010063] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/23/2022] [Accepted: 12/25/2022] [Indexed: 12/29/2022]
Abstract
The interstitial cells of Cajal (ICC) represent a particular network formed by some peculiar cells that were first described by the great neuroanatomist, S. Ramon y Cajal. Nowadays, the ICC have become a fascinating topic for scientists, arousing their curiosity; as a result, there is a vast number of published articles related to the ICC. Today, everybody widely accepts that the ICC represent the pacemaker of the gastrointestinal tract and are highly probable to be the origin cells for gastrointestinal tumors (GISTs). Recently, Cajal-like cells (ICLC) were described, which are found in different organs but with an as yet unknown physiological role that needs further study. New information regarding intestinal development indicates that the ICC (fibroblast-like and muscle-like) and intestinal muscle cells have the same common embryonic cells, thereby presenting the same cellular ultrastructure. Nowadays, there is a vast quantity of information that proves the connection of the ICC and GISTs. Both of them are known to present c-kit expression and the same ultrastructural cell features, which includes minimal myoid differentiation that is noticed in GISTs, therefore, supporting the hypothesis that GISTs are ICC-related tumors. In this review, we have tried to highlight the origin and distribution of Cajal interstitial cells based on their ultrastructural features as well as their relationship with gastrointestinal stromal tumors.
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Affiliation(s)
- Petru Radu
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
| | - Mihai Zurzu
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
| | - Vlad Paic
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
| | - Mircea Bratucu
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
| | - Dragos Garofil
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
| | - Anca Tigora
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
| | - Valentin Georgescu
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
| | - Virgiliu Prunoiu
- Oncological Institute “Prof. Dr. Alexandru Trestioreanu”, 022328 Bucharest, Romania
| | - Florian Popa
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
| | - Valeriu Surlin
- Sixth Department of Surgery, University of Medicine and Pharmacy of Craiova, Craiova Emergency Clinical Hospital, 200642 Craiova, Romania
| | - Victor Strambu
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
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27
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Wang X, Abi-Raad R, Tang H, Cai G. Ki-67 index assessment on FNA specimens of gastrointestinal stromal tumor: Correlation with mitotic rate and potential predictive value for risk stratification. Cancer Cytopathol 2022; 130:974-982. [PMID: 35876606 DOI: 10.1002/cncy.22630] [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: 04/25/2022] [Revised: 06/12/2022] [Accepted: 06/28/2022] [Indexed: 01/04/2023]
Abstract
BACKGROUND Risk assessment of gastrointestinal stromal tumor (GIST) is challenging on cytology specimens. This study aims to determine whether Ki-67 index evaluated on fine-needle aspiration (FNA) specimens can correlate with the mitotic rate of GIST in surgical specimens and provide further risk assessment. METHODS Cases with cell blocks containing adequate tumor cells and surgical resections were included. Ki-67 immunostain was retrospectively performed on cell block sections, and Ki-67 index was calculated on the "hot spot" areas. RESULTS This study included 50 GIST cases from stomach (n = 45; 90%), duodenum (n = 4; 8%), and distal esophagus (n = 1; 2%). The tumor size ranged from 1.5 cm to 21 cm (mean, 5.4 cm). Based on the mitotic count, 37 GISTs (74%) had low mitotic rate (LMR) and 13 GISTs (26%) had high mitotic rate (HMR). The spindle cell, epithelioid, and mixed types accounted for 60%, 14%, and 26% of GIST, respectively. Ki-67 index counted on cell block sections correlated well with mitotic count evaluated in surgical specimens (r = 0.8031). Mean Ki-67 index was higher in HMR than LMR groups (3.5% vs. 1%, p < .001). The receiver operating characteristic curve using Ki-67 index to predict mitotic rate was further analyzed, and area under the curve was 0.839. Using a cutoff of 2.5% yielded a sensitivity of 70% at 92% specificity. CONCLUSIONS This study demonstrates good correlations between Ki-67 index and mitotic count or risk stratification, suggesting that Ki-67 index evaluated on cytology specimens may offer a promising approach to preoperatively predict the mitotic rate and risk of GIST.
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Affiliation(s)
- Xi Wang
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Rita Abi-Raad
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Haiming Tang
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Guoping Cai
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.,Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut, USA
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28
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Wu CE, Chen CP, Huang WK, Pan YR, Aptullahoglu E, Yeh CN, Lunec J. p53 as a biomarker and potential target in gastrointestinal stromal tumors. Front Oncol 2022; 12:872202. [PMID: 35965531 PMCID: PMC9372431 DOI: 10.3389/fonc.2022.872202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 07/06/2022] [Indexed: 12/07/2022] Open
Abstract
KIT and PDGFRA play a major role in the oncogenic process in gastrointestinal stroma tumors (GIST) and small molecules have been employed with great success to target the KIT and PDGFRA pathways in this cancer. However, approximately 10% of patients with GIST are resistant to current targeted drug therapy. There is a need to explore other potential targets. Although p53 alterations frequently occur in most cancers, studies regarding p53 in GIST have been limited. The CDKN2A/MDM2/p53 axis regulates cell cycle progression and DNA damage responses, which in turn control tumor growth. This axis is the major event required for transformation from low- to high-risk GIST. Generally, p53 mutation is infrequent in GIST, but p53 overexpression has been reported to be associated with high-risk GIST and unfavorable prognosis, implying that p53 should play a critical role in GIST. Also, Wee1 regulates the cell cycle and the antitumor activity of Wee1 inhibition was reported to be p53 mutant dependent. In addition, Wee1 was reported to have potential activity in GIST through the regulation of KIT protein and this mechanism may be dependent on p53 status. In this article, we review previous reports regarding the role of p53 in GIST and propose targeting the p53 pathway as a novel additional treatment strategy for GIST.
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Affiliation(s)
- Chiao-En Wu
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chiao-Ping Chen
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Wen-Kuan Huang
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Yi-Ru Pan
- Department of General Surgery and Liver Research Center, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan
| | - Erhan Aptullahoglu
- Department of Molecular Biology and Genetics, Bilecik Seyh Edebali University, Bilecik, Turkey
| | - Chun-Nan Yeh
- Department of General Surgery and Liver Research Center, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan
- *Correspondence: Chun-Nan Yeh, ; John Lunec,
| | - John Lunec
- Newcastle University Cancer Center, Bioscience Institute, Medical Faculty, Newcastle University, Newcastle upon Tyne, United Kingdom
- *Correspondence: Chun-Nan Yeh, ; John Lunec,
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29
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Frosio F, Rausa E, Marra P, Boutron-Ruault MC, Lucianetti A. Delayed-release oral mesalamine tablet mimicking a small jejunal gastrointestinal stromal tumor: A case report. World J Clin Cases 2022; 10:6710-6715. [PMID: 35979321 PMCID: PMC9294894 DOI: 10.12998/wjcc.v10.i19.6710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 04/13/2022] [Accepted: 05/17/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Enteric-coated medications are supposed to pass intact through the gastric environment and to release the drug content into the small intestine or the colon. Before dissolution of the enteric coating, they may appear hyperdense on computed tomography (CT). Unfortunately, few reports have been published on this topic so far. In this case report, the hyperdense appearance on contrast-enhanced CT of an enteric-coated mesalamine tablet was initially misinterpreted as a jejunal gastrointestinal stromal tumor (GIST).
CASE SUMMARY An asymptomatic 81-year-old male patient, who had undergone laparoscopic right nephrectomy four years earlier for stage 1 renal carcinoma, was diagnosed with a jejunal GIST at the 4-year follow-up thoraco-abdominal CT scan. He was referred to our hub hospital for gastroenterological evaluation, and subsequently underwent 18-fluorodeoxyglucose positron emission tomography, abdominal magnetic resonance imaging, and video capsule endoscopy. None of these examinations detected any lesion of the small intestine. After reviewing all the CT images in a multidisciplinary setting, the panel estimated that the hyperdense jejunal image was consistent with a tablet rather than a GIST. The tablet was an 800 mg delayed-release enteric-coated oral mesalamine tablet (Asacol®), which had been prescribed for non-specific colitis, while not informing the hospital physicians.
CONCLUSION Delayed-release oral mesalamine (Asacol®), like other enteric-coated medications, can appear as a hyperdense image on a CT scan, mimicking a small intestinal GIST. Therefore, a detailed knowledge of the patients’ medications and a multidisciplinary review of the images are essential.
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Affiliation(s)
- Fabio Frosio
- Department of General Surgery, ASST Papa Giovanni XXIII Hospital, Bergamo 24127, Italy
| | - Emanuele Rausa
- Department of General Surgery, ASST Papa Giovanni XXIII Hospital, Bergamo 24127, Italy
| | - Paolo Marra
- Department of Radiology, ASST Papa Giovanni XXIII Hospital, Bergamo 24127, Italy
| | - Marie-Christine Boutron-Ruault
- Paris-Saclay University, UVSQ, Inserm, Gustave Roussy, Exposome and Heredity Team, Centre for Epidemiology and Population Health (CESP U1018), Villejuif 94800, France
| | - Alessandro Lucianetti
- Department of General Surgery, ASST Papa Giovanni XXIII Hospital, Bergamo 24127, Italy
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Ravegnini G, Fosso B, Ricci R, Gorini F, Turroni S, Serrano C, Pilco-Janeta DF, Zhang Q, Zanotti F, De Robertis M, Nannini M, Pantaleo MA, Hrelia P, Angelini S. Analysis of microbiome in GISTs: looking for different players in tumorigenesis and novel therapeutic options. Cancer Sci 2022; 113:2590-2599. [PMID: 35633186 PMCID: PMC9357631 DOI: 10.1111/cas.15441] [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: 01/18/2022] [Revised: 04/20/2022] [Accepted: 05/23/2022] [Indexed: 12/02/2022] Open
Abstract
Preclinical forms of gastrointestinal stromal tumor (GIST), small asymptomatic lesions, called microGIST, are detected in approximately 30% of the general population. Gastrointestinal stromal tumor driver mutation can be already detected in microGISTs, even if they do not progress into malignant cancer; these mutations are necessary, but insufficient events to foster tumor progression. Here we profiled the tissue microbiota of 60 gastrointestinal specimens in three different patient cohorts—micro, low‐risk, and high‐risk or metastatic GIST—exploring the compositional structure, predicted function, and microbial networks, with the aim of providing a complete overview of microbial ecology in GIST and its preclinical form. Comparing microGISTs and GISTs, both weighted and unweighted UniFrac and Bray–Curtis dissimilarities showed significant community‐level separation between them and a pronounced difference in Proteobacteria, Firmicutes, and Bacteroidota was observed. Through the LEfSe tool, potential microbial biomarkers associated with a specific type of lesion were identified. In particular, GIST samples were significantly enriched in the phylum Proteobacteria compared to microGISTs. Several pathways involved in sugar metabolism were also highlighted in GISTs; this was expected as cancer usually displays high aerobic glycolysis in place of oxidative phosphorylation and rise of glucose flux to promote anabolic request. Our results highlight that specific differences do exist in the tissue microbiome community between GIST and benign lesions and that microbiome restructuration can drive the carcinogenesis process.
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Affiliation(s)
- Gloria Ravegnini
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Bruno Fosso
- National Research Council, Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), Bari, Italy.,Department of Biosciences, Biotechnology and Biopharmaceutics (DBBB), University of Bari "A. Moro", Bari, Italy
| | - Riccardo Ricci
- UOC di Anatomia Patologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Francesca Gorini
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Silvia Turroni
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Cesar Serrano
- Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Daniel F Pilco-Janeta
- Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.,Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Qianqian Zhang
- UOC di Anatomia Patologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Federica Zanotti
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Mariangela De Robertis
- Department of Biosciences, Biotechnology and Biopharmaceutics (DBBB), University of Bari "A. Moro", Bari, Italy
| | - Margherita Nannini
- Department of Experimental, Diagnostic and Specialized Medicine (DIMES), Alma Mater Studiorum, University of Bologna, Bologna, Italy.,Medical Oncology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Maria Abbondanza Pantaleo
- Department of Experimental, Diagnostic and Specialized Medicine (DIMES), Alma Mater Studiorum, University of Bologna, Bologna, Italy.,Medical Oncology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Patrizia Hrelia
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Sabrina Angelini
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
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Schaefer IM, DeMatteo RP, Serrano C. The GIST of Advances in Treatment of Advanced Gastrointestinal Stromal Tumor. Am Soc Clin Oncol Educ Book 2022; 42:1-15. [PMID: 35522913 DOI: 10.1200/edbk_351231] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin and a compelling clinical and biologic model for the rational development of molecularly targeted agents. This is because the majority of GISTs are driven by gain-of-function mutations in KIT or PDGFRA receptor tyrosine kinases. Specific GIST mutations circumscribe well-defined molecular subgroups that must be determined during the diagnostic work-up to guide clinical management, including therapeutic decisions. Surgery is the cornerstone treatment in localized disease and can also be clinically relevant in the metastatic setting. The correct combination and sequence of targeted agents and surgical procedures improves outcomes for patients with GIST and should be discussed individually within multidisciplinary expert teams. All currently approved agents for the treatment of GIST are based on orally available tyrosine kinase inhibitors targeting KIT and PDGFRA oncogenic activation. Although first-line imatinib achieves remarkable prolonged disease control, the benefit of subsequent lines of treatment is more modest. Novel therapeutic strategies focus on overcoming the heterogeneity of KIT or PDGFRA secondary mutations and providing more potent inhibition of specific challenging mutations. This article reviews the current understanding and treatment of GIST, with an emphasis on recent advances.
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Affiliation(s)
- Inga-Marie Schaefer
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | | | - César Serrano
- Sarcoma Translational Research Program, Vall d'Hebron Institute of Oncology, Barcelona, Spain.,Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain
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Ki67 for evaluating the prognosis of gastrointestinal stromal tumors: A systematic review and meta‑analysis. Oncol Lett 2022; 23:189. [PMID: 35527778 PMCID: PMC9073573 DOI: 10.3892/ol.2022.13309] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 04/07/2022] [Indexed: 11/13/2022] Open
Abstract
Overexpression of Ki67 is observed in tumor cells, and it has been suggested to be a marker for cancer prognosis. However, the relationship between Ki67 expression and the risk of recurrence of gastrointestinal stromal tumors (GISTs) remains poorly defined. In the present study, a meta-analysis was used to examine the associations between Ki67 levels and GIST recurrence. Studies reporting GIST and Ki67 were found by searching Cochrane Library, PubMed and Embase until October 14, 2021. The Newcastle-Ottawa Scale (NOS) was used to verify the quality of the evidence. Totally, 1682 patient cases were included. The odds ratio (OR) estimates and 95% confidence interval (CI) for each publication were determined by a fixed-effects (Mantel-Haenszel) model. A total of 20 studies that fulfilled the inclusion criteria were finally included in the analysis. The average score of quality evaluation was 6.4 points according to NOS. It was found that Ki67 levels were significantly higher in the NIH L group compared with the NIH VL group (OR: 0.51; 95% CI: 0.26-0.99; P=0.04; P heterogeneity=0.44). There was also greater Ki67 overexpression in the NIH I group compared with the NIH L group (OR: 0.45, 95% CI: 0.31-0.65; P<0.0001; P heterogeneity=0.32), while Ki67 levels were greater in the NIH H group than in the NIH I group (OR: 0.20; 95% CI: 0.15-0.28; P<0.00001; P heterogeneity=0.56). In conclusion, Ki67 overexpression may be a useful marker of the risk of recurrent GIST transformation.
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33
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Gorunova L, Boye K, Panagopoulos I, Berner JM, Bjerkehagen B, Hompland I, Lobmaier I, Hølmebakk T, Hveem TS, Heim S, Micci F. Cytogenetic and molecular analyses of 291 gastrointestinal stromal tumors: site-specific cytogenetic evolution as evidence of pathogenetic heterogeneity. Oncotarget 2022; 13:508-517. [PMID: 35284037 PMCID: PMC8901076 DOI: 10.18632/oncotarget.28209] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 02/17/2022] [Indexed: 12/02/2022] Open
Abstract
Gastrointestinal stromal tumor (GIST) is a mesenchymal neoplasm with variable behavior. An increased understanding of the tumor pathogenesis may improve clinical decision-making. Our aim was to obtain more data about the overall chromosome aberrations and intratumor cytogenetic heterogeneity in GIST. We analyzed 306 GIST samples from 291 patients using G-banding, direct sequencing, and statistics. Clonal chromosome aberrations were found in 81% of samples, with 34% of 226 primary tumors demonstrating extensive cytogenetic heterogeneity. 135 tumors had simple (≤5 changes) and 91 had complex (>5 changes) karyotypes. The karyotypically complex tumors more often were non-gastric (P < 0.001), larger (P < 0.001), more mitotically active (P = 0.009) and had a higher risk of rupture (P < 0.001) and recurrence (P < 0.001). Significant differences between gastric and non-gastric tumors were found also in the frequency of main chromosome losses: of 14q (79% vs. 63%), 22q (38% vs. 67%), 1p (23% vs. 88%), and 15q (18% vs. 77%). Gastric PDGFRA-mutated tumors, compared with gastric KIT-mutated, had a lower incidence of 22q losses (18% vs. 43%) but a higher rate of 1p losses (42% vs. 22%). The present, largest by far karyotypic study of GISTs provides further evidence for the existence of variable pathogenetic pathways operating in these tumors’ development.
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Affiliation(s)
- Ludmila Gorunova
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Kjetil Boye
- Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
- Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Ioannis Panagopoulos
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Jeanne-Marie Berner
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Bodil Bjerkehagen
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Institute of Oral Biology, Faculty of Dentistry, University of Oslo, Oslo, Norway
| | - Ivar Hompland
- Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Ingvild Lobmaier
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Toto Hølmebakk
- Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Tarjei S. Hveem
- Section for Applied Informatics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Sverre Heim
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Francesca Micci
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
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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.
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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
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Shim YR, Kim A, Gu MJ. Prognostic significance of MCM6 expression in gastrointestinal stromal tumor. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2021; 14:1119-1127. [PMID: 35027992 PMCID: PMC8748012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 12/07/2021] [Indexed: 06/14/2023]
Abstract
Minichromosome maintenance (MCM) proteins are essential for the initiation of DNA replication and they are prognostic markers in various human cancers. The aim of this study was to investigate the role of the MCM6 protein in gastrointestinal stromal tumor (GIST) and its clinical and prognostic significance. We evaluated MCM6 expression in 211 GIST samples using immunohistochemistry. We used the receiver operating characteristic curve (ROC) to identify optimal cut-off values. High MCM6 expression was associated with tumor size, mitosis, tumor necrosis, presence of recurrence/metastasis, and the National Institute of Health (NIH) and Armed Forces Institute of Pathology (AFIP) malignant risk criteria. Patients with high MCM6 expression had significantly shorter overall survival (OS) and disease-free survival (DFS) than those with low MCM6 expression. Univariate analysis indicated that tumor size, mitosis, AFIP and NIH malignant risk criteria, and high MCM6 expression were significantly associated with poor OS and DFS. High MCM6 expression and high-risk group categorization based on the NIH criteria were independent prognostic factors for OS and DFS. High MCM6 expression is significantly associated with tumor progression and aggressiveness and is an independent factor for shorter survival in GIST patients. MCM6 expression could be a predictive biomarker for tumor aggressiveness as well as a treatment target.
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Affiliation(s)
- Young-Ran Shim
- Department of Pathology, Yeungnam University Yeongcheon HospitalYeongcheon, South Korea
| | - Aeri Kim
- Department of Pathology, Daegu Fatima HospitalDaegu, South Korea
| | - Mi-Jin Gu
- Department of Pathology, Yeungnam University College of MedicineDaegu, South Korea
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Yadav SC, Menon S, Bakshi G, Katdare A, Ramadwar M, Desai SB. Gastrointestinal stromal tumor presenting with lower urinary tract symptoms - A series of five cases with unusual clinical presentation. Indian J Urol 2021; 37:357-360. [PMID: 34759530 PMCID: PMC8555570 DOI: 10.4103/iju.iju_267_21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 08/30/2021] [Accepted: 09/14/2021] [Indexed: 11/05/2022] Open
Abstract
Spindle cell tumors of the prostate are very uncommon and the majority involve the prostate secondarily from adjacent organs. Gastrointestinal stromal tumors (GISTs) are specific C-kit (CD 117) expressing mesenchymal tumors occurring in the gastrointestinal tract, commonly in the stomach and intestine; however, it is seldom seen involving the prostate. Although primary prostatic GISTs have been described, majority of them are secondary involvement from rectal GIST. The patient usually presents with urinary tract symptoms or prostate enlargement simulating a prostatic neoplasm. GIST as a differential diagnosis for prostatic mass is never thought of. We present a series of five cases of GIST arising from/involving the prostate mimicking a primary prostatic malignancy and the challenges associated with them for diagnosis and treatment.
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Affiliation(s)
- Subhash C Yadav
- Department of Surgical Pathology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Santosh Menon
- Department of Surgical Pathology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Ganesh Bakshi
- Department of Urologic Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Aparna Katdare
- Department of Radiodiagnosis, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Mukta Ramadwar
- Department of Surgical Pathology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Sangeeta B Desai
- Department of Surgical Pathology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
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Spiridon IA, Ciobanu DGA, Giușcă SE, Ferariu D, Pleşca IC, Căruntu ID. GIST and Ghrelin: To Be or Not to Be? Diagnostics (Basel) 2021; 11:1361. [PMID: 34441296 PMCID: PMC8393501 DOI: 10.3390/diagnostics11081361] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/22/2021] [Accepted: 07/24/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Ghrelin is the orexigenic hormone secreted mainly by the stomach. Its involvement in neoplastic development has been studied in gastrointestinal adenocarcinomas. Our paper aims to evaluate the influence of the ghrelin axis in gastrointestinal stromal tumors (GISTs). MATERIALS AND METHODS The study design included two groups of patients, 46 with gastric GISTs and 30 with obesity. Archived tissue samples were evaluated for the presence of gastritis and H. pylori. Immunohistochemical expression of ghrelin and its receptor (GHS-R) was assessed. RESULTS All GISTs showed absent immunohistochemical expression for ghrelin, while GHS-R displayed a particular pattern, with notable differences in intensity (p = 0.0256) and percentage of stained cells (p < 0.00001) in the periphery vs. core of tumors. Positive ghrelin expression was lower in the gastric mucosa of the first group compared to the second group (p < 0.001). CONCLUSION The ghrelin axis can influence GISTs carcinogenesis through activation of GHS-R. A previously described direct autocrine/paracrine mechanism is not supported by our findings.
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Affiliation(s)
- Irene Alexandra Spiridon
- Department of Morpho-Functional Sciences I—Morphopathology, “Grigore T. Popa” University of Medicine and Pharmacy, Strada Universității 16, 700115 Iași, Romania;
| | - Delia Gabriela Apostol Ciobanu
- Department of Morpho-Functional Sciences I—Morphopathology, “Grigore T. Popa” University of Medicine and Pharmacy, Strada Universității 16, 700115 Iași, Romania;
| | - Simona Eliza Giușcă
- Department of Morpho-Functional Sciences I—Morphopathology, “Grigore T. Popa” University of Medicine and Pharmacy, Strada Universității 16, 700115 Iași, Romania;
| | - Dan Ferariu
- Department of Pathology, Regional Institute of Oncology, Str. General Henri Mathias Berthelot 2-4, 700483 Iași, Romania;
| | - Iulia Cătălina Pleşca
- Science Research Department, Institute of Interdisciplinary Research, “Alexandru Ioan Cuza” University, Strada Lascăr Catargi 54, 700107 Iași, Romania;
| | - Irina Draga Căruntu
- Department of Morpho-Functional Sciences I—Histology, “Grigore T. Popa” University of Medicine and Pharmacy, Strada Universității 16, 700115 Iași, Romania;
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Arshad J, Costa PA, Barreto-Coelho P, Valdes BN, Trent JC. Immunotherapy Strategies for Gastrointestinal Stromal Tumor. Cancers (Basel) 2021; 13:3525. [PMID: 34298737 PMCID: PMC8306810 DOI: 10.3390/cancers13143525] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 07/06/2021] [Accepted: 07/06/2021] [Indexed: 01/13/2023] Open
Abstract
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal soft tissue sarcoma of the gastrointestinal tract. The management of locally advanced or metastatic unresectable GIST involves detecting KIT, PDGFR, or other molecular alterations targeted by imatinib and other tyrosine kinase inhibitors. The role of immunotherapy in soft tissue sarcomas is growing fast due to multiple clinical and pre-clinical studies with no current standard of care. The potential therapies include cytokine-based therapy, immune checkpoint inhibitors, anti-KIT monoclonal antibodies, bi-specific monoclonal antibodies, and cell-based therapies. Here we provide a comprehensive review of the immunotherapeutic strategies for GIST.
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Affiliation(s)
- Junaid Arshad
- Hematology-Oncology Department, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA;
| | - Philippos A. Costa
- Internal Medicine Department, Jackson Memorial Hospital, University of Miami, Miami, FL 33136, USA; (P.A.C.); (P.B.-C.)
| | - Priscila Barreto-Coelho
- Internal Medicine Department, Jackson Memorial Hospital, University of Miami, Miami, FL 33136, USA; (P.A.C.); (P.B.-C.)
| | | | - Jonathan C. Trent
- Hematology-Oncology Department, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA;
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Pretze M, Reffert L, Diehl S, Schönberg SO, Wängler C, Hohenberger P, Wängler B. GMP-compliant production of [ 68Ga]Ga-NeoB for positron emission tomography imaging of patients with gastrointestinal stromal tumor. EJNMMI Radiopharm Chem 2021; 6:22. [PMID: 34228236 PMCID: PMC8260665 DOI: 10.1186/s41181-021-00137-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 06/09/2021] [Indexed: 12/15/2022] Open
Abstract
Background [68Ga]Ga-NeoB is a novel DOTA-coupled Gastrin Releasing Peptide Receptor (GRPR) antagonist with high affinity for GRPR and good in vivo stability. This study aimed at (1) the translation of preclinical results to the clinics and establish the preparation of [68Ga]Ga-NeoB using a GMP conform kit approach and a licensed 68Ge/68Ga generator and (2) to explore the application of [68Ga]Ga-NeoB in patients with gastrointestinal stromal tumors (GIST) before and/or after interventional treatment (selective internal radiotherapy, irreversible electroporation, microwave ablation). Results Validation of the production and quality control of [68Ga]Ga-NeoB for patient use had to be performed before starting the GMP production. Six independent batches of [68Ga]Ga-NeoB were produced, all met the quality and sterility criteria and yielded 712 ± 73 MBq of the radiotracer in a radiochemical purity of > 95% and a molar activity of 14.2 ± 1.5 GBq/μmol within 20 min synthesis time and additional 20 min quality control. Three patients (2 females, 1 male, 51–77 yrs. of age) with progressive gastrointestinal stromal tumor metastases in the liver or peritoneum not responsive to standard tyrosine kinase inhibitor therapy underwent both [68Ga]Ga-NeoB scans prior and after interventional therapy. Radiosynthesis of 68Ga-NeoB was performed using a kit approach under GMP conditions. No specific patient preparation such as fasting or hydration was required for [68Ga]Ga-NeoB PET/CT imaging. Contrast-enhanced PET/CT studies were performed. A delayed, second abdominal image after the administration of the of [68Ga]Ga-NeoB was acquired at 120 min post injection. Conclusions A fully GMP compliant kit preparation of [68Ga]Ga-NeoB enabling the routine production of the tracer under GMP conditions was established for clinical routine PET/CT imaging of patients with metastatic GIST and proved to adequately visualize tumor deposits in the abdomen expressing GRPR. Patients could benefit from additional information derived from [68Ga]Ga-NeoB diagnosis to assess the presence of GRPR in the tumor tissue and monitor antitumor treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s41181-021-00137-w.
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Affiliation(s)
- Marc Pretze
- Department of Nuclear Medicine, University Hospital Carl Gustav Carus, TU Dresden, Fetscherstr. 74, 01307, Dresden, Germany. .,Molecular Imaging and Radiochemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
| | - Laura Reffert
- Department of Nuclear Medicine, University Hospital Carl Gustav Carus, TU Dresden, Fetscherstr. 74, 01307, Dresden, Germany
| | - Steffen Diehl
- Department of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Mannheim, Germany
| | - Stefan O Schönberg
- Department of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Mannheim, Germany
| | - Carmen Wängler
- Biomedical Chemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, Mannheim, Germany
| | - Peter Hohenberger
- Division of Surgical Oncology and Thoracic Surgery, University Medical Center Mannheim, Mannheim, Germany
| | - Björn Wängler
- Molecular Imaging and Radiochemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
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Bertero L, Gambella A, Barreca A, Osella-Abate S, Chiusa L, Francia di Celle P, Lista P, Papotti M, Cassoni P. Caveolin-1 expression predicts favourable outcome and correlates with PDGFRA mutations in gastrointestinal stromal tumours (GISTs). J Clin Pathol 2021; 75:825-831. [PMID: 34155091 DOI: 10.1136/jclinpath-2021-207595] [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: 04/01/2021] [Accepted: 06/08/2021] [Indexed: 11/04/2022]
Abstract
AIMS Novel prognostic markers are warranted for gastrointestinal stromal tumours. Caveolin-1 is a multifunctional protein that proved to be associated with outcome in multiple tumour types. Aim of this study was to investigate Caveolin-1 expression and prognostic efficacy in a series of gastrointestinal stromal tumours. METHODS Caveolin-1 expression was assessed by immunohistochemistry in a retrospective series of 66 gastrointestinal stromal tumours representative of the different molecular subtypes. Correlations with clinical, histopathological and molecular features were investigated. Statistical analyses were performed as appropriate. RESULTS Thirty-five cases out of 66 (53.0%) expressed Caveolin-1. Presence of Caveolin-1 expression correlated with favourable histopathologic and clinical traits, including a lower mitotic count (p=0.003) and lower relapse rate (p=0.005). Caveolin-1 expression also resulted associated with the presence of PDGFRA mutations (p=0.010). Outcome analyses showed a favourable prognostic significance of Caveolin-1 expression in terms of relapse-free survival (HR=0.14; 95% CI=0.03 to 0.63) and overall survival (HR=0.29; 95% CI=0.11 to 0.74), even after adjusting for the mutational subgroup (relapse-free survival: HR=0.14, 95% CI=0.04 to 0.44; overall survival: HR=0.29, 95% CI=0.11 to 0.51) and imatinib treatment (relapse-free survival: HR=0.14, 95% CI=0.02 to 0.81; overall survival: HR=0.29, 95% CI=0.17 to 0.48). CONCLUSION Caveolin-1 represents a novel prognostic marker in gastrointestinal stromal tumours. Further studies are warranted to validate these results and to explore the mechanisms linking Caveolin-1 expression with the PDGFRA oncogenic pathway.
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Affiliation(s)
- Luca Bertero
- Pathology Unit, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Alessandro Gambella
- Pathology Unit, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Antonella Barreca
- Pathology Unit, "Città della Salute e della Scienza di Torino" University Hospital, Turin, Italy
| | - Simona Osella-Abate
- Molecular Pathology Unit, "Città della Salute e della Scienza di Torino" University Hospital, Turin, Italy
| | - Luigi Chiusa
- Pathology Unit, "Città della Salute e della Scienza di Torino" University Hospital, Turin, Italy
| | - Paola Francia di Celle
- Molecular Pathology Unit, "Città della Salute e della Scienza di Torino" University Hospital, Turin, Italy
| | - Patrizia Lista
- Oncology Unit, "Città della Salute e della Scienza di Torino" University Hospital, Turin, Italy
| | - Mauro Papotti
- Pathology Unit, Department of Oncology, University of Turin, Turin, Italy
| | - Paola Cassoni
- Pathology Unit, Department of Medical Sciences, University of Turin, Turin, Italy
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Li T, Liu G, Li J, Cui J, Wang X, Li W, Zhao Z, Zhang K, Liu T. Gastric tumorigenesis after radical resection combined with adjuvant chemotherapy for colorectal cancer: two case reports and a literature review. J Int Med Res 2021; 49:3000605211007050. [PMID: 33858250 PMCID: PMC8059046 DOI: 10.1177/03000605211007050] [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: 11/17/2022] Open
Abstract
Radical resection with or without adjuvant chemotherapy is a common option for stage II and III colorectal cancer. Few reports exist regarding gastric tumorigenesis, including gastric cancer, gastric intraepithelial neoplasia, and gastric stromal tumor, in patients who received this protocol as the standard treatment for colorectal cancer. We present two cases of gastric tumorigenesis in patients with colorectal cancer following radical resection combined with adjuvant chemotherapy. Both patients underwent gastrectomy and D2 lymphadenectomy for their gastric tumors; neither patient developed recurrence up to 2 years after treatment. These cases indicate that patients should be monitored closely for gastric tumorigenesis after treatment for colorectal cancer. Early detection and active surgical treatment can provide satisfactory results for colorectal cancer followed by gastric tumorigenesis. Long-term follow-up and regular examinations, especially gastroscopy, are necessary to detect gastric tumorigenesis after colorectal cancer. The focus on monitoring colorectal cancer alone in colorectal cancer patients should be changed to include a broader range of cancers in addition to precancers and other tumors, such as gastric stromal tumor.
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Affiliation(s)
- Tao Li
- Department of Colorectal and Anal Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Guoliang Liu
- Operating Theater and Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Jiannan Li
- Department of Colorectal and Anal Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Jian Cui
- Department of General Surgery, Beijing Hospital, Beijing, China
| | - Xinyu Wang
- Department of Colorectal and Anal Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Wei Li
- Department of Colorectal and Anal Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Zeyun Zhao
- Department of Colorectal and Anal Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Kai Zhang
- Department of Colorectal and Anal Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Tongjun Liu
- Department of Colorectal and Anal Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China
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Fudalej MM, Badowska-Kozakiewicz AM. Improved understanding of gastrointestinal stromal tumors biology as a step for developing new diagnostic and therapeutic schemes. Oncol Lett 2021; 21:417. [PMID: 33841578 DOI: 10.3892/ol.2021.12678] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 02/10/2021] [Indexed: 12/12/2022] Open
Abstract
A gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the human gastrointestinal tract, with an estimated incidence of 10-15 per 1 million per year. While preparing holistic care for patients with GIST diagnosis, scientists might face several difficulties - insufficient risk stratification, acquired or secondary resistance to imatinib, or the need for an exceptional therapy method associated with wild-type tumors. This review summarizes recent advances associated with GIST biology that might enhance diagnostic and therapeutic strategies. New molecules might be incorporated into risk stratification schemes due to their proven association with outcomes; however, further research is required. Therapies based on the significant role of angiogenesis, immunology, and neural origin in the GIST biology could become a valuable enhancement of currently implemented treatment schemes. Generating miRNA networks that would predict miRNA regulatory functions is a promising approach that might help in better selection of potential biomarkers and therapeutical targets in cancer, including GISTs.
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Affiliation(s)
- Marta Magdalena Fudalej
- Department of Cancer Prevention, Medical University of Warsaw, 02-091 Warsaw, Poland.,Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
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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.
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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
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Abstract
Gastrointestinal stromal tumours (GIST) have an incidence of ~1.2 per 105 individuals per year in most countries. Around 80% of GIST have varying molecular changes, predominantly mutually exclusive activating KIT or PDGFRA mutations, but other, rare subtypes also exist. Localized GIST are curable, and surgery is their standard treatment. Risk factors for relapse are tumour size, mitotic index, non-gastric site and tumour rupture. Patients with GIST with KIT or PDGFRA mutations sensitive to the tyrosine kinase inhibitor (TKI) imatinib that are at high risk of relapse have improved survival with adjuvant imatinib treatment. In advanced disease, median overall survival has improved from 18 months to >70 months since the introduction of TKIs. The role of surgery in the advanced setting remains unclear. Resistance to TKIs arise mainly from subclonal selection of cells with resistance mutations in KIT or PDGFRA when they are the primary drivers. Advanced resistant GIST respond to second-line sunitinib and third-line regorafenib, as well as to the new broad-spectrum TKI ripretinib. Rare molecular forms of GIST with alterations involving NF1, SDH genes, BRAF or NTRK genes generally show primary resistance to standard TKIs, but some respond to specific inhibitors of the activated genes. Despite major advances, many questions in both advanced and localized disease remain unanswered.
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Affiliation(s)
- Jean-Yves Blay
- Department of Medicine, Centre Leon Berard, UNICANCER & University Lyon I, Lyon, France.
| | - Yoon-Koo Kang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Toshiroo Nishida
- Surgery Department, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
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Zhao X, Li X, Huang X, Shang L, Zhang J, Wu J. Gastric plexiform fibromyxoma resected by endoscopic submucosal dissection: A case report and review of literature. HUMAN PATHOLOGY: CASE REPORTS 2021. [DOI: 10.1016/j.ehpc.2020.200468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Brčić I, Argyropoulos A, Liegl-Atzwanger B. Update on Molecular Genetics of Gastrointestinal Stromal Tumors. Diagnostics (Basel) 2021; 11:194. [PMID: 33525726 PMCID: PMC7912114 DOI: 10.3390/diagnostics11020194] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/21/2021] [Accepted: 01/23/2021] [Indexed: 12/14/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. The majority are sporadic, solitary tumors that harbor mutually exclusive KIT or PDGFRA gain-of-function mutations. The type of mutation in addition to risk stratification corresponds to the biological behavior of GIST and response to treatment. Up to 85% of pediatric GISTs and 10-15% of adult GISTs are devoid of these (KIT/PDGFRA) mutations and are referred to as wild-type GISTs (wt-GIST). It has been shown that these wt-GISTs are a heterogeneous tumor group with regard to their clinical behavior and molecular profile. Recent advances in molecular pathology helped to further sub-classify the so-called "wt-GISTs". Based on their significant clinical and molecular heterogeneity, wt-GISTs are divided into a syndromic and a non-syndromic (sporadic) subgroup. Recently, the use of succinate dehydrogenase B (SDHB) by immunohistochemistry has been used to stratify GIST into an SDHB-retained and an SDHB-deficient group. In this review, we focus on GIST sub-classification based on clinicopathologic, and molecular findings and discuss the known and yet emerging prognostic and predictive genetic alterations. We also give insights into the limitations of targeted therapy and highlight the mechanisms of secondary resistance.
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Affiliation(s)
| | | | - Bernadette Liegl-Atzwanger
- Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria; (I.B.); (A.A.)
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Mao X, Yang X, Chen X, Yu S, Yu S, Zhang B, Ji Y, Chen Y, Ouyang Y, Luo W. Single-cell transcriptome analysis revealed the heterogeneity and microenvironment of gastrointestinal stromal tumors. Cancer Sci 2021; 112:1262-1274. [PMID: 33393143 PMCID: PMC7935798 DOI: 10.1111/cas.14795] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 12/15/2020] [Accepted: 12/31/2020] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the human gastrointestinal tract. In this study, we performed single-cell RNA sequencing (RNA-seq) on intra- and peri-tumor tissues from GIST patients with the aim of discovering the heterogeneity of tumor cells in GIST and their interactions with other cells. We found four predominating cell types in GIST tumor tissue, including T cells, macrophages, tumor cells, and NK cells. Tumor cells could be clustered into two groups: one was highly proliferating and associated with high risk of metastasis, the other seemed "resting" and associated with low risk. Their clinical relevance and prognostic values were confirmed by RNA-seq of 65 GIST samples. T cells were the largest cell type in our single-cell data. Two groups of CD8+ effector memory (EM) cells were in the highest clonal expansion and performed the highest cytotoxicity but were also the most exhausted among all T cells. A group of macrophages were found polarized to possess both M1 and M2 signatures, and increased along with tumor progression. Cell-to-cell interaction analysis revealed that adipose endothelial cells had high interactions with tumor cells to facilitate their progression. Macrophages were at the center of the tumor microenvironment, recruiting immune cells to the tumor site and having most interactions with both tumor and nontumor cells. In conclusion, we obtained an overview of the GIST microenvironment and revealed the heterogeneity of each cell type and their relevance to risk classifications, which provided a novel theoretical basis for learning and curing GISTs.
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Affiliation(s)
- Xiaofan Mao
- Clinical Research Institute, The First People's Hospital of Foshan & Sun Yat-Sen University Foshan Hospital, Foshan, China.,Medical Engineering Technology Research and Development Center of Immune Repertoire in Foshan, The First People's Hospital of Foshan & Sun Yat-Sen University Foshan Hospital, Foshan, China
| | - Xuezhu Yang
- Gastroenterology, The First People's Hospital of Foshan & Sun Yat-Sen University Foshan Hospital, Foshan, China
| | - Xiangping Chen
- Clinical Research Institute, The First People's Hospital of Foshan & Sun Yat-Sen University Foshan Hospital, Foshan, China.,Medical Engineering Technology Research and Development Center of Immune Repertoire in Foshan, The First People's Hospital of Foshan & Sun Yat-Sen University Foshan Hospital, Foshan, China
| | - Sifei Yu
- Clinical Research Institute, The First People's Hospital of Foshan & Sun Yat-Sen University Foshan Hospital, Foshan, China.,Medical Engineering Technology Research and Development Center of Immune Repertoire in Foshan, The First People's Hospital of Foshan & Sun Yat-Sen University Foshan Hospital, Foshan, China
| | - Si Yu
- Gastroenterology, The First People's Hospital of Foshan & Sun Yat-Sen University Foshan Hospital, Foshan, China
| | - Beiying Zhang
- Clinical Research Institute, The First People's Hospital of Foshan & Sun Yat-Sen University Foshan Hospital, Foshan, China.,Medical Engineering Technology Research and Development Center of Immune Repertoire in Foshan, The First People's Hospital of Foshan & Sun Yat-Sen University Foshan Hospital, Foshan, China
| | - Yong Ji
- Gastroenterology, The First People's Hospital of Foshan & Sun Yat-Sen University Foshan Hospital, Foshan, China
| | - Yihao Chen
- Clinical Research Institute, The First People's Hospital of Foshan & Sun Yat-Sen University Foshan Hospital, Foshan, China.,Medical Engineering Technology Research and Development Center of Immune Repertoire in Foshan, The First People's Hospital of Foshan & Sun Yat-Sen University Foshan Hospital, Foshan, China
| | - Ying Ouyang
- Clinical Research Institute, The First People's Hospital of Foshan & Sun Yat-Sen University Foshan Hospital, Foshan, China.,Medical Engineering Technology Research and Development Center of Immune Repertoire in Foshan, The First People's Hospital of Foshan & Sun Yat-Sen University Foshan Hospital, Foshan, China
| | - Wei Luo
- Clinical Research Institute, The First People's Hospital of Foshan & Sun Yat-Sen University Foshan Hospital, Foshan, China.,Medical Engineering Technology Research and Development Center of Immune Repertoire in Foshan, The First People's Hospital of Foshan & Sun Yat-Sen University Foshan Hospital, Foshan, China
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48
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Pitsava G, Settas N, Faucz FR, Stratakis CA. Carney Triad, Carney-Stratakis Syndrome, 3PAS and Other Tumors Due to SDH Deficiency. Front Endocrinol (Lausanne) 2021; 12:680609. [PMID: 34012423 PMCID: PMC8126684 DOI: 10.3389/fendo.2021.680609] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 04/12/2021] [Indexed: 12/20/2022] Open
Abstract
Succinate dehydrogenase (SDH) is a key respiratory enzyme that links Krebs cycle and electron transport chain and is comprised of four subunits SDHA, SDHB, SDHC and SDHD. All SDH-deficient tumors are caused by or secondary to loss of SDH activity. As many as half of the familial cases of paragangliomas (PGLs) and pheochromocytomas (PHEOs) are due to mutations of the SDHx subunits. Gastrointestinal stromal tumors (GISTs) associated with SDH deficiency are negative for KIT/PDGFRA mutations and present with distinctive clinical features such as early onset (usually childhood or adolescence) and almost exclusively gastric location. SDH-deficient GISTs may be part of distinct clinical syndromes, Carney-Stratakis syndrome (CSS) or dyad and Carney triad (CT). CSS is also known as the dyad of GIST and PGL; it affects both genders equally and is inherited in an autosomal dominant manner with incomplete penetrance. CT is a very rare disease; PGL, GIST and pulmonary chondromas constitute CT which shows female predilection and may be a mosaic disorder. Even though there is some overlap between CT and CSS, as both are due to SDH deficiency, CSS is caused by inactivating germline mutations in genes encoding for the SDH subunits, while CT is mostly caused by a specific pattern of methylation of the SDHC gene and may be due to germline mosaicism of the responsible genetic defect.
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Affiliation(s)
- Georgia Pitsava
- Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Nikolaos Settas
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Fabio R. Faucz
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
- *Correspondence: Fabio R. Faucz,
| | - Constantine A. Stratakis
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
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Zhou G, Xiao K, Gong G, Wu J, Zhang Y, Liu X, Jiang Z, Ma C. A novel nomogram for predicting liver metastasis in patients with gastrointestinal stromal tumor: a SEER-based study. BMC Surg 2020; 20:298. [PMID: 33238982 PMCID: PMC7689971 DOI: 10.1186/s12893-020-00969-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 11/17/2020] [Indexed: 02/07/2023] Open
Abstract
Background Liver metastasis (LIM) of gastrointestinal stromal tumor (GIST) is associated with poor prognosis. The present study aimed at developing and validating nomogram to predict LIM in patients with GIST, thus helping clinical diagnosis and treatment. Methods The data of GIST patients derived from Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2016, which were then screened by univariate and multivariate logistic regression for the construction of LIM nomogram. The model discrimination of LIM nomogram was evaluated by concordance index (C-index) and calibration plots, while the predictive accuracy and clinical values were measured by decision curve analysis (DCA) and clinical impact plot. Furthermore, we validated predictive nomogram in the internal testing set. Results A total of 3797 patients were enrolled and divided randomly into training and validating groups in a 3-to-1 ratio. After logistic regression, the significant variables were sex, tumor location, tumor size, N stage and mitotic rate. The calibration curves showed the perfect agreement between nomogram predictions and actual observations, while the DCA and clinical impact plot showed the clinical utility of LIM nomogram. C-index of the nomogram was 0.812. What’s more, receiver operating characteristic curves (ROC) also showed good discrimination and calibration in the training set (AUC = 0.794, 95% CI 0.778–0.808) and the testing set (AUC = 0.775, 95% CI 0.748–0.802). Conclusion The nomogram for patients with GIST can effectively predict the individualized risk of liver metastasis and provide insightful information to clinicians to optimize therapeutic regimens.
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Affiliation(s)
- Guowei Zhou
- Department of General Surgery, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China
| | - Keshuai Xiao
- Department of General Surgery, Xinyang Central Hospital, Xin Yang, 464000, Henan Province, China
| | - Guanwen Gong
- Department of General Surgery, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China.
| | - Jiabao Wu
- Department of Pediatrics, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China
| | - Ya Zhang
- Department of Gynecology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China
| | - Xinxin Liu
- Department of General Surgery, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China
| | - Zhiwei Jiang
- Department of General Surgery, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China
| | - Chaoqun Ma
- Department of General Surgery, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China.
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50
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Yang L, Zheng T, Dong Y, Wang Z, Liu D, Du J, Wu S, Shi Q, Liu L. MRI Texture-Based Models for Predicting Mitotic Index and Risk Classification of Gastrointestinal Stromal Tumors. J Magn Reson Imaging 2020; 53:1054-1065. [PMID: 33037745 DOI: 10.1002/jmri.27390] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 09/23/2020] [Accepted: 09/25/2020] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Treatment regimens and prognoses of gastrointestinal stromal tumors (GIST) are quite different for tumors in different risk categories. Accurate preoperative grading of tumors is important for avoiding under- or overtreatment. PURPOSE To develop and validate an MRI texture-based model to predict the mitotic index and its risk classification. STUDY TYPE Retrospective. POPULATION Ninety-one patients with histologically-confirmed GIST; 64 patients in a training cohort, and 27 patients in a test cohort. FIELD STRENGTH/SEQUENCE T2 -weighted imaging (T2 WI), diffusion-weighted imaging (DWI), and dynamic contrast-enhanced three-dimensional volumetric interpolated breath-hold examination (3D-VIBE) at 1.5T. ASSESSMENT GIST images were manually segmented by two independent radiologists using ITK-SNAP software and MRI features were extracted using Pyradiomics. Two pathologists reviewed the tissue specimens of the tumors to identify the mitotic index and risk classification in consensus. STATISTICAL TESTS The least absolute shrinkage and selection operator (LASSO) regression method was used to select texture features. A logistic regression model was established based on the radiomic score (radscore), tumor location, and maximum diameter to predict tumor classification and develop a nomogram. Receiver operator characteristic (ROC) curves were used to evaluate the ability of the nomogram to distinguish between two tumors with different risk classifications, and a calibration curve was used to evaluate the consistency between the predicted risk and the actual risk. RESULTS The texture signature achieved high efficacy in predicting the mitotic index area under the curve ([AUC], 0.906; 95% confidence interval [CI]: 0.813, 0.961). A nomogram for prediction of the risk classification of GIST, which incorporated this texture signature together with maximum tumor diameter and location, allowed good discrimination in the training cohort (AUC, 0.878; 95% CI: 0.769, 0.960) and the validation cohort (AUC, 0.903; 95% CI: 0.732, 0.922). DATA CONCLUSION The texture-based model can be used to predict GIST mitotic index and risk classification preoperatively. LEVEL OF EVIDENCE 2. TECHNICAL EFFICACY STAGE 3.
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Affiliation(s)
- Linsha Yang
- Department of Magnetic Resonance Imaging, Qinhuangdao Municipal No. 1 Hospital, Qinhuangdao, China
| | - Tao Zheng
- Department of Magnetic Resonance Imaging, Qinhuangdao Municipal No. 1 Hospital, Qinhuangdao, China
| | - Yanchao Dong
- Department of Intervention, Qinhuangdao Municipal No. 1 Hospital, Qinhuangdao, China
| | - Zhanqiu Wang
- Department of Magnetic Resonance Imaging, Qinhuangdao Municipal No. 1 Hospital, Qinhuangdao, China
| | - Defeng Liu
- Department of Magnetic Resonance Imaging, Qinhuangdao Municipal No. 1 Hospital, Qinhuangdao, China
| | - Juan Du
- Department of Magnetic Resonance Imaging, Qinhuangdao Municipal No. 1 Hospital, Qinhuangdao, China
| | - Shuo Wu
- Department of Magnetic Resonance Imaging, Qinhuangdao Municipal No. 1 Hospital, Qinhuangdao, China
| | - Qinglei Shi
- Scientific Clinical Specialist, Siemens Ltd., Beijing, China
| | - Lanxiang Liu
- Department of Magnetic Resonance Imaging, Qinhuangdao Municipal No. 1 Hospital, Qinhuangdao, China
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