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Xu JX, Su YX, Chen YY, Huang YY, Chen ZS, Peng YC, Qi LN. Immune infiltration landscape and potential drug-targeted implications for hepatocellular carcinoma with 'progression/hyper-progression' recurrence. Ann Med 2025; 57:2456113. [PMID: 39865865 PMCID: PMC11774162 DOI: 10.1080/07853890.2025.2456113] [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: 01/03/2024] [Revised: 12/20/2024] [Accepted: 01/08/2025] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND AND AIMS Hepatocellular carcinoma (HCC) recurrence was previously characterized into four types, and patients with progression/hyper-progression recurrence (type III-IV) have an extremely poor prognosis. However, the immune background of resectable HCC, particularly in patients who experience recurrence, remains underexplored. Therefore, this study aimed to describe the immune landscape of resectable HCC, especially postoperative type III-IV recurrent HCC, and explore potential immune-targeted anti-relapse strategies for treated populations. METHODS The differences in gene expression in patients with recurrent HCC (type I-II (solitary or multi-intrahepatic oligo recurrence) vs. type III-IV) were investigated using bulk sequencing. Multiple immune infiltration methods (single-sample gene set enrichment analysis (GSEA), Microenvironment Cell Populations-counter and ESTIMATE) were used, and patients were divided into four groups to identify four distinct immune subtypes: immune-enrichment/matrix-poor (IE1), immune-enrichment/matrix-rich (IE2), immune intermediate/matrix-rich (ITM) and immune desert/matrix-poor (ID). Co-expression and protein interaction analyses were used to identify characteristic genes in ITM closely associated with type III-IV recurrence, which was matched with drug targets for Huaier granules (HG) and lenvatinib. Virtual docking was used to identify potential therapeutic targets, and the results were verified using single-nuclei RNA sequencing and histological analysis. RESULTS ITM was closely related to type III-IV recurrence and exhibited immunotherapy potential. The potential efficacy of inhibiting CCNA2, VEGFA, CXCL8, PLK2, TIMP1, ITGB2, ALDOA, ANXA5 and CSK in ITM reversal was determined. Molecular docking demonstrated that the proteins of these genes could bind to HG or lenvatinib. The immunohistochemical findings demonstrated differential VEGFA (p < .01) and PLK2 (p < .001) expression in ITM type and ID in type III-IV recurrent HCC. CONCLUSIONS Three primary immunotypes of resectable HCC (IE2, ITM and ID) were identified, and HG and lenvatinib could potentially overcome immune checkpoint blockade (ICB) resistance in ITM patients with HCC, particularly those classified as type III-IV.
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Affiliation(s)
- Jing-Xuan Xu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumour, Ministry of Education, Nanning, China
| | - Yue-Xiang Su
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumour, Ministry of Education, Nanning, China
| | - Yuan-Yuan Chen
- Department of Ultrasound, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yi-Yue Huang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumour, Ministry of Education, Nanning, China
| | - Zu-Shun Chen
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yu-Chong Peng
- Department of General Surgery, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Lu-Nan Qi
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumour, Ministry of Education, Nanning, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, China
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Luo L, Liang H, Yuan L, Wu YK. Potential synergistic effects of lenvatinib and aspirin in aortic dissection: a case report and literature review. Front Oncol 2025; 15:1520770. [PMID: 40330834 PMCID: PMC12052901 DOI: 10.3389/fonc.2025.1520770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 03/31/2025] [Indexed: 05/08/2025] Open
Abstract
Background Although numerous anticancer drugs targeting vascular endothelial growth factor (VEGF) are commonly used in clinical practice, life-threatening drug-drug interactions (DDIs) involving these drugs are rarely reported. Case summary A male patient had been taking aspirin for two years following a stroke. He was subsequently diagnosed with hepatocellular carcinoma (HCC) and initiated lenvatinib therapy. Shortly after, he developed lenvatinib-induced hypertension (191/102 mmHg) and was prescribed amlodipine for blood pressure control. At his first routine follow-up for HCC treatment, he was asymptomatic but was incidentally diagnosed with acute aortic dissection (AD). The patient declined endovascular treatment, and his AD lesions remained temporarily stable. Although lenvatinib is generally considered a safe and effective option for advanced HCC, this case raises concerns about a potential link between lenvatinib and aspirin in the development of AD due to their temporal association. This case highlights the need for increased clinical awareness regarding possible DDIs between these two drugs, particularly in patients with untreated acute AD. Conclusion The concurrent use of lenvatinib and aspirin may increase the risk of AD in patients with cancer. To prevent life-threatening complications, patients receiving both therapies should be closely monitored and strictly adhere to treatment guidelines. For patients who decline invasive AD treatment, continued lenvatinib therapy might be a cost-effective option to improve prognosis, though the continuation of aspirin therapy requires careful consideration.
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Affiliation(s)
- Lan Luo
- Department of Pharmacy, Suining Central Hospital, Suining, Sichuan, China
| | - Hao Liang
- Department of Hepatobiliary Surgery, Suining Central Hospital, Suining, Sichuan, China
| | - Lin Yuan
- Department of Pharmacy, Suining Central Hospital, Suining, Sichuan, China
| | - Ya-Kun Wu
- Department of Hepatobiliary Surgery, Suining Central Hospital, Suining, Sichuan, China
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Nihei S, Saito K, Ikeda T, Oikawa T, Asahi K, Asaka J, Kudo K. Potential role of endothelial dysfunction in hypertension and proteinuria in patients with hepatocellular carcinoma receiving atezolizumab plus bevacizumab: a pilot prospective observational study. Cancer Chemother Pharmacol 2025; 95:55. [PMID: 40244305 DOI: 10.1007/s00280-025-04776-7] [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: 02/17/2025] [Accepted: 04/04/2025] [Indexed: 04/18/2025]
Abstract
PURPOSE Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), is the first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). Its inhibition of VEGF signaling may lead to proteinuria due to endothelial dysfunction but the association between endothelial function and clinical outcomes has not been established. This study aimed to investigate vascular endothelial function in patients with HCC receiving atezolizumab plus bevacizumab, and to assess the correlation between reactive hyperemia index (RHI) and adverse renal outcomes. METHODS This pilot prospective observational study included 20 patients with HCC who received atezolizumab plus bevacizumab. We used reactive hyperemia-peripheral arterial tonometry (RH-PAT) and evaluated vascular endothelial function on the basis of RHI. RHI, blood pressure, and proteinuria were recorded at baseline and at 3 and 6 months after initiation of atezolizumab plus bevacizumab treatment. Statistical analyses were performed to investigate the relationship of RHI to blood pressure and proteinuria. RESULTS Following initiation of atezolizumab plus bevacizumab treatment, systolic blood pressure and urine protein-creatinine ratio increased significantly, and RHI decreased. Patients with borderline or low baseline RHI had a higher incidence of grade ≥ 2 proteinuria than those with normal baseline RHI but not hypertension. A significant inverse correlation was found between RHI and urine protein-creatinine ratio. CONCLUSION Bevacizumab administration may cause endothelial dysfunction in patients with HCC. The vascular endothelial function status before and during atezolizumab plus bevacizumab treatment is associated with the risk of bevacizumab-induced proteinuria.
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Affiliation(s)
- Satoru Nihei
- Department of Pharmacy, Iwate Medical University Hospital, 2-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3695, Japan.
- Division of Clinical Pharmaceutics and Pharmacy Practice, Department of Clinical Pharmacy, School of Pharmacy, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694, Japan.
| | - Kazuki Saito
- Department of Pharmacy, Iwate Medical University Hospital, 2-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3695, Japan
| | - Tatsuki Ikeda
- Department of Pharmacy, Iwate Medical University Hospital, 2-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3695, Japan
| | - Takayoshi Oikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694, Japan
| | - Koichi Asahi
- Division of Nephrology and Hypertension, Department of Internal Medicine, School of Medicine, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694, Japan
| | - Junichi Asaka
- Department of Pharmacy, Iwate Medical University Hospital, 2-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3695, Japan
- Division of Clinical Pharmaceutics and Pharmacy Practice, Department of Clinical Pharmacy, School of Pharmacy, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694, Japan
| | - Kenzo Kudo
- Department of Pharmacy, Iwate Medical University Hospital, 2-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3695, Japan
- Division of Clinical Pharmaceutics and Pharmacy Practice, Department of Clinical Pharmacy, School of Pharmacy, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694, Japan
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Uekusa S, Nakashin M, Hanai Y, Nemoto M, Yanagino S, Arita Y, Matsumoto T, Wakui N, Nagai H, Higai K, Matsuo K. Risk factors for lenvatinib-induced hypertension in patients with hepatocellular carcinoma: A retrospective study. Br J Clin Pharmacol 2025; 91:894-902. [PMID: 39568177 PMCID: PMC11862797 DOI: 10.1111/bcp.16337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 10/11/2024] [Accepted: 10/20/2024] [Indexed: 11/22/2024] Open
Abstract
AIMS Lenvatinib mesylate (LEN) is an orally administered tyrosine kinase inhibitor used to treat various cancers, including hepatocellular carcinoma (HCC). LEN therapy for HCC is associated with a high incidence of adverse events, including hypertension (HTN). However, the risk factors associated with LEN therapy remain unclear. This study investigated the incidence of LEN-induced HTN (LENiHTN), and the relationship between HTN incidence and patient demographics in patients with HCC receiving LEN therapy. METHODS This was a single-centre, retrospective study of patients with HCC who received LEN therapy between 19 April 2018 and 30 September 2020. The observation period was from 1 week before the start to 1 month after the end of LEN administration. RESULTS Seventy-five patients with HCC were enrolled. Any grade LENiHTN was found in 74.7% of patients. Among patients with LENiHTN, the use of 2 or more antihypertensive agents before starting LEN was less common (P = .007); serum potassium (K) and albumin-bilirubin score (ALBI) were lower (P = .013 and 0.038, respectively); and albumin (Alb) was higher (P = .025). The cut-off values of K, Alb and ALBI for HTN were estimated at 4.1 mEq L-1, 3.1 g dL-1 and -1.736, respectively. In the multivariable analysis, low K (adjusted HR: 2.078) and low ALBI (adjusted HR: 2.845) were independent risk factors for LENiHTN. CONCLUSION Low K, high Alb and low ALBI were independent risk factors for LENiHTN. Systematic evaluation of HTN risk and early intervention for HTN prevention among high-risk patients can markedly enhance LEN therapy efficacy and use.
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Affiliation(s)
- Shusuke Uekusa
- Department of Clinical Pharmacy, Faculty of Pharmaceutical SciencesToho UniversityChibaJapan
| | - Misaki Nakashin
- Department of Clinical Pharmacy, Faculty of Pharmaceutical SciencesToho UniversityChibaJapan
| | - Yuki Hanai
- Department of Clinical Pharmacy, Faculty of Pharmaceutical SciencesToho UniversityChibaJapan
| | - Maho Nemoto
- Department of Clinical Pharmacy, Faculty of Pharmaceutical SciencesToho UniversityChibaJapan
- Toho University Ohashi Medical CenterTokyoJapan
| | | | | | | | - Noritaka Wakui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori)School of Medicine, Faculty of MedicineTokyoJapan
| | - Hidenari Nagai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori)School of Medicine, Faculty of MedicineTokyoJapan
| | - Koji Higai
- Laboratory of Medical BiochemistryFaculty of Pharmaceutical Sciences Toho UniversityChibaJapan
| | - Kazuhiro Matsuo
- Department of Clinical Pharmacy, Faculty of Pharmaceutical SciencesToho UniversityChibaJapan
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Zhu H, Pan L, Lui H, Zhang J. Drug-Related Hypertension: A Disproportionality Analysis Leveraging the FDA Adverse Event Reporting System. J Clin Hypertens (Greenwich) 2025; 27:e70029. [PMID: 40065662 PMCID: PMC11894037 DOI: 10.1111/jch.70029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Revised: 02/13/2025] [Accepted: 02/25/2025] [Indexed: 03/14/2025]
Abstract
Hypertension exerts a significant global disease burden, adversely affecting the well-being of billions. Alarmingly, drug-related hypertension remains an area that has not been comprehensively investigated. Therefore, this study is designed to utilize the adverse event reports (AERs) from the US Food and Drug Administration's Adverse Event Reporting System (FAERS) to more comprehensively identify drugs that may potentially lead to hypertension. Specifically, a total of 207 233 AERs were extracted from FAERS, spanning the time period from 2004 to 2024. Based on these reports, this study presented the top 40 drugs most frequently reported to be associated with post-administration hypertension in different genders. Furthermore, we employed four disproportionality analysis methods, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayes Geometric Mean (EBGM), to pinpoint the top three drugs with strongest signals in relation to hypertension across different age and gender subgroups. Some drugs, such as rofecoxib, lenvatinib, and celecoxib, were found to appear on both the frequency and signal strength lists. These results contribute to a more comprehensive understanding of the cardiovascular safety profiles of pharmacological agents, suggesting the necessity of blood pressure monitoring following administration.
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Affiliation(s)
- Hao Zhu
- Department of Pediatrics and Adolescent MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina
| | - Linwei Pan
- Graduate SchoolTsinghua UniversityBeijingChina
| | - Hannah Lui
- Department of Pediatrics and Adolescent MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina
| | - Jing Zhang
- The Second Department of Infectious DiseaseShanghai Fifth People's HospitalFudan UniversityShanghaiChina
- Center of Community‐Based Health ResearchFudan UniversityShanghaiChina
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Si F, Ma X, Liu Q, Yu J. Reviewing the path to balance: mechanisms and management of hypertension associated with targeting vascular endothelium in cancer therapy. Hypertens Res 2025; 48:1034-1047. [PMID: 39820066 DOI: 10.1038/s41440-024-02086-8] [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: 10/22/2024] [Revised: 12/13/2024] [Accepted: 12/21/2024] [Indexed: 01/19/2025]
Abstract
Contemporary anticancer drugs are often accompanied by varying degrees of cardiovascular toxicity, with hypertension emerging as one of the most prevalent side effects, particularly linked to inhibitors of vascular endothelial growth factor receptor (VEGFR) and tyrosine kinase inhibitors (TKIs). Hypertension induced by cancer therapies contributes to increased cardiovascular mortality in cancer patients and survivors. Given the shared common risk factors and overlapping pathophysiological mechanisms, hypertension is also a prevalent comorbidity in this patient population. The mechanisms underlying hypertension induced by therapies targeting the vascular endothelial growth factor (VEGF) signaling pathway primarily involve reduced nitric oxide (NO) synthesis, increased endothelin-1 (ET-1) production, oxidative stress, microvascular rarefaction and dysfunction, decreased natriuresis, activation of the renin-angiotensin system (RAS), and partial endothelial cell death. Research into hypertension associated with therapies targeting the VEGF signaling pathway (VSP) could facilitate the optimization of cancer treatments, improve the evaluation and management of hypertension during targeted therapy, and help to reduce cardiovascular event rates and overall patient mortality. This review aims to provide a comprehensive summary of the current advancements in this area.
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Affiliation(s)
- Fei Si
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Xin Ma
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Qian Liu
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Jing Yu
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China.
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Ekram J, Rathore A, Avila C, Hussein R, Alomar M. Unveiling the Cardiotoxicity Conundrum: Navigating the Seas of Tyrosine Kinase Inhibitor Therapies. Cancer Control 2024; 31:10732748241285755. [PMID: 39318033 PMCID: PMC11440564 DOI: 10.1177/10732748241285755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/26/2024] Open
Abstract
Background: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of various solid and hematologic malignancies by targeting dysregulated signaling pathways critical for malignant cell growth. However, these therapeutic benefits are often accompanied by cardiotoxicities, such as hypertension, left ventricular dysfunction, QT prolongation, and tachyarrhythmias, among others. These cardiotoxicities post a significant challenge in clinical management, often limiting the use of otherwise effective therapies. The underlying mechanism of TKI-induced cardiotoxicity appears to be multifaceted, involving several pathways including: direct cardiomyocyte damage, mitochondrial dysfunction, endothelial damage, and disruption of signaling pathways critical for cardiac function. The range and severity of cardiotoxicities vary significantly across different TKIs, necessitating a comprehensive understanding of each agent's specific cardiovascular risk profile. Preventing and managing TKI-induced cardiotoxicity requires a comprehensive, multidisciplinary approach. Early identification of at-risk patients through baseline cardiovascular risk assessments and appropriate monitoring during therapy is crucial. Strategies to mitigate cardiotoxic effects include dose modification, the use of cardioprotective agents, and temporary discontinuation of therapy. Additionally, decision making via multidisciplinary teams ensures minimization of cardiovascular complications while also continuing effective cancer treatment. Historically, data have been limited regarding cardiotoxicity and most cancer therapies, which certainly includes TKIs. This review aims to synthesize the current body of knowledge on TKI-associated cardiotoxicities, while highlighting the importance of vigilance and proactive management to minimize cardiovascular complications.
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Affiliation(s)
- Jahanzaib Ekram
- Morsani College of Medicine, University of South Florida, Tampa, FL, USA
- Department of Cardio-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Azeem Rathore
- Department of Internal Medicine, University of Florida Health Science Center, Gainesville, FL, USA
| | - Carlos Avila
- Department of Internal Medicine, Manatee Memorial Hospital, Bradenton, FL, USA
| | - Rahbia Hussein
- Department of Internal Medicine, Manatee Memorial Hospital, Bradenton, FL, USA
| | - Mohammed Alomar
- Morsani College of Medicine, University of South Florida, Tampa, FL, USA
- Department of Cardio-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
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Sukrithan V, Kim L, Sipos JA, Goyal A, Zhou Y, Addison D, Shah M, Konda B, Vallakati A. Coronary Artery and Peripheral Vascular Disease in a Patient with Poorly Differentiated Thyroid Cancer Treated with the Tyrosine Kinase Inhibitor Lenvatinib. Case Rep Endocrinol 2023; 2023:8841696. [PMID: 37941892 PMCID: PMC10629999 DOI: 10.1155/2023/8841696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 10/03/2023] [Accepted: 10/05/2023] [Indexed: 11/10/2023] Open
Abstract
A subset of patients with differentiated thyroid carcinoma develop radioiodine refractory (RAIR) incurable disease, which typically has a poor prognosis. The multitargeted tyrosine kinase inhibitor lenvatinib has demonstrated significant improvements in progression-free survival in RAIR thyroid cancers compared to placebos. However, in the phase III SELECT trial of the drug in thyroid cancer, 5.4% of patients on lenvatinib experienced arterial thromboembolic events, with 2.7% experiencing severe grade ≥3 toxicities associated with arterial vascular events. This case study reports a patient with metastatic poorly differentiated follicular thyroid cancer who developed significant obstructive coronary artery disease following initiation of lenvatinib treatment, despite no predisposing cardiovascular risk factors apart from a remote smoking history. The possibility of developing coronary or peripheral artery disease should be considered in patients who are on targeted therapies, such as lenvatinib, even in the absence of traditional cardiovascular risk factors. In addition, baseline cardiac risk assessment and early treatment should be pursued to minimize interruptions to potentially lifesaving cancer therapy.
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Affiliation(s)
- Vineeth Sukrithan
- Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Lisa Kim
- Department of Internal Medicine, Division of Cardiology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Jennifer A. Sipos
- Department of Internal Medicine, Division of Endocrinology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Ashima Goyal
- Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Ye Zhou
- Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Daniel Addison
- Department of Internal Medicine, Division of Cardiology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Manisha Shah
- Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Bhavana Konda
- Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Ajay Vallakati
- Department of Internal Medicine, Division of Cardiology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
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Hokimoto S, Kaikita K, Yasuda S, Tsujita K, Ishihara M, Matoba T, Matsuzawa Y, Mitsutake Y, Mitani Y, Murohara T, Noda T, Node K, Noguchi T, Suzuki H, Takahashi J, Tanabe Y, Tanaka A, Tanaka N, Teragawa H, Yasu T, Yoshimura M, Asaumi Y, Godo S, Ikenaga H, Imanaka T, Ishibashi K, Ishii M, Ishihara T, Matsuura Y, Miura H, Nakano Y, Ogawa T, Shiroto T, Soejima H, Takagi R, Tanaka A, Tanaka A, Taruya A, Tsuda E, Wakabayashi K, Yokoi K, Minamino T, Nakagawa Y, Sueda S, Shimokawa H, Ogawa H. JCS/CVIT/JCC 2023 guideline focused update on diagnosis and treatment of vasospastic angina (coronary spastic angina) and coronary microvascular dysfunction. J Cardiol 2023; 82:293-341. [PMID: 37597878 DOI: 10.1016/j.jjcc.2023.06.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/21/2023]
Affiliation(s)
| | - Koichi Kaikita
- Division of Cardiovascular Medicine and Nephrology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Japan
| | - Satoshi Yasuda
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Japan
| | - Kenichi Tsujita
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan
| | - Masaharu Ishihara
- Department of Cardiovascular and Renal Medicine, School of Medicine, Hyogo Medical University, Japan
| | - Tetsuya Matoba
- Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Japan
| | - Yasushi Matsuzawa
- Division of Cardiology, Yokohama City University Medical Center, Japan
| | - Yoshiaki Mitsutake
- Division of Cardiovascular Medicine, Kurume University School of Medicine, Japan
| | - Yoshihide Mitani
- Department of Pediatrics, Mie University Graduate School of Medicine, Japan
| | - Toyoaki Murohara
- Department of Cardiology, Nagoya University Graduate School of Medicine, Japan
| | - Takashi Noda
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Japan
| | - Koichi Node
- Department of Cardiovascular Medicine, Saga University, Japan
| | - Teruo Noguchi
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Japan
| | - Hiroshi Suzuki
- Division of Cardiology, Department of Internal Medicine, Showa University Fujigaoka Hospital, Japan
| | - Jun Takahashi
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Japan
| | - Yasuhiko Tanabe
- Department of Cardiology, Niigata Prefectural Shibata Hospital, Japan
| | - Atsushi Tanaka
- Department of Cardiovascular Medicine, Wakayama Medical University, Japan
| | - Nobuhiro Tanaka
- Division of Cardiology, Tokyo Medical University Hachioji Medical Center, Japan
| | - Hiroki Teragawa
- Department of Cardiovascular Medicine, JR Hiroshima Hospital, Japan
| | - Takanori Yasu
- Department of Cardiovascular Medicine and Nephrology, Dokkyo Medical University Nikko Medical Center, Japan
| | - Michihiro Yoshimura
- Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, Japan
| | - Yasuhide Asaumi
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Japan
| | - Shigeo Godo
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Japan
| | - Hiroki Ikenaga
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Japan
| | - Takahiro Imanaka
- Department of Cardiovascular and Renal Medicine, School of Medicine, Hyogo Medical University, Japan
| | - Kohei Ishibashi
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Japan
| | - Masanobu Ishii
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan
| | | | - Yunosuke Matsuura
- Division of Cardiovascular Medicine and Nephrology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Japan
| | - Hiroyuki Miura
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Japan
| | - Yasuhiro Nakano
- Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Japan
| | - Takayuki Ogawa
- Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, Japan
| | - Takashi Shiroto
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Japan
| | | | - Ryu Takagi
- Department of Cardiovascular Medicine, JR Hiroshima Hospital, Japan
| | - Akihito Tanaka
- Department of Cardiology, Nagoya University Graduate School of Medicine, Japan
| | - Atsushi Tanaka
- Department of Cardiovascular Medicine, Saga University, Japan
| | - Akira Taruya
- Department of Cardiovascular Medicine, Wakayama Medical University, Japan
| | - Etsuko Tsuda
- Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, Japan
| | - Kohei Wakabayashi
- Division of Cardiology, Cardiovascular Center, Showa University Koto-Toyosu Hospital, Japan
| | - Kensuke Yokoi
- Department of Cardiovascular Medicine, Saga University, Japan
| | - Toru Minamino
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Japan
| | - Yoshihisa Nakagawa
- Department of Cardiovascular Medicine, Shiga University of Medical Science, Japan
| | - Shozo Sueda
- Department of Cardiology, Pulmonology, Hypertension & Nephrology, Ehime University Graduate School of Medicine, Japan
| | - Hiroaki Shimokawa
- Graduate School, International University of Health and Welfare, Japan
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Drożdż D, Drożdż M, Wójcik M. Endothelial dysfunction as a factor leading to arterial hypertension. Pediatr Nephrol 2023; 38:2973-2985. [PMID: 36409370 PMCID: PMC10432334 DOI: 10.1007/s00467-022-05802-z] [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: 02/11/2022] [Revised: 10/20/2022] [Accepted: 10/24/2022] [Indexed: 11/22/2022]
Abstract
Hypertension remains the main cause of cardiovascular complications leading to increased mortality. The discoveries of recent years underline the important role of endothelial dysfunction (ED) in initiating the development of arterial hypertension. The endothelium lines the interior of the entire vascular system in the body and acts as a physical barrier between blood and tissues. Substances and mediators produced by the endothelium exhibit antithrombotic and anti-inflammatory properties. Oxidative stress and inflammation are conditions that damage the endothelium and shift endothelial function from vasoprotective to vasoconstrictive, prothrombotic, and pro-apoptotic functions. A dysfunctional endothelium contributes to the development of hypertension and further cardiovascular complications. Reduced nitric oxide (NO) bioavailability plays an essential role in the pathophysiology of ED-associated hypertension. New technologies provide tools to identify pathological changes in the structure and function of the endothelium. Endothelial dysfunction (ED) contributes to the development of arterial hypertension and should be considered in therapeutic strategies for children with hypertension.
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Affiliation(s)
- Dorota Drożdż
- Department of Pediatric Nephrology and Hypertension, Chair of Pediatrics, Pediatric Institute, Jagiellonian University Medical College, Krakow, Poland.
| | - Monika Drożdż
- Department of Pediatric Nephrology and Hypertension, Chair of Pediatrics, Pediatric Institute, Jagiellonian University Medical College, Krakow, Poland
| | - Małgorzata Wójcik
- Deapartment of Pediatric and Adolescent Endocrinology, Chair of Pediatrics, Pediatric Institute, Jagiellonian University Medical College, Krakow, Poland
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11
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Hokimoto S, Kaikita K, Yasuda S, Tsujita K, Ishihara M, Matoba T, Matsuzawa Y, Mitsutake Y, Mitani Y, Murohara T, Noda T, Node K, Noguchi T, Suzuki H, Takahashi J, Tanabe Y, Tanaka A, Tanaka N, Teragawa H, Yasu T, Yoshimura M, Asaumi Y, Godo S, Ikenaga H, Imanaka T, Ishibashi K, Ishii M, Ishihara T, Matsuura Y, Miura H, Nakano Y, Ogawa T, Shiroto T, Soejima H, Takagi R, Tanaka A, Tanaka A, Taruya A, Tsuda E, Wakabayashi K, Yokoi K, Minamino T, Nakagawa Y, Sueda S, Shimokawa H, Ogawa H. JCS/CVIT/JCC 2023 Guideline Focused Update on Diagnosis and Treatment of Vasospastic Angina (Coronary Spastic Angina) and Coronary Microvascular Dysfunction. Circ J 2023; 87:879-936. [PMID: 36908169 DOI: 10.1253/circj.cj-22-0779] [Citation(s) in RCA: 88] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/11/2023]
Affiliation(s)
| | - Koichi Kaikita
- Division of Cardiovascular Medicine and Nephrology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki
| | - Satoshi Yasuda
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
| | - Kenichi Tsujita
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University
| | - Masaharu Ishihara
- Department of Cardiovascular and Renal Medicine, School of Medicine, Hyogo Medical University
| | - Tetsuya Matoba
- Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences
| | | | - Yoshiaki Mitsutake
- Division of Cardiovascular Medicine, Kurume University School of Medicine
| | - Yoshihide Mitani
- Department of Pediatrics, Mie University Graduate School of Medicine
| | - Toyoaki Murohara
- Department of Cardiology, Nagoya University Graduate School of Medicine
| | - Takashi Noda
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
| | - Koichi Node
- Department of Cardiovascular Medicine, Saga University
| | - Teruo Noguchi
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
| | - Hiroshi Suzuki
- Division of Cardiology, Department of Internal Medicine, Showa University Fujigaoka Hospital
| | - Jun Takahashi
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
| | - Yasuhiko Tanabe
- Department of Cardiology, Niigata Prefectural Shibata Hospital
| | - Atsushi Tanaka
- Department of Cardiovascular Medicine, Wakayama Medical University
| | - Nobuhiro Tanaka
- Division of Cardiology, Tokyo Medical University Hachioji Medical Center
| | - Hiroki Teragawa
- Department of Cardiovascular Medicine, JR Hiroshima Hospital
| | - Takanori Yasu
- Department of Cardiovascular Medicine and Nephrology, Dokkyo Medical University Nikko Medical Center
| | - Michihiro Yoshimura
- Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine
| | - Yasuhide Asaumi
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
| | - Shigeo Godo
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
| | - Hiroki Ikenaga
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences
| | - Takahiro Imanaka
- Department of Cardiovascular and Renal Medicine, School of Medicine, Hyogo Medical University
| | - Kohei Ishibashi
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
| | - Masanobu Ishii
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University
| | | | - Yunosuke Matsuura
- Division of Cardiovascular Medicine and Nephrology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki
| | - Hiroyuki Miura
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
| | | | - Takayuki Ogawa
- Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine
| | - Takashi Shiroto
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
| | | | - Ryu Takagi
- Division of Cardiology, Tokyo Medical University Hachioji Medical Center
| | - Akihito Tanaka
- Department of Cardiology, Nagoya University Graduate School of Medicine
| | | | - Akira Taruya
- Department of Cardiovascular Medicine, Wakayama Medical University
| | - Etsuko Tsuda
- Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center
| | - Kohei Wakabayashi
- Division of Cardiology, Cardiovascular Center, Showa University Koto-Toyosu Hospital
| | - Kensuke Yokoi
- Department of Cardiovascular Medicine, Saga University
| | - Toru Minamino
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine
| | - Yoshihisa Nakagawa
- Department of Cardiovascular Medicine, Shiga University of Medical Science
| | - Shozo Sueda
- Department of Cardiology, Pulmonology, Hypertension & Nephrology, Ehime University Graduate School of Medicine
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12
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Nihei S, Ikeda T, Aoki T, Murasato F, Yaegashi M, Asahi K, Kudo K. Plasma endothelin-1 may predict bevacizumab-induced proteinuria in patients with colorectal cancer. Cancer Chemother Pharmacol 2023; 91:427-434. [PMID: 37036487 DOI: 10.1007/s00280-023-04532-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 03/30/2023] [Indexed: 04/11/2023]
Abstract
PURPOSE Proteinuria is one of the most common adverse events leading to the discontinuation of bevacizumab therapy. We analyzed plasma ET-1 levels as an indicator of renal endothelial dysfunction in colorectal cancer patients, to determine the utility of plasma ET-1 for identification of patients at high risk of proteinuria when treated with bevacizumab. METHODS Patients (n = 40) were recruited from an outpatient chemotherapy center between December 2020 and January 2022. Blood samples for plasma ET-1 levels were collected before treatment with bevacizumab (baseline), and after treatment for 3 and 6 months, and plasma ET-1 was determined by ELISA. Proteinuria was evaluated based on CTCAE v5.0 using urine protein-creatinine ratio instead of 24-h urine protein. RESULTS Plasma ET-1 levels at baseline were significantly higher in the group with grade ≥ 2 proteinuria than in the non-proteinuria group (p = 0.019). After adjusting for age, systolic and diastolic blood pressure, and hypertension following bevacizumab, plasma ET-1 levels at baseline were found to be an independent predictor of development of grade ≥ 2 proteinuria (OR = 17.8, 95% CI 1.42-223, and p = 0.026). Receiver operating characteristic curve analysis indicated an optimal cut-off value of the plasma ET-1 level of 1.19 pg/mL for predicting grade ≥ 2 proteinuria, with a sensitivity of 80.0% and specificity of 73.3%. CONCLUSION In conclusion, higher plasma ET-1 levels before treatment might increase the risk of proteinuria in colorectal cancer patients treated with bevacizumab. This might have important implications in the early detection of the risk of proteinuria.
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Affiliation(s)
- Satoru Nihei
- Department of Pharmacy, Iwate Medical University Hospital, 2-1-1 Idaidori, Yahaba-Cho, Shiwa-Gun, Iwate, 028-3695, Japan.
- Division of Clinical Pharmaceutics and Pharmacy Practice, Department of Clinical Pharmacy, School of Pharmacy, Iwate Medical University, 1-1-1 Idaidori, Yahaba-Cho, Shiwa-Gun, Iwate, 028-3694, Japan.
| | - Tatsuki Ikeda
- Department of Pharmacy, Iwate Medical University Hospital, 2-1-1 Idaidori, Yahaba-Cho, Shiwa-Gun, Iwate, 028-3695, Japan
| | - Tomohiko Aoki
- Department of Pharmacy, Iwate Medical University Hospital, 2-1-1 Idaidori, Yahaba-Cho, Shiwa-Gun, Iwate, 028-3695, Japan
| | - Futa Murasato
- Department of Pharmacy, Iwate Medical University Hospital, 2-1-1 Idaidori, Yahaba-Cho, Shiwa-Gun, Iwate, 028-3695, Japan
| | - Mizunori Yaegashi
- Department of Surgery, School of Medicine, Iwate Medical University, 1-1-1 Idaidori, Yahaba-Cho, Shiwa-Gun, Iwate, 028-3694, Japan
| | - Koichi Asahi
- Division of Nephrology and Hypertension, Department of Internal Medicine, School of Medicine, Iwate Medical University, 1-1-1 Idaidori, Yahaba-Cho, Shiwa-Gun, Iwate, 028-3694, Japan
| | - Kenzo Kudo
- Department of Pharmacy, Iwate Medical University Hospital, 2-1-1 Idaidori, Yahaba-Cho, Shiwa-Gun, Iwate, 028-3695, Japan
- Division of Clinical Pharmaceutics and Pharmacy Practice, Department of Clinical Pharmacy, School of Pharmacy, Iwate Medical University, 1-1-1 Idaidori, Yahaba-Cho, Shiwa-Gun, Iwate, 028-3694, Japan
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13
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Wassermann J, Bagnis CI, Leenhardt L, Ederhy S, Buffet C. Pre-therapeutic evaluation and practical management of cardiovascular and renal toxicities in patients with metastatic radioiodine-refractory thyroid cancer treated with lenvatinib. Expert Opin Drug Saf 2022; 21:1401-1410. [DOI: 10.1080/14740338.2022.2153115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Affiliation(s)
- Johanna Wassermann
- Medical Oncology Department and Thyroïd and Endocrine Tumors Department, Groupe de Recherche Clinique n°16, GRC Tumeurs Thyroïdiennes, APHP Sorbonne University, Pitié-Salpêtrière Hospital, Paris
| | - Corinne Isnard Bagnis
- Nephrology Department, APHP Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France
| | - Laurence Leenhardt
- Thyroïd and Endocrine Tumors Department, Sorbonne Université, Groupe de Recherche Clinique n°16GRC Tumeurs Thyroïdiennes, AP-HP, Hôpital Pitié-Salpêtrière, 75013 Paris, France
| | - Stéphane Ederhy
- UNICO-GRECO Cardio-oncology Program, Sorbonne University, Cardiology Department, , Hôpital Saint Antoine 184 rue du FaubourgSaint Antoine, 75012 Paris, France
| | - Camille Buffet
- Thyroïd and Endocrine Tumors Department, Sorbonne Université, Groupe de Recherche Clinique n°16GRC Tumeurs Thyroïdiennes, AP-HP, Hôpital Pitié-Salpêtrière, 75013 Paris, France
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14
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Rapposelli IG, Tada T, Shimose S, Burgio V, Kumada T, Iwamoto H, Hiraoka A, Niizeki T, Atsukawa M, Koga H, Hirooka M, Torimura T, Iavarone M, Tortora R, Campani C, Lonardi S, Tamburini E, Piscaglia F, Masi G, Cabibbo G, Giuseppe Foschi F, Silletta M, Tsuji K, Ishikawa T, Takaguchi K, Kariyama K, Itobayashi E, Tajiri K, Shimada N, Shibata H, Ochi H, Yasuda S, Toyoda H, Fukunishi S, Ohama H, Kawata K, Tani J, Nakamura S, Nouso K, Tsutsui A, Nagano T, Tanaka T, Itokawa N, Okubo T, Arai T, Imai M, Joko K, Koizumi Y, Hiasa Y, Rimini M, Ratti F, Aldrighetti L, Cascinu S, Casadei-Gardini A. Adverse events as potential predictive factors of activity in patients with advanced hepatocellular carcinoma treated with lenvatinib. Liver Int 2021; 41:2997-3008. [PMID: 34250737 DOI: 10.1111/liv.15014] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 07/02/2021] [Accepted: 07/08/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM Lenvatinib is a standard of care option in first-line therapy of advanced hepatocellular carcinoma (HCC). In the present study, we aim to identify, in patients with HCC treated with lenvatinib, a possible association between occurrence and grading of adverse events (AEs) and outcome. METHODS We performed a retrospective analysis of 606 Japanese and Italian patients treated with lenvatinib in first-line setting and investigated the possible correlation between the onset of AEs, toxicity grade (G) and outcome measures such as overall survival (OS) and progression-free survival (PFS). RESULTS The appearance of arterial hypertension G ≥ 2 independently predicted prolonged OS [hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.46-0.93, P = .0188], whereas decreased appetite G ≥ 2 independently predicted decreased OS (HR 1.70, 95% CI 1.25-2.32, P = .0007) by multivariate analysis. Appearance of hand-foot skin reaction independently predicted prolonged PFS (HR 0.72, 95% CI 0.56-0.93, P = .0149), whereas decreased appetite G ≥ 2 predicted decreased PFS (HR 1.36, 95% CI 1.04-1.77, P = .0277). CONCLUSIONS Our main findings are that the occurrence of arterial hypertension G ≥ 2 is a predictor of longer survival, whereas decreased appetite G ≥ 2 predicts for a poor prognosis. A careful management of AEs under lenvatinib treatment for HCC is required, to improve patients' quality of life, minimize the need for treatment discontinuation and achieve optimal outcome.
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Affiliation(s)
- Ilario Giovanni Rapposelli
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"-IRST, Meldola, Italy
| | - Toshifumi Tada
- Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan
| | - Shigeo Shimose
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Valentina Burgio
- Department of Medical Oncology, San Raffaele Scientific Institute IRCCS, Milan, Italy
| | - Takashi Kumada
- Faculty of Nursing, Gifu Kyoritsu University, Ogaki, Japan
| | - Hideki Iwamoto
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Takashi Niizeki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Masanori Atsukawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
| | - Hironori Koga
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Massimo Iavarone
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy
| | | | - Claudia Campani
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Sara Lonardi
- Early Phase Clinical Trial Unit, Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
- Medical Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Emiliano Tamburini
- Department of Medical Oncology, Card. G. Panico Hospital of Tricase, Tricase, Italy
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, Azienda Ospedaliero Universitaria di Bologna, Italy
| | - Gianluca Masi
- Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Giuseppe Cabibbo
- Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, PROMISE, Gastroenterology & Hepatology Unit, University of Palermo, Palermo, Italy
| | | | | | - Kunihiko Tsuji
- Center of Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Toru Ishikawa
- Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan
| | - Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Kazuya Kariyama
- Department of Gastroenterology, Okayama City Hospital, Okayama, Japan
| | - Ei Itobayashi
- Department of Gastroenterology, Asahi General Hospital, Asahi, Japan
| | - Kazuto Tajiri
- Department of Gastroenterology, Toyama University Hospital, Toyama, Japan
| | - Noritomo Shimada
- Division of Gastroenterology and Hepatology, Otakanomori Hospital, Kashiwa, Japan
| | - Hiroshi Shibata
- Department of Gastroenterology, Tokushima Prefectural Central Hospital, Tokushima, Japan
| | - Hironori Ochi
- Hepato-biliary Center, Matsuyama Red Cross Hospital, Matsuyama, Japan
| | - Satoshi Yasuda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Shinya Fukunishi
- Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Japan
| | - Hideko Ohama
- Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Japan
| | - Kazuhito Kawata
- Hepatology Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa, Japan
| | - Shinichiro Nakamura
- Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan
| | - Kazuhiro Nouso
- Department of Gastroenterology, Okayama City Hospital, Okayama, Japan
| | - Akemi Tsutsui
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Takuya Nagano
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Takaaki Tanaka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Norio Itokawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
| | - Tomomi Okubo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
| | - Taeang Arai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
| | - Michitaka Imai
- Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan
| | - Kouji Joko
- Hepato-biliary Center, Matsuyama Red Cross Hospital, Matsuyama, Japan
| | - Yohei Koizumi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama, Japan
| | - Margherita Rimini
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Francesca Ratti
- Hepatobiliary Surgery Division, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Luca Aldrighetti
- Hepatobiliary Surgery Division, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Stefano Cascinu
- Department of Medical Oncology, San Raffaele Scientific Institute IRCCS, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Andrea Casadei-Gardini
- Department of Medical Oncology, San Raffaele Scientific Institute IRCCS, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
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15
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Maki Y, Sueta D, Ishii M, Yamanouchi Y, Fujisue K, Yamanaga K, Nakamura T, Tabata N, Arima Y, Araki S, Yamamoto E, Kaikita K, Chikamoto A, Matsushita K, Matsuoka M, Usuku K, Tsujita K. Associations of cardiovascular risk factors with survival outcomes in a cancer registration: Findings from the KUMAMON registry. Medicine (Baltimore) 2021; 100:e27921. [PMID: 34964764 PMCID: PMC8615348 DOI: 10.1097/md.0000000000027921] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 11/08/2021] [Indexed: 01/05/2023] Open
Abstract
Although the relationship between cardiovascular diseases and malignant diseases has recently attracted attention, the associations of cardiovascular risk factors and clinical outcomes in cancer patients remain to be elucidated. We performed a retrospective, observational study that explored the clinical outcomes of patients with cancer or with a history of cancer.We enrolled 30,706 consecutive adult cancer patients from Kumamoto University Hospital. We investigated mortality and morbidity, including cardiovascular conditions (dyslipidemia [DL]/diabetes mellitus [DM]/hypertension [HT]). The primary endpoint was all-cause mortality.Of the enrolled patients, 9032 patients (29.4%) died within the follow-up period. The Kaplan-Meier analysis demonstrated that in the groups classified according to the number of DL/DM/HT (LDH) factors, the LDH1 and LDH2 groups had a significantly higher probability of the primary endpoint than the LDH0 group (P < .001 and P < .001, respectively), whereas there were no significant differences between the LDH0 group and LDH3 group (P = .963). Univariate Cox proportional hazards regression analyses of mortality complemented by the multiple imputation method including various factors demonstrated that the presence of DL in cancer patients was a significant negative predictor of mortality (hazard ratio = 0.79, P < .01).The all-cause mortality rate did not always increase as the number of LDH factors increased. The present study revealed that the presence of DL is a negative risk factor for all-cause mortality in cancer patients.
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Affiliation(s)
- Yuji Maki
- Department of Cardiovascular Medicine, Miyazaki Prefectural Nobeoka Hospital, Nobeoka, Japan
| | - Daisuke Sueta
- Department of Cardiovascular Medicine, Miyazaki Prefectural Nobeoka Hospital, Nobeoka, Japan
| | - Masanobu Ishii
- Department of Cardiology, Miyazaki Prefectural Nobeoka Hospital, Nobeoka, Japan
| | - Yoshinori Yamanouchi
- Department of Department of Clinical Investigation, Kumamoto University Hospital, Kumamoto, Japan
| | - Koichiro Fujisue
- Department of Cardiovascular Medicine, Miyazaki Prefectural Nobeoka Hospital, Nobeoka, Japan
- Medical Quality and Safety Management, Kumamoto University Hospital, Kumamoto, Japan
| | - Kenshi Yamanaga
- Department of Cardiovascular Medicine, Miyazaki Prefectural Nobeoka Hospital, Nobeoka, Japan
| | - Taishi Nakamura
- Department of Cardiovascular Medicine, Miyazaki Prefectural Nobeoka Hospital, Nobeoka, Japan
- Medical Information Science and Administration Planning, Kumamoto University Hospital, Kumamoto, Japan
| | - Noriaki Tabata
- Department of Cardiovascular Medicine, Miyazaki Prefectural Nobeoka Hospital, Nobeoka, Japan
| | - Yuichiro Arima
- Department of Cardiovascular Medicine, Miyazaki Prefectural Nobeoka Hospital, Nobeoka, Japan
| | - Satoshi Araki
- Department of Cardiovascular Medicine, Miyazaki Prefectural Nobeoka Hospital, Nobeoka, Japan
| | - Eiichiro Yamamoto
- Department of Cardiovascular Medicine, Miyazaki Prefectural Nobeoka Hospital, Nobeoka, Japan
| | - Koichi Kaikita
- Department of Cardiovascular Medicine, Miyazaki Prefectural Nobeoka Hospital, Nobeoka, Japan
| | - Akira Chikamoto
- Medical Quality and Safety Management, Kumamoto University Hospital, Kumamoto, Japan
- Gastroenterological Surgery, Kumamoto University Hospital, Kumamoto, Japan
| | - Kenichi Matsushita
- Department of Cardiovascular Medicine, Miyazaki Prefectural Nobeoka Hospital, Nobeoka, Japan
- Division of Advanced Cardiovascular Therapeutics, Kumamoto University Hospital, Kumamoto, Japan
| | - Masao Matsuoka
- Hematology, Rheumatology, and Infectious Diseases, Kumamoto University School of Medicine, Kumamoto Japan
| | - Koichiro Usuku
- Medical Information Science and Administration Planning, Kumamoto University Hospital, Kumamoto, Japan
| | - Kenichi Tsujita
- Department of Cardiovascular Medicine, Miyazaki Prefectural Nobeoka Hospital, Nobeoka, Japan
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16
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Kaae AC, Kreissl MC, Krüger M, Infanger M, Grimm D, Wehland M. Kinase-Inhibitors in Iodine-Refractory Differentiated Thyroid Cancer-Focus on Occurrence, Mechanisms, and Management of Treatment-Related Hypertension. Int J Mol Sci 2021; 22:12217. [PMID: 34830100 PMCID: PMC8623313 DOI: 10.3390/ijms222212217] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 11/08/2021] [Accepted: 11/09/2021] [Indexed: 12/26/2022] Open
Abstract
Differentiated thyroid cancer (DTC) usually has a good prognosis when treated conventionally with thyroidectomy, radioactive iodine (RAI) and thyroid-stimulating hormone suppression, but some tumors develop a resistance to RAI therapy, requiring alternative treatments. Sorafenib, lenvatinib and cabozantinib are multikinase inhibitors (MKIs) approved for the treatment of RAI-refractory DTC. The drugs have been shown to improve progression-free survival (PFS) and overall survival (OS) via the inhibition of different receptor tyrosine kinases (RTKs) that are involved in tumorigenesis and angiogenesis. Both sorafenib and lenvatinib have been approved irrespective of the line of therapy for the treatment of RAI-refractory DTC, whereas cabozantinib has only been approved as a second-line treatment. Adverse effects (AEs) such as hypertension are often seen with MKI treatment, but are generally well manageable. In this review, current clinical studies will be discussed, and the toxicity and safety of sorafenib, lenvatinib and cabozantinib treatment will be evaluated, with a focus on AE hypertension and its treatment options. In short, treatment-emergent hypertension (TE-HTN) occurs with all three drugs, but is usually well manageable and leads only to a few dose modifications or even discontinuations. This is emphasized by the fact that lenvatinib is widely considered the first-line drug of choice, despite its higher rate of TE-HTN.
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Affiliation(s)
- Anne Christine Kaae
- Department of Biomedicine, Aarhus University, Ole Worms Allé 4, 8000 Aarhus, Denmark; (A.C.K.); (D.G.)
| | - Michael C. Kreissl
- Division of Nuclear Medicine, Department of Radiology and Nuclear Medicine, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany;
| | - Marcus Krüger
- Department of Microgravity and Translational Regenerative Medicine, Otto von Guericke University, Universitätsplatz 2, 39106 Magdeburg, Germany; (M.K.); (M.I.)
| | - Manfred Infanger
- Department of Microgravity and Translational Regenerative Medicine, Otto von Guericke University, Universitätsplatz 2, 39106 Magdeburg, Germany; (M.K.); (M.I.)
- Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany
| | - Daniela Grimm
- Department of Biomedicine, Aarhus University, Ole Worms Allé 4, 8000 Aarhus, Denmark; (A.C.K.); (D.G.)
- Department of Microgravity and Translational Regenerative Medicine, Otto von Guericke University, Universitätsplatz 2, 39106 Magdeburg, Germany; (M.K.); (M.I.)
- Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany
| | - Markus Wehland
- Department of Microgravity and Translational Regenerative Medicine, Otto von Guericke University, Universitätsplatz 2, 39106 Magdeburg, Germany; (M.K.); (M.I.)
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17
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Enokida T, Tahara M. Management of VEGFR-Targeted TKI for Thyroid Cancer. Cancers (Basel) 2021; 13:5536. [PMID: 34771698 PMCID: PMC8583039 DOI: 10.3390/cancers13215536] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 10/26/2021] [Accepted: 10/29/2021] [Indexed: 12/31/2022] Open
Abstract
Recent advances in the development of multitarget tyrosine kinase inhibitors (MTKIs), which mainly target the vascular endothelial growth factor receptor (VEGFR), have improved prognoses and dramatically changed the treatment strategy for advanced thyroid cancer. However, adverse events related to this inhibition can interrupt treatment and sometimes lead to discontinuation. In addition, they can be annoying and potentially jeopardize the subjects' quality of life, even allowing that the clinical outcome of patients with advanced thyroid cancer remains limited. In this review, we summarize the potential mechanisms underlying these adverse events (hypertension, proteinuria and renal impairment, hemorrhage, fistula formation/gastrointestinal perforation, wound healing, cardiovascular toxicities, hematological toxicity, diarrhea, fatigue, and acute cholecystitis), their characteristics, and actual management. Furthermore, we also discuss the importance of related factors, including alternative treatments that target other pathways, the necessity of subject selection for safer administration, and patient education.
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Affiliation(s)
| | - Makoto Tahara
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa 277-8577, Japan;
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18
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Catalano M, Casadei-Gardini A, Vannini G, Campani C, Marra F, Mini E, Roviello G. Lenvatinib: established and promising drug for the treatment of advanced hepatocellular carcinoma. Expert Rev Clin Pharmacol 2021; 14:1353-1365. [PMID: 34289756 DOI: 10.1080/17512433.2021.1958674] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 07/19/2021] [Indexed: 02/07/2023]
Abstract
INTRODUCTION : The evolving therapeutic landscape of advanced hepatocellular carcinoma (HCC) includes the increasing implementation of target-therapy and immunotherapy. Lenvatinib, a multi-target tyrosine kinase inhibitor (TKI), is an emerging first-line therapy for hepatocellular carcinoma. Its approval has changed the scenario of first-line therapies for advanced HCC, where just sorafenib proved clinical efficacy for over a decade. AREAS COVERED : The current evidence on the role of lenvatinib for patients with advanced HCC is reviewed in this article. Particularly, therapeutic mechanisms and clinical efficacy of lenvatinib are summarized and the management of adverse events is discussed. In addition, future perspectives on the emerging role of combine therapy for HCC are highlighted. EXPERT OPINION In the first line, lenvatinib was found to be non-inferior to sorafenib for overall survival, with significantly better progression-free survival and objective response rate. Immune checkpoint inhibitors (ICIs) are now part of HCC treatment, and recently the combination of atezolizumab plus bevacizumab has become the recommended standard of care first-line therapy for selected patients. The antitumor and immunomodulatory activities that lenvatinib shows in preclinical studies, and the positive outcomes achieved using a combination of lenvatinib plus ICIs, open new perspectives for advanced HCC treatment.
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Affiliation(s)
- Martina Catalano
- School of Human Health Sciences, University of Florence, Florence, Italy
| | - Andrea Casadei-Gardini
- Department of Medical Oncology, Università Vita-Salute, San Raffaele Hospital IRCCS, Milan, Italy
| | - Gianmarco Vannini
- School of Human Health Sciences, University of Florence, Florence, Italy
| | - Claudia Campani
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
- Excellence Center for Research, Transfer snd High Education DenoTHE, Florence, Italy
| | - Enrico Mini
- Department of Health Sciences, University of Florence, Florence, Italy
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19
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Mantsopoulos K, Mueller SK, Pavel M, Kuwert T, Meidenbauer N, Fietkau R, Sievert M, Iro H. [Treatment strategy by radioiodine refractory differentiated thyroid cancer]. Laryngorhinootologie 2021; 101:298-303. [PMID: 34583388 DOI: 10.1055/a-1580-7327] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Traditionally, the multimodal therapy concept for differentiated thyroid carcinomas consists of thyroidectomy with neck dissection (for cN + neck) and adjuvant radioiodine ablation with subsequent risk-adapted TSH suppression. The extent of radioiodine uptake in metastatic thyroid carcinomas plays a significant role is significant in terms of prognosis. Radioiodine refractory lesions are characterized by the lack of radioiodine uptake in combination with the lack of decrease in the tumor marker thyroglobulin as well as signs of progression on imaging. Due to the mostly indolent course over a long period of time, a wait-and-see strategy in combination with local management of distant metastase symptom relief appears to be primarily sufficient. By evidence for change in tumor dynamics, the need for a multi-tyrosine kinase inhibitor (sorafenib, lenvatinib)-based systemic therapy should be thoroughly evaluated. These substances are mostly associated with an unfavorable side-effect profile (diarrhea, rash, arterial hypertension, local wound healing disorders), which leads to a non-negligible rate of treatment-associated morbidity and a high number of treatment interruptions. For this reason, two selective RET inhibitors (selpercatinib, pralsetinib) for differentiated thyroid carcinomas were approved by the FDA in 2020. A new perspective for the future would be the variable re-differentiation strategies, which aim to increase the sensitivity of tumor cells to radioiodine.
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Affiliation(s)
- Konstantinos Mantsopoulos
- Otolaryngology, Head and Neck surgery, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Sarina K Mueller
- Otolaryngology, Head and Neck surgery, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Marianne Pavel
- Department of Medicine I, Lead Division of Endocrinology & Neuroendocrine Tumors, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Torsten Kuwert
- Nuclear Medicine, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Norbert Meidenbauer
- Department of Medicine V, Haematology and Oncology, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Rainer Fietkau
- Radiation Oncology, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Matti Sievert
- Otolaryngology, Head and Neck surgery, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Heinrich Iro
- Otolaryngology, Head and Neck surgery, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
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20
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Validation of the Khorana Venous Thromboembolism Risk Score in Japanese Cancer Patients. JACC: ASIA 2021; 1:259-270. [PMID: 36338156 PMCID: PMC9627826 DOI: 10.1016/j.jacasi.2021.07.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 06/17/2021] [Accepted: 07/07/2021] [Indexed: 11/24/2022]
Abstract
Background Although the Khorana venous thromboembolism (VTE) risk score (KRS) is well recognized as a simple VTE risk assessment method in patients with cancer, whether it is suitable for Asian populations is unclear. Objectives This study validated KRS for the prediction of VTE and investigated the value of the KRS in predicting mortality in Japanese patients with cancer. Methods A body mass index value of 25 kg/m2 or more was defined as obesity according to World Health Organization consensus. A total of 27,687 patients with cancer were subdivided into low- (0), intermediate- (1-2), and high-score (3) groups by the KRS. The primary and secondary endpoints were VTE and all-cause mortality, respectively. Results The prevalence of VTE was 1.7%, 7.3%, and 11.0% for low-, intermediate-, and high-score patients, respectively. Receiver operating characteristic (ROC) analysis showed that the KRS significantly predicted VTE (area under the curve, 0.679; 95% confidence interval [CI] 0.666-0.692; P < 0.001). The cutoff value for the KRS was 1.0. Logistic regression analysis demonstrated that the KRS was an independent predictor of VTE (odds ratio 1.766; 95% CI 1.673-1.865; P < 0.01). The cutoff value of the KRS for all-cause mortality determined by ROC analysis was 2.0. Kaplan–Meier analysis demonstrated a significantly higher incidence of mortality in the KRS ≥2 group than in the KRS 0-1 group (log-rank: P < 0.01). Conclusions The KRS was useful in Japanese patients with cancer and might be a potentially useful marker for the prediction of mortality. Establishing optimal scores for Japanese subjects is mandatory because of its low diagnostic ability. (KUMAMON Cancer registry; UMIN000047554)
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21
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Kishikawa M, Inoue J, Hamamoto H, Kobayashi K, Asakage T, Inazawa J. Augmentation of lenvatinib efficacy by topical treatment of miR-634 ointment in anaplastic thyroid cancer. Biochem Biophys Rep 2021; 26:101009. [PMID: 34027135 PMCID: PMC8131394 DOI: 10.1016/j.bbrep.2021.101009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/20/2021] [Accepted: 04/23/2021] [Indexed: 11/18/2022] Open
Abstract
Anaplastic thyroid cancer (ATC) is one of the most lethal types of human tumors. Lenvatinib can improve the disease control and prognosis in patients with ATC. However, there is an unmet need to develop a therapeutically safer and non-invasive strategy that improves the efficacy of lenvatinib for advanced ATC tumors, which grow larger close to the skin. We previously demonstrated that the topical application of an ointment incorporating tumor suppressive microRNA (TS-miR), miR-634, is a useful strategy as a TS-miR therapeutics. Here, we found that the overexpression of miR-634 synergistically increased lenvatinib-induced cytotoxicity by concurrently downregulating multiple genes related to cytoprotective processes, including ASCT2, a glutamine transporter, in ATC cell lines. Furthermore, the topical application of a miR-634 ointment on subcutaneous tumors effectively augmented the anti-tumor effects of lenvatinib in an ATC xenograft mouse model. Thus, we propose topical treatment of a miR-634 ointment as a rational strategy for improving lenvatinib-based therapy for ATC.
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Affiliation(s)
- Masahiro Kishikawa
- Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
- Department of Head and Neck Surgery, TMDU, Tokyo, Japan
| | - Jun Inoue
- Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | | | | | | | - Johji Inazawa
- Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
- Bioresource Research Center, TMDU, Tokyo, Japan
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22
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Butt MI, Khalid Bakhsh AM, Nadri QJ. Lenvatinib-induced multiorgan adverse events in Hurthle cell thyroid cancer: A case report. World J Clin Oncol 2021; 12:272-281. [PMID: 33959480 PMCID: PMC8085512 DOI: 10.5306/wjco.v12.i4.272] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/30/2021] [Accepted: 03/08/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The management of metastatic progressive radioiodine-resistant differentiated thyroid cancer remains challenging for clinicians. The availability of tyrosine kinase inhibitors (TKIs), sorafenib and lenvatinib, within the last decade has expanded treatment options; however, these lead to significant adverse effects, which may curtail their use.
CASE SUMMARY We report the case of a 47-year-old female with Hurthle cell thyroid cancer who underwent total thyroidectomy followed by radioiodine ablation. During follow-up, she developed noniodine-avid renal and pulmonary metastases. With respect to her pre-existing diabetes, hypertension, and polycystic kidney disease, the tumor board decided against performing renal metastasectomy because of the risk of future renal decline requiring dialysis. Metastases were treated using sorafenib, which provided stability followed by progression within a year. We switched to lenvatinib, which led to disease regression. However, the patient experienced severe adverse effects, including cardiomyopathy, bicytopenia, renal impairment, and the rarely reported nephrotic syndrome. Renal metastasis is a rare manifes-tation of Hurthle cell thyroid cancer with only two reported cases in literature. We report the experience of our first case of renal metastasis and its treatment with TKIs. This case serves as a reminder of the adverse drug reactions associated with TKI use.
CONCLUSION We advocate close monitoring of patients’ hematological and renal profiles as well as their cardiac status using an echocardiogram.
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Affiliation(s)
- Muhammad Imran Butt
- Department of Medicine, King Faisal Specialist Hospital, Research Centre, Al Faisal University, Riyadh 12713, Saudi Arabia
| | | | - Quaid Johar Nadri
- Department of Medicine, King Faisal Specialist Hospital, Research Centre, Al Faisal University, Riyadh 12713, Saudi Arabia
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Kobat H, Elkonaissi I, Dorak MT, Nabhani-Gebara S. Management of COVID-19 in cancer patients receiving cardiotoxic anti-cancer therapy. Future recommendations for cardio-oncology. Oncol Rev 2021; 15:510. [PMID: 33747366 PMCID: PMC7967496 DOI: 10.4081/oncol.2021.510] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 01/26/2021] [Indexed: 12/15/2022] Open
Abstract
Cardiotoxicity induced by anti-cancer treatment has become a significant threat as the number of cardiotoxic anti-cancer agents is growing. Cancer patients are at an increased risk of contracting coronavirus disease 2019 (COVID-19) because of immune suppression caused by anti-cancer drugs and/or supportive treatment. Deterioration in lung functions due to COVID-19 is responsible for many cardiac events. The presence of COVID-19 and some of its treatment modalities may increase the chance of cardiotoxicity development in cancer patients receiving potentially cardiotoxic agents. This review provides evidence-based information on the cardiotoxicity risk in cancer patients clinically diagnosed with COVID-19 who are receiving potentially cardiotoxic anti-cancer agents. Proposed strategies relating to the management of this patient cohorts are also discussed.
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Affiliation(s)
- Hasan Kobat
- Department of Pharmacy, School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Penrhyn Road, Kingston Upon Thames
| | - Islam Elkonaissi
- Pharmacy Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge
| | - Mehmet Tevfik Dorak
- Head of School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Penrhyn Road, Kingston Upon Thames, United Kingdom
| | - Shereen Nabhani-Gebara
- Department of Pharmacy, School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Penrhyn Road, Kingston Upon Thames
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Liu Y, Yin HL, Li C, Jiang F, Zhang SJ, Zhang XR, Li YL. Sinapine Thiocyanate Ameliorates Vascular Endothelial Dysfunction in Hypertension by Inhibiting Activation of the NLRP3 Inflammasome. Front Pharmacol 2021; 11:620159. [PMID: 33633569 PMCID: PMC7901921 DOI: 10.3389/fphar.2020.620159] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 12/22/2020] [Indexed: 12/23/2022] Open
Abstract
The increase of blood pressure is accompanied by the changes in the morphology and function of vascular endothelial cells. Vascular endothelial injury and hypertension actually interact as both cause and effect. A large number of studies have proved that inflammation plays a significant role in the occurrence and development of hypertension, but the potential mechanism between inflammation and hypertensive endothelial injury is still ambiguous. The purpose of this study was to explore the association between the activation of NLRP3 inflammasome and hypertensive endothelial damage, and to demonstrate the protective effect of sinapine thiocyanate (ST) on endothelia in hypertension. The expression of NLRP3 gene was silenced by tail vein injection of adeno-associated virus (AAVs) in spontaneously hypertensive rats (SHRs), indicating that activation of NLRP3 inflammasome accelerated hypertensive endothelial injury. ST not only protected vascular endothelial function in SHRs by inhibiting the activation of NLRP3 inflammasome and the expression of related inflammatory mediators, but also improved AngII-induced huvec injury. In summary, our results show that alleviative NLRP3 inflammasome activation attenuates hypertensive endothelial damage and ST ameliorates vascular endothelial dysfunction in hypertension via inhibiting activation of the NLRP3 inflammasome.
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Affiliation(s)
- Yang Liu
- First Faculty of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.,ICU, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Hong-Lin Yin
- Faculty of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Chao Li
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Feng Jiang
- First Faculty of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.,Cardiovascular Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Shi-Jun Zhang
- First Faculty of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xin-Rong Zhang
- Faculty of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yun-Lun Li
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, China.,Cardiovascular Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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25
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Saito K, Fujii H, Kono K, Hirabayashi K, Yamatani S, Watanabe K, Goto S, Komatsu S, Fukumoto T, Nishi S. Changes in blood pressure during treatment with the tyrosine kinase inhibitor lenvatinib. Clin Kidney J 2020; 14:325-331. [PMID: 33564435 PMCID: PMC7857786 DOI: 10.1093/ckj/sfaa137] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 05/26/2020] [Indexed: 12/22/2022] Open
Abstract
Background Within the class of tyrosine kinase inhibitors (TKIs), which are used for the treatment of numerous advanced cancers, lenvatinib is associated with a higher prevalence of hypertension (HT) compared with other TKIs. In this study, we investigated the effect of lenvatinib on blood pressure (BP) and associated factors. Methods This single-centre, retrospective observational study included 25 consecutive patients treated with lenvatinib for unresectable hepatocellular carcinoma from April 2018 to December 2018 at the study institution. We assessed changes in BP using ambulatory BP monitoring, urinary sodium excretion, kidney function, use of antihypertensive agents and diuretics, and fluid retention following treatment initiation with lenvatinib. Results At 1 week after treatment initiation, the mean BP and the percentage of patients with riser pattern significantly increased compared with those at the baseline. Although there were no significant changes at 1 week, urinary sodium excretion (153.4 ± 51.7 and 112.5 ± 65.0 mEq/day at 1 and 3 weeks, respectively, P < 0.05) and estimated glomerular filtration rate significantly decreased and the number of patients with fluid retention increased at 3 weeks. Furthermore, patients with fluid retention had significantly higher BP or required more intensive BP treatment compared with those without fluid retention. Conclusions Lenvatinib might lead to HT without fluid retention soon after the initiation of treatment, subsequently leading to a reduction in urinary sodium excretion, thereby contributing to a rise in BP by fluid retention.
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Affiliation(s)
- Kei Saito
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hideki Fujii
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Keiji Kono
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Ken Hirabayashi
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Satoshi Yamatani
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kentaro Watanabe
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shunsuke Goto
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shohei Komatsu
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takumi Fukumoto
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shinichi Nishi
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Japan
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26
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Zhao Y, Zhang YN, Wang KT, Chen L. Lenvatinib for hepatocellular carcinoma: From preclinical mechanisms to anti-cancer therapy. Biochim Biophys Acta Rev Cancer 2020; 1874:188391. [PMID: 32659252 DOI: 10.1016/j.bbcan.2020.188391] [Citation(s) in RCA: 130] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 07/06/2020] [Accepted: 07/07/2020] [Indexed: 12/12/2022]
Abstract
Lenvatinib, a multi-target tyrosine kinase inhibitor (TKI), is an emerging first-line therapy for hepatocellular carcinoma (HCC). Its application has changed the status of sorafenib as the only first-line TKI treatment for HCC for more than a decade. Evidence has shown that lenvatinib possesses antitumor proliferation and immunomodulatory activity in preclinical studies. In comparison, lenvatinib was non-inferior to sorafenib in overall survival (OS), and even shows superiority with regard to all the secondary efficacy endpoints. Immune-checkpoint inhibitors(ICIs)are now being incorporated into HCC treatment. Positive outcomes have been achieved in the combination of lenvatinib plus ICIs, bringing broader prospects for HCC. This review presents an overview on the therapeutic mechanisms and clinical efficacy of lenvatinib in HCC, and we discuss the future perspectives of lenvatinib in HCC management with focus on biomarker-guided precision medicine.
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Affiliation(s)
- Yan Zhao
- School of Life Sciences, Fudan University, Shanghai 200438, China.
| | - Ya-Ni Zhang
- School of Life Sciences, Fudan University, Shanghai 200438, China.
| | - Kai-Ting Wang
- School of Life Sciences, Fudan University, Shanghai 200438, China.
| | - Lei Chen
- International Cooperation Laboratory of Signal Transduction, Eastern Hepatobiliary Surgery Institute, China.
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27
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Jiang L, Ping L, Yan H, Yang X, He Q, Xu Z, Luo P. Cardiovascular toxicity induced by anti-VEGF/VEGFR agents: a special focus on definitions, diagnoses, mechanisms and management. Expert Opin Drug Metab Toxicol 2020; 16:823-835. [PMID: 32597258 DOI: 10.1080/17425255.2020.1787986] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
INTRODUCTION Vascular endothelial growth factor (VEGF) is a key target in cancer therapy. However, cardiovascular safety has been one of the most challenging aspects of anti-VEGF/VEGF receptor (VEGFR) agent development and therapy. While accurate diagnostic modalities for assessment of cardiac function have been developed over the past few decades, a lack of an optimal definition and precise mechanism still places a significant limit on the effective management of cardiovascular toxicity. AREAS COVERED Here, we report the cardiovascular toxicity profile associated with anti-VEGF/VEGFR agents and summarize the clinical diagnoses as well as management that are already performed in clinical practice or are currently being investigated. Furthermore, the review discusses the potential molecular toxicological mechanisms, which may provide strategies to prevent toxicity and drive drug discovery. EXPERT OPINION Cardiovascular toxicity associated with anti-VEGF/VEGFR agents has been a substantial risk for cancer treatment. To improve its management, the development of guidelines for prevention, monitoring and treatment of cardiovascular toxicity has become a hot topic. The summary of cardiovascular toxicity profile, mechanisms and management given in this review is not only significant for the optimal use of existing anti-VEGF/VEGFR agents to protect patients predisposed to cardiovascular toxicity but is also beneficial for drug development.
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Affiliation(s)
- Liyu Jiang
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang,China
| | - Li Ping
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang,China
| | - Hao Yan
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang,China
| | - Xiaochun Yang
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang,China
| | - Qiaojun He
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang,China
| | - Zhifei Xu
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang,China
| | - Peihua Luo
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang,China
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Ghione S, Mabrouk N, Paul C, Bettaieb A, Plenchette S. Protein kinase inhibitor-based cancer therapies: Considering the potential of nitric oxide (NO) to improve cancer treatment. Biochem Pharmacol 2020; 176:113855. [PMID: 32061562 DOI: 10.1016/j.bcp.2020.113855] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 02/10/2020] [Indexed: 12/14/2022]
Abstract
The deregulation of a wide variety of protein kinases is associated with cancer cell initiation and tumor progression. Owing to their indispensable function in signaling pathways driving malignant cell features, protein kinases constitute major therapeutic targets in cancer. Over the past two decades, intense efforts in drug development have been dedicated to this field. The development of protein kinase inhibitors (PKIs) have been a real breakthrough in targeted cancer therapy. Despite obvious successes across patients with different types of cancer, the development of PKI resistance still prevails. Combination therapies are part of a comprehensive approach to address the problem of drug resistance. The therapeutic use of nitric oxide (NO) donors to bypass PKI resistance in cancer has never been tested in clinic yet but several arguments suggest that the combination of PKIs and NO donors may exert a potential anticancer effect. The present review summarized the current state of knowledge on common targets to both PKIs and NO. Herein, we attempt to provide the rationale underlying a potential combination of PKIs and NO donors for future directions and design of new combination therapies in cancer.
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Affiliation(s)
- Silvia Ghione
- Laboratoire d'Immunologie et Immunothérapie des Cancers, EPHE, PSL Research University, 75000 Paris, France; LIIC, EA7269, Université de Bourgogne Franche-Comté, 21000 Dijon, France
| | - Nesrine Mabrouk
- Laboratoire d'Immunologie et Immunothérapie des Cancers, EPHE, PSL Research University, 75000 Paris, France; LIIC, EA7269, Université de Bourgogne Franche-Comté, 21000 Dijon, France
| | - Catherine Paul
- Laboratoire d'Immunologie et Immunothérapie des Cancers, EPHE, PSL Research University, 75000 Paris, France; LIIC, EA7269, Université de Bourgogne Franche-Comté, 21000 Dijon, France
| | - Ali Bettaieb
- Laboratoire d'Immunologie et Immunothérapie des Cancers, EPHE, PSL Research University, 75000 Paris, France; LIIC, EA7269, Université de Bourgogne Franche-Comté, 21000 Dijon, France
| | - Stéphanie Plenchette
- Laboratoire d'Immunologie et Immunothérapie des Cancers, EPHE, PSL Research University, 75000 Paris, France; LIIC, EA7269, Université de Bourgogne Franche-Comté, 21000 Dijon, France.
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Reed N, Glen H, Gerrard G, Good J, Lei M, Lyon AR, Strachan M, Wadsley J, Newbold K. Expert Consensus on the Management of Adverse Events During Treatment with Lenvatinib for Thyroid Cancer. Clin Oncol (R Coll Radiol) 2019; 32:e145-e153. [PMID: 31843241 DOI: 10.1016/j.clon.2019.11.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 11/04/2019] [Accepted: 11/07/2019] [Indexed: 12/23/2022]
Abstract
AIMS Lenvatinib is an oral multi-kinase inhibitor approved for the treatment of adults with progressive, locally advanced or metastatic, differentiated thyroid carcinoma refractory to radioactive iodine. MATERIALS AND METHODS A literature review was undertaken to inform the development of consensus-based guidance for the routine management of adverse events associated with lenvatinib. PubMed was searched on 24 October 2017; the search terms were 'lenvatinib' and 'thyroid cancer'. RESULTS Hypertension, diarrhoea, weight loss, skin toxicities and cardiovascular adverse events were considered. For grade 1/2 diarrhoea, initial treatment should be loperamide with a 1-week treatment interruption if diarrhoea persists and dose reduction if diarrhoea recurs on reinitiation of lenvatinib. Blood pressure should be monitored daily in patients with pre-existing hypertension, otherwise from 1 week after the initiation of lenvatinib and weekly for the first 2 months. For patients with systolic blood pressure ≥135 mmHg to <160 mmHg or diastolic blood pressure ≥85 mmHg to <100 mmHg, lenvatinib should be continued but antihypertensive therapy initiated/intensified. For patients who remain hypertensive, a treatment break can be considered with lenvatinib reinitiated at a reduced dose once the patient's blood pressure has stabilised for at least 48 h. Weight loss of 10% of baseline body weight or the onset of anorexia should be managed with a 1-week treatment break; patients should maintain a healthy, active lifestyle. For patients with grade 2 proteinuria, lenvatinib may be continued, but an angiotensin II receptor blocker or angiotensin converting enzyme inhibitor should be commenced. For grade >3 proteinuria, lenvatinib should be interrupted until proteinuria returns to 1+. For chronic proteinuria, lenvatinib should be stopped. Skin toxicities should be managed with moisturisers or emollients and soap substitutes. CONCLUSIONS Prophylaxis, regular monitoring and symptomatic management with appropriate short treatment breaks and, for persistent adverse events, dose reductions, are recommended to enable patients to remain on the optimal dose regimen.
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Affiliation(s)
- N Reed
- Beatson West of Scotland Cancer Centre, Glasgow, UK.
| | - H Glen
- Beatson West of Scotland Cancer Centre, Glasgow, UK
| | | | - J Good
- QE Hospital, Birmingham, UK
| | - M Lei
- Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - A R Lyon
- Royal Brompton & Harefield NHS Foundation Trust and Imperial College London, London, UK
| | | | | | - K Newbold
- Royal Marsden NHS Foundation Trust, London, UK
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30
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Sueta D, Tabata N, Ikeda S, Saito Y, Ozaki K, Sakata K, Matsumura T, Yamamoto-Ibusuki M, Murakami Y, Jodai T, Fukushima S, Yoshida N, Kamba T, Araki E, Iwase H, Fujii K, Ihn H, Kobayashi Y, Minamino T, Yamagishi M, Maemura K, Baba H, Matsui K, Tsujita K. Differential predictive factors for cardiovascular events in patients with or without cancer history. Medicine (Baltimore) 2019; 98:e17602. [PMID: 31689764 PMCID: PMC6946347 DOI: 10.1097/md.0000000000017602] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 09/16/2019] [Accepted: 09/19/2019] [Indexed: 11/25/2022] Open
Abstract
Although attention has been paid to the relationship between malignant diseases and cardiovascular diseases, few data have been reported. Moreover, there have also been few reports in which the preventive factors were examined in patients with or without malignant disease histories requiring percutaneous coronary intervention (PCI).This was a retrospective, single-center, observational study. A total of 1003 post-PCI patients were divided into a malignant group, with current or past malignant disease, and a nonmalignant group. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, stroke, revascularization, and admission due to heart failure within 5 years of PCI. Kaplan-Meier analysis showed a significantly higher probability of the primary endpoint in the malignant group (P = .002). Multivariable Cox hazard analyses showed that in patients without a history of malignant, body mass index (BMI) and the presence of dyslipidemia were independent and significant negative predictors of the primary endpoint (BMI: hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.53-0.99, P = .041; prevalence of dyslipidemia: HR 0.72, 95% CI 0.52-0.99, P = .048), and the presence of multi-vessel disease (MVD) and the prevalence of peripheral artery disease (PAD) were independent and significant positive predictors of the primary endpoint (prevalence of MVD: HR 1.68, 95% CI 1.18-2.40, P = .004; prevalence of PAD: HR 1.51, 95% CI 1.03-2.21, P = .034). In patients with histories of malignancy, no significant independent predictive factors were identified.Patients undergoing PCI with malignancy had significantly higher rates of adverse cardiovascular events but might not have the conventional prognostic factors.
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Affiliation(s)
- Daisuke Sueta
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences
- Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto
| | - Noriaki Tabata
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences
- Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto
| | - Satoshi Ikeda
- Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki
| | - Yuichi Saito
- Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba
| | - Kazuyuki Ozaki
- Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata
| | - Kenji Sakata
- Department of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medicine, Kanazawa
| | - Takeshi Matsumura
- Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto
- Department of Metabolic Medicine, Faculty of Life Sciences
| | | | | | - Takayuki Jodai
- Department of Respiratory Medicine, Graduate School of Medical Sciences
| | - Satoshi Fukushima
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences
| | - Naoya Yoshida
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences
- Division of Translational Research and Advanced Treatment Against Gastrointestinal Cancer
| | | | - Eiichi Araki
- Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto
- Department of Metabolic Medicine, Faculty of Life Sciences
| | - Hirotaka Iwase
- Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences
| | - Kazuhiko Fujii
- Department of Respiratory Medicine, Graduate School of Medical Sciences
| | - Hironobu Ihn
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences
| | - Yoshio Kobayashi
- Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba
| | - Tohru Minamino
- Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata
| | - Masakazu Yamagishi
- Department of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medicine, Kanazawa
| | - Koji Maemura
- Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki
| | - Hideo Baba
- Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences
| | - Kunihiko Matsui
- Community, Family, and General Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Kenichi Tsujita
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences
- Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto
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31
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Latorre A, Fioretti AM, Giotta F, Lorusso V. Efficacy and safety of lenvatinib in an elderly patient with metastatic papillary thyroid carcinoma and cardiological comorbidity: a case report. Future Oncol 2019; 15:27-33. [PMID: 31393171 DOI: 10.2217/fon-2019-0114] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Lenvatinib significantly prolonged progression-free survival versus placebo in patients with radio-iodine refractory differentiated thyroid carcinoma. However, the primary adverse effects of any grade that occurred in >40% of patients in the lenvatinib group of the Phase III SELECT trial was hypertension (67.8%). Therefore, this drug should be used with caution in patients with cardiological morbidity. Here, we describe the case of a 73-year-old man with hypertension, obesity and chronic atrial fibrillation, who received lenvatinib for 6 months in the absence of cardiological symptoms.
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Affiliation(s)
- Agnese Latorre
- UO Oncologia Medica, Istituto Tumori "G Paolo II" Bari, Bari, Italy
| | | | - Francesco Giotta
- UO Oncologia Medica, Istituto Tumori "G Paolo II" Bari, Bari, Italy
| | - Vito Lorusso
- UO Oncologia Medica, Istituto Tumori "G Paolo II" Bari, Bari, Italy
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32
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Tabata N, Sueta D, Yamamoto E, Takashio S, Arima Y, Araki S, Yamanaga K, Ishii M, Sakamoto K, Kanazawa H, Fujisue K, Hanatani S, Soejima H, Hokimoto S, Izumiya Y, Kojima S, Yamabe H, Kaikita K, Matsui K, Tsujita K. A retrospective study of arterial stiffness and subsequent clinical outcomes in cancer patients undergoing percutaneous coronary intervention. J Hypertens 2019; 37:754-764. [PMID: 30817457 DOI: 10.1097/hjh.0000000000001949] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Increasing attention is being paid to the relationship between cancer and cardiovascular diseases. In this study, we examined arterial stenosis and stiffness in patients with malignant diseases requiring percutaneous coronary intervention. METHODS This was a retrospective, single-center, observational study. Participants (n = 1003) were divided into a malignant group, with current or past malignant disease, and a nonmalignant group. The ankle-brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV) were evaluated. The endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, stroke, and revascularization within 1 year. RESULTS We observed significantly impaired ABI and baPWV in the malignant group. A total of 148 patients had a cardiovascular event. Kaplan-Meier analysis showed a significantly higher probability of cardiovascular events in the malignant group (P = 0.012). The combination of malignancy with ABI/baPWV identified subgroups with significantly different probabilities of cardiovascular events. Multivariate Cox hazard analysis identified malignancy as an independent predictor of cardiovascular events (hazard ratio, 1.54; 95% confidence interval, 1.06-2.26; P = 0.025) with an increased hazard ratio by adding the status of low ABI/high baPWV to malignancy (hazard ratio, 2.36; 95% confidence interval, 1.35-4.12; P = 0.003). We found significantly higher follow-up baPWV values in the malignancy group (P = 0.016). CONCLUSION Atherosclerosis is advanced and accelerated in patients with malignancy, and these patients had significantly higher rates of adverse cardiovascular events, and their risk might be stratified by ABI and baPWV. REGISTRATION University Hospital Medical Information Network-CTR (http://www.umin.ac.jp/ctr/). IDENTIFIER Kumamoto University Malignancy and Atherosclerosis study (UMIN000028652). PUBLIC ACCESS INFORMATION Opt-out materials are available at the following website: http://www.kumadai-junnai.com/home/wp-content/uploads/akusei.pdf.
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Affiliation(s)
- Noriaki Tabata
- Department of Cardiovascular Medicine
- Center for Metabolic Regulation of Healthy Aging
| | - Daisuke Sueta
- Department of Cardiovascular Medicine
- Center for Metabolic Regulation of Healthy Aging
| | - Eiichiro Yamamoto
- Department of Cardiovascular Medicine
- Center for Metabolic Regulation of Healthy Aging
| | - Seiji Takashio
- Department of Cardiovascular Medicine
- Center for Metabolic Regulation of Healthy Aging
| | - Yuichiro Arima
- Department of Cardiovascular Medicine
- Center for Metabolic Regulation of Healthy Aging
| | - Satoshi Araki
- Department of Cardiovascular Medicine
- Center for Metabolic Regulation of Healthy Aging
| | - Kenshi Yamanaga
- Department of Cardiovascular Medicine
- Center for Metabolic Regulation of Healthy Aging
| | - Masanobu Ishii
- Department of Cardiovascular Medicine
- Center for Metabolic Regulation of Healthy Aging
| | - Kenji Sakamoto
- Department of Cardiovascular Medicine
- Center for Metabolic Regulation of Healthy Aging
| | - Hisanori Kanazawa
- Department of Cardiovascular Medicine
- Center for Metabolic Regulation of Healthy Aging
| | - Koichiro Fujisue
- Department of Cardiovascular Medicine
- Center for Metabolic Regulation of Healthy Aging
| | - Shinsuke Hanatani
- Department of Cardiovascular Medicine
- Center for Metabolic Regulation of Healthy Aging
| | - Hirofumi Soejima
- Department of Cardiovascular Medicine
- Center for Metabolic Regulation of Healthy Aging
| | - Seiji Hokimoto
- Department of Cardiovascular Medicine
- Center for Metabolic Regulation of Healthy Aging
| | - Yasuhiro Izumiya
- Department of Cardiovascular Medicine
- Center for Metabolic Regulation of Healthy Aging
| | - Sunao Kojima
- Department of Cardiovascular Medicine
- Center for Metabolic Regulation of Healthy Aging
| | - Hiroshige Yamabe
- Department of Cardiovascular Medicine
- Center for Metabolic Regulation of Healthy Aging
| | - Koichi Kaikita
- Department of Cardiovascular Medicine
- Center for Metabolic Regulation of Healthy Aging
| | - Kunihiko Matsui
- Department of Community, Family, and General Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Kenichi Tsujita
- Department of Cardiovascular Medicine
- Center for Metabolic Regulation of Healthy Aging
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Cabanillas ME, Takahashi S. Managing the adverse events associated with lenvatinib therapy in radioiodine-refractory differentiated thyroid cancer. Semin Oncol 2018; 46:57-64. [PMID: 30685073 DOI: 10.1053/j.seminoncol.2018.11.004] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 11/21/2018] [Indexed: 02/06/2023]
Abstract
Lenvatinib is a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor receptors 1-4, RET, KIT, and platelet-derived growth factor receptor-α. Lenvatinib is approved as a monotherapy for the treatment of radioiodine-refractory differentiated thyroid cancer and in combination with everolimus for the second-line treatment of advanced renal cell carcinoma. Lenvatinib is also under investigation for the treatment of several malignancies including unresectable hepatocellular carcinoma. Although lenvatinib is associated with favorable efficacy, it is associated with adverse events (AEs) that the clinician will have to closely monitor for and proactively manage. Most of these AEs are known class effects of VEGF-targeted therapies, including hypertension, diarrhea, fatigue or asthenia, decreased appetite, and weight loss. This review summarizes the safety profile of lenvatinib and offers guidance for the management of both frequent and rare AEs. We discuss the potential mechanisms underlying these AEs and present practical recommendations for managing toxicities. The development of treatment plans that include prophylactic and therapeutic strategies for the management of lenvatinib-associated AEs has the potential to improve patient quality of life, optimize adherence, minimize the need for dose reductions, treatment interruptions, or discontinuations, and maximize patient outcomes.
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Affiliation(s)
- Maria E Cabanillas
- Department of Endocrine Neoplasia & Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Shunji Takahashi
- Department of Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
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34
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Optimisation of treatment with lenvatinib in radioactive iodine-refractory differentiated thyroid cancer. Cancer Treat Rev 2018; 69:164-176. [DOI: 10.1016/j.ctrv.2018.06.019] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 06/28/2018] [Accepted: 06/29/2018] [Indexed: 12/15/2022]
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Tori M, Shimo T. Long-term efficacy of lenvatinib for recurrent papillary thyroid carcinoma after multimodal treatment and management of complications: a case report. BMC Cancer 2018; 18:698. [PMID: 29954369 PMCID: PMC6022486 DOI: 10.1186/s12885-018-4612-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Accepted: 06/20/2018] [Indexed: 12/28/2022] Open
Abstract
Background The advent of tyrosine kinase inhibitors (TKIs) has changed the treatment of RAI refractory, unresectable recurrent differentiated thyroid cancer (DTC), which was formerly treated with multidisciplinary remedies. Case presentation Here we describe the case of a 64-year-old woman who underwent total thyroidectomy with tracheal resection and suffered from a recurrent tumor in the neck and multiple lung and bone metastases 3 and 11 months, respectively, after the operation. Multimodal therapies, RI (I-131), EBRT, and taxane-based chemotherapy were ineffective, and sorafenib was started as a TKI. However, because of disease progression, sorafenib was replaced by lenvatinib after 9 months. The effect of lenvatinib has continued for more than 1 year and 9 months, and the patient has well survived. During the treatment period, a tracheal pin-hole fistula suddenly emerged, which was naturally cured by the temporary cessation of lenvatinib. Adverse events such as hypertension, proteinuria, and diabetes as innate complications have been successfully managed until the present according to our institute regulations. Conclusions Even where multimodal treatment was ineffective, lenvatinib was suggested to be an alternative treatment option for RAI refractory recurrent DTC and patient could have a chance to be controlled successfully.
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Affiliation(s)
- Masayuki Tori
- Department of Endocrine Surgery, Osaka Police Hospital, Kitayamacho 10-31, Tnnoujiku, Osaka, 543-0035, Japan.
| | - Toshirou Shimo
- Department of Endocrine Surgery, Osaka Police Hospital, Kitayamacho 10-31, Tnnoujiku, Osaka, 543-0035, Japan
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Tabata N, Sueta D, Yamamoto E, Takashio S, Arima Y, Araki S, Yamanaga K, Ishii M, Sakamoto K, Kanazawa H, Fujisue K, Hanatani S, Soejima H, Hokimoto S, Izumiya Y, Kojima S, Yamabe H, Kaikita K, Tsujita K, Tabata N, Sueta D, Yamamoto E, Takashio S, Arima Y, Araki S, Yamanaga K, Ishii M, Sakamoto K, Kanazawa H, Fujisue K, Hanatani S, Soejima H, Hokimoto S, Izumiya Y, Kojima S, Yamabe H, Kaikita K, Tanaka T, Yamamuro M, Sugamura K, Komura N, Miyazaki T, Akasaka T, Onoue Y, Ogawa H, Tsujita K. Outcome of current and history of cancer on the risk of cardiovascular events following percutaneous coronary intervention: a Kumamoto University Malignancy and Atherosclerosis (KUMA) study. EUROPEAN HEART JOURNAL. QUALITY OF CARE & CLINICAL OUTCOMES 2017; 4:290-300. [DOI: 10.1093/ehjqcco/qcx047] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Accepted: 11/29/2017] [Indexed: 01/01/2023]
Affiliation(s)
- Noriaki Tabata
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan
| | - Daisuke Sueta
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan
| | - Eiichiro Yamamoto
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan
| | - Seiji Takashio
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan
| | - Yuichiro Arima
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan
| | - Satoshi Araki
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan
| | - Kenshi Yamanaga
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan
| | - Masanobu Ishii
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan
| | - Kenji Sakamoto
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan
| | - Hisanori Kanazawa
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan
| | - Koichiro Fujisue
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan
| | - Shinsuke Hanatani
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan
| | - Hirofumi Soejima
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan
| | - Seiji Hokimoto
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan
| | - Yasuhiro Izumiya
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan
| | - Sunao Kojima
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan
| | - Hiroshige Yamabe
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan
| | - Koichi Kaikita
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan
| | - Kenichi Tsujita
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan
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Bendtsen MAF, Grimm D, Bauer J, Wehland M, Wise P, Magnusson NE, Infanger M, Krüger M. Hypertension Caused by Lenvatinib and Everolimus in the Treatment of Metastatic Renal Cell Carcinoma. Int J Mol Sci 2017; 18:ijms18081736. [PMID: 28796163 PMCID: PMC5578126 DOI: 10.3390/ijms18081736] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 08/04/2017] [Accepted: 08/08/2017] [Indexed: 12/15/2022] Open
Abstract
Multikinase inhibitors (MKI) and mammalian target of rapamycin (mTOR) inhibitors prolong progression-free (PFS) and overall survival (OS) in the treatment of metastatic renal cell carcinoma (mRCC) by reducing angiogenesis and tumor growth. In this regard, the MKI lenvatinib and the mTOR inhibitor everolimus proved effective when applied alone, but more effective when they were administered combined. Recently, both drugs were included in clinical trials, resulting in international clinical guidelines for the treatment of mRCC. In May 2016, lenvatinib was approved by the American Food and Drug Administration (FDA) for the use in combination with everolimus, as treatment of advanced renal cell carcinoma following one prior antiangiogenic therapy. A major problem of treating mRCC with lenvatinib and everolimus is the serious adverse event (AE) of arterial hypertension. During the treatment with everolimus and lenvatinib combined, 42% of the patients developed hypertension, while 10% of the patients treated with everolimus alone and 48% of the of the lenvatinib only treated patients developed hypertension. Lenvatinib carries warnings and precautions for hypertension, cardiac failure, and other adverse events. Therefore, careful monitoring of the patients is necessary.
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Affiliation(s)
| | - Daniela Grimm
- Institute of Biomedicine, Pharmacology, Aarhus University, Wilhelm Meyers Allé 4, DK-8000 Aarhus C, Denmark.
| | - Johann Bauer
- Max Planck Institute for Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
| | - Markus Wehland
- Clinic and Policlinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany.
| | - Petra Wise
- Hematology/Oncology, University of Southern California, Children's Hospital Los Angeles, 4650 Sunset Blvd. MS #57, Los Angeles, CA 90027, USA.
| | - Nils E Magnusson
- Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, Nørrebrogade 44, DK-8000 Aarhus C, Denmark.
| | - Manfred Infanger
- Clinic and Policlinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany.
| | - Marcus Krüger
- Clinic and Policlinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany.
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