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Lin P, Ji M, Sun T, Sun H, Ma H. Racial Disparities and Trends in Outcomes of Patients with Gastrointestinal Stromal Tumors. J Gastrointest Cancer 2025; 56:72. [PMID: 40019688 DOI: 10.1007/s12029-025-01195-y] [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] [Accepted: 02/17/2025] [Indexed: 03/01/2025]
Abstract
BACKGROUND Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. However, there are limited studies on the latest survival trends and the impact of racial disparities on GIST patients' outcomes. METHODS We obtained 12,808 GIST patients between 2001 and 2020 from the Surveillance, Epidemiology, and End Results (SEER) database in 17 original sites. Analysis utilizing the Kaplan-Meier method explored survival disparities and Cox regression was employed to assess the impact of prognostic factors. RESULTS Our study revealed an increase in the GIST incidence per 100,000 people over the past two decades, along with a rise in relative survival rate (RSR). Age, gender, social groups, tumor site, size, stage, socioeconomic status, marital status, surgery, and systemic therapy are prognostic factors. Subgroup analysis indicated higher incidence and poorer survival trends among Non-Hispanic Blacks (NHB) (Incidence, 1.88 per 100,000 people; 120 Mo RSR, 61.6%, 2001 to 2020). Colonic GIST has the worst prognosis among different locations, while rectal and anal GIST has the best. Within these groups, Non-Hispanic White (NHW) with colonic GIST have the poorest prognosis (HR, 2.032; 95% CI, 1.476-2.798), whereas NHB with rectal and anal GIST have the best prognosis. CONCLUSION The incidence and RSR of GIST both increased during 2001-2020. NHW with colonic GIST showed poorer survival, while NHB with rectal and anal GIST revealed better survival, highlighting the importance of targeted clinical management for GIST.
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Affiliation(s)
- Peixu Lin
- Medical Research Institute, Guangdong Provincial People'S Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan Second Road, Guangzhou, 510080, Guangdong, China
| | - Meichen Ji
- Department of Oncology, Heyuan Hospital of Guangdong Provincial People'S Hospital, Heyuan People'S Hospital, Heyuan, 517000, Guangdong, China
| | - Tiantian Sun
- Department of Hematology, the Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Huanhuan Sun
- Medical Research Institute, Guangdong Provincial People'S Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan Second Road, Guangzhou, 510080, Guangdong, China.
| | - Haiqing Ma
- Department of Oncology, Heyuan Hospital of Guangdong Provincial People'S Hospital, Heyuan People'S Hospital, Heyuan, 517000, Guangdong, China.
- Medical Research Institute, Guangdong Provincial People'S Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan Second Road, Guangzhou, 510080, Guangdong, China.
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Suto H, Kawamura M, Morita M, Sakai H, Onoe T, Ikeuchi K, Kajimoto K, Matsumoto K. Low-dose Imatinib Efficacy in a Gastrointestinal Stromal Tumor Patient With KIT Exon 11 W557_K558 Deletion. In Vivo 2025; 39:532-538. [PMID: 39740915 PMCID: PMC11705098 DOI: 10.21873/invivo.13857] [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: 10/10/2024] [Revised: 10/21/2024] [Accepted: 10/22/2024] [Indexed: 01/02/2025]
Abstract
BACKGROUND/AIM Gastrointestinal stromal tumors (GISTs) are rare cancers originating from Cajal's stromal cells in the gastrointestinal tract. The most common driver mutation in these cancers is the KIT mutation. This report presents a case of response to low-dose imatinib in a patient with GIST harboring KIT exon 11 W557_K558 deletion. CASE REPORT In June 2023, an 82-year-old male developed perineal pain. Computed tomography (CT) imaging revealed a mass measuring >9 cm, extending from the rectum to the prostate. Submucosal tumor biopsy revealed a tumor with CD117-positive and DOG1-positive spindle-shaped cells leading to a diagnosis of GIST. c-Kit gene mutation analysis detected a W557_K558 deletion in exon 11. Treatment with imatinib (400 mg/day) was initiated in late October 2023 to preserve organ function; the dose was reduced to 300 mg/day after 5 days of treatment and further reduced to 200 mg/day after 10 days, with continued treatment at this dose. The CT performed in January, April, and June 2024 showed that the rectal GIST had shrunk. The blood imatinib concentration remained at approximately 650 ng/ml from January to March 2024 and decreased to 391 ng/ml in May 2024. CONCLUSION The response rate of GISTs to imatinib is influenced by genetic mutations. GIST with KIT exon 11 W557_K558 deletion is associated with a high risk of recurrence. In vitro data showed that low-dose imatinib was effective in such cases. Low-dose imatinib is a treatment option for patients with GIST harboring KIT exon 11 W557_K558 deletion who are intolerant to high-dose imatinib.
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Affiliation(s)
- Hirotaka Suto
- Department of Medical Oncology, Hyogo Cancer Center, Akashi, Japan;
| | - Miyuki Kawamura
- Department of Medical Oncology, Hyogo Cancer Center, Akashi, Japan
| | - Mitsunori Morita
- Department of Medical Oncology, Hyogo Cancer Center, Akashi, Japan
| | - Hideki Sakai
- Department of Medical Oncology, Hyogo Cancer Center, Akashi, Japan
| | - Takuma Onoe
- Department of Medical Oncology, Hyogo Cancer Center, Akashi, Japan
| | - Kyoko Ikeuchi
- Department of Medical Oncology, Hyogo Cancer Center, Akashi, Japan
| | | | - Koji Matsumoto
- Department of Medical Oncology, Hyogo Cancer Center, Akashi, Japan
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Moreno-Fuquen R, Avellaneda-Tamayo JF, Arango-Daraviña K, Ellena J, Kennedy AR. A novel imatinib analogue inhibitor of chronic myeloid leukaemia: design, synthesis and characterization-explanation of its folded conformation. ROYAL SOCIETY OPEN SCIENCE 2025; 12:241654. [PMID: 39881787 PMCID: PMC11774592 DOI: 10.1098/rsos.241654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 12/04/2024] [Accepted: 12/12/2024] [Indexed: 01/31/2025]
Abstract
Chronic myeloid leukaemia (CML) is primarily treated using imatinib mesylate, a tyrosine kinase inhibitor (TKI) targeting the BCR::ABL1 oncoprotein. However, the development of drug resistance and adverse side effects necessitate the exploration of alternative therapeutic agents. This study presents the synthesis and characterization of a novel imatinib analogue, 3-chloro-N-(2-methyl-5-((4-(pyridin-2-yl)pyrimidin-2-yl)amino)phenyl)benzamide (PAPP1). The compound's structure was elucidated using X-ray crystallography and spectroscopic techniques, including NMR, infrared and UV-visible. Crystallographic analysis reveals that PAPP1 consists of a phenyl-amino-pyridine-pyrimidine (PAPP) scaffold with substituted aromatic rings forming a nearly coplanar geometry. Additionally, supramolecular interactions in the crystal are mediated by hydrogen bonds and dispersion forces, forming dimers and layered structures. Molecular docking studies demonstrate strong binding affinity to the ABL1 enzyme, with PAPP1 showing comparable binding energy to imatinib, indicating its potential as a lead compound for further development. Computational studies, including molecular electrostatic potential and vibrational analysis, provide further support for the structural stability and bioactivity of PAPP1. These findings suggest that PAPP could be a promising scaffold for future CML drug design, offering a potential alternative to existing TKIs, and PAPP1 is a promising lead susceptible to optimization.
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Affiliation(s)
- Rodolfo Moreno-Fuquen
- Grupo de Cristalografía, Departamento de Química, Universidad del Valle, Calle 13 Carrera 100, Santiago de Cali, 760042, Colombia
| | - Juan F. Avellaneda-Tamayo
- Grupo de Cristalografía, Departamento de Química, Universidad del Valle, Calle 13 Carrera 100, Santiago de Cali, 760042, Colombia
- DIFACQUIM Research Group, Department of Pharmacy, School of Chemistry, Universidad Nacional Autónoma de México, Avenida Universidad 3000, Mexico City, 04510, Mexico
| | - Kevin Arango-Daraviña
- Grupo de Cristalografía, Departamento de Química, Universidad del Valle, Calle 13 Carrera 100, Santiago de Cali, 760042, Colombia
| | - Javier Ellena
- Instituto de Física de São Carlos, Universidade de São Paulo, USP, Avenida Trabalhador São-carlense 400, Parque Arnold Schmidt, CEP 13566-590, São Carlos, SP, Brazil
| | - Alan R. Kennedy
- WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, GlasgowG1 1XL, UK
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Pain P, Tripathi A, Pillai PP. Involvement of PDGFR-integrin interactions in the regulation of anoikis resistance in glioblastoma progression. Cell Biol Int 2025; 49:3-15. [PMID: 39523497 DOI: 10.1002/cbin.12257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 07/22/2024] [Accepted: 07/31/2024] [Indexed: 11/16/2024]
Abstract
The interactions between platelet-derived growth factor/PDGF receptor and integrin signaling are crucial for cells to respond to extracellular stimuli. Integrin interactions with PDGFR within the lipid rafts activate downstream cellular signaling pathways that regulate cell proliferation, cell migration, cell differentiation, and cell death processes. The mechanisms underlying PDGFR activation mediated receptor internalization, interactions with other cell-surface receptors, particularly extracellular matrix receptors, integrins, and how these cellular mechanisms switch on anchorage-independent cell survival, leading to anoikis resistance are discussed. The role of regulatory molecules such as noncoding RNAs, that can modulate several molecular and cellular processes, including autophagy, in the acquisition of anoikis resistance is also discussed. Overall, the review provides a new perspective on a complex interplay of regulatory cellular machineries involving autophagy, noncoding RNAs and cellular mechanisms of PDGFR activation, PDGFR-integrin interactions, and involvement of lipids rafts in the acquisition of anoikis resistance that regulates glioblastoma progression along with potential future strategies to develop novel therapeutics for glioblastoma multiforme.
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Affiliation(s)
- Pampa Pain
- Division of Neurobiology, Department of Zoology, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India
| | - Ashutosh Tripathi
- Division of Neurobiology, Department of Zoology, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India
| | - Prakash P Pillai
- Division of Neurobiology, Department of Zoology, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India
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Sun X, Lin X, Zhang Q, Li C, Shu P, Gao X, Shen K. Safety, effectiveness and the optimal duration of preoperative imatinib in locally advanced gastric gastrointestinal stromal tumors: A retrospective cohort study. Cancer Med 2024; 13:e70237. [PMID: 39300931 PMCID: PMC11413410 DOI: 10.1002/cam4.70237] [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: 01/04/2024] [Revised: 07/14/2024] [Accepted: 09/02/2024] [Indexed: 09/22/2024] Open
Abstract
BACKGROUND The optimal duration of preoperative imatinib (IM) remains controversial. This study aimed to evaluate the safety, therapeutic effectiveness, and optimal duration of preoperative IM in patients with locally advanced gastric gastrointestinal stromal tumors (GIST). METHODS The clinicopathologic data of 41 patients with locally advanced gastric GIST who received preoperative IM and underwent surgical resection from January 2014 and December 2021 were retrospectively analyzed. RESULTS After a median of 7.0 (IQR: 4.5-10) months of preoperative IM treatment, 30 patients experienced adverse events (AEs), 80% of which were grade 1/2 AEs. The mean tumor size decreased from 12.71 ± 5.34 cm to 8.26 ± 4.00 cm, with a reduction rate of 35%. Setting 8 months as the cut-off value according to the results of ROC analysis. The proportion of laparoscopic surgery was higher in patients with short-term (≤8 months) versus long-term (>8 months) preoperative IM. Compared with the subtotal/total gastrectomy group, patients in the local gastrectomy group exhibited less intraoperative blood loss, shorter length of postoperative hospital stay, and fewer postoperative complications. The 3-year recurrence-free survival (RFS) and overall survival (OS) rates were 82.9% and 97.6%, and the expected 5-year RFS and OS rates were 75.6% and 90.2% respectively. RFS was better in the short-term than in the long-term preoperative IM treatment group, and it was also better in pre- plus postoperative IM treatment group than that in the preoperative IM alone group. Both univariate and multivariate COX analysis showed that a higher mitotic index and long-term preoperative IM treatment were associated with worse RFS, while postoperative IM treatment could significantly improve RFS. CONCLUSIONS The study suggests that in patients with locally advanced gastric GIST, preoperative short-term (≤8 months) use of IM is associated with higher RFS than long-term use.
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Affiliation(s)
- Xiangfei Sun
- Department of General Surgery, Zhongshan HospitalFudan University School of MedicineShanghaiChina
| | - Xiaohan Lin
- Department of General Surgery, Zhongshan HospitalFudan University School of MedicineShanghaiChina
| | - Qiang Zhang
- Department of General SurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Chao Li
- Department of General Surgery, Zhongshan HospitalFudan University School of MedicineShanghaiChina
| | - Ping Shu
- Department of General Surgery, Zhongshan HospitalFudan University School of MedicineShanghaiChina
| | - Xiaodong Gao
- Department of General Surgery, Zhongshan HospitalFudan University School of MedicineShanghaiChina
| | - Kuntang Shen
- Department of General Surgery, Zhongshan HospitalFudan University School of MedicineShanghaiChina
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6
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Cui Z, Sun H, Gao Z, Li C, Xiao T, Bian Y, Liu Z, Gu T, Zhang J, Li T, Zhou Q, He Z, Li B, Li F, Xu Z, Xu H. TRIM21/USP15 balances ACSL4 stability and the imatinib resistance of gastrointestinal stromal tumors. Br J Cancer 2024; 130:526-541. [PMID: 38182686 PMCID: PMC10876985 DOI: 10.1038/s41416-023-02562-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 12/09/2023] [Accepted: 12/15/2023] [Indexed: 01/07/2024] Open
Abstract
BACKGROUND Imatinib has become an exceptionally effective targeted drug for treating gastrointestinal stromal tumors (GISTs). Despite its efficacy, the resistance to imatinib is common in GIST patients, posing a significant challenge to the effective treatment. METHODS The expression profiling of TRIM21, USP15, and ACSL4 in GIST patients was evaluated using Western blot and immunohistochemistry. To silence gene expression, shRNA was utilized. Biological function of TRIM21, USP15, and ACSL4 was examined through various methods, including resistance index calculation, colony formation, shRNA interference, and xenograft mouse model. The molecular mechanism of TRIM21 and USP15 in GIST was determined by conducting Western blot, co-immunoprecipitation, and quantitative real-time PCR (qPCR) analyses. RESULTS Here we demonstrated that downregulation of ACSL4 is associated with imatinib (IM) resistance in GIST. Moreover, clinical data showed that higher levels of ACSL4 expression are positively correlated with favorable clinical outcomes. Mechanistic investigations further indicated that the reduced expression of ACSL4 in GIST is attributed to excessive protein degradation mediated by the E3 ligase TRIM21 and the deubiquitinase USP15. CONCLUSION These findings demonstrate that the TRIM21 and USP15 control ACSL4 stability to maintain the IM sensitive/resistant status of GIST.
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Affiliation(s)
- Zhiwei Cui
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, 211166, China
| | - Haoyu Sun
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, 211166, China
| | - Zhishuang Gao
- Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Chao Li
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, #180 Fenglin Road, Shanghai, 200032, China
| | - Tingting Xiao
- Department of Cardiology, the Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, 213003, Jiangsu, China
| | - Yibo Bian
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Rd, Xi'an, 710032, Shaanxi, China
| | - Zonghang Liu
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, 211166, China
| | - Tianhao Gu
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, 211166, China
| | - Jianan Zhang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, 211166, China
| | - Tengyun Li
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, 211166, China
| | - Qianzheng Zhou
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, 211166, China
| | - Zhongyuan He
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, 211166, China
| | - Bowen Li
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, 211166, China
| | - Fengyuan Li
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, 211166, China
| | - Zekuan Xu
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, 211166, China
| | - Hao Xu
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, 211166, China.
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Sebro R. Advancing Diagnostics and Patient Care: The Role of Biomarkers in Radiology. Semin Musculoskelet Radiol 2024; 28:3-13. [PMID: 38330966 DOI: 10.1055/s-0043-1776426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2024]
Abstract
The integration of biomarkers into medical practice has revolutionized the field of radiology, allowing for enhanced diagnostic accuracy, personalized treatment strategies, and improved patient care outcomes. This review offers radiologists a comprehensive understanding of the diverse applications of biomarkers in medicine. By elucidating the fundamental concepts, challenges, and recent advancements in biomarker utilization, it will serve as a bridge between the disciplines of radiology and epidemiology. Through an exploration of various biomarker types, such as imaging biomarkers, molecular biomarkers, and genetic markers, I outline their roles in disease detection, prognosis prediction, and therapeutic monitoring. I also discuss the significance of robust study designs, blinding, power and sample size calculations, performance metrics, and statistical methodologies in biomarker research. By fostering collaboration between radiologists, statisticians, and epidemiologists, I hope to accelerate the translation of biomarker discoveries into clinical practice, ultimately leading to improved patient care.
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Affiliation(s)
- Ronnie Sebro
- Department of Radiology, Center for Augmented Intelligence, Mayo Clinic, Jacksonville, Florida
- Department of Biostatistics, Center for Quantitative Health Sciences, Mayo Clinic, Jacksonville, Florida
- Department of Orthopedic Surgery, Mayo Clinic, Jacksonville, Florida
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8
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Vitiello L, Lixi F, Coco G, Giannaccare G. Ocular Surface Side Effects of Novel Anticancer Drugs. Cancers (Basel) 2024; 16:344. [PMID: 38254833 PMCID: PMC10814578 DOI: 10.3390/cancers16020344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Revised: 01/10/2024] [Accepted: 01/11/2024] [Indexed: 01/24/2024] Open
Abstract
Surgery, anticancer drugs (chemotherapy, hormonal medicines, and targeted treatments), and/or radiation are common treatment strategies for neoplastic diseases. Anticancer drugs eliminate malignant cells through the inhibition of specific pathways that contribute to the formation and development of cancer. Given the ability of such pharmacological medications to combat cancerous cells, their role in the management of neoplastic diseases has become essential. However, these drugs may also lead to undesirable systemic and ocular adverse effects due to cyto/neuro-toxicity and inflammatory reactions. Ocular surface side effects are recognized to significantly impact patient's quality of life and quality of vision. Blepharoconjunctivitis is known to be a common side effect caused by oxaliplatin, cyclophosphamide, cytarabine, and docetaxel, while anastrozole, methotrexate, and 5-fluorouracil can all determine dry eye disease. However, the potential processes involved in the development of these alterations are yet not fully understood, especially for novel drugs currently available for cancer treatment. This review aims at analyzing the potential ocular surface and adnexal side effects of novel anticancer medications, trying to provide a better understanding of the underlying pharmacological processes and useful insights on the choice of proper management.
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Affiliation(s)
- Livio Vitiello
- Eye Unit, “Luigi Curto” Hospital, Azienda Sanitaria Locale Salerno, 84035 Polla, SA, Italy;
| | - Filippo Lixi
- Eye Clinic, Department of Surgical Sciences, University of Cagliari, 09124 Cagliari, CA, Italy;
| | - Giulia Coco
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, 00133 Rome, RM, Italy;
| | - Giuseppe Giannaccare
- Eye Clinic, Department of Surgical Sciences, University of Cagliari, 09124 Cagliari, CA, Italy;
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Kannampuzha S, Murali R, Gopalakrishnan AV, Mukherjee AG, Wanjari UR, Namachivayam A, George A, Dey A, Vellingiri B. Novel biomolecules in targeted cancer therapy: a new approach towards precision medicine. Med Oncol 2023; 40:323. [PMID: 37804361 DOI: 10.1007/s12032-023-02168-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 08/18/2023] [Indexed: 10/09/2023]
Abstract
Cancer is a major threat to human life around the globe, and the discovery of novel biomolecules continue to be an urgent therapeutic need that is still unmet. Precision medicine relies on targeted therapeutic strategies. Researchers are better equipped to develop therapies that target proteins as they understand more about the genetic alterations and molecules that cause progression of cancer. There has been a recent diversification of the sorts of targets exploited in treatment. Therapeutic antibody and biotechnology advancements enabled curative treatments to reach previously inaccessible sites. New treatment strategies have been initiated for several undruggable targets. The application of tailored therapy has been proven to have efficient results in controlling cancer progression. Novel biomolecules like SMDCs, ADCs, mABs, and PROTACS has gained vast attention in the recent years. Several studies have shown that using these novel technology helps in reducing the drug dosage as well as to overcome drug resistance in different cancer types. Therefore, it is crucial to fully untangle the mechanism and collect evidence to understand the significance of these novel drug targets and strategies. This review article will be discussing the importance and role of these novel biomolecules in targeted cancer therapies.
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Affiliation(s)
- Sandra Kannampuzha
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Reshma Murali
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India.
| | - Anirban Goutam Mukherjee
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Uddesh Ramesh Wanjari
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Arunraj Namachivayam
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Alex George
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur, Kerala, India
| | - Abhijit Dey
- Department of Medical Services, MGM Cancer Institute, Chennai, Tamil Nadu, 600029, India
| | - Balachandar Vellingiri
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu, 641046, India
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10
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de Nigris F, Meo C, Palinski W. Combination of Genomic Landsscape and 3D Culture Functional Assays Bridges Sarcoma Phenotype to Target and Immunotherapy. Cells 2023; 12:2204. [PMID: 37681936 PMCID: PMC10486752 DOI: 10.3390/cells12172204] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 08/24/2023] [Accepted: 08/30/2023] [Indexed: 09/09/2023] Open
Abstract
Genomic-based precision medicine has not only improved tumour therapy but has also shown its weaknesses. Genomic profiling and mutation analysis have identified alterations that play a major role in sarcoma pathogenesis and evolution. However, they have not been sufficient in predicting tumour vulnerability and advancing treatment. The relative rarity of sarcomas and the genetic heterogeneity between subtypes also stand in the way of gaining statistically significant results from clinical trials. Personalized three-dimensional tumour models that reflect the specific histologic subtype are emerging as functional assays to test anticancer drugs, complementing genomic screening. Here, we provide an overview of current target therapy for sarcomas and discuss functional assays based on 3D models that, by recapitulating the molecular pathways and tumour microenvironment, may predict patient response to treatments. This approach opens new avenues to improve precision medicine when genomic and pathway alterations are not sufficient to guide the choice of the most promising treatment. Furthermore, we discuss the aspects of the 3D culture assays that need to be improved, such as the standardisation of growth conditions and the definition of in vitro responses that can be used as a cut-off for clinical implementation.
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Affiliation(s)
- Filomena de Nigris
- Department of Precision Medicine, School of Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
| | - Concetta Meo
- Department of Precision Medicine, School of Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
| | - Wulf Palinski
- Department of Medicine, University of California San Diego, La Jolla, CA 92037, USA;
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Fu Y, Karanian M, Perret R, Camara A, Le Loarer F, Jean-Denis M, Hostein I, Michot A, Ducimetiere F, Giraud A, Courreges JB, Courtet K, Laizet Y, Bendjebbar E, Du Terrail JO, Schmauch B, Maussion C, Blay JY, Italiano A, Coindre JM. Deep learning predicts patients outcome and mutations from digitized histology slides in gastrointestinal stromal tumor. NPJ Precis Oncol 2023; 7:71. [PMID: 37488222 PMCID: PMC10366108 DOI: 10.1038/s41698-023-00421-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 06/29/2023] [Indexed: 07/26/2023] Open
Abstract
Risk assessment of gastrointestinal stromal tumor (GIST) according to the AFIP/Miettinen classification and mutational profiling are major tools for patient management. However, the AFIP/Miettinen classification depends heavily on mitotic counts, which is laborious and sometimes inconsistent between pathologists. It has also been shown to be imperfect in stratifying patients. Molecular testing is costly and time-consuming, therefore, not systematically performed in all countries. New methods to improve risk and molecular predictions are hence crucial to improve the tailoring of adjuvant therapy. We have built deep learning (DL) models on digitized HES-stained whole slide images (WSI) to predict patients' outcome and mutations. Models were trained with a cohort of 1233 GIST and validated on an independent cohort of 286 GIST. DL models yielded comparable results to the Miettinen classification for relapse-free-survival prediction in localized GIST without adjuvant Imatinib (C-index=0.83 in cross-validation and 0.72 for independent testing). DL splitted Miettinen intermediate risk GIST into high/low-risk groups (p value = 0.002 in the training set and p value = 0.29 in the testing set). DL models achieved an area under the receiver operating characteristic curve (AUC) of 0.81, 0.91, and 0.71 for predicting mutations in KIT, PDGFRA and wild type, respectively, in cross-validation and 0.76, 0.90, and 0.55 in independent testing. Notably, PDGFRA exon18 D842V mutation, which is resistant to Imatinib, was predicted with an AUC of 0.87 and 0.90 in cross-validation and independent testing, respectively. Additionally, novel histological criteria predictive of patients' outcome and mutations were identified by reviewing the tiles selected by the models. As a proof of concept, our study showed the possibility of implementing DL with digitized WSI and may represent a reproducible way to improve tailoring therapy and precision medicine for patients with GIST.
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Affiliation(s)
- Yu Fu
- Owkin, Inc., New York, NY, USA
| | - Marie Karanian
- Cancer Research Center of Lyon, Centre Léon Bérard, Lyon, France
| | - Raul Perret
- Department of Biopathology, Institut Bergonié, Bordeaux, France
| | | | - François Le Loarer
- Department of Biopathology, Institut Bergonié, Bordeaux, France
- Faculty of Medicine, University of Bordeaux, Bordeaux, France
| | | | | | - Audrey Michot
- Department of Surgical Oncology, Institut Bergonié, Bordeaux, France
| | | | - Antoine Giraud
- Clinical Research and Clinical Epidemiology Unit, Institut Bergonié, Bordeaux, France
| | | | - Kevin Courtet
- Department of Biopathology, Institut Bergonié, Bordeaux, France
| | - Yech'an Laizet
- Department of Biopathology, Institut Bergonié, Bordeaux, France
| | | | | | | | | | - Jean-Yves Blay
- Cancer Research Center of Lyon, Centre Léon Bérard, Lyon, France
| | - Antoine Italiano
- Faculty of Medicine, University of Bordeaux, Bordeaux, France
- Department of Medicine, Institut Bergonié, Bordeaux, France
| | - Jean-Michel Coindre
- Department of Biopathology, Institut Bergonié, Bordeaux, France
- Faculty of Medicine, University of Bordeaux, Bordeaux, France
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12
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Ligon JA, Sundby RT, Wedekind MF, Arnaldez FI, del Rivero J, Wiener L, Srinivasan R, Spencer M, Carbonell A, Lei H, Shern J, Steinberg SM, Figg WD, Peer CJ, Zimmerman S, Moraly J, Xu X, Fox S, Chan K, Barbato MI, Andresson T, Taylor N, Pacak K, Killian JK, Dombi E, Linehan WM, Miettinen M, Piekarz R, Helman LJ, Meltzer P, Widemann B, Glod J. A Phase II Trial of Guadecitabine in Children and Adults with SDH-Deficient GIST, Pheochromocytoma, Paraganglioma, and HLRCC-Associated Renal Cell Carcinoma. Clin Cancer Res 2023; 29:341-348. [PMID: 36302175 PMCID: PMC9851965 DOI: 10.1158/1078-0432.ccr-22-2168] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/22/2022] [Accepted: 10/25/2022] [Indexed: 01/22/2023]
Abstract
PURPOSE Succinate dehydrogenase (dSDH)-deficient tumors, including pheochromocytoma/paraganglioma, hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinoma (HLRCC-RCC), and gastrointestinal stromal tumors (GIST) without KIT or platelet-derived growth factor receptor alpha mutations are often resistant to cytotoxic chemotherapy, radiotherapy, and many targeted therapies. We evaluated guadecitabine, a dinucleotide containing the DNA methyltransferase inhibitor decitabine, in these patient populations. PATIENTS AND METHODS Phase II study of guadecitabine (subcutaneously, 45 mg/m2/day for 5 consecutive days, planned 28-day cycle) to assess clinical activity (according to RECISTv.1.1) across three strata of patients with dSDH GIST, pheochromocytoma/paraganglioma, or HLRCC-RCC. A Simon optimal two-stage design (target response rate 30% rule out 5%) was used. Biologic correlates (methylation and metabolites) from peripheral blood mononuclear cells (PBMC), serum, and urine were analyzed. RESULTS Nine patients (7 with dSDH GIST, 1 each with paraganglioma and HLRCC-RCC, 6 females and 3 males, age range 18-57 years) were enrolled. Two patients developed treatment-limiting neutropenia. No partial or complete responses were observed (range 1-17 cycles of therapy). Biologic activity assessed as global demethylation in PBMCs was observed. No clear changes in metabolite concentrations were observed. CONCLUSIONS Guadecitabine was tolerated in patients with dSDH tumors with manageable toxicity. Although 4 of 9 patients had prolonged stable disease, there were no objective responses. Thus, guadecitabine did not meet the target of 30% response rate across dSDH tumors at this dose, although signs of biologic activity were noted.
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Affiliation(s)
- John A Ligon
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA,Department of Pediatrics, Division of Hematology/Oncology, University of Florida, Gainesville, FL
| | - R. Taylor Sundby
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Mary F Wedekind
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | | | - Jaydira del Rivero
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA,Developmemtal Therapeutics Branch, CCR, NCI, Bethesda, MD
| | - Lori Wiener
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | | | - Melissa Spencer
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Amanda Carbonell
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Haiyan Lei
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - John Shern
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | | | | | - Cody J Peer
- Clinical Pharmacology Program, NCI/NIH, Bethesda, MD
| | | | - Josquin Moraly
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA,Laboratory of physiopathology and treatment of Hematological malignancies, Institut imagine, INSERM U1153, Université de Paris, Paris, France
| | - Xia Xu
- Cancer Research Technology Program, Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD
| | - Stephen Fox
- Cancer Research Technology Program, Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD
| | - King Chan
- Cancer Research Technology Program, Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD
| | - Michael I Barbato
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Thorkell Andresson
- Cancer Research Technology Program, Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD
| | - Naomi Taylor
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Karel Pacak
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD
| | | | - Eva Dombi
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | | | | | - Richard Piekarz
- Cancer Therapy Evaluation Program, Division of Cancer Treatments and Diagnosis, NCI, Bethesda, MD
| | | | | | - Brigitte Widemann
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - John Glod
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
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13
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Khosroyani HM, Klug LR, Heinrich MC. TKI Treatment Sequencing in Advanced Gastrointestinal Stromal Tumors. Drugs 2023; 83:55-73. [PMID: 36607590 PMCID: PMC10029090 DOI: 10.1007/s40265-022-01820-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/23/2022] [Indexed: 01/07/2023]
Abstract
Prior to the early 2000s, patients with advanced gastrointestinal stromal tumors (GIST) had very poor prognoses owing to a lack of effective therapies. The development of tyrosine kinase inhibitors at the turn of the century significantly improved the overall survival for patients with GIST. The resounding success of imatinib in the first clinical trial of a tyrosine kinase inhibitor to treat GIST led to its approval for first-line therapy for advanced GIST; this study was open to all comers and not restricted to any GIST subtype(s). The trials that led to the approvals of second-, third-, and fourth-line therapy for advanced GIST were also open to all patients with advanced/metastatic GIST. Only in retrospect do we realize the role that the molecular subtypes played in the results observed in these studies. In this review, we discuss the studies that led to the US Food and Drug Administration approval of imatinib (first line), sunitinib (second line), regorafenib (third line), and ripretinib (fourth line) for advanced KIT-mutant GIST. In addition, we review how information about GIST molecular subtypes has been used to accelerate the approval of other targeted therapies for non-KIT mutant GIST, leading to the approval of five additional drugs indicated for the treatment of specific GIST molecular subtypes. We also discuss how our understanding of the molecular subtypes will play a role in the next generation of therapeutic approaches for treating advanced GIST.
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Affiliation(s)
- Homma M Khosroyani
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, R&D-19, 3710 SW US Veterans Hospital Road, Portland, OR, 97239, USA
| | - Lillian R Klug
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, R&D-19, 3710 SW US Veterans Hospital Road, Portland, OR, 97239, USA
| | - Michael C Heinrich
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, R&D-19, 3710 SW US Veterans Hospital Road, Portland, OR, 97239, USA.
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14
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Vasella M, Gousopoulos E, Guidi M, Storti G, Song SY, Grieb G, Pauli C, Lindenblatt N, Giovanoli P, Kim BS. Targeted therapies and checkpoint inhibitors in sarcoma. QJM 2022; 115:793-805. [PMID: 33486519 DOI: 10.1093/qjmed/hcab014] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 01/11/2021] [Indexed: 12/15/2022] Open
Abstract
Sarcomas are defined as a group of mesenchymal malignancies with over 100 heterogeneous subtypes. As a rare and difficult to diagnose entity, micrometastasis is already present at the time of diagnosis in many cases. Current treatment practice of sarcomas consists mainly of surgery, (neo)adjuvant chemo- and/or radiotherapy. Although the past decade has shown that particular genetic abnormalities can promote the development of sarcomas, such as translocations, gain-of-function mutations, amplifications or tumor suppressor gene losses, these insights have not led to established alternative treatment strategies so far. Novel therapeutic concepts with immunotherapy at its forefront have experienced some remarkable success in different solid tumors while their impact in sarcoma remains limited. In this review, the most common immunotherapy strategies in sarcomas, such as immune checkpoint inhibitors, targeted therapy and cytokine therapy are concisely discussed. The programmed cell death (PD)-1/PD-1L axis and apoptosis-inducing cytokines, such as TNF-related apoptosis-inducing ligand (TRAIL), have not yielded the same success like in other solid tumors. However, in certain sarcoma subtypes, e.g. liposarcoma or undifferentiated pleomorphic sarcoma, encouraging results in some cases when employing immune checkpoint inhibitors in combination with other treatment options were found. Moreover, newer strategies such as the targeted therapy against the ancient cytokine macrophage migration inhibitory factor (MIF) may represent an interesting approach worth investigation in the future.
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Affiliation(s)
- M Vasella
- From the Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland
| | - E Gousopoulos
- From the Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland
| | - M Guidi
- From the Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland
| | - G Storti
- Department of Surgical Sciences, Plastic and Reconstructive Surgery, University of Rome-'Tor Vergata', Via Montepellier, 1, 00133 Rome, Italy
| | - S Y Song
- Department of Plastic and Reconstructive Surgery, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, Korea
| | - G Grieb
- Department of Plastic Surgery and Hand Surgery, Gemeinschaftskrankenhaus Havelhoehe, Kladower Damm 221, 14089 Berlin, Germany
- Department of Plastic Surgery, Hand Surgery and Burn Center, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany
| | - C Pauli
- Institute of Pathology and Molecular Pathology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland
| | - N Lindenblatt
- From the Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland
| | - P Giovanoli
- From the Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland
| | - B-S Kim
- From the Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland
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15
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Hu X, Zhang Q, Wang Z, Ren H, Su P, Kou Y. Retrospective study of the clinicopathological characteristics and prognostic factors of gastrointestinal stromal tumors in Chinese patients. Ann Diagn Pathol 2022; 61:152050. [DOI: 10.1016/j.anndiagpath.2022.152050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 09/17/2022] [Accepted: 10/03/2022] [Indexed: 11/01/2022]
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16
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Brennan MF, Singer S. Five decades of sarcoma care at Memorial Sloan Kettering Cancer Center. J Surg Oncol 2022; 126:896-901. [PMID: 36087086 DOI: 10.1002/jso.27032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 07/02/2022] [Indexed: 11/07/2022]
Abstract
Early studies of the management of soft tissue sarcoma at Memorial Sloan Kettering Cancer Center were influenced by development of robust prospective long-term databases. Increasing capacity for molecular diagnostics has identified a myriad of subtypes with definable natural history. Accurate identification of tissue-specific risk of recurrence and disease-specific survival have increasingly allowed selective use of surgery, radiation therapy, and target-specific cytotoxic and immune therapies.
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Affiliation(s)
- Murray F Brennan
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Samuel Singer
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
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17
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Sun Y, Yue L, Xu P, Hu W. An overview of agents and treatments for PDGFRA-mutated gastrointestinal stromal tumors. Front Oncol 2022; 12:927587. [PMID: 36119525 PMCID: PMC9471148 DOI: 10.3389/fonc.2022.927587] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 08/15/2022] [Indexed: 11/25/2022] Open
Abstract
Platelet-derived growth factor receptor A (PDGFRA) mutations occur in approximately 10-15% of gastrointestinal stromal tumors (GISTs). These tumors with PDGFRA mutations have a different pathogenesis, clinical characteristics, and treatment response compared to tumors with receptor tyrosine kinase protein (KIT) mutations (60-70%). Many clinical studies have investigated the use of tyrosine kinase inhibitors mainly in patients with KIT mutations; however, there is a lack of attention to the PDGFRA-mutated molecular subtype. The main effective inhibitors of PDGFRA are ripretinib, avapritinib, and crenolanib, and their mechanisms and efficacy in GIST (as confirmed in clinical trials) are described in this review. Some multi-targeted tyrosine kinase inhibitors with inhibitory effects on this molecular subtype are also introduced and summarized in this paper. This review focuses on PDGFRA-mutated GISTs, introduces their clinical characteristics, downstream molecular signaling pathways, and existing resistance mechanisms. We focus on the most recent literature that describes the development of PDGFRA inhibitors and their use in clinical trials, as well as the potential benefits from different combination therapy strategies.
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Affiliation(s)
- Yingchao Sun
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou, China
| | - Lei Yue
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou, China
| | - Pengfu Xu
- Department of Gastrointestinal Surgery, Taizhou Hospital, Zhejiang University, Taizhou, China
| | - Weiling Hu
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou, China
- Institute of Gastroenterology, Zhejiang University (IGZJU), Hangzhou, China
- Zhejiang University Cancer Center, Hangzhou, China
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18
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Zhou C, Chen X, Huang Y, Zhang Q, Zhu S, Fu W. Nanomaterial Technology and Soft Tissue Sarcomas. Front Oncol 2022; 12:921983. [PMID: 35814363 PMCID: PMC9257037 DOI: 10.3389/fonc.2022.921983] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Accepted: 05/24/2022] [Indexed: 11/24/2022] Open
Abstract
Soft tissue sarcomas (STSs) are relatively rare heterogeneous solid tumors of the mesenchymal origin. They account for approximately 1% of all malignant tumors in adults and have more than 70 histological subtypes. Consequently, the rarity and heterogeneity of STSs make their diagnosis and treatment very challenging. Nanotechnology has attracted increasing attention from researchers due to the unique physicochemical and biological properties of nanomaterials with potential medical applications as nanoprobes, drug delivery systems, photosensitizers, radioenhancers, antitumor agents, and their combinations for cancer diagnosis and treatment. This review discusses the progress made in the use of nanotechnology for the diagnosis and treatment of STSs and highlights future prospects of the STS multimodality therapy.
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Affiliation(s)
- Changkai Zhou
- Department of Burn and Plastic Surgery, Affiliated Hospital 2 of Nantong University, Nantong First People’s Hospital, Nantong, China
| | - Xue Chen
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ying Huang
- Department of Operation Room, Affiliated Hospital 2 of Nantong University, Nantong First People’s Hospital, Nantong, China
| | - Qi Zhang
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Wei Fu, ; Shu Zhu, ; Qi Zhang,
| | - Shu Zhu
- Department of Medical Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Wei Fu, ; Shu Zhu, ; Qi Zhang,
| | - Wei Fu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Wei Fu, ; Shu Zhu, ; Qi Zhang,
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19
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Klug LR, Khosroyani HM, Kent JD, Heinrich MC. New treatment strategies for advanced-stage gastrointestinal stromal tumours. Nat Rev Clin Oncol 2022; 19:328-341. [PMID: 35217782 PMCID: PMC11488293 DOI: 10.1038/s41571-022-00606-4] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/08/2022] [Indexed: 02/06/2023]
Abstract
When gastrointestinal stromal tumour (GIST), the most common form of sarcoma, was first recognized as a distinct pathological entity in the 1990s, patients with advanced-stage disease had a very poor prognosis owing to a lack of effective medical therapies. The discovery of KIT mutations as the first and most prevalent drivers of GIST and the subsequent development of the first KIT tyrosine kinase inhibitor (TKI), imatinib, revolutionized the treatment of patients with this disease. We can now identify the driver mutation in 99% of patients with GIST via molecular diagnostic testing, and therapies have been developed to treat many, but not all, molecular subtypes of the disease. At present, seven drugs are approved by the FDA for the treatment of advanced-stage GIST (imatinib, sunitinib, regorafenib, ripretinib, avapritinib, larotrectinib and entrectinib), all of which are TKIs. Although these agents can be very effective for treating certain GIST subtypes, challenges remain and new therapeutic approaches are needed. In this Review, we discuss the molecular subtypes of GIST and the evolution of current treatments, as well as their therapeutic limitations. We also highlight emerging therapeutic approaches that might overcome clinical challenges through novel strategies predicated on the biological features of the distinct GIST molecular subtypes.
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Affiliation(s)
- Lillian R Klug
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Homma M Khosroyani
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Jason D Kent
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Michael C Heinrich
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
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20
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Feng M, Yang Y, Liao W, Li Q. Cost-Effectiveness Analysis of Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumor: A Systematic Review. Front Public Health 2022; 9:768765. [PMID: 35083189 PMCID: PMC8784780 DOI: 10.3389/fpubh.2021.768765] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 12/13/2021] [Indexed: 02/05/2023] Open
Abstract
Background: The introduction of tyrosine kinase inhibitor (TKI) therapy has dramatically improved the clinical effectiveness of patients with locally advanced and/or metastatic gastrointestinal stromal tumors (GIST), and this systematic review was conducted aiming at the cost-effectiveness analysis of TKIs in GIST. Methods: A thorough literature search of online databases was performed, using appropriate terms such as “gastrointestinal stromal tumor or GIST,” “cost-effectiveness,” and “economic evaluation.” Data extraction was conducted independently by two authors, and completeness of reporting and quality of the evaluation were assessed. The systematic review was conducted following the PRISMA statement. Results: Published between 2005 and 2020, 15 articles were incorporated into the systematic review. For advanced GIST, imatinib followed by sunitinib was considered cost-effective, and regorafenib was cost-effective compared with imatinib re-challenge therapy in the third-line treatment. For resectable GIST, 3-year adjuvant imatinib therapy represented a cost-effective treatment option. The precision medicine-assisted imatinib treatment was cost-effective compared with empirical treatment. Conclusion: Although identified studies varied in predicted costs and quality-adjusted life years, there was general agreement in study conclusions. More cost-effectiveness analysis should be conducted regarding more TKIs that have been approved for the treatment of GIST. Systematic Review Registration:https://www.crd.york.ac.uk/, PROSPERO: CRD42021225253.
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Affiliation(s)
- Mingyang Feng
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.,West China Biomedical Big Data Center, Sichuan University, Chengdu, China
| | - Yang Yang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.,West China Biomedical Big Data Center, Sichuan University, Chengdu, China
| | - Weiting Liao
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.,West China Biomedical Big Data Center, Sichuan University, Chengdu, China
| | - Qiu Li
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.,West China Biomedical Big Data Center, Sichuan University, Chengdu, China
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21
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Foo T, Goldstein D, Segelov E, Shapiro J, Pavlakis N, Desai J, Yip D, Zalcberg J, Price TJ, Nagrial A, Chantrill L, Burge M, Karapetis CS, Tebbutt N, Roy AC. The Management of Unresectable, Advanced Gastrointestinal Stromal Tumours. Target Oncol 2022; 17:95-110. [PMID: 35290591 PMCID: PMC8995292 DOI: 10.1007/s11523-022-00869-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/23/2022] [Indexed: 12/11/2022]
Abstract
Gastrointestinal stromal tumours (GISTs) are the most common gastrointestinal tract mesenchymal tumours. Tyrosine kinase inhibitors (TKIs) have transformed the management of advanced GIST. Imatinib was the first TKI to gain approval as management for patients with advanced GIST, establishing a new standard of care. Since then, as a result of several trials including the GRID and INVICTUS studies, we now have five lines of approved targeted therapy, including imatinib, sunitinib, regorafenib, ripretinib and avapritinib for the treatment of unresectable, advanced GISTs. In this review, the Australasian Gastrointestinal Trials Group (AGITG) provide an overview of the key trials that have changed clinical practice, discuss the molecular drivers of GISTs, the importance of molecular testing and directing therapy according to molecular targets, as well as future strategies in the management of advanced GISTs.
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Affiliation(s)
- Tiffany Foo
- Flinders Centre for Innovation in Cancer/Flinders University, Bedford Park, SA, 5042, Australia
| | - David Goldstein
- Department of Medical Oncology, Prince of Wales Hospital, University of NSW, Sydney, NSW, Australia
| | - Eva Segelov
- Department of Medical Oncology, School of Clinical Sciences, Monash University and Monash Health, Melbourne, VIC, Australia
| | - Jeremy Shapiro
- Cabrini Health, Monash University, Melbourne, VIC, Australia
| | - Nick Pavlakis
- Department of Medical Oncology, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia
| | - Jayesh Desai
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Desmond Yip
- Department of Medical Oncology, Canberra Region Cancer Centre, The Canberra Hospital, Canberra, ACT, Australia
| | - John Zalcberg
- Alfred Health, Monash University, Melbourne, VIC, Australia
| | - Timothy J Price
- The Queen Elizabeth Hospital/University of Adelaide, Adelaide, SA, Australia
| | - Adnan Nagrial
- Department of Medical Oncology, Westmead and Blacktown Hospitals, University of Sydney, Sydney, NSW, Australia
| | - Lorraine Chantrill
- Department of Medical Oncology, Wollongong Hospital, Illawarra Shoalhaven Local Health District, Illawarra, NSW, Australia
| | - Matt Burge
- Department of Cancer Care Services, Royal Brisbane Hospital, University of Queensland, Herston, QLD, Australia
| | - Christos S Karapetis
- Flinders Centre for Innovation in Cancer/Flinders University, Bedford Park, SA, 5042, Australia
| | - Niall Tebbutt
- Department of Medical Oncology, Olivia Newton-John Cancer Wellness and Research Centre, Austin Health, Heidelberg, VIC, Australia
| | - Amitesh C Roy
- Flinders Centre for Innovation in Cancer/Flinders University, Bedford Park, SA, 5042, Australia.
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22
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Song H, Xiao X, Liu G, Zhou J. Sarcopenia as a novel prognostic factor in the patients of primary localized gastrointestinal stromal tumor. BMC Cancer 2022; 22:179. [PMID: 35177018 PMCID: PMC8851766 DOI: 10.1186/s12885-022-09278-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 01/10/2022] [Indexed: 01/06/2023] Open
Abstract
Background Sarcopenia predicts poor prognosis of a variety of gastrointestinal malignancies. However, there is a lack of study on the association between skeletal muscle index (SMI) and the prognosis of gastrointestinal stromal tumor (GIST). The aim of this study is to develop a novel nomogram based on sarcopenia for GIST patients to predict overall survival (OS). Methods SMI was measured by computed tomography scan of 107 patients who underwent resection for primary localized gastrointestinal stromal tumor (GIST). Sarcopenia was defined by cutoff values for SMI as 40.1 cm2/m2 and 39.8 cm2/m2 using optimum stratification for males and females respectively. Factors were included in the nomogram were specified by univariate and multiple Cox proportional hazard analysis. Concordance index (C-index) and calibration curves were conducted to measure the discrimination and accuracy of the nomogram. The utility of the nomogram was assessed by the decision curve analysis (DCA). Results Twenty-eight (26.2%) of 107 patients were sarcopenic. Sarcopenia was correlated significantly with body mass index, albumin, female sex, resection style, mitotic index, rupture status, survival. Sarcopenia was significantly related to decreased overall survival (p = 0.003).The nomogram including sarcopenia status, resection style and mitotic index had an excellent discrimination with C-index 0.794. The calibration curves represented a good accordance between the actual observation and nomogram prediction for overall survival. Decision curve analysis illustrated that the nomogram was helpful in clinic. Conclusions We developed a nomogram based on sarcopenia to predict overall survival after resection of GISTs which is an effective and favorable prognostication tool.
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Affiliation(s)
- He Song
- The First Affiliated Hospital of China Medical University, 155 Nanjing Street, Shenyang, Liaoning, China
| | - Xianhao Xiao
- China Medical University, Shenyang, Liaoning, China
| | - Gang Liu
- The First Affiliated Hospital of China Medical University, 155 Nanjing Street, Shenyang, Liaoning, China
| | - Jianping Zhou
- The First Affiliated Hospital of China Medical University, 155 Nanjing Street, Shenyang, Liaoning, China.
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23
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Ayala-Aguilera CC, Valero T, Lorente-Macías Á, Baillache DJ, Croke S, Unciti-Broceta A. Small Molecule Kinase Inhibitor Drugs (1995-2021): Medical Indication, Pharmacology, and Synthesis. J Med Chem 2021; 65:1047-1131. [PMID: 34624192 DOI: 10.1021/acs.jmedchem.1c00963] [Citation(s) in RCA: 144] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The central role of dysregulated kinase activity in the etiology of progressive disorders, including cancer, has fostered incremental efforts on drug discovery programs over the past 40 years. As a result, kinase inhibitors are today one of the most important classes of drugs. The FDA approved 73 small molecule kinase inhibitor drugs until September 2021, and additional inhibitors were approved by other regulatory agencies during that time. To complement the published literature on clinical kinase inhibitors, we have prepared a review that recaps this large data set into an accessible format for the medicinal chemistry community. Along with the therapeutic and pharmacological properties of each kinase inhibitor approved across the world until 2020, we provide the synthesis routes originally used during the discovery phase, many of which were only available in patent applications. In the last section, we also provide an update on kinase inhibitor drugs approved in 2021.
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Affiliation(s)
- Cecilia C Ayala-Aguilera
- Cancer Research UK Edinburgh Centre, Institute of Genetics & Cancer, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, United Kingdom
| | - Teresa Valero
- Cancer Research UK Edinburgh Centre, Institute of Genetics & Cancer, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, United Kingdom
| | - Álvaro Lorente-Macías
- Cancer Research UK Edinburgh Centre, Institute of Genetics & Cancer, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, United Kingdom
| | - Daniel J Baillache
- Cancer Research UK Edinburgh Centre, Institute of Genetics & Cancer, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, United Kingdom
| | - Stephen Croke
- Cancer Research UK Edinburgh Centre, Institute of Genetics & Cancer, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, United Kingdom
| | - Asier Unciti-Broceta
- Cancer Research UK Edinburgh Centre, Institute of Genetics & Cancer, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, United Kingdom
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24
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Kihara T, Yuan J, Watabe T, Kitajima K, Kimura N, Ohkouchi M, Hashikura Y, Ohkubo S, Takahashi T, Hirota S. Pimitespib is effective on cecal GIST in a mouse model of familial GISTs with KIT-Asp820Tyr mutation through KIT signaling inhibition. Exp Mol Pathol 2021; 123:104692. [PMID: 34606780 DOI: 10.1016/j.yexmp.2021.104692] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 08/10/2021] [Accepted: 09/28/2021] [Indexed: 01/01/2023]
Abstract
Three families with multiple gastrointestinal stromal tumors (GISTs) caused by a germline Asp820Tyr mutation at exon 17 of the c-kit gene (KIT-Asp820Tyr) have been reported. We previously generated a knock-in mouse model of the family, and the mice with KIT-Asp818Tyr corresponding to human KIT-Asp820Tyr showed a cecal tumor equivalent to human GIST. In the model mice, we reported that tyrosine kinase inhibitor, imatinib, could stabilize but not decrease the cecal tumor volume. In this report, we examined whether a heat shock protein 90 inhibitor, pimitespib (TAS-116), has an inhibitory effect on phosphorylation of KIT-Asp818Tyr and can decrease the cecal tumor volume in the model mice. First, we showed that pimitespib inhibited KIT phosphorylation both dose- and time-dependently in KIT-Asp818Tyr transfected murine Ba/F3 cells. Then, four 1-week courses of pimitespib were orally administered to heterozygous (KIT-Asp818Tyr/+) model mice. Each course consisted of once-daily administration for consecutive 5 days followed by 2 days-off. Cecal tumors were dissected, and tumor volume was histologically analyzed, Ki-67 labeling index was immunohistochemically examined, and apoptotic figures were counted. Compared to the vehicle treated mice, pimitespib administered mice showed statistically significantly smaller cecal tumor volume, lower Ki-67 labeling index, and higher number of apoptotic figures in 10 high power fields (P = 0.0344, P = 0.0019 and P = 0.0269, respectively). Western blotting revealed that activation of KIT signaling molecules was strongly inhibited in the tumor tissues of pimitespib-administered mice compared to control mice. Thus, pimitespib seemed to inhibit in vivo tumor progression effectively in the model mice. These results suggest that the progression of multiple GISTs in patients with germline KIT-Asp820Tyr might be controllable by pimitespib.
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Affiliation(s)
- Takako Kihara
- Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Jiayin Yuan
- Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Tadashi Watabe
- Department of Radiology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Kazuhiro Kitajima
- Department of Radiology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Neinei Kimura
- Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Mizuka Ohkouchi
- Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Yuka Hashikura
- Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Shuichi Ohkubo
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd, Tsukuba, Japan
| | - Tsuyoshi Takahashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan
| | - Seiichi Hirota
- Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan.
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25
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Singh AS, Hecht JR, Rosen L, Wainberg ZA, Wang X, Douek M, Hagopian A, Andes R, Sauer L, Brackert SR, Chow W, DeMatteo R, Eilber FC, Glaspy JA, Chmielowski B. A Randomized Phase 2 Study Of Nivolumab Monotherapy Or Nivolumab Combined with Ipilimumab In Patients with Advanced Gastrointestinal Stromal Tumors. Clin Cancer Res 2021; 28:84-94. [PMID: 34407970 DOI: 10.1158/1078-0432.ccr-21-0878] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/27/2021] [Accepted: 08/16/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Most GISTs are driven by KIT/PDGFRa mutations. TKI benefit is progressively less after imatinib failure. This phase II trial analyzed the efficacy of nivolumab (N) or nivolumab + ipilimumab (N + I) in refractory GIST patients. PATIENTS AND METHODS Advanced/metastatic GIST patients refractory to at least imatinib were randomized 1:1 in a noncomparative, parallel group, unblinded Phase 2 trial of N (240mg Q2wks) or N + I (240 mg Q2wks + 1mg/kg Q6wks). The primary endpoint was the ORR of N alone or N+I by RECIST 1.1 in the ITT population. RESULTS 36 patients with a median of 3 (1-6) prior lines of therapies were enrolled. 10/19(52.6%) patients had SD for a CBR of 52.6 % in the N arm and the median PFS was 11.7 wks (95% CI, 7.0, 17.4). In the N+I arm, 1/16(6.7%) patients had a CR and 4/16(25.0%) had SD for a CBR of 31.3% and a median PFS of 8.3wks (95% CI, 5.6, 22.2). The 4 and 6 month PFS were 42.1% and 26.3%, respectively for N and 31.3% and 18.8%, respectively for N+I. The most common adverse events (AEs) attributed to N and N+I were fatigue: 13.9% and 22.2%, respectively. There were 9 total attributable grade 3-4 AEs. CONCLUSIONS The primary endpoint of RR>15% was not observed for N or N + I. In a heavily pretreated GIST population, responses and long term disease control with both N and N+I were observed. No new safety signals have been observed.
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Affiliation(s)
- Arun S Singh
- Department of Hematology/Oncology, University of California, Los Angeles
| | - J Randolph Hecht
- Division of Hematology/Oncology, David Geffen School of Medicine at UCLA
| | - Lee Rosen
- Medicine, UCLA Santa Monica Hematology-Oncology
| | - Zev A Wainberg
- Division of Hematology/Oncology, David Geffen School of Medicine at UCLA
| | - Xiaoyan Wang
- Department of General Internal Medicine and Healthy Services Research, University of California, Los Angeles
| | | | - Anahis Hagopian
- Department of Hematology/Oncology, University of California, Los Angeles
| | - Rachel Andes
- Department of Hematology/Oncology, University of California, Los Angeles
| | - Lauren Sauer
- Department of Hematology/Oncology, University of California, Los Angeles
| | - Sandra R Brackert
- Department of Hematology/Oncology, University of California, Los Angeles
| | - Warren Chow
- Medical Oncology, City Of Hope National Medical Center
| | | | | | - John A Glaspy
- Department of Medicine, David Geffen School of Medicine at UCLA
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26
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Bauer S, George S, von Mehren M, Heinrich MC. Early and Next-Generation KIT/PDGFRA Kinase Inhibitors and the Future of Treatment for Advanced Gastrointestinal Stromal Tumor. Front Oncol 2021; 11:672500. [PMID: 34322383 PMCID: PMC8313277 DOI: 10.3389/fonc.2021.672500] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 06/22/2021] [Indexed: 12/21/2022] Open
Abstract
The majority of gastrointestinal stromal tumors (GIST) harbor an activating mutation in either the KIT or PDGFRA receptor tyrosine kinases. Approval of imatinib, a KIT/PDGFRA tyrosine kinase inhibitor (TKI), meaningfully improved the treatment of advanced GIST. Other TKIs subsequently gained approval: sunitinib as a second-line therapy and regorafenib as a third-line therapy. However, resistance to each agent occurs in almost all patients over time, typically due to secondary kinase mutations. A major limitation of these 3 approved therapies is that they target the inactive conformation of KIT/PDGFRA; thus, their efficacy is blunted against secondary mutations in the kinase activation loop. Neither sunitinib nor regorafenib inhibit the full spectrum of KIT resistance mutations, and resistance is further complicated by extensive clonal heterogeneity, even within single patients. To combat these limitations, next-generation TKIs were developed and clinically tested, leading to 2 new USA FDA drug approvals in 2020. Ripretinib, a broad-spectrum KIT/PDGFRA inhibitor, was recently approved for the treatment of adult patients with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib. Avapritinib, a type I kinase inhibitor that targets active conformation, was approved for the treatment of adults with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. In this review, we will discuss how resistance mutations have driven the need for newer treatment options for GIST and compare the original GIST TKIs with the next-generation KIT/PDGFRA kinase inhibitors, ripretinib and avapritinib, with a focus on their mechanisms of action.
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Affiliation(s)
- Sebastian Bauer
- Department of Medical Oncology, West German Cancer Center, Essen University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Suzanne George
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Margaret von Mehren
- Department of Hematology and Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, United States
| | - Michael C. Heinrich
- Department of Medicine, Portland VA Health Care System and OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR, United States
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27
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Li L, Hu ZQ, Yang CG, Gan JH, Tian JH, Ke CJ, Zeng X. Current knowledge of primary prostatic extra-gastrointestinal stromal tumor: a case report and review of the literature. J Int Med Res 2021; 49:3000605211013172. [PMID: 33983064 PMCID: PMC8127774 DOI: 10.1177/03000605211013172] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
The patient was a 62-year-old man diagnosed as having prostatic extra-gastrointestinal stromal tumor (EGIST) who was treated with imatinib. No recurrence or metastasis was found after a 6-month follow-up. We identified 14 cases of prostatic primary EGIST in PubMed and summarized these cases with our case. The patients' ages ranged from 31 to 78 years (average: 53.6 years), and most patients' prostate-specific antigen (PSA) concentrations were within normal limits (92.9%, 13/14). All patients underwent imaging examinations; prostatic masses measured 6 to 14.2 cm (mean: 9.43 cm), and imaging excluded secondary prostatic masses from the intestinal tract. By immunohistochemical staining, the tumors were positive for cluster of differentiation (CD)117 (71.4%, 10/14), DOG1 (100%, 7/7), and CD34 (100%, 14/14), and negative for smooth muscle actin (SMA) (71.4%, 10/14), desmin (100%, 11/11), and S100 (100%, 12/12). Treatment depended on the results of the gene mutation detection as well as the risk estimation according to tumor size and microscopic mitotic rates (>5 per 50 high-power fields: 60%, 6/10). Among the 12 patients with reported outcomes, nine achieved good results (no recurrence or metastasis), one achieved reduced mass volume, one experienced recurrence, and one died.
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Affiliation(s)
- Le Li
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhi Quan Hu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chun Guang Yang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Hua Gan
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ji Hua Tian
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chun Jin Ke
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xing Zeng
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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28
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Patel SR, Reichardt P. An updated review of the treatment landscape for advanced gastrointestinal stromal tumors. Cancer 2021; 127:2187-2195. [PMID: 33974733 PMCID: PMC8252111 DOI: 10.1002/cncr.33630] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/14/2021] [Accepted: 04/19/2021] [Indexed: 12/21/2022]
Abstract
Before the introduction of tyrosine kinase inhibitors (TKIs), the overall survival of patients with advanced or metastatic gastrointestinal stromal tumors (GISTs) was 10 to 20 months because of the lack of approved therapies. In the last 20 years, a treatment algorithm for patients with advanced GISTs, which includes imatinib, sunitinib, and regorafenib as first‐, second‐, and third‐line therapies, respectively, has been established. Recently, 2 new TKIs have been approved: ripretinib for fourth‐line therapy and avapritinib as first‐line therapy in patients harboring platelet‐derived growth factor receptor α (PDGFRA) exon 18 D842V mutations. Additionally, there are several experimental therapies under investigation that could advance individualized patient care. All of these therapies have varying efficacies and safety profiles that warrant an updated treatment landscape review. This review article summarizes the efficacy and safety data currently available for conventional TKIs along with recently approved and experimental therapies. With evolving treatment options and effective toxicity management, patients with advanced gastrointestinal stromal tumors are living longer than ever before. Recently approved targeted therapies and the investigation of experimental treatment options have the potential to alter the current treatment algorithm and encourage personalized patient care.
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Affiliation(s)
- Shreyaskumar R Patel
- Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Peter Reichardt
- Oncology and Palliative Care, Sarcoma Center, Helios Klinikum Berlin-Buch, Berlin, Germany
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29
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Al-Share B, Alloghbi A, Al Hallak MN, Uddin H, Azmi A, Mohammad RM, Kim SH, Shields AF, Philip PA. Gastrointestinal stromal tumor: a review of current and emerging therapies. Cancer Metastasis Rev 2021; 40:625-641. [PMID: 33876372 DOI: 10.1007/s10555-021-09961-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 03/29/2021] [Indexed: 02/07/2023]
Abstract
Gastrointestinal stromal tumors (GIST) are rare neoplasms arising from the interstitial cell of Cajal in the gastrointestinal tract. Two thirds of GIST in adult patients have c-Kit mutation and smaller fractions have platelet derived growth factor receptor alpha (PDGFRA) mutation. Surgery is the only curative treatment for localized disease. Imatinib improves survival when used adjuvantly and in advanced disease. Several targeted therapies have also improved survival in GIST patients after progression on imatinib including sunitinib and regorafenib. Recently, United States Federal and Drug Administration (FDA) approved two new tyrosine kinase inhibitors for the treatment of heavily pretreated advanced/unresectable GIST including avapritinib (a selective inhibitor for PDGFRA exon 18 mutation including D842V mutations) and ripretinib (a broad-spectrum kinase inhibitor of c-Kit and PDGFRA). In this article, we will provide a comprehensive review of GIST including the current standard of care treatment and exploring future paradigm shifts in therapy.
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Affiliation(s)
- Bayan Al-Share
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Abdulrahman Alloghbi
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Mohammed Najeeb Al Hallak
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Hafiz Uddin
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Asfar Azmi
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Ramzi M Mohammad
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Steve H Kim
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Anthony F Shields
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Philip A Philip
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA.
- Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI, USA.
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30
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Abstract
The SMARCB1/INI1 gene was first discovered in the mid-1990s, and since then it has been revealed that loss of function mutations in this gene result in aggressive rhabdoid tumors. Recently, the term "rhabdoid tumor" has become synonymous with decreased SMARCB1/INI1 expression. When genetic aberrations in the SMARCB1/INI1 gene occur, the result can cause complete loss of expression, decreased expression, and mosaic expression. Although SMARCB1/INI1-deficient tumors are predominantly sarcomas, this is a diverse group of tumors with mixed phenotypes, which can often make the diagnosis challenging. Prognosis for these aggressive tumors is often poor. Moreover, refractory and relapsing progressive disease is common. As a result, accurate and timely diagnosis is imperative. Despite the SMARCB1/INI1 gene itself and its implications in tumorigenesis being discovered over two decades ago, there is a paucity of rhabdoid tumor cases reported in the literature that detail SMARCB1/INI1 expression. Much work remains if we hope to provide additional therapeutic strategies for patients with aggressive SMARCB1/INI1-deficient tumors.
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Affiliation(s)
- Nathaniel A Parker
- University of Kansas School of Medicine, 1010 N Kansas St, Wichita, KS, 67214, USA
| | - Ammar Al-Obaidi
- University of Kansas School of Medicine, 1010 N Kansas St, Wichita, KS, 67214, USA
| | - Jeremy M Deutsch
- Cancer Center of Kansas, 818 N. Emporia #403, Wichita, KS, 67214, USA
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31
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Sabbah M, Najem A, Krayem M, Awada A, Journe F, Ghanem GE. RTK Inhibitors in Melanoma: From Bench to Bedside. Cancers (Basel) 2021; 13:1685. [PMID: 33918490 PMCID: PMC8038208 DOI: 10.3390/cancers13071685] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/12/2021] [Accepted: 03/15/2021] [Indexed: 02/06/2023] Open
Abstract
MAPK (mitogen activated protein kinase) and PI3K/AKT (Phosphatidylinositol-3-Kinase and Protein Kinase B) pathways play a key role in melanoma progression and metastasis that are regulated by receptor tyrosine kinases (RTKs). Although RTKs are mutated in a small percentage of melanomas, several receptors were found up regulated/altered in various stages of melanoma initiation, progression, or metastasis. Targeting RTKs remains a significant challenge in melanoma, due to their variable expression across different melanoma stages of progression and among melanoma subtypes that consequently affect response to treatment and disease progression. In this review, we discuss in details the activation mechanism of several key RTKs: type III: c-KIT (mast/stem cell growth factor receptor); type I: EGFR (Epidermal growth factor receptor); type VIII: HGFR (hepatocyte growth factor receptor); type V: VEGFR (Vascular endothelial growth factor), structure variants, the function of their structural domains, and their alteration and its association with melanoma initiation and progression. Furthermore, several RTK inhibitors targeting the same receptor were tested alone or in combination with other therapies, yielding variable responses among different melanoma groups. Here, we classified RTK inhibitors by families and summarized all tested drugs in melanoma indicating the rationale behind the use of these drugs in each melanoma subgroups from preclinical studies to clinical trials with a specific focus on their purpose of treatment, resulted effect, and outcomes.
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Affiliation(s)
- Malak Sabbah
- Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium; (M.S.); (A.N.); (M.K.); (F.J.)
| | - Ahmad Najem
- Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium; (M.S.); (A.N.); (M.K.); (F.J.)
| | - Mohammad Krayem
- Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium; (M.S.); (A.N.); (M.K.); (F.J.)
| | - Ahmad Awada
- Medical Oncolgy Clinic, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium;
| | - Fabrice Journe
- Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium; (M.S.); (A.N.); (M.K.); (F.J.)
| | - Ghanem E. Ghanem
- Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium; (M.S.); (A.N.); (M.K.); (F.J.)
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32
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Klug LR, Corless CL, Heinrich MC. Inhibition of KIT Tyrosine Kinase Activity: Two Decades After the First Approval. J Clin Oncol 2021; 39:1674-1686. [PMID: 33797935 DOI: 10.1200/jco.20.03245] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Lillian R Klug
- Oregon Health & Science University, Knight Cancer Institute, Portland, OR.,Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR.,VA Portland Health Care System, Portland, OR
| | - Christopher L Corless
- Oregon Health & Science University, Knight Cancer Institute, Portland, OR.,Department of Pathology, Oregon Health & Science University, Portland, OR
| | - Michael C Heinrich
- Oregon Health & Science University, Knight Cancer Institute, Portland, OR.,Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR.,VA Portland Health Care System, Portland, OR
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33
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Abstract
The proliferation of targeted anticancer agents over the last two decades has revolutionized cancer treatment and improved survival in many previously refractory malignancies. However, many agents are associated with characteristic ophthalmic adverse effects. It is important that ophthalmologists recognize and maintain a high index of suspicion for these side effects in patients on targeted therapy. Most ophthalmic adverse effects can be treated with specific ocular therapy without discontinuation of cancer treatment, although it is important to be aware of the life-threatening and vision-threatening circumstances that would require therapy cessation in conjunction with the patient's oncologist. This review aims to summarize the ophthalmic adverse effects of targeted and hormonal anticancer agents and briefly describe their management.
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34
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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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Outcome of 1000 Patients With Gastrointestinal Stromal Tumor (GIST) Treated by Surgery in the Pre- and Post-imatinib Eras. Ann Surg 2021; 273:128-138. [PMID: 30946076 DOI: 10.1097/sla.0000000000003277] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To characterize the results of surgery for gastrointestinal stromal tumor (GIST) in the pre and post-imatinib eras at a single institution and to identify current prognostic clinicopathologic factors. BACKGROUND Imatinib has radically changed the management of GIST, yet the magnitude of impact on outcome across the spectrum of GIST presentation and relevance of historical prognostic factors are not well defined. METHODS We retrospectively analyzed 1000 patients who underwent surgery for GIST at our institution from 1982 to 2016. Patients were stratified by presentation status as primary tumor only (PRIM), primary with synchronous metastasis (PRIM + MET), or metachronous recurrence/metastases (MET), and also imatinib era (before and after it became available). Cox proportional-hazard models and Kaplan-Meier methods were used to model and estimate overall survival (OS) and recurrence-free survival (RFS). RESULTS OS was longer in the imatinib era compared with the pre-imatinib era in each presentation group, including in Miettinen high-risk primary tumors. Among PRIM patients from the pre-imatinib era, tumor site, size, and mitotic rate were independently associated with OS and RFS on multivariate analysis. PRIM patients in the imatinib era who received imatinib (neoadjuvant and/or adjuvant) had higher risk tumors, but after adjusting for treatment, only size >10 cm remained independently prognostic of RFS [hazard ratio (HR) 3.85, 95% confidence interval (CI) 2.00-7.40, P < 0.0001) and OS (HR 3.37, 95% CI 1.60-7.13, P = 0.001)]. CONCLUSIONS Patients treated in the imatinib era had prolonged OS across all presentations. In the imatinib era, among site, size, and mitotic rate, high-risk features were associated with treatment with the drug, but only size >10 cm correlated with outcome. Imatinib should still be prescribed for patients with high-risk features.
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Preservation of Organ Function in Locally Advanced Non-Metastatic Gastrointestinal Stromal Tumors (GIST) of the Stomach by Neoadjuvant Imatinib Therapy. Cancers (Basel) 2021; 13:cancers13040586. [PMID: 33546113 PMCID: PMC7913129 DOI: 10.3390/cancers13040586] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 01/25/2021] [Accepted: 01/28/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary This study reports a single-center analysis of 55 patients with primary, locally advanced gastric GIST treated with imatinib mesylate (IM) preoperatively for a median of 10 months. The therapy yielded shrinkage of median tumor size from 113 mm to 62 mm. This facilitated 50 patients to undergo significantly less-extensive surgical procedures and resulted in a stomach preservation rate of 96%. The rate of R0 resections was 94% and was followed by a mean recurrence-free-survival time of 132 months with the median not reached. The approach was successful even for patients starting IM during an episode of upper gastrointestinal bleeding. Neoadjuvant IM therapy for locally advanced, non-metastatic gastrointestinal stromal tumors (GIST) of the stomach may play an important role in preserving organ function which might be important for IM plasma levels in an adjuvant or metastatic setting. Abstract Background: Neoadjuvant imatinib mesylate (IM) for advanced, non-metastatic gastrointestinal stromal tumors (GIST) of stomach is recommended to downsize the tumor prompting less-extensive operations and preservation of organ function. Methods: We analyzed the clinical-histopathological profile and oncological outcome of 55 patients (median age 58.2 years; range, 30–86 years) with biopsy-proven, cM0, gastric GIST who underwent IM therapy followed by surgery with a median follow-up of 82 months. Results: Initial median tumor size was 113 mm (range, 65–330 mm) and 10 patients started with acute upper GI bleeding. After a median 10 months (range, 2–21 months) of treatment, tumor size had shrunk to 62 mm (range, 22–200 mm). According to Response Evaluation Criteria In Solid Tumors version 1.0 and version 1.1 (RECIST 1.1), 39 (75%) patients had partial response and 14 patients had stable disease, with no progressive disease. At plateau response, 50 patients underwent surgery with an R0 resection rate of 94% and pathological complete response in 24%. In 12 cases (24%), downstaging allowed laparoscopic resection. The mean recurrence-free survival (RFS) was 123 months (95%CI; 99–147) and the estimated 5-year RFS was 84%. Conclusions: Neoadjuvant IM allowed stomach preservation in 96% of our patients with excellent long-term RFS, even when starting treatment during an episode of upper GI bleeding. Preservation of the stomach provides the physiological basis for the use of oral IM in the adjuvant or metastatic setting.
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Song LJ, Ge HJ, Shi XQ, Shen WW. Prognostic and predictive values of the KIT11-mutated grading system in patients with gastrointestinal stromal tumors: a retrospective study. Hum Pathol 2021; 110:31-42. [PMID: 33476644 DOI: 10.1016/j.humpath.2021.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 01/05/2021] [Accepted: 01/11/2021] [Indexed: 01/10/2023]
Abstract
The KIT11 mutation is the most frequent mutation pattern in gastrointestinal stromal tumors (GISTs). However, few studies have investigated the correlation between the KIT11-mutated grading system and imatinib mesylate (IM) sensitivity (the first choice for adjuvant treatment of GISTs). Here, we elucidated the clinical value of the KIT11-mutated grading system for prognostic prediction in patients with GISTs treated with IM. A total of 106 patients with GIST were treated with IM (8: intermediate-risk, 98: high-risk; 10: KIT9-mutated, 86: KIT11-mutated, 5: wild-type, and 5: other mutations). KIT11-mutated patients were divided into 3 grades based on the KIT11-mutated site and type. Clinical backgrounds and prognostic outcomes were retrospectively compared between the 3 groups. Of 86 KIT11-mutated patients treated with IM, 32 (37.21%) had grade 1 tumors, 37 (43.02%) had grade 2 tumors, and 17 (19.77%) had grade 3 tumors. The 5-year disease-free survival (DFS) was significantly worse in patients with grade 3 KIT11-mutated GISTs (41.96%, p = 0.001) than in those with grade 1 (93%) and grade 2 (70.64%) cases. The multivariable analysis suggested that the KIT11-mutated grading system was an independent risk factor for DFS in patients treated with IM (hazard risk, 2.512; 95% confidence interval, 1.370-4.607; p = 0.003). In conclusion, the KIT11-mutated grading system provides good prognostic stratification for DFS in patients treated with IM. Grade 1 tumors predict a favorable response to IM.
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Affiliation(s)
- Ling-Jun Song
- Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080 China.
| | - Hui-Juan Ge
- Department of Pathology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 PR China
| | - Xiao-Qin Shi
- Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080 China
| | - Wei-Wei Shen
- Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080 China; Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China
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Co-Incidence of Paraesophageal Hernia and Perforated Gastrointestinal Stromal Tumor: A Case Report on Rare Presentation of GIST. INTERNATIONAL JOURNAL OF CANCER MANAGEMENT 2021. [DOI: 10.5812/ijcm.111041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Introduction: The most common connective tissue neoplasm of the gastrointestinal tract is gastrointestinal stromal tumors (GISTs). Its presentations are usually abdominal pain and gastrointestinal bleeding. Case Presentation: We report a 31-year-old man with abdominal pain presented to our hospital with 10 days history of abdominal pain. After radiologic investigations, total distended stomach paraesophageal hernia and antral deformity were seen in the CT scan. Subsequently, the patient underwent surgery and after releasing the stomach, a large sealed perforated mass was seen in the antrum near the diaphragmatic hiatus and small localized abscess that subtotal gastrectomy and hernia repair was done. Pathologic examination revealed that the perforated mass is a GIST. Conclusions: We report a rare complication of gist that is perforation and the first report of simultaneous paraesophageal hernia and perforated gist.
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Translating Knowledge About the Immune Microenvironment of Gastrointestinal Stromal Tumors into Effective Clinical Strategies. Curr Treat Options Oncol 2021; 22:9. [PMID: 33400014 DOI: 10.1007/s11864-020-00806-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/11/2020] [Indexed: 12/25/2022]
Abstract
OPINION STATEMENT The role of targeted therapy is firmly established for gastrointestinal stromal tumors (GISTs); other modalities for targeting this disease are necessary for recurrent and refractory disease. There are several lines of evidence pointing to an active role of the immune system in GIST. Preclinical and clinical studies revealed that the most common type of immune cell infiltration in GISTs is tumor-associated macrophages (TAMs). The mechanism of how TAMs sculpt the tumor microenvironment in GIST is not clear, but it seems that the presence of immunosuppressive regulatory T cells (Tregs) is correlated with the number of TAMs, thus linking macrophages to immunosuppression. CD3+ T cells and NK infiltrates are found in the GIST microenvironment and carry some prognostic value. In early clinical trials, there is evidence for an active role for immunotherapy in treating GIST patients. Moreover, preclinical evidence has indicated that combining TKIs with checkpoint blockers may be synergistic in murine GIST models. Overall, there is substantial preclinical and clinical evidence to support a role for immunoregulation in GIST and further studies will be important for the development of immunotherapies for GIST.
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Xu H, Liu Q. Individualized Management of Blood Concentration in Patients with Gastrointestinal Stromal Tumors. Onco Targets Ther 2021; 13:13345-13355. [PMID: 33456310 PMCID: PMC7804055 DOI: 10.2147/ott.s279998] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 11/18/2020] [Indexed: 01/29/2023] Open
Abstract
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor, and surgical resection is the first choice for the treatment of the disease, but since the advent of tyrosine kinase inhibitors (TKIs) such as imatinib (IM), the prognosis of the disease has undergone revolutionary changes. According to the current version of the guidelines, most GIST patients receive a fixed dose without taking into account their own individual differences, resulting in a wide difference in blood concentration, adverse reactions and prognosis. With more studies on the relationship between blood drug concentrations and prognosis, the concept of individualized therapy has been paid more attention by researchers. Therapeutic drug monitoring (TDM) has also been made available for the research field of GIST targeted therapy. How to reduce the incidence of drug resistance and adverse reactions in patients with GISTs has become the focus of the current research. This article reviews the common monitoring methods and timing of TKIs blood concentration, the reasonable range of blood drug concentration, the toxic or adverse effects caused by high blood drug concentration, some possible factors affecting blood drug concentration and recent research progress, in order to discuss and summarize the treatment strategy of individual blood drug concentration, improve the prognosis of patients and reduce the adverse effects as much as possible.
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Affiliation(s)
- Hao Xu
- Department of Gastrointestinal Surgery, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Qi Liu
- Trauma Center, The First Hospital of China Medical University, Shenyang, People's Republic of China
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41
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Molecular Genetics in the Multidisciplinary Management of Sarcoma. Sarcoma 2021. [DOI: 10.1007/978-981-15-9414-4_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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Immunohistochemistry in Bone and Soft Tissue Tumours. Sarcoma 2021. [DOI: 10.1007/978-981-15-9414-4_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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43
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Kurokawa R, Hagiwara A, Amemiya S, Gonoi W, Fujita N, Kurokawa M, Yamaguchi H, Nakai Y, Ota Y, Baba A, Kawahara T, Abe O. Imatinib-induced pancreatic hypertrophy in patients with gastrointestinal stromal tumor: Association with overall survival. Pancreatology 2021; 21:246-252. [PMID: 33281059 DOI: 10.1016/j.pan.2020.11.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 10/19/2020] [Accepted: 11/22/2020] [Indexed: 12/11/2022]
Abstract
OBJECTIVES To investigate the frequency of imatinib-induced pancreatic complications and determine whether these are survival prognostic factors in patients with gastrointestinal stromal tumor (GIST). METHODS This retrospective multicenter study included patients with histopathologically diagnosed GIST treated with imatinib who underwent computed tomography (CT) within 100 days before (pretreatment CT) and 500 days after (post-treatment CT) imatinib initiation (January 2004-December 2019). Forty-eight patients (63.0 ± 12.1 years, 30 men) were included. Two blinded radiologists independently measured pancreatic volumes. Pancreatic volume on pretreatment CT was compared with that of the control (within 1 year prior to pretreatment CT) and the first two post-treatment CTs using paired t-tests. Thresholds for pancreatic hypertrophy and atrophy were defined using a log-rank test. The prognostic importance of pancreatic hypertrophy was further analyzed using multivariate Cox proportional hazard regression models. RESULTS Pancreatic volume was significantly higher for the first post-treatment CT than pretreatment CT (71.5 cm3 vs. 67.4 cm3, P = .027), whereas no significant difference was observed between the pretreatment and control CTs. Optimal thresholds for pancreatic hypertrophy and atrophy were defined as an 22% increase and 30% decrease and found in 20 and three patients, respectively. Pancreatic hypertrophy was significantly associated with reduced survival [hazard ratio = 2.9 (95% confidence interval, 1.3-6.5), P = .0088]. No patients showed serum lipase elevation, nor were they suspected of having acute pancreatitis. CONCLUSION There was frequent asymptomatic pancreatic swelling in patients with GIST after imatinib treatment, and a ≥22% increase in pancreatic volume was a predictor of reduced survival.
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Affiliation(s)
- Ryo Kurokawa
- Department of Radiology, Graduate School of Medicine, The University of Tokyo, Japan
| | | | - Shiori Amemiya
- Department of Radiology, Graduate School of Medicine, The University of Tokyo, Japan
| | - Wataru Gonoi
- Department of Radiology, Graduate School of Medicine, The University of Tokyo, Japan.
| | - Nana Fujita
- Department of Radiology, Graduate School of Medicine, The University of Tokyo, Japan
| | - Mariko Kurokawa
- Department of Radiology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Japan
| | - Haruomi Yamaguchi
- Department of Radiology, Graduate School of Medicine, The University of Tokyo, Japan
| | - Yudai Nakai
- Department of Radiology, Graduate School of Medicine, The University of Tokyo, Japan
| | - Yoshiaki Ota
- Division of Neuroradiology, Department of Radiology, Michigan Medicine, Japan
| | - Akira Baba
- Department of Radiology, The Jikei University School of Medicine, Japan
| | - Takuya Kawahara
- Clinical Research Promotion Center, The University of Tokyo Hospital, Japan
| | - Osamu Abe
- Department of Radiology, Graduate School of Medicine, The University of Tokyo, Japan
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Suresh Babu MC, Chaudhuri T, Babu KG, Lakshmaiah KC, Lokanatha D, Jacob LA, Rudresha AH, Lokesh KN, Rajeev LK. Metastatic gastrointestinal stromal tumor: A regional cancer center experience of 44 cases. South Asian J Cancer 2020; 6:118-121. [PMID: 28975120 PMCID: PMC5615881 DOI: 10.4103/sajc.sajc_290_16] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Historically, a poor prognosis for metastatic disease has been reported with systemic chemotherapy. Significant advances have been made in the last decade, since the introduction of different tyrosine kinase inhibitors (TKIs). Unfortunately, even though the TKIs have been used for a long time, there are very few published data of the experience of TKI therapy in metastatic GIST from India. MATERIALS AND METHODS Patients diagnosed with metastatic GIST from January 2005 to October 2016 at our center, who received first-line therapy with imatinib 400 mg/day, were reviewed retrospectively. Patients' profile, response to treatment, toxicity of TKI therapy, time to progression, and survival were evaluated. RESULTS Of the 44 metastatic GIST patients, 23 (52.2%) were males. Median age at diagnosis was 48 years. The most common presenting symptom was an abdominal pain (52%), followed by weight loss (23%). Most frequently affected metastatic site was liver (57%), followed by peritoneum (16%), and lungs (4.5%). Metastases to both liver and peritoneum were found in 10 patients (22.5%). All patients were initially treated with imatinib at a dose of 400 mg/day. Disease stabilization was documented in 21 cases (48%), and 13 patients (29%) achieved a partial response. TKI therapy was well-tolerated in most cases. Median progression-free survival (PFS) was 26 months, and estimated median survival was 48 months. Patients with lung metastases have a significantly inferior median PFS and overall survival, in comparison to patients with other metastatic sites (P < 0.05). CONCLUSIONS Imatinib therapy was well tolerated and induced a sustained clinical benefit in more than half of the patients with metastatic GIST. Lung metastases seemed to be a poor prognostic factor in this patient population.
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Affiliation(s)
- M C Suresh Babu
- Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
| | - Tamojit Chaudhuri
- Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
| | - K Govind Babu
- Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
| | - K C Lakshmaiah
- Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
| | - D Lokanatha
- Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
| | - Linu Abraham Jacob
- Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
| | - A H Rudresha
- Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
| | - K N Lokesh
- Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
| | - L K Rajeev
- Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
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El-Damasy AK, Haque MM, Park JW, Shin SC, Lee JS, EunKyeong Kim E, Keum G. 2-Anilinoquinoline based arylamides as broad spectrum anticancer agents with B-RAF V600E/C-RAF kinase inhibitory effects: Design, synthesis, in vitro cell-based and oncogenic kinase assessments. Eur J Med Chem 2020; 208:112756. [PMID: 32942186 DOI: 10.1016/j.ejmech.2020.112756] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 07/27/2020] [Accepted: 08/12/2020] [Indexed: 11/15/2022]
Abstract
Prompted by the urgent demand for identification of new anticancer agents with improved potency and efficacy, a new series of arylamides incorporating the privileged 2-anilinoquinoline scaffold has been designed, synthesized, and biologically assessed. Aiming at extensive evaluation of the target compounds' potency and spectrum, a panel of 60 clinically important cancer cell lines representing nine cancer types has been used. Compounds 9a and 9c, with piperazine substituted phenyl ring, emerged as the most active members surpassing the anticancer potencies of the FDA-approved drug imatinib. They elicited sub-micromolar or one-digit micromolar GI50 values over the majority of tested cancer cells including multidrug resistant (MDR) cells like colon HCT-15, renal TK-10 and UO-31, and ovarian NCI/ADR-RES. In vitro mechanistic study showed that compounds 9a and 9c could trigger morphological changes, apoptosis and cell cycle arrest in HCT-116 colon cancer cells. Besides, compound 9c altered microtubule polymerization pattern in a similar fashion to paclitaxel. Kinase screening of 9c disclosed its inhibitory activity over B-RAFV600E and C-RAF kinases with IC50 values of 0.888 μM and 0.229 μM, respectively. Taken together, the current report presents compounds 9a and 9c as promising broad-spectrum potent anticancer candidates, which could be considered for further development of new anticancer drugs.
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Affiliation(s)
- Ashraf K El-Damasy
- Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul, 136-791, Republic of Korea; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
| | - Md Mamunul Haque
- Molecular Recognition Research Center, KIST, Seoul, 02792, Republic of Korea
| | - Jung Woo Park
- Center for Supercomputing Applications, Div. of National Supercomputing R&D, Korea Institute of Science and Technology Information, 245, Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Sang Chul Shin
- Biomedical Research Institute, KIST, Hwarangro 14-gil 5, Seongbuk-gu, Seoul, 02792, Republic of Korea
| | - Jun-Seok Lee
- Molecular Recognition Research Center, KIST, Seoul, 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Seoul, 02792, Republic of Korea
| | - Eunice EunKyeong Kim
- Biomedical Research Institute, KIST, Hwarangro 14-gil 5, Seongbuk-gu, Seoul, 02792, Republic of Korea
| | - Gyochang Keum
- Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul, 136-791, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Seoul, 02792, Republic of Korea.
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Mohammadi M, Gelderblom H. Systemic therapy of advanced/metastatic gastrointestinal stromal tumors: an update on progress beyond imatinib, sunitinib, and regorafenib. Expert Opin Investig Drugs 2020; 30:143-152. [PMID: 33252274 DOI: 10.1080/13543784.2021.1857363] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Introduction: Discovery of oncogenic mutations in the KIT and PDGFRA tyrosine kinase receptor was a crucial step for the development of tyrosine kinase inhibitors (TKIs). Since then, GIST became a model for the development of molecular-targeted therapy, which led to dramatically improved median overall survival of advanced GIST. Still, further progress is needed after third-line or for TKI resistant mutations. Areas covered: In this review, after a brief introduction on imatinib, sunitinib, and regorafenib, an overview of TKIs that was evaluated beyond these drugs is provided, with a main focus on the novel approved TKIs. Expert opinion: Combination therapies have thus far not fulfilled their promise in GIST, nor did immunotherapy. Increased understanding of GIST and advances in the development of molecular-targeted drugs led to the introduction of ripretinib and avapritinib. Furthermore, NTRK inhibitors became available for ultrarare NTRK fusions. Solutions for NF1 and BRAF mutated and SDH-deficient GIST are still to be awaited. This all underlines the need for adequate molecular profiling of high-risk GISTs before treatment is started. Possibly by using circulating tumor DNA in the future, targeting resistance mutations with specific drugs along the course of the disease would be easier, avoiding multiple tumor biopsies.
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Affiliation(s)
- Mahmoud Mohammadi
- Department of Medical Oncology, Leiden University Medical Center , Leiden, The Netherlands
| | - Hans Gelderblom
- Department of Medical Oncology, Leiden University Medical Center , Leiden, The Netherlands
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Donnell CC, Walton RL, Carrozzo M. The blue palate-A case series of imatinib-related oral pigmentation and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol 2020; 131:49-61. [PMID: 33199217 DOI: 10.1016/j.oooo.2020.10.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 09/22/2020] [Accepted: 10/13/2020] [Indexed: 12/28/2022]
Abstract
Pigmented oral mucosal lesions are diverse, and differential diagnosis can range from benign conditions such as oral melanotic macule to malignancies such as oral malignant melanoma. Imatinib mesylate is a tyrosine kinase inhibitor used as a first-line medication in the management of oncohematological conditions such as chronic myeloid leukemia and gastrointestinal stromal tumors. Side effects of imatinib therapy are common, and paradoxically imatinib has been associated with both hypo- and hyperpigmented lesions, the underlying mechanism for which is still unclear. Hyperpigmentation associated with imatinib therapy is a potentially underreported phenomenon. This article presents an in-depth, clinicopathological review of the literature surrounding imatinib-related hyperpigmentation, alongside a case series of imatinib-related oral pigmentation with notable practical learning points. A pragmatic flowchart to help clinicians in the diagnosis and management of oral pigmented lesions is provided, as well as advice on the application of the ABCDE criteria to standardize recording of oral pigmented lesions.
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Affiliation(s)
- Christopher C Donnell
- Dental Core Trainee, Newcastle Dental Hospital, Newcastle upon Tyne NHS Hospitals Foundation Trust, Newcastle, UK.
| | - Richard L Walton
- NIHR Academic Clinical Fellow, Specialty Trainee in Oral Medicine, Newcastle School of Dental Sciences, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
| | - Marco Carrozzo
- Professor, Honorary Consultant in Oral Medicine, Newcastle School of Dental Sciences Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
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Zhao W, Deng J, Sun L, Sun Y, Liang H. Combination therapy for inoperable ileal gastrointestinal stromal tumour. ANZ J Surg 2020; 91:E346-E349. [PMID: 33045132 DOI: 10.1111/ans.16382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 09/15/2020] [Accepted: 09/21/2020] [Indexed: 10/23/2022]
Affiliation(s)
- Wei Zhao
- Department of Gastric Cancer Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Jingyu Deng
- Department of Gastric Cancer Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Lin Sun
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yan Sun
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Han Liang
- Department of Gastric Cancer Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China
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Martin‐Broto J, Hindi N, Aguiar S, Badilla‐González R, Castro‐Oliden V, Chacón M, Correa‐Generoso R, de Álava E, Donati DM, Eriksson M, Falla‐Jimenez M, German G, Gobo Silva ML, Gouin F, Gronchi A, Haro‐Varas JC, Jiménez‐Brenes N, Kasper B, Lopes de Mello CA, Maki R, Martínez‐Delgado P, Martínez‐Said H, Martinez‐Tlahuel JL, Morales‐Pérez JM, Muñoz‐Casares FC, Nakagawa SA, Ortiz‐Cruz EJ, Palmerini E, Patel S, Moura DS, Stacchiotti S, Sunyach MP, Valverde CM, Waisberg F, Blay J. Sarcoma European and Latin American Network (SELNET) Recommendations on Prioritization in Sarcoma Care During the COVID-19 Pandemic. Oncologist 2020; 25:e1562-e1573. [PMID: 32888360 PMCID: PMC7543334 DOI: 10.1634/theoncologist.2020-0516] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 08/14/2020] [Indexed: 01/12/2023] Open
Abstract
Background The COVID‐19 outbreak has resulted in collision between patients infected with SARS‐CoV‐2 and those with cancer on different fronts. Patients with cancer have been impacted by deferral, modification, and even cessation of therapy. Adaptive measures to minimize hospital exposure, following the precautionary principle, have been proposed for cancer care during COVID‐19 era. We present here a consensus on prioritizing recommendations across the continuum of sarcoma patient care. Material and Methods A total of 125 recommendations were proposed in soft‐tissue, bone, and visceral sarcoma care. Recommendations were assigned as higher or lower priority if they cannot or can be postponed at least 2–3 months, respectively. The consensus level for each recommendation was classified as “strongly recommended” (SR) if more than 90% of experts agreed, “recommended” (R) if 75%–90% of experts agreed and “no consensus” (NC) if fewer than 75% agreed. Sarcoma experts from 11 countries within the Sarcoma European‐Latin American Network (SELNET) consortium participated, including countries in the Americas and Europe. The European Society for Medical Oncology‐Magnitude of clinical benefit scale was applied to systemic‐treatment recommendations to support prioritization. Results There were 80 SRs, 35 Rs, and 10 NCs among the 125 recommendations issued and completed by 31 multidisciplinary sarcoma experts. The consensus was higher among the 75 higher‐priority recommendations (85%, 12%, and 3% for SR, R, and NC, respectively) than in the 50 lower‐priority recommendations (32%, 52%, and 16% for SR, R, and NC, respectively). Conclusion The consensus on 115 of 125 recommendations indicates a high‐level of convergence among experts. The SELNET consensus provides a tool for sarcoma multidisciplinary treatment committees during the COVID‐19 outbreak. Implications for Practice The Sarcoma European‐Latin American Network (SELNET) consensus on sarcoma prioritization care during the COVID‐19 era issued 125 pragmatical recommendations distributed as higher or lower priority to protect critical decisions on sarcoma care during the COVID‐19 pandemic. A multidisciplinary team from 11 countries reached consensus on 115 recommendations. The consensus was lower among lower‐priority recommendations, which shows reticence to postpone actions even in indolent tumors. The European Society for Medical Oncology‐Magnitude of Clinical Benefit scale was applied as support for prioritizing systemic treatment. Consensus on 115 of 125 recommendations indicates a high level of convergence among experts. The SELNET consensus provides a practice tool for guidance in the decisions of sarcoma multidisciplinary treatment committees during the COVID‐19 outbreak. The COVID‐19 pandemic has caused deferral, modification, or cessation of treatment for patients with cancer. This article presents a consensus on prioritizing recommendations across the continuum of sarcoma patient care.
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Affiliation(s)
- Javier Martin‐Broto
- Group of Advanced Therapies and Biomarkers in Sarcoma, Institute of Biomedicine of Seville (IBIS, HUVR, CSIC, Universidad de Sevilla)SevillaSpain
- Department of Medical Oncology, University Hospital Virgen del RocioSevilleSpain
| | - Nadia Hindi
- Group of Advanced Therapies and Biomarkers in Sarcoma, Institute of Biomedicine of Seville (IBIS, HUVR, CSIC, Universidad de Sevilla)SevillaSpain
- Department of Medical Oncology, University Hospital Virgen del RocioSevilleSpain
| | - Samuel Aguiar
- Department of Pelvic Surgery, A.C. Camargo Cancer CenterSão PauloBrazil
| | | | - Victor Castro‐Oliden
- Department of Medical Oncology, Instituto Nacional de Enfermedades NeoplásicasLimaPeru
| | - Matias Chacón
- Department of Medical Oncology, Alexander Fleming Cancer InstituteBuenos AiresArgentina
| | | | - Enrique de Álava
- Pathology Department, University Hospital Virgen del RocíoSevilleSpain
- CIBERONCMadridSpain
- Department of Normal and Pathological Cytology and Histology, School of Medicine, University of SevilleSevilleSpain
| | - Davide María Donati
- Unit of Orthopedic Pathology and Osteoarticular Tissue Regeneration, Rizzoli Orthopedic InstituteBolognaItaly
| | - Mikael Eriksson
- Department of Medical Oncology, Skane University Hospital‐LundLundSweden
| | - Martin Falla‐Jimenez
- Department of Breast and Soft Tissues Surgery, Instituto Nacional de Enfermedades NeoplásicasLimaPeru
| | - Gisela German
- Department of Medical Oncology, Hospital Oncológico ProvincialCórdobaArgentina
| | | | - Francois Gouin
- Department of Orthopedic Surgery, Centre León BérardLyonFrance
| | - Alessandro Gronchi
- Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori and University of MilanMilanItaly
| | | | | | - Bernd Kasper
- Department of Medical Oncology, Mannheim University Medical CenterMannheimGermany
| | | | - Robert Maki
- Department of Medical Oncology, Abramson Cancer Center, University of Pennsylvania Perelman School of MedicinePhiladelphiaPennsylvaniaUSA
| | - Paula Martínez‐Delgado
- Group of Advanced Therapies and Biomarkers in Sarcoma, Institute of Biomedicine of Seville (IBIS, HUVR, CSIC, Universidad de Sevilla)SevillaSpain
| | - Hector Martínez‐Said
- Department of Medical Oncology, Instituto Nacional de CancerologíaMexico CityMexico
| | | | | | | | - Suely A. Nakagawa
- Department of Orthopedics, A.C. Camargo Cancer CenterSão PauloBrazil
| | | | - Emanuela Palmerini
- Department of Medical Oncology, Rizzoli Orthopedic InstituteBolognaItaly
| | - Shreyaskumar Patel
- Department of Melanoma Medical Oncology, University of Texas M. D. Anderson Cancer CenterHoustonTexasUSA
| | - David S. Moura
- Group of Advanced Therapies and Biomarkers in Sarcoma, Institute of Biomedicine of Seville (IBIS, HUVR, CSIC, Universidad de Sevilla)SevillaSpain
| | - Silvia Stacchiotti
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori and University of MilanMilanItaly
| | | | | | - Federico Waisberg
- Department of Medical Oncology, Alexander Fleming Cancer InstituteBuenos AiresArgentina
| | - Jean‐Yves Blay
- Department of Medical Oncology, Centre León BérardLyonFrance
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Non-Coding RNAs, a Novel Paradigm for the Management of Gastrointestinal Stromal Tumors. Int J Mol Sci 2020; 21:ijms21186975. [PMID: 32972022 PMCID: PMC7555847 DOI: 10.3390/ijms21186975] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 09/14/2020] [Accepted: 09/16/2020] [Indexed: 12/12/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal malignancies found in the gastrointestinal tract. At a molecular level, most GISTs are characterized by gain-of-function mutations in V-Kit Hardy-Zuckerman 4 Feline Sarcoma Viral Oncogene Homolog (KIT) and Platelet Derived Growth Factor Receptor Alpha (PDGFRA), leading to constitutive activated signaling through these receptor tyrosine kinases, which drive GIST pathogenesis. In addition to surgery, treatment with the tyrosine kinase inhibitor imatinib forms the mainstay of GIST treatment, particularly in the advanced setting. Nevertheless, the majority of GISTs develop imatinib resistance. Biomarkers that indicate metastasis, drug resistance and disease progression early on could be of great clinical value. Likewise, novel treatment strategies that overcome resistance mechanisms are equally needed. Non-coding RNAs, particularly microRNAs, can be employed as diagnostic, prognostic or predictive biomarkers and have therapeutic potential. Here we review which non-coding RNAs are deregulated in GISTs, whether they can be linked to specific clinicopathological features and discuss how they can be used to improve the clinical management of GISTs.
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