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Sun Y, Zhang Z, Jia K, Liu H, Zhang F. Autoimmune-related adverse events induced by immune checkpoint inhibitors. Curr Opin Immunol 2025; 94:102556. [PMID: 40220485 DOI: 10.1016/j.coi.2025.102556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2025] [Revised: 03/18/2025] [Accepted: 03/23/2025] [Indexed: 04/14/2025]
Abstract
Targeted immunotherapies, particularly immune checkpoint inhibitors (ICIs), have transformed cancer treatment by significantly improving patient response and survival rates. However, ICIs could disrupt self-tolerance, inducing the development of immune-related adverse events (irAEs). Most irAEs are classified as autoimmune conditions mediated by ICI-activated CD8+ cytotoxic T cells or activated B cells producing pathogenic autoantibodies. These irAEs phenotypically resemble spontaneous autoimmune disease and lead to considerable morbidity, health care costs, and compromised treatment efficacy. With the widespread use and new emergence of ICIs, the spectrum of ICI-induced irAEs has become increasingly extensive and complex. Concurrently, research in this field is advancing rapidly, a review summarizing the latest progress on irAEs is timely and essential. In this review, we highlight numerous recent research advances, covering the epidemiology, immune mechanisms, and diverse manifestations of irAEs, with a particular focus on organ-specific autoimmunity. We also discuss current strategies, challenges, and future directions for the prevention and therapeutic management of these adverse events.
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Affiliation(s)
- Yuanqiang Sun
- Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Ziyang Zhang
- Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Ke Jia
- Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Hong Liu
- Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China.
| | - Furen Zhang
- Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China
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Dong H, Li S, Peng Y, Zhang X, Zheng J, Xue C, Zheng Y, Yu Y, Lu X, Hu Z, Cui H. Durvalumab‑induced type 1 diabetes mellitus in lung adenocarcinoma: A case report and literature review. Oncol Lett 2025; 29:277. [PMID: 40247987 PMCID: PMC12005073 DOI: 10.3892/ol.2025.15023] [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: 11/15/2024] [Accepted: 03/19/2025] [Indexed: 04/19/2025] Open
Abstract
Immune checkpoint inhibitor-induced type 1 diabetes mellitus (ICI-T1DM) is a rare adverse reaction associated with durvalumab. Among the adverse reactions to durvalumab, the incidence of new-onset diabetes is relatively rare, occurring in ~0.2% of cases. The present study reports the case of a 62-year-old woman who developed ICI-T1DM following two cycles of durvalumab, presenting with thirst, polydipsia and polyuria. Laboratory examinations (glycated hemoglobin and glutamic acid decarboxylase antibody), along with consultations from an endocrinologist, led to the patient being diagnosed with ICI-T1DM. Immunotherapy was discontinued, and insulin replacement therapy was initiated. Blood glucose levels were closely monitored using a subcutaneous meter. The onset of diabetic ketoacidosis (DKA) was prevented due to timely treatment. In conclusion, medical oncologists need to be aware that durvalumab, an immunotherapy agent, can induce ICI-T1DM. Therefore, regular monitoring of blood glucose levels and collaborative consultations with endocrinologists are essential for an accurate diagnosis when elevated blood sugar levels are detected. The prompt diagnosis of ICI-T1DM is crucial to prevent the occurrence of DKA.
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Affiliation(s)
- Huijing Dong
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Shengfu Li
- Department of Tuberculosis, Tai Yuan Fourth Peoples (Tuberculosis) Hospital, Taiyuan, Shanxi 030053, P.R. China
| | - Yanmei Peng
- Department of Oncology, Fangshan Hospital Beijing University of Chinese Medicine, Beijing 102400, P.R. China
| | - Xu Zhang
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Jiabin Zheng
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, P.R. China
| | - Chongxiang Xue
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Yumin Zheng
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Yixuan Yu
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Xingyu Lu
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Zixin Hu
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Huijuan Cui
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, P.R. China
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Shibutani Y, Kawanobe A, Suzuki S, Imaoka T, Tajiri K. Effects of Immune Checkpoint Inhibitor-induced Thyroid Dysfunction on Cardiac Troponin Levels. J Immunother 2025; 48:183-188. [PMID: 40333085 DOI: 10.1097/cji.0000000000000555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 03/04/2025] [Indexed: 03/27/2025]
Abstract
Immune checkpoint inhibitor (ICI)-induced thyroid dysfunction is the most frequent endocrine immune-related adverse event (irAE). Thyroid hormones have various effects on the cardiovascular system; however, the impact of thyroid irAEs on the development of cardiovascular diseases is not fully understood. This retrospective study included 94 patients who received ICIs and had thyroid function and troponin T levels, markers of cardiac damage, measured at the National Cancer Center Hospital East between January 2017 and July 2022. Of the 94 patients, 36 (38%) showed elevated troponin levels after ICI treatment during the follow-up period. The median observation period was 249 days (interquartile range, 124-502 d). Thyroid irAEs [hypothyroidism (n=13) and hyperthyroidism (n=3)] associations were found in 16 (44%) of these 36 patients. None of the patients developed overt cardiovascular disease or died of heart disease, regardless of whether they experienced thyroid irAEs. The troponin levels increased with increasing thyroid stimulating hormone (TSH) levels. In particular, troponin levels were significantly elevated in patients with TSH >20 μIU/mL after ICI treatment ( P =0.009). In conclusion, thyroid irAEs may cause cardiac damage indicated by elevated troponin levels, necessitating special attention, particularly in cases of hypothyroidism where TSH exceeds 20 μIU/mL. Therefore, it is important to monitor cardiac markers along with thyroid function after ICI treatment.
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Affiliation(s)
- Yuma Shibutani
- Department of Pharmacy, National Cancer Center Hospital East, Kashiwa, Japan
| | - Atsushi Kawanobe
- Department of Pharmacy, National Cancer Center Hospital East, Kashiwa, Japan
| | - Shinya Suzuki
- Department of Pharmacy, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takuro Imaoka
- Department of Cardiology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Kazuko Tajiri
- Department of Cardiology, National Cancer Center Hospital East, Kashiwa, Japan
- Tsukuba Life Science Innovation Program (T-LSI), School of Integrative and Global Majors (SIGMA), University of Tsukuba, Tsukuba, Japan
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Rajak P. Immune checkpoint inhibitors: From friend to foe. Toxicol Rep 2025; 14:102033. [PMID: 40353246 PMCID: PMC12063143 DOI: 10.1016/j.toxrep.2025.102033] [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: 11/30/2024] [Revised: 04/18/2025] [Accepted: 04/20/2025] [Indexed: 05/14/2025] Open
Abstract
Immune checkpoints are crucial in regulating the activation of cell-mediated and humoral immune responses. However, cancer cells hijack this mechanism to evade the immune surveillance and anti-cancer response. Typically, receptors like PD-1 and CTLA4, expressed on immune cells, prevent the activation and differentiation of T cells. They also inhibit the development of autoimmune reactions. However, ligands such as PD-L1 for the receptor PD-1 are also expressed on the surface of cancer cells that help prevent the activation of anti-cancer immune responses by blocking the signalling pathways mediated by PD-1 and CTLA4. Immune checkpoint inhibitors (ICIs) have promising therapeutic efficacy for treating several cancers by activating T cells and their differentiation into effector cells against tumours. Nonetheless, hyperactivated immune cells usually contribute to detrimental issues, also known as immune-related adverse effects (IrAE). IrAEs have been observed in multiple organs, leading to neurological issues, colitis, endocrine dysfunction, renal issues, hepatitis, pneumonitis, and dermatitis. The interplay between hyperactivated T cells and Treg cells helps in orchestrating the development of autoimmunity. Moreover, the crosstalk between proinflammatory interleukins and the development of autoantibodies also mediates the multiorgan effects of ICIs in cancer patients. IrAEs are generally managed by terminating the ICI therapy, reducing the ICI dose, and by using corticosteroids to subvert inflammation. Therefore, the present review aims to delineate the impacts of ICIs on the development of autoimmune diseases and inflammatory outcomes in cancer patients. In addition, mechanistic insight involving immune cells, cytokines, and autoantibodies for ICI-mediated IrAEs will also be discussed with updated findings in this field.
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Affiliation(s)
- Prem Rajak
- Toxicology Research Laboratory, Department of Animal Science, Kazi Nazrul University, Asansol, West Bengal, India
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Ding J, Yin X, Lin Y, Liao X, Chen L, Hong J, Yan L, Chen S, Yan X, Li Z, Hu K, Zhai R, Chen C, Fei Z. Transforming the management of radiotherapy-induced hypothyroidism in nasopharyngeal carcinoma through an Innovative individualized radiation dosage model: A multicenter retrospective analysis. Radiother Oncol 2025:110943. [PMID: 40409363 DOI: 10.1016/j.radonc.2025.110943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Revised: 05/14/2025] [Accepted: 05/17/2025] [Indexed: 05/25/2025]
Abstract
PURPOSE Current guidelines for thyroid radiation dose prescription lack uniformity and fail to consider the unique characteristics of individual patients. This study aimed to develop an individualized thyroid dosing regimen to enhance thyroid protection during radiotherapy. METHODS AND MATERIALS In this study, we enrolled 621 patients with nasopharyngeal carcinoma (NPC) across four distinct cancer centers, stratifying the data into a training cohort and two external validation cohorts. The specific clinical characteristic-matched tolerated dose values were fitted using binary logistic regression and time-to-event Cox methods in the training cohort. The TSH-volume index (TVI), calculated as thyroid-stimulating hormone (TSH) level divided by thyroid volume (TV), was introduced as a novel parameter. A radiation-induced hypothyroidism (RIHT) parameter was developed using the volume of thyroid spared at the tolerated dose (VStd) and compared with classical normal tissue complication probability (NTCP) and machine learning models using the area under the curve (AUC) and concordance index (C-index). RESULTS The follow-up periods spanned 28 (range, 1-66), 33.5 (range, 3-82), and 17 months (range, 2-56), respectively, across these cohorts. RIHT was observed in 27.7 % and 35.3 % of patients at 2 and 3 years in the training cohort, respectively; 30.0 % and 41.5 % in the external validation cohort 1; and 27.2 % and 38.0 % in the external validation cohort 2. Univariable analysis identifies sex, equivalent uniform dose (EUD), TV, TSH, and the TVI as predictors of RIHT, while multivariable analysis confirms EUD and TVI as independent prognostic factors. The TVI-based VStd parameter outperformed the VS40, VS45, and VS50 indices (representing volumes spared at 40 Gy, 45 Gy, and 50 Gy, respectively), classical NTCP models, and even machine learning models in predictive performance. To enhance clinical applicability, we have developed a thyroid dose prescription table based on TVI. CONCLUSIONS We developed a high-accuracy model for individualized thyroid dosing in NPC radiotherapy. The model, supported by a clinically relevant table, offers a customized approach to thyroid protection, enhancing both predictive accuracy and clinical utility.
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Affiliation(s)
- Jianming Ding
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Xiaoyan Yin
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yuhao Lin
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Xiyi Liao
- Department of Radiation Oncology, The First Affiliated Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, China
| | - Lisha Chen
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Jiabiao Hong
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Linghui Yan
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Sijia Chen
- Department of Radiation Oncology, The First Affiliated Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, China
| | - Xueting Yan
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zirong Li
- Manteia Technologies Company, Xiamen, Fujian, China.
| | - Kai Hu
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
| | - Ruiping Zhai
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
| | - Chuanben Chen
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China.
| | - Zhaodong Fei
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China.
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Miquel L, Testud B, Albarel F, Sahakian N, Cuny T, Graillon T, Brue T, Dufour H, Schleinitz N, Kaplanski G, Ebbo M, Castinetti F. Deciphering the Presentation and Etiologies of Hypophysitis Highlights the Need for Repeated Systematical Investigation. J Clin Endocrinol Metab 2025; 110:e1767-e1775. [PMID: 39312231 DOI: 10.1210/clinem/dgae664] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Indexed: 05/20/2025]
Abstract
CONTEXT Hypophysitis is defined as an inflammation of the pituitary gland and/or infundibulum. OBJECTIVE Our aim was to characterize the initial course and evolution of patients with hypophysitis according to the different etiologies. METHODS Retrospective observational study conducted in a university referral hospital center. Patients over 15 years of age were included if they had a diagnosis of hypophysitis between January 2014 and October 2023, with the exclusion of hypophysitis secondary to immune checkpoint inhibitors. RESULTS Sixty-one patients (64% women; median age, 34 years) were included. Polyuria-polydipsia, headache, and asthenia were present in 64%, 48%, and 44% of cases respectively. At diagnosis, at least 1 anterior pituitary deficiency was present in 91.5% of cases and vasopressin deficiency in 56%. Magnetic resonance imaging was abnormal in 97% of cases. Secondary hypophysitis was found in 46% of cases (n = 28), including sarcoidosis in 28% (n = 17) and L (Langerhans) group histiocytoses in 13.1% (n = 8). Among patients with secondary hypophysitis, pituitary deficiency preceded systemic manifestations in 23% and occurred concomitantly in 23% of cases. Patients were treated in 36% of cases (glucocorticoids, surgery), without improvement of pituitary hormone deficits. CONCLUSION A systemic etiology of hypophysitis was found in almost half of the patients. Pituitary disorders preceded the systemic disease in a quarter of the cases. This emphasizes the importance of a systematic repeated workup looking for a secondary etiology of hypophysitis in these patients.
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Affiliation(s)
- Lea Miquel
- Service de Médecine Interne et d'Immunologie Clinique, Hôpital de La Conception, Assistance Publique Hôpitaux de Marseille (AP-HM), 13005 Marseille, France
| | - Benoit Testud
- Service de radiologie, Hôpital de la Conception, Assistance Publique Hôpitaux de Marseille (AP-HM), 13005 Marseille, France
| | - Frederique Albarel
- Aix Marseille Université, MMG, INSERM U1251, Marmara Institute, Assistance Publique Hôpitaux de Marseille (AP-HM), Hôpital de la Conception, CRMR HYPO, 13005 Marseille, France
| | - Nicolas Sahakian
- Aix Marseille Université, MMG, INSERM U1251, Marmara Institute, Assistance Publique Hôpitaux de Marseille (AP-HM), Hôpital de la Conception, CRMR HYPO, 13005 Marseille, France
| | - Thomas Cuny
- Aix Marseille Université, MMG, INSERM U1251, Marmara Institute, Assistance Publique Hôpitaux de Marseille (AP-HM), Hôpital de la Conception, CRMR HYPO, 13005 Marseille, France
| | - Thomas Graillon
- Service de neurochirurgie, Hôpital de La Timone, Assistance Publique-Hôpitaux de Marseille (AP-HM), 13005 Marseille, France
| | - Thierry Brue
- Aix Marseille Université, MMG, INSERM U1251, Marmara Institute, Assistance Publique Hôpitaux de Marseille (AP-HM), Hôpital de la Conception, CRMR HYPO, 13005 Marseille, France
| | - Henri Dufour
- Service de neurochirurgie, Hôpital de La Timone, Assistance Publique-Hôpitaux de Marseille (AP-HM), 13005 Marseille, France
| | - Nicolas Schleinitz
- Service de médecine interne, Hôpital de la Timone, Assistance Publique Hôpitaux de Marseille (AP-HM), 13005 Marseille, France
| | - Gilles Kaplanski
- Service de Médecine Interne et d'Immunologie Clinique, Hôpital de La Conception, Assistance Publique Hôpitaux de Marseille (AP-HM), 13005 Marseille, France
| | - Mikael Ebbo
- Service de médecine interne, Hôpital de la Timone, Assistance Publique Hôpitaux de Marseille (AP-HM), 13005 Marseille, France
| | - Frederic Castinetti
- Aix Marseille Université, MMG, INSERM U1251, Marmara Institute, Assistance Publique Hôpitaux de Marseille (AP-HM), Hôpital de la Conception, CRMR HYPO, 13005 Marseille, France
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Vitale E, Rizzo A, Maistrello L, Guven DC, Cauli O, Galetta D, Longo V. Treatment-Related Adverse Events in Extended Stage Small Cell Lung Cancer Patients Receiving First-Line Chemoimmunotherapy Versus Chemotherapy Alone: A Systematic Review and Meta-Analysis. Cancers (Basel) 2025; 17:1571. [PMID: 40361497 PMCID: PMC12072015 DOI: 10.3390/cancers17091571] [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: 03/06/2025] [Revised: 04/28/2025] [Accepted: 05/03/2025] [Indexed: 05/15/2025] Open
Abstract
Introduction: Nowadays the prognosis of extended stage (ES) small cell lung cancer (SCLC) patients is poor. However, a high response rate to first-line chemotherapy (CT) and the addition of immune checkpoint inhibitors (ICIs) have notably ameliorated the outcome of these patients. The aim of our study is to compare treatment-related adverse events (TRAEs) between ES- SCLC patients receiving first-line ICIs adding CT and those receiving only CT. Methods: All phase III clinical trials published between 15 June 2008, and 30 June 2024, likenessing ICIs adding systemic CT and only CT in treatment-naïve ES-SCLC patients were retrieved. Results: Twenty-six types of adverse events were included, grouped into ten categories, for a total of 43,391 observations (observations in immune group n = 22,643 and in placebo group n = 20,748) and 9831 events. Our analysis suggested a statistically significant increase in hematological events in patients receiving ICIs plus CT compared with CT alone. Conversely, blood pressure alterations such as hypertension were more frequent in patients treated with CT alone. Conclusions: Despite our analysis confirming the manageable safety profile of chemoimmunotherapy, this remains an issue to be further investigated.
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Affiliation(s)
- Elsa Vitale
- Medical Thoracic Oncology Unit, IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy; (E.V.); (D.G.)
| | - Alessandro Rizzo
- Struttura S.S.D.C.O.r.O., Bed Management Presa in Carico, TDM, IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy;
| | | | - Deniz Can Guven
- Medical Oncology Clinic, Health Sciences University, Elazig City Hospital, Elazig 23280, Turkey;
| | - Omar Cauli
- Nursing Department, Faculty of Nursing and Podiatrics, Universitat de València, 46010 Valencia, Spain;
| | - Domenico Galetta
- Medical Thoracic Oncology Unit, IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy; (E.V.); (D.G.)
| | - Vito Longo
- Medical Thoracic Oncology Unit, IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy; (E.V.); (D.G.)
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Colombo C, De Leo S, Campisi I, Palesandro E, Turco F, Buttigliero C, Fugazzola L, Tucci M. Endocrinological toxicities related to immunotherapy combinations for advanced renal cell carcinoma: Practical expert-based management recommendations. Crit Rev Oncol Hematol 2025; 209:104627. [PMID: 39922397 DOI: 10.1016/j.critrevonc.2025.104627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 01/19/2025] [Accepted: 01/21/2025] [Indexed: 02/10/2025] Open
Abstract
Nowadays immune-based combinations are the standard first-line treatment for metastatic renal cell carcinoma and involve the use of either two immunotherapy agents or an immunotherapeutic drug associated with a tyrosine kinase inhibitor. Treatment-related toxicity is the primary cause of drug discontinuation or dose reduction. A thorough understanding of the prevention and management of adverse events of the immune-based combinations is critical to ensure the success of treatment. Endocrinological toxicities during treatment with immune-based combinations are frequent and often manageable. However, in some cases, diagnosis can be complex, and the treatment requires multidisciplinary discussion. In addition, it is often challenging to determine which agent in the combination is responsible for a specific toxicity. In this review, we analyze the evidence regarding treatment-related endocrinopathies in renal cell carcinoma first-line therapy. We also discuss monitoring strategies to diagnose endocrinological adverse events and provide some practical tools for their daily management.
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Affiliation(s)
- Carla Colombo
- Endocrine Oncology Unit, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Simone De Leo
- Endocrine Oncology Unit, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy
| | - Ilaria Campisi
- Department of Oncology, University of Turin, Turin, Italy
| | | | - Fabio Turco
- Department of Oncology, Institute of Southern Switzerland, Bellinzona, Switzerland
| | - Consuelo Buttigliero
- Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Turin, Italy
| | - Laura Fugazzola
- Endocrine Oncology Unit, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Marcello Tucci
- Department of Oncology, Cardinal Massaia Hospital, Asti, Italy.
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Wang A, Huang H, Chen Y, Zhao Z, Cong L, Li M. Association between platelet-to-lymphocyte ratio and immune checkpoint inhibitor-induced thyroid dysfunction. Endocrine 2025; 88:491-500. [PMID: 39838195 DOI: 10.1007/s12020-025-04164-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 01/09/2025] [Indexed: 01/23/2025]
Abstract
PURPOSE To investigate the relationship between platelet-to-lymphocyte ratio (PLR) or neutrophil-to-lymphocyte ratio (NLR) and Immune checkpoint inhibitor (ICI)-induced thyroid dysfunction. METHODS This was a single-center retrospective observational study of patients with solid tumors receiving ICI therapy. Clinical characteristics of patients were assessed at baseline and during ICI therapy. Logistic regression was implemented to assess the association of PLR and NLR with thyroid dysfunction. Kaplan-Meier method was used to analyze the difference in time between the onset of hypothyroidism and thyrotoxicosis. RESULTS A total of 355 patients with solid tumors were included in our study. Sixty-nine (19.44%) patients developed ICI-induced thyroid dysfunction after receiving ICI therapy, with a median (IQR) time to onset of 91(34-203.5) days. Patients with high PLR (H-PLR) had an increased risk of ICI-induced thyroid dysfunction (OR = 1.87, 95% CI 1.07-3.28, P = 0.028) compared to those with low PLR (L-PLR). Specifically, H-PLR was associated with ICI-induced thyrotoxicosis but not hypothyroidism (OR = 2.40, 95% CI 1.09-5.29, P = 0.030). Meanwhile, NLR was not correlated with ICI-induced thyroid dysfunction as a continuous (P = 0.699) or categorical variable (P = 0.914). The sensitivity analysis showed that H-PLR remains positively correlated with ICI-induced thyroid dysfunction. CONCLUSION PLR rather than NLR was associated with the occurrence of ICI-induced thyroid dysfunction. Furthermore, PLR may serve as a predictive biomarker for ICI-induced thyroid dysfunction.
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Affiliation(s)
- Ai Wang
- Department of Endocrinology and Metabolism, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China
| | - Huijie Huang
- Department of Endocrinology and Metabolism, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China
| | - Yangli Chen
- Department of Endocrinology and Metabolism, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China
| | - Zhi Zhao
- Department of Endocrinology and Metabolism, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China
| | - Li Cong
- Department of Endocrinology and Metabolism, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China.
| | - Man Li
- Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China.
- Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China.
- Biobank, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China.
- Department of Information Technology and Data Center, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China.
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10
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Iwama S, Kobayashi T, Arima H. Management, biomarkers and prognosis in people developing endocrinopathies associated with immune checkpoint inhibitors. Nat Rev Endocrinol 2025; 21:289-300. [PMID: 39779950 DOI: 10.1038/s41574-024-01077-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/28/2024] [Indexed: 01/11/2025]
Abstract
Immune-related adverse events (irAEs), including endocrine irAEs, can occur in response to cancer immunotherapy using immune checkpoint inhibitors (ICIs). Of the endocrine irAEs, pituitary and thyroid irAEs are most frequently observed, followed by primary adrenal insufficiency, type 1 diabetes mellitus and hypoparathyroidism. Notably, pituitary irAEs and type 1 diabetes mellitus can be lethal if overlooked, potentially leading to adrenal crisis and diabetic ketoacidosis, respectively. On the other hand, pituitary and thyroid irAEs are reported to be associated with more favourable prognoses in some cancers if treated appropriately with hormone-replacement therapies. It would be useful to identify those people who are likely to develop endocrine irAEs before initiating therapy with ICIs. Anti-pituitary antibodies and thyroid autoantibodies have been identified as potential biomarkers for the development of pituitary and thyroid irAEs, respectively. This Review elaborates on the clinical characteristics and management strategies of several endocrine irAEs, using the latest research findings and guidelines published by several academic societies.
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Affiliation(s)
- Shintaro Iwama
- Department of Endocrinology and Diabetes, Nagoya University Hospital, Nagoya, Japan.
| | - Tomoko Kobayashi
- Department of Endocrinology and Diabetes, Nagoya University Hospital, Nagoya, Japan
| | - Hiroshi Arima
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.
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Yu R, Ji X, Zhang P, Zhang H, Qu H, Dong W. The potential of chimeric antigen receptor -T cell therapy for endocrine cancer. World J Surg Oncol 2025; 23:153. [PMID: 40264184 PMCID: PMC12012980 DOI: 10.1186/s12957-025-03745-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 03/07/2025] [Indexed: 04/24/2025] Open
Abstract
Endocrine cancer, a relatively rare and heterogeneous tumor with diverse clinical features. The facile synthesis of hormones further complicates endocrine cancer treatment. Thus, the development of safe and effective systemic treatment approaches, such as chimeric antigen receptor (CAR) T cell therapy, is imperative to enhance the prognosis of patients with endocrine cancer. Although this therapy has achieved good results in the treatment of hematological malignancies, it encounters diverse complications and challenges in the context of endocrine cancer. This review delineates the generation of CAR-T cells, examines the potential of CAR-T cell therapy for endocrine cancer, enumerates pivotal antigens linked to endocrine cancer, encapsulates the challenges confronted with CAR-T cell therapy for endocrine cancer, and expounds upon strategies to overcome these limitations. The primary objective is to provide insightful perspectives that can contribute to the advancement of CAR-T cell therapy in the field of endocrine cancer.
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Affiliation(s)
- Ruonan Yu
- Department of Thyroid Surgery, The First Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang, Liaoning, 110001, China
| | - Xiaoyu Ji
- Department of Thyroid Surgery, The First Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang, Liaoning, 110001, China
| | - Ping Zhang
- Department of Thyroid Surgery, The First Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang, Liaoning, 110001, China
| | - Hao Zhang
- Department of Thyroid Surgery, The First Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang, Liaoning, 110001, China
| | - Huiling Qu
- Department of Neurology, The General Hospital of Northern Theater Command, 83 Wen Hua Road, Shenyang, Liaoning, 110840, China.
| | - Wenwu Dong
- Department of Thyroid Surgery, The First Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang, Liaoning, 110001, China.
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12
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Mo Y, Qin Y, Li P, Wu M, Yu J, Chen D. Thyroxine alleviates interstitial lung disease induced by combined radiotherapy and immunotherapy. Cancer Lett 2025; 615:217504. [PMID: 39880326 DOI: 10.1016/j.canlet.2025.217504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 01/20/2025] [Accepted: 01/24/2025] [Indexed: 01/31/2025]
Abstract
Immune checkpoint blockade (ICB) combined with radiotherapy (RT) has improved patients survival, but also increased the risk of pulmonary adverse effects (AEs). Therefore, to explore potential drug targets for interstitial lung disease (ILD). We investigated the interaction of ICB and RT in pulmonary AEs using the disproportionality analysis and COX regression. Genome-wide association studies, transcriptome analysis, and vivo models highlighted the role of programmed death-ligand-1 (PD-L1) in ILD. Mendelian randomization analysis identified drug targets. Clinical data on pulmonary AEs in patients with non-small cell lung cancer (NSCLC) were used to validate the finding. Herein, we confirmed ICB combined with RT posed the highest risk of pulmonary AEs, with reporting odds ratio of interaction effect was 3.727. Anti-PD-L1 posed a greater risk of pulmonary AEs compared to anti-PD-1 (Hazard Ratio = 9.355) or anti-cytotoxic lymphocyte antigen-4 (CTLA-4) (Hazard Ratio = 6.985). In vivo study, PD-L1 expression in radiation induced lung injury negatively correlated with collagen deposition. Notably, thyroid hormone receptors were identified as drug targets for ILD. Our results demonstrate that thyroxine exerts a significant inhibitory effect on pulmonary fibrosis progression. Clinical evidence robustly supports the correlation between thyroid function and ILD. These findings highlight the importance of PD-L1 and thyroxine in understanding and managing ILD.
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Affiliation(s)
- You Mo
- Laboratory of Molecular Cardiology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China; Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yiwei Qin
- Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China; Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Pengwei Li
- Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Meng Wu
- Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Jinming Yu
- Laboratory of Molecular Cardiology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China; Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China; Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
| | - Dawei Chen
- Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
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Sakaue TA, Obata Y, Sakai K, Onishi A, Mukai K, Miyashita K, Kozawa J, Nishizawa H, Shimomura I. Immune checkpoint inhibitor-related type 1 diabetes mellitus with closely monitored dynamics of glutamic acid decarboxylase antibody levels before and after disease onset. Diabetol Int 2025; 16:427-431. [PMID: 40166447 PMCID: PMC11954774 DOI: 10.1007/s13340-025-00795-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 01/15/2025] [Indexed: 04/02/2025]
Abstract
Immune checkpoint inhibitor (ICI)-related type 1 diabetes mellitus (T1DM) is a severe immune-related adverse event (irAE), occurring in < 1% of cases. ICI-related T1DM typically progresses more rapidly than conventional acute-onset T1DM, but is slower than conventional fulminant T1DM, suggesting different processes of onset and progression. Positivity rates for glutamic acid decarboxylase (GAD) antibodies differ, with ICI-related T1DM showing a lower positivity rate than conventional acute-onset T1DM. However, no detailed follow-up studies have examined the GAD antibody levels before and after the onset of ICI-related T1DM. We report the case of a 58-year-old Japanese man with type 2 diabetes mellitus diagnosed with renal carcinoma and multiple lung metastases. Chemotherapy with pembrolizumab (an anti-programmed death-1 antibody) was initiated. On the first day of treatment, the patient's insulin secretion capacity was preserved, and GAD antibodies were negative. Thirty-four days after chemotherapy initiation, the patient developed diabetic ketoacidosis and was diagnosed with ICI-related T1DM. Interestingly, GAD antibodies became positive (17.7 U/mL) approximately one month after the initial ICI administration. Subsequently, GAD antibody levels declined rapidly, with negative conversion occurring in only 205 days (approximately 6.5 months). To the best of our knowledge, this is the first reported case of closely monitoring GAD antibody dynamics before and after the onset of ICI-related T1DM. Here, the dynamics of the GAD antibodies were clearly distinct from those in conventional acute-onset T1DM. This case report may provide valuable insights into the differences between the autoimmune responses of ICI-related and conventional T1DM in their disease onset and progression.
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Affiliation(s)
- Taka-aki Sakaue
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamada-Oka, Suita, Osaka 565-0871 Japan
| | - Yoshinari Obata
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamada-Oka, Suita, Osaka 565-0871 Japan
| | - Kumiko Sakai
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamada-Oka, Suita, Osaka 565-0871 Japan
| | - Ayano Onishi
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamada-Oka, Suita, Osaka 565-0871 Japan
| | - Kosuke Mukai
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamada-Oka, Suita, Osaka 565-0871 Japan
| | - Kazuyuki Miyashita
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamada-Oka, Suita, Osaka 565-0871 Japan
| | - Junji Kozawa
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamada-Oka, Suita, Osaka 565-0871 Japan
- Department of Diabetes Care Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita, Osaka 565-0871 Japan
| | - Hitoshi Nishizawa
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamada-Oka, Suita, Osaka 565-0871 Japan
- Department of Metabolism and Atherosclerosis, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita, Osaka 565-0871 Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamada-Oka, Suita, Osaka 565-0871 Japan
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Gasimova Z, Khandanpour C, Luley K, von Bubnoff NCC. [Which Immunotherapies are Standard Today? And What Side Effects Should be Expected?]. Zentralbl Chir 2025; 150:170-174. [PMID: 40199376 DOI: 10.1055/a-2544-9630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/10/2025]
Abstract
In comparison to earlier treatment standards (including chemotherapy, radiation therapy, and surgery), immunotherapy has significantly improved patients' survival and quality of life. Immunotherapy is ultimately a broad term that encompasses a variety of therapeutics. Immunotherapeutic approaches have firmly established themselves as a new pillar of cancer care, ranging from neoadjuvant and adjuvant strategies to the metastatic phase in various entities. In this review article, we highlight which immunotherapies are currently standard in oncological care, with a strong focus on immune checkpoint inhibitors (ICIs), their limitations, and the commonly occurring side effects.
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Affiliation(s)
| | - Cyrus Khandanpour
- Klinik für Hämatoonkologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Deutschland
| | - Kim Luley
- Klinik für Hämatoonkologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Deutschland
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15
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Marsiglio J, McPherson J, Wahl M, Hu-Lieskovan S. Pembrolizumab-induced acquired lipodystrophy: a case report and review of the literature. Melanoma Res 2025; 35:109-114. [PMID: 39704080 DOI: 10.1097/cmr.0000000000000998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2024]
Abstract
Acquired generalized lipodystrophy (AGL) is a rare complication of immune checkpoint inhibitors (ICIs) and is associated with immune-mediated loss of adipose tissue, peripheral resistance to insulin, and serious metabolic complications. Here we report a new case of ICI-induced AGL and provide an updated literature review of published cases. We report a 39-year-old female patient treated with adjuvant pembrolizumab for stage IIIC nevoid melanoma with ICI-induced AGL. After six cycles of pembrolizumab, she developed a 40 lb weight loss with fat wasting, a decreased leptin level, significant liver function abnormalities, hepatic steatosis, hypertriglyceridemia, and subsequently was found to have severe insulin dependence and resistance. No corticosteroids were given and pembrolizumab was discontinued. AGL persists at 3-year follow up and patient remains free of melanoma progression. Literature review identified an additional seven patients who developed ICI-induced acquired lipodystrophy, predominantly female. Of the identified cases, three patients received steroids without resolution of their acquired lipodystrophy, while one patient had resolution without steroid treatment. Five patients and our case were treated with ICIs for melanoma, and all had at least a partial response to treatment. ICI-induced acquired lipodystrophy is an exceedingly rare event with profound clinical consequences. Our case report and literature review better characterized the clinical course and treatment outcomes of these patients. With the increasing utilization of ICIs in treating cancer, further studies to better understand the underlying mechanism and to guide clinical management of the metabolic complications are needed.
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Affiliation(s)
- John Marsiglio
- Department of Medicine, School of Medicine, University of Utah
| | - Jordan McPherson
- Huntsman Cancer Institute
- Department of Pharmacotherapy, College of Pharmacy
| | - Matthew Wahl
- Department of Endocrinology, School of Medicine, University of Utah, Salt Lake City, Utah, USA
| | - Siwen Hu-Lieskovan
- Department of Medicine, School of Medicine, University of Utah
- Huntsman Cancer Institute
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Maccio U, Wicki A, Ruschitzka F, Beuschlein F, Wolleb S, Varga Z, Moch H. Frequency and Consequences of Immune Checkpoint Inhibitor-Associated Inflammatory Changes in Different Organs: An Autopsy Study Over 13 -Years. Mod Pathol 2025; 38:100683. [PMID: 39675428 DOI: 10.1016/j.modpat.2024.100683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 11/21/2024] [Accepted: 11/27/2024] [Indexed: 12/17/2024]
Abstract
Although immune checkpoint inhibitors (ICIs) have revolutionized modern oncology, they are also associated with immune-related adverse events (irAEs). Previous histopathologic descriptions of organ-related inflammatory changes do not consider systemic effects of ICIs, because of the absence of comprehensive autopsy studies. We performed a retrospective study on 42 whole-body autopsies of patients treated with ICIs from January 2011 to March 2024 to determine the frequency, organ distribution, and morphology of ICI-associated inflammatory changes as well as their clinical relevance. Twenty-three of 42 (54.8%) patients presented irAEs with inflammatory changes in at least one organ. Most frequent irAEs were ICI-related hypophysitis (N = 12; 28.6%), myocarditis (N = 8; 19.0%), pneumonitis (N = 5; 11.9%), hepatitis (N = 6; 14.3%), and adrenalitis (N = 5; 11.9%). ICI-related inflammation was mainly characterized by lymphohistiocytic and macrophage-rich tissue infiltrates, whereas a granulomatous "sarcoid-like" reaction was observed in 1 patient. Cause of death was attributable to ICI therapy in 7 (16.7%) patients, with ICI-associated myocarditis as the most common cause of death (N = 5; 71.4%). Clinically, irAEs were unsuspected in 5 of 7 ICI-related deaths (71.4%). Among irAEs, myocarditis has been clinically undiagnosed in 5 out of 8 cases (62.5%). Encephalitis was identified only at autopsy in all cases (N = 2). Hypophysitis was clinically unsuspected in 8 of 12 (66.7%) cases. Patients who died from irAEs developed more frequently a complete tumor regression than patients who died from other causes (P = .018). Of note, ICI-related myocarditis and pneumonitis were both associated with a systemic occurrence irAEs. Our study demonstrates that some irAEs, especially myocarditis, hypophysitis, and encephalitis, are clinically underdiagnosed. Autopsy remains a valuable tool to monitor diagnostic accuracy and therapeutic side effects in patients who died under ICI therapy.
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Affiliation(s)
- Umberto Maccio
- Department of Pathology and Molecular Pathology, University Hospital of Zurich, Zurich, Switzerland.
| | - Andreas Wicki
- Department of Medical Oncology and Hematology, University Hospital of Zurich, Zurich, Switzerland; University of Zurich, Zurich, Switzerland
| | - Frank Ruschitzka
- University of Zurich, Zurich, Switzerland; Department of Cardiology, University Heart Center, University Hospital of Zurich and University of Zurich, Zurich, Switzerland; Department of Cardiology, Center for Translational and Experimental Cardiology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland
| | - Felix Beuschlein
- University of Zurich, Zurich, Switzerland; Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital of Zurich, Zurich, Switzerland; The LOOP Zurich-Medical Research Center, Zurich, Switzerland
| | - Sibylle Wolleb
- Division of Medical Oncology, Hospital of Uster, Uster, Switzerland
| | - Zsuzsanna Varga
- Department of Pathology and Molecular Pathology, University Hospital of Zurich, Zurich, Switzerland
| | - Holger Moch
- Department of Pathology and Molecular Pathology, University Hospital of Zurich, Zurich, Switzerland; University of Zurich, Zurich, Switzerland
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Fang W, Wang H, Zhang X, Zhu H, Yan W, Gao Y. Immune checkpoint inhibitors-induced pancreatitis: a systematic review and real-world pharmacovigilance analysis. Front Pharmacol 2025; 16:1426847. [PMID: 40176908 PMCID: PMC11962026 DOI: 10.3389/fphar.2025.1426847] [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: 05/02/2024] [Accepted: 02/25/2025] [Indexed: 04/05/2025] Open
Abstract
Purpose Immune checkpoint inhibitors-induced pancreatitis (ICIs-P) is an uncommon immune-related adverse event. The available evidence consists mostly of case reports, case series, and narrative reviews. This research focuses on the clinical characteristics and management options for ICIs-P to provide a practice-based global perspective on this disease. Methods Five electronic databases were systematically reviewed to identify the relevant studies. Furthermore, we performed a disproportionality analysis utilizing OpenVigil 2.1 to interrogate the United States Food and Drug Administration's Adverse Event Reporting System (FAERS) database. Results A total of 61 patients from 58 studies were included in this study. Most patients with ICIs-P were males (60.7%). Most patients received anti-PD-1/PD-L1 monotherapy (78.7%) or anti-PD-1/PD-L1 monotherapy in conjunction with CTLA-4 blockade (19.7%). The median time from the initiation of immune checkpoint inhibitors treatment to pancreatitis was 108 days (range 52-278). Most cases were severe or life-threatening (G3-G4; 64.0%). Corticosteroids were administered to 73.8% of the patients during the treatment of pancreatitis. Regarding treatment outcomes, ICIs-P was reversible in most cases (83.6%), despite the 8.2% relapse and 8.2% deaths. We identified 606 reports of pancreatitis associated with ICIs in the FAERS database, with the greatest proportion of males (50.7%), 62.0% of PD-1 inhibitors, and 22.1% of all reports of death or life-threatening outcomes. Signals indicating pancreatitis were observed across all ICIs, with particular emphasis on Cemiplimab, Pembrolizumab and Nivolumab. Conclusion By using a pharmacovigilance database, we discovered an elevated risk of pancreatitis following ICIs therapy, especially with PD-1 inhibitors. Meanwhile, risk factors for ICIs-P remain poorly understood, and diagnosis is challenging. Which may manifest as asymptomatic elevated pancreatic enzyme levels or clinical pancreatitis. Patients with pancreatitis symptoms should have their lipase and amylase levels and radiology evaluated. Diagnosis should be made by excluding other causes. Steroids are the cornerstone of ICIs-P treatment and slow dose reduction is recommended to reduce recurrence.
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Affiliation(s)
- Wei Fang
- Department of Endocrinology, Chengdu Shuangliu Hospital of Traditional Chinese Medicine, Chengdu, China
| | - Huanping Wang
- Department of Endocrinology, Chengdu Shuangliu Hospital of Traditional Chinese Medicine, Chengdu, China
| | - Xiaoran Zhang
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hongxia Zhu
- Department of Endocrinology, Chengdu Shuangliu Hospital of Traditional Chinese Medicine, Chengdu, China
| | - Wei Yan
- Department of Endocrinology, Chengdu Shuangliu Hospital of Traditional Chinese Medicine, Chengdu, China
| | - Yang Gao
- Laboratory of Ultrasound Medicine, West China Hospital, Sichuan University, Chengdu, China
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Brumer RP, Angarita FA. Perioperative Considerations of Breast Cancer Neoadjuvant Treatments. Clin Breast Cancer 2025:S1526-8209(25)00050-3. [PMID: 40240236 DOI: 10.1016/j.clbc.2025.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 03/02/2025] [Accepted: 03/03/2025] [Indexed: 04/18/2025]
Abstract
Neoadjuvant treatment is increasingly being used in patients with breast cancer. Understanding the effects of neoadjuvant agents in the perioperative setting is crucial as it can affect morbidity. Understanding how these agents should be used to maximize optimal time to surgery is crucial as delays can negatively affective cancer outcomes. This review aims to discuss the perioperative considerations surgeons should be aware of prior to scheduling surgery for patients receiving chemotherapy, endocrine therapy, chemotherapy, targeted therapy, and immunotherapy.
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Affiliation(s)
- Robert P Brumer
- Department of Surgery, Houston Methodist Hospital, Houston, TX
| | - Fernando A Angarita
- Department of Surgery, Houston Methodist Hospital, Houston, TX; Division of Surgical Oncology and Gastrointestinal Surgery, Department of Surgery, Houston Methodist Hospital, Houston, TX.
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Sanji EW, Arrey Agbor DB, Orians M, Portnoy D. Onset of Type 1 Diabetes Mellitus Five Months After Pembrolizumab Therapy for Nodular Melanoma: A Case Report. Cureus 2025; 17:e80083. [PMID: 40190870 PMCID: PMC11970438 DOI: 10.7759/cureus.80083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/05/2025] [Indexed: 04/09/2025] Open
Abstract
Pembrolizumab and other immune checkpoint inhibitors (ICIs) have revolutionized the treatment of melanoma. Nonetheless, they have been linked to endocrinopathies and other immune-related adverse events (irAEs). A rare but potentially fatal side effect, ICI-induced type 1 diabetes mellitus (ICI-DM), usually develops during or soon after therapy. We underscore the significance of long-term monitoring for irAEs by presenting a case of delayed-onset ICI-DM, discovered five months after stopping pembrolizumab. Our case involves a 47-year-old male diagnosed with nodular melanoma (Breslow thickness, 7 mm; mitotic index, 3), who received adjuvant pembrolizumab for 12 months. Five months after completing therapy, he presented with polyuria and polydipsia and was diagnosed with diabetic ketoacidosis (DKA). Laboratory findings included an HbA1c of 8.3%, low C-peptide (0.49 ng/mL), and negative diabetes autoantibodies. He was diagnosed with pembrolizumab-induced type 1 diabetes and managed with IV insulin in the hospital before being discharged on basal insulin (Tresiba). This case highlights the risk of delayed-onset ICI-DM, even after ICI discontinuation. Clinicians should maintain a high index of suspicion for metabolic complications in ICI-treated patients and provide lifelong monitoring for diabetes.
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Affiliation(s)
- Eric Wah Sanji
- Internal Medicine, Magnolia Regional Health Center, Corinth, USA
| | | | - Mary Orians
- Oncology, West Cancer Center and Research Institute, Memphis, USA
| | - David Portnoy
- Oncology, West Cancer Center and Research Institute, Memphis, USA
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Kani ER, Karaviti E, Karaviti D, Gerontiti E, Paschou IA, Saltiki K, Stefanaki K, Psaltopoulou T, Paschou SA. Pathophysiology, diagnosis, and management of immune checkpoint inhibitor-induced diabetes mellitus. Endocrine 2025; 87:875-890. [PMID: 39316333 DOI: 10.1007/s12020-024-04050-5] [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: 06/16/2024] [Accepted: 09/14/2024] [Indexed: 09/25/2024]
Abstract
Immune Checkpoint Inhibitors (ICIs) have revolutionized cancer treatment, offering hope for patients with various malignancies. However, along with their remarkable anticancer effects, ICIs can also trigger immune-related adverse events (irAEs). One such noteworthy complication is the development of Diabetes Mellitus (DM), which particularly resembles Type 1 Diabetes Mellitus (T1DM). The aim of this review is to provide insights into the epidemiology, pathophysiology, diagnostic issues, and treatment considerations of ICI-induced DM (ICI-DM), emphasizing the importance of early recognition and management to mitigate adverse outcomes. Although still rare, the incidence has increased with the widespread use of ICIs, especially PD-1/PD-L1 blockers (from 0.2% to 1.9%). Factors affecting the development of ICI-DM, such as specific ICIs, patient demographics, and genetic predispositions, are discussed. The complex interplay between immune dysregulation and pancreatic β-cell destruction contributes to diagnostic challenges, with presentations varying from asymptomatic hyperglycemia to diabetic ketoacidosis (DKA). Management strategies prioritize meticulous glycemic and electrolyte regulation along with tailored intravenous insulin therapy in cases of DKA. DM remission is rare, therefore treatment with both long-acting insulin at bedtime and short-acting insulin before meals is needed in longterm. Total daily insulin requirements can be estimated at 0.3-0.4 units/kg/day for most patients as a starting dose.
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Affiliation(s)
- Eleni-Rafaela Kani
- Endocrine Unit and Diabetes Center, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Eleftheria Karaviti
- Endocrine Unit and Diabetes Center, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitra Karaviti
- Endocrine Unit and Diabetes Center, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Eleni Gerontiti
- Endocrine Unit and Diabetes Center, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Ioanna A Paschou
- First Department of Dermatology and Venereology, Andreas Syggros Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Katerina Saltiki
- Endocrine Unit and Diabetes Center, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Katerina Stefanaki
- Endocrine Unit and Diabetes Center, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Theodora Psaltopoulou
- Endocrine Unit and Diabetes Center, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Stavroula A Paschou
- Endocrine Unit and Diabetes Center, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
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Tang Y, Shi J, Wang L, Zhang Y, Xu L, Sun T. Development of a predictive model for immune‑related adverse events in patients with cancer. Oncol Lett 2025; 29:103. [PMID: 39736926 PMCID: PMC11683521 DOI: 10.3892/ol.2024.14849] [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: 07/18/2024] [Accepted: 11/25/2024] [Indexed: 01/01/2025] Open
Abstract
It is crucial to accurately identify patients with cancer at high risk for immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs). The present retrospective study analyzed the risk factors for irAEs in 992 patients with cancer treated with ICIs at Xi'an International Medical Center Hospital from December 2021 to December 2023. The patients were categorized into one group that experienced irAEs (n=276) and a control group (n=716) based on the occurrence of irAEs. The clinical characteristics of irAEs group (n=276) and control group (n=716) were analyzed to identify the risk factors of irAEs in patients with cancer. Multivariate regression analysis revealed significant differences between the two groups in terms of hypertension, primary cancer, metastasis, targeted drug combination and radiotherapy (P<0.05). A nomogram predictive model for irAEs was developed based on the relevant risk factors. The predictive model for irAEs in patients with cancer yielded an area under the receiver operating characteristic (ROC) curve of 0.672 (95% confidence interval: 0.630-0.714). In the validation set, the Hosmer-Lemeshow goodness-of-fit test demonstrated a favorable fit with a chi-square value of 0.787 and a P-value of 0.978. The developed predictive model can effectively identify high-risk patients with irAEs, facilitate early identification of irAEs, thereby optimizing the management strategies of irAEs, and ultimately improving the quality of life for patients.
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Affiliation(s)
- Yajuan Tang
- Department of Pharmacy, Xi'an International Medical Center Hospital, Xi'an, Shaanxi 710100, P.R. China
| | - Jinping Shi
- Department of Pharmacy, Xi'an International Medical Center Hospital, Xi'an, Shaanxi 710100, P.R. China
| | - Liping Wang
- Department of Pharmacy, Xi'an International Medical Center Hospital, Xi'an, Shaanxi 710100, P.R. China
| | - Yan Zhang
- Department of Pharmacy, Xi'an International Medical Center Hospital, Xi'an, Shaanxi 710100, P.R. China
| | - Liting Xu
- Department of Pharmacy, Xi'an International Medical Center Hospital, Xi'an, Shaanxi 710100, P.R. China
| | - Tao Sun
- Department of Pharmacy, The Second Affiliated Hospital of Air Force Medical University, Xi'an, Shaanxi 710038, P.R. China
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22
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Song P, Pan G, Zhang Y, Ni Y, Wang Q, Shi J, Peng Y, Jing R, Luo D. Prospects and Challenges of Immunotherapy for Thyroid Cancer. Endocr Pract 2025; 31:373-379. [PMID: 39631664 DOI: 10.1016/j.eprac.2024.11.012] [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: 08/16/2024] [Revised: 10/21/2024] [Accepted: 11/26/2024] [Indexed: 12/07/2024]
Abstract
BACKGROUND Thyroid cancer generally boasts a favorable prognosis; however, advanced and refractory cases exhibit aggressive characteristics and resistance to conventional therapies, necessitating the investigation of innovative treatment modalities. Immunotherapy, which harnesses the body's immune system to target cancer cells, has shown considerable promise for specific thyroid cancer subtypes. OBJECTIVE This review article aims to encapsulate the latest advancements in immunotherapy for thyroid cancer, examining its mechanisms, therapeutic efficacy, ongoing challenges, and the potential benefits of combination therapy approaches. METHODS An extensive literature review and critical analysis of clinical trial data were conducted to inform this synthesis. RESULTS The review reveals that immunotherapy strategies, encompassing immune checkpoint inhibitors, CAR-T cell therapy, tumor vaccines, and immunomodulators, are demonstrating efficacy in the treatment of thyroid cancer. Notably, checkpoint inhibitors have been particularly effective in anaplastic and poorly differentiated thyroid cancers, albeit with challenges such as treatment resistance and adverse effects. The application of CAR-T cell therapy, successful in hematologic cancers, provides a novel perspective for thyroid cancer treatment, although its efficacy in solid tumors requires further study. Additionally, research into tumor vaccines and immunomodulators is advancing, with preliminary evidence suggesting their therapeutic potential for thyroid cancer patients. CONCLUSION The recognition of the immune microenvironment's role in treatment responsiveness is pivotal for enhancing the care of thyroid cancer patients. This review underscores the significance of combination therapy as a means to optimize treatment outcomes and charts a course for future research endeavors to broaden the spectrum of effective treatment options available to thyroid cancer patients.
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Affiliation(s)
- Ping Song
- Department of Surgical Oncology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China
| | - Gang Pan
- Department of Surgical Oncology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China
| | - Yu Zhang
- Department of Surgical Oncology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China
| | - Yeqin Ni
- Department of Surgical Oncology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China
| | - Qianyu Wang
- The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jingjng Shi
- Department of Surgical Oncology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China
| | - You Peng
- Department of Surgical Oncology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China
| | - Ruirui Jing
- Department of Translational Medicine and Clinical Research, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
| | - Dingcun Luo
- Department of Surgical Oncology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China; The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China; College of Mathematical Medicine, Zhejiang Normal University, Jinhua, Zhejiang, China.
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23
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Yan X, Wang Y, Wu F, Zhou G, Shen J, Yu S. Comparison of camrelizumab, pembrolizumab, tislelizumab, and sintilimab as first-line treatment in patients with non-small cell lung cancer: a retrospective study. J Thorac Dis 2025; 17:859-871. [PMID: 40083528 PMCID: PMC11898342 DOI: 10.21037/jtd-24-1495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 12/20/2024] [Indexed: 03/16/2025]
Abstract
Background Immune checkpoint inhibitors (ICIs) have significantly altered the first-line treatment paradigm for non-small cell lung cancer (NSCLC) without driver gene alterations. The efficacy and safety of different programmed cell death protein-1 (PD-1) inhibitors in the treatment of advanced NSCLC in Chinese real-world clinical practice remain unclear. This study aimed to analyze the efficacy and safety of camrelizumab, pembrolizumab, tislelizumab, and sintilimab retrospectively as first-line treatment options for advanced NSCLC in Chinese real-world applications. Methods A total of 452 NSCLC patients treated with camrelizumab, pembrolizumab, tislelizumab, or sintilimab as first-line treatment between January 2019 and June 2023 in Jiangsu Cancer Hospital were retrospectively evaluated. Adverse events and patient responses were assessed using Common Terminology Criteria for Adverse Events v5.0 and Response Evaluation Criteria for Solid Tumors v1.1. The progression-free survival (PFS) was estimated using the Kaplan-Meier method or Cox survival regression model and compared using the log-rank test. Results There were no significant differences in objective response rate (ORR) and median progression-free survival (mPFS) among the camrelizumab, pembrolizumab, tislelizumab, and sintilimab groups (ORR: 43.0% vs. 40.5% vs. 49.3% vs. 51.0%, P=0.33; mPFS: 8.51 vs. 10.97 vs. 9.43 vs. 9.79 months, P=0.31). Similar incidences of immune-related adverse events (irAEs) at any grade were observed in different PD-1 inhibitors (P=0.21). Similarly, no statistically significant differences in the incidence of grade 3 and 4 irAEs were observed (P=0.63). The Cox proportional hazard modeling analysis suggested that physical performance, occurrence of irAEs were all connected with the prognosis. The type of PD-1 inhibitors was not an independent prognostic factor affecting PFS. Conclusions Camrelizumab, pembrolizumab, tislelizumab, and sintilimab possess similar efficacy as first-line treatment options for patients with advanced NSCLC in Chinese clinical practice. Any grade or grade ≥3 irAEs are comparable between the four PD-1 inhibitors.
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Affiliation(s)
- Xiaoqi Yan
- Department of Medical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Yizong Wang
- Department of Medical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
- Department of Oncology, Rizhao Hospital of TCM, Rizhao, China
| | - Fei Wu
- Department of Medical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Guoren Zhou
- Department of Medical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Jiannan Shen
- Department of Thoracic Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Shaorong Yu
- Department of Medical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
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24
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Yi XM, Cai HQ, Jiao Y. Programmed cell death receptor 1 inhibitor Pembrolizumab in the treatment of advanced gastric cancer. World J Gastrointest Surg 2025; 17:100257. [DOI: 10.4240/wjgs.v17.i2.100257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Revised: 12/18/2024] [Accepted: 12/25/2024] [Indexed: 01/22/2025] Open
Abstract
This editorial discusses Christodoulidis et al's article, which appeared in the most recent edition. The clinical trials have demonstrated the programmed cell death receptor 1 (PD-1) inhibitor Pembrolizumab involved combination therapy can improve the efficacy of advanced gastric cancer (AGC). Pembrolizumab combined with chemotherapy can enhance its sensitivity, and further eliminate tumor cells that develop resistance to chemotherapy. The combination of Pembrolizumab and Trastuzumab targeting human epidermal growth factor receptor 2 showed improved prognosis. The overall toxic effects of Pembrolizumab are significantly lower than traditional chemotherapy, and the safety is controllable. PD-1 inhibitor Pembrolizumab sheds a light on the treatment of AGC and brings new hope to the clinical practice.
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Affiliation(s)
- Xue-Mei Yi
- Department of Second Operation Room, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Hong-Qiao Cai
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Yan Jiao
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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25
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Zhao X, Wang X, Liu S, Cheng P, Chen J, Liu J. Severe thyroiditis induced by sintilimab monotherapy in a patient with non-small cell lung cancer: a case report and literature review. Front Immunol 2025; 16:1548452. [PMID: 40070833 PMCID: PMC11893825 DOI: 10.3389/fimmu.2025.1548452] [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: 12/19/2024] [Accepted: 02/06/2025] [Indexed: 03/14/2025] Open
Abstract
Thyroid dysfunction is a common immune-related adverse event (irAE) associated with immune checkpoint inhibitors (ICIs) that target PD-1, PD-L1, and CTLA-4. Nevertheless, the incidence of severe cases, defined as grade 3 or higher, remains rare. This report presents a detailed case study of severe thyroiditis in a patient with non-small cell lung cancer (NSCLC) who developed grade 3 thyroiditis following a single cycle of sintilimab monotherapy. The clinical presentation in this patient was remarkable for its early onset, occurring one week after the initiation of sintilimab therapy, and for its severe manifestations. During hospitalization, a prompt and accurate differential diagnosis was performed. Sintilimab treatment was discontinued, and the patient was promptly started on high-dose glucocorticoids, with a tapering schedule implemented as the condition improved or reached Common Terminology Criteria for Adverse Events (CTCAE) grade 1 or lower. The patient subsequently developed overt hypothyroidism, necessitating the initiation of thyroxine replacement therapy. Furthermore, we provide a comprehensive review of the mechanisms and risk factors associated with thyroid dysfunction immune-related adverse events (TD-irAEs). It is imperative for clinicians to meticulously monitor the clinical symptoms exhibited by patients. For those presenting with symptoms, prompt diagnosis and appropriate symptomatic management are essential. Additionally, regular thyroid function testing is recommended for high-risk patients, and we advocate for the assessment of baseline levels of thyroid peroxidase antibodies (TPOAb) and thyroglobulin antibodies (TGAb) prior to initiating ICI treatment.
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Affiliation(s)
- Xiaolin Zhao
- School of Clinical Medicine, Shandong Second Medical University, Weifang, China
| | - Xiaoyu Wang
- School of Clinical Medicine, Shandong Second Medical University, Weifang, China
| | - Surui Liu
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Pian Cheng
- School of Clinical Medicine, Shandong Second Medical University, Weifang, China
| | - Jinjuan Chen
- School of Clinical Medicine, Shandong Second Medical University, Weifang, China
| | - Jie Liu
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
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26
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Yuan M, Han N, Shu L, Yan L, Tang H. Case report: Multi-organ injuries induced by tislelizumab. Front Immunol 2025; 16:1508293. [PMID: 39967654 PMCID: PMC11832704 DOI: 10.3389/fimmu.2025.1508293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 01/13/2025] [Indexed: 02/20/2025] Open
Abstract
The use of immune checkpoint inhibitors (ICIs) often develops immune-related adverse events (irAEs). However, irAEs-induced multi-organ injuries remain a rare event. We herein report a case of multi-organ injuries induced by tislelizumab in a lung squamous cell carcinoma (LUSC) patient. A 68-year-old man had undergone neoadjuvant chemotherapy with paclitaxel, carboplatin, and tislelizumab. He presented with a 1-month history of nausea and poor appetite after the second dose of therapy. During investigations, rhabdomyolysis, liver, kidney, and thyroid damage were detected. After multi-disciplinary consultation, multi-organ injuries related to ICIs (striated muscle, liver, kidney, and thyroid) were considered to result from cumulated irAEs induced by tislelizumab. The patient was treated with levothyroxine, methylprednisolone, intravenous immunoglobulins, and continuous renal replacement therapy. After treatment, the patient recovered and was discharged from the hospital. The patient presented with multiple organ damage, not single immunity treatment adverse reactions, relatively rare. In clinical work, irAEs are likely not a single-system organ disorder and many kinds of attention need to be combined with the risk of multi-system damage.
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Affiliation(s)
- Man Yuan
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Ning Han
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Li Shu
- Department of Infectious Diseases, Suining Central Hospital, Suining, China
| | - Libo Yan
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
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27
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Rico-López D, Ortiz-Parra A, Vázquez-Alonso F, Roa-Chamorro R. Secondary adrenal insufficiency due to ipilimumab/nivolumab treatment for metastatic renal cancer. Rev Clin Esp 2025; 225:111-113. [PMID: 39694190 DOI: 10.1016/j.rceng.2024.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2024]
Affiliation(s)
- D Rico-López
- Medicina Interna, Hospital Universitario Virgen de las Nieves de Granada, Spain.
| | - A Ortiz-Parra
- Medicina Interna, Hospital Universitario Virgen de las Nieves de Granada, Spain
| | - F Vázquez-Alonso
- Urología, Hospital Universitario Virgen de las Nieves de Granada, Spain
| | - R Roa-Chamorro
- Medicina Interna, Hospital Universitario Virgen de las Nieves de Granada, Spain
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28
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Westermann CR, Davidson TB, Waters K, Margol AS, Cheung CC. Immune checkpoint inhibitors and endocrinopathies in pediatric brain tumor patients. J Pediatr Endocrinol Metab 2025; 38:58-64. [PMID: 39680426 PMCID: PMC11832116 DOI: 10.1515/jpem-2024-0243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 10/17/2024] [Indexed: 12/17/2024]
Abstract
OBJECTIVES Immune checkpoint inhibitors (ICIs) are emerging treatment options for children with brain tumors, who are already at risk for developing endocrinopathies due to tumor location and treatment. Endocrine ICI-related adverse effects (irAEs) are common in adults but poorly characterized in the pediatric population. The aims of this study were to determine in pediatric brain tumor patients in a single institution (1) if endocrine surveillance took place before and after ICIs were initiated, and (2) the occurrence of endocrine irAEs. METHODS This is a retrospective chart review of 22 pediatric brain tumor patients treated with ICIs at Children's Hospital Los Angeles between 2010 and 2022. We analyzed endocrine laboratory results, patient demographics, and treatment course. RESULTS Most patients (82 %) received surveillance in at least one endocrine system before ICI treatment - all had thyroid function tested (100 %) whereas non-thyroid endocrine functions were seldomly assessed (6-22 %). Only those patients with surveillance prior to treatment had ongoing surveillance after ICI initiation - 100 % for thyroid function and 17-39 % for other endocrine systems. Hypothyroidism was the only endocrine problem diagnosed after ICI initiation, in two patients (9 %). Of note, most patients (68 %) expired during or shortly after ICI treatment. CONCLUSIONS This is one of the first institutional surveys of pediatric ICIs in a high-volume pediatric brain tumor center. Thyroid surveillance commonly occurred in pediatric patients, revealing diagnoses of hypothyroidism, which is consistent with adult data. However, little information is available for non-thyroid endocrine conditions, reflecting the need for comprehensive and systematic endocrine surveillance.
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Affiliation(s)
- Carly R. Westermann
- Frank H. Netter MD School of Medicine at Quinnipiac University, North Haven, CT, USA
| | - Tom B. Davidson
- Cancer and Blood Disease Institute and Division of Hematology and Oncology, Children’s Hospital Los Angeles, Los Angeles, CA, USA; and Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Kaaren Waters
- Cancer and Blood Disease Institute and Division of Hematology and Oncology, Children’s Hospital Los Angeles, Los Angeles, CA, USA
| | - Ashley S. Margol
- Cancer and Blood Disease Institute and Division of Hematology and Oncology, Children’s Hospital Los Angeles, Los Angeles, CA, USA; and Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Clement C. Cheung
- The Division for Endocrinology, Diabetes, and Metabolism, Children’s Hospital Los Angeles 4650 Sunset Blvd, MS#61 90027, Los Angeles, CA, USA; and Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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29
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Di Stasi V, La Sala D, Cozzi R, Scavuzzo F, De Geronimo V, Poggi M, Vitale M, Tortora A. Immunotherapy-Related Hypophysitis: A Narrative Review. Cancers (Basel) 2025; 17:436. [PMID: 39941803 PMCID: PMC11815778 DOI: 10.3390/cancers17030436] [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: 11/30/2024] [Revised: 01/17/2025] [Accepted: 01/23/2025] [Indexed: 02/16/2025] Open
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized oncology, providing a groundbreaking therapeutic option for patients with various advanced-stage cancers. While these treatments can significantly extend survival, they also carry a substantial risk of immune-related adverse events, among which hypophysitis is particularly detrimental to endocrine function. This narrative review synthesizes current knowledge on the pathogenesis, clinical features, diagnosis, and management of ICI-induced hypophysitis (IH) based on an in-depth analysis of the recent literature and clinical trials. The diagnosis of IH presents unique challenges due to its overlap with systemic symptoms commonly associated with the underlying malignancy. These symptoms can include asthenia, anorexia, headache, vomiting, weight loss, hypotension, dizziness, decreased libido, and visual disturbances. Diagnostic evaluation typically combines clinical assessment, hormonal profiling, and findings from magnetic resonance imaging (MRI). Effective management of IH requires a personalized, multidisciplinary approach, focusing on hormone replacement therapy and vigilant monitoring. Long-term care depends on the severity of hypophysitis, and the specific hormonal axes involved. This review aims to enhance awareness of the critical aspects of recognizing and managing IH, underscoring the importance of early diagnosis and timely intervention to reduce its long-term effects on patient quality of life.
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Affiliation(s)
- Vincenza Di Stasi
- Center of Nutrition for the Research and the Care of Obesity and Metabolic Diseases, National Institute of Gastroentherology IRCCS Saverio De Bellis, 70013 Castellana Grotte, Italy;
| | - Domenico La Sala
- UOSD Malattie Endocrine Nutrizione e Ricambio, AORN, San Giuseppe Moscati, 83100 Avellino, Italy
| | - Renato Cozzi
- Endocrine Unit Grande Ospedale Metropolitano, Niguarda, 20162 Milano, Italy;
| | | | | | - Maurizio Poggi
- UOC Medicina Specialistica Endocrino-Metabolica, AOU Sant’Andrea, 00189 Roma, Italy;
| | - Mario Vitale
- Dipartimento di Medicina, Chirurgia e Odontoiatria, Università di Salerno, 84081 Baronissi, Italy;
| | - Anna Tortora
- UOC Clinica Endocrinologica e Diabetologica, AOU San Giovanni di Dio e Ruggi d’Aragona, 84131 Salerno, Italy
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30
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Zhao L, Gui Y, Cai J, Deng X. Biometallic ions and derivatives: a new direction for cancer immunotherapy. Mol Cancer 2025; 24:17. [PMID: 39815289 PMCID: PMC11734411 DOI: 10.1186/s12943-025-02225-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 01/01/2025] [Indexed: 01/18/2025] Open
Abstract
Biometallic ions play a crucial role in regulating the immune system. In recent years, cancer immunotherapy has become a breakthrough in cancer treatment, achieving good efficacy in a wide range of cancers with its specificity and durability advantages. However, existing therapies still face challenges, such as immune tolerance and immune escape. Biometallic ions (e.g. zinc, copper, magnesium, manganese, etc.) can assist in enhancing the efficacy of immunotherapy through the activation of immune cells, enhancement of tumor antigen presentation, and improvement of the tumor microenvironment. In addition, biometallic ions and derivatives can directly inhibit tumor cell progression and offer the possibility of effectively overcoming the limitations of current cancer immunotherapy by promoting immune responses and reducing immunosuppressive signals. This review explores the role and potential application prospects of biometallic ions in cancer immunotherapy, providing new ideas for future clinical application of metal ions as part of cancer immunotherapy and helping to guide the development of more effective and safe therapeutic regimens.
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Affiliation(s)
- Lin Zhao
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 41001l, China
- Hunan Clinical Medical Research Center for Cancer Pathogenic Genes Testing and Diagnosis, Changsha, Human, 410011, China
| | - Yajun Gui
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 41001l, China
- Hunan Clinical Medical Research Center for Cancer Pathogenic Genes Testing and Diagnosis, Changsha, Human, 410011, China
| | - Jing Cai
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 41001l, China
- Hunan Clinical Medical Research Center for Cancer Pathogenic Genes Testing and Diagnosis, Changsha, Human, 410011, China
| | - Xiangying Deng
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 41001l, China.
- Hunan Clinical Medical Research Center for Cancer Pathogenic Genes Testing and Diagnosis, Changsha, Human, 410011, China.
- Institute of Medical Sciences, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
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31
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Argente J, Farooqi IS, Chowen JA, Kühnen P, López M, Morselli E, Gan HW, Spoudeas HA, Wabitsch M, Tena-Sempere M. Hypothalamic obesity: from basic mechanisms to clinical perspectives. Lancet Diabetes Endocrinol 2025; 13:57-68. [PMID: 39547253 DOI: 10.1016/s2213-8587(24)00283-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 08/31/2024] [Accepted: 09/02/2024] [Indexed: 11/17/2024]
Abstract
Despite the diverse nature of obesity, there is compelling genetic, clinical, and experimental evidence that endorses the important contribution of brain circuits to this condition. The hypothalamus contains major regulatory circuits for bodyweight homoeostasis, the deregulation of which can lead to obesity. Although functional perturbation of hypothalamic pathways could lie at the basis of common forms of obesity, the term hypothalamic obesity has been created to define those rare forms of severe obesity where a clear hypothalamic substrate can be identified, either of genetic or acquired origin. An in-depth understanding of the pathogenesis, clinical presentation, and therapeutic targets of hypothalamic obesity relies on the comprehension of the physiological basis of hypothalamic pathways governing bodyweight control, the mechanisms (either genetic or acquired) whereby they are perturbed, and the consequences of such perturbation. In this Review, we provide a synoptic overview of hypothalamic obesity, from basic mechanisms to clinical perspectives, with a major focus on current developments and new avenues for the diagnosis and precise treatment of these rare forms of obesity.
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Affiliation(s)
- Jesús Argente
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain; IMDEA-Food Institute, Madrid, Spain; Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.
| | - I Sadaf Farooqi
- Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Julie A Chowen
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain; IMDEA-Food Institute, Madrid, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Peter Kühnen
- Department of Pediatric Endocrinology, Charité-Universitätsmedizin Berlin, Berlin, Germany; German Centre for Child and Adolescent Health, Berlin, Germany
| | - Miguel López
- CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain; Department of Physiology, CiMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Eugenia Morselli
- Department of Basic Sciences, Faculty of Medicine and Sciences, Universidad San Sebastián, Santiago, Chile
| | - Hoong-Wei Gan
- UCL Great Ormond Street Institute of Child Health, London, UK; Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Helen A Spoudeas
- Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK; SUCCESS Charity, London, UK
| | - Martin Wabitsch
- German Centre for Child and Adolescent Health, Berlin, Germany; Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, Ulm University Medical Centre, Ulm, Germany
| | - Manuel Tena-Sempere
- CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain; Instituto Maimónides de Investigación Biomédica de Córdoba, Córdoba, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain.
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Meng K, Fu S, Huang Y, Chen W, Zou W. Fulminant type 1 diabetes mellitus: a neglected but high-risk adverse event associated with immune checkpoint inhibitors. Expert Opin Drug Saf 2024:1-8. [PMID: 39714126 DOI: 10.1080/14740338.2024.2446422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 10/06/2024] [Accepted: 10/18/2024] [Indexed: 12/24/2024]
Abstract
BACKGROUND Immune checkpoint inhibitor (ICI) therapy has revolutionized cancer treatment but is associated with fulminant type 1 diabetes mellitus (FT1DM). Our study aims to investigate the association between ICI therapy and FT1DM using the FDA Adverse Event Reporting System (FAERS) database. METHODS We conducted a retrospective analysis from the first quarter of 2004 to the first quarter of 2023. The disproportionality analysis incorporating the reporting odds ratio (ROR) and information component (IC) was performed to assess the magnitude of the adverse event signal between ICIs and FT1DM. RESULTS A total of 520 cases of FT1DM were identified in association with ICI therapy, representing 75.9% of all FT1DM cases reported in the FAERS database. Descriptive analyses revealed a predominance in males (60.2%) and the elderly (70.6%). The median time to onset was 69 days and 337 patients (64.81%) were hospitalized while 35 (6.73%) cases resulted in death. Disproportionality analysis showed a strong signal for FT1DM with ICI treatment (ROR 438.84) versus other drugs. CONCLUSION These findings provide compelling evidence linking ICI therapy to the development of FT1DM, underscoring the need for clinical vigilance and early intervention strategies to optimize patient outcomes while leveraging the remarkable therapeutic potential of cancer immunotherapy.
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Affiliation(s)
- Kelin Meng
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shengling Fu
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yaochen Huang
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Chen
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenbin Zou
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Ata F, Khan AA, Algorani E, Alsharafi AFM, Shdid RA, Nofal M, Ibrahim AR, Abdullah L, Annan KYE, Al-Bkoor TEH, Rasul KI, Elhadd T, Surchi H. The burden and clinical trajectory of immune checkpoint inhibitor-induced endocrinopathies: an 8-year experience. BMC Med 2024; 22:588. [PMID: 39695571 DOI: 10.1186/s12916-024-03812-2] [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: 03/21/2024] [Accepted: 12/10/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have revolutionized the management of cancer patients, but the emergence of ICI-related endocrinopathies (IREs) has introduced new clinical challenges. Despite worldwide recognition of these adverse effects, data from the Middle East is scarce. METHODS This retrospective-observational study included adult cancer patients who received at least one dose of ICI between January 2015 and January 2023. Descriptive statistics and multivariable regression (MVR) models were applied to delineate the incidence and clinical impact of IREs. RESULTS The median age of 649 included patients was 55 years, with male preponderance (70.7%). The incidence of IREs was 26.7%, dominated by primary hypothyroidism (62.4%), insulin deficiency (15%), and primary hyperthyroidism (13.9%). Pembrolizumab (62%) was the most utilized ICI among the study cohort, followed by nivolumab (23.7%), atezolizumab (12.5%), durvalumab (0.9%), avelumab (0.6%) and ipilimumab (0.1%). The mortality rates in the cohort and the IRE subgroup were 43.4% and 42.2%. MVR revealed age (OR 1.02, 95% CI (1.003-1.03), P = 0.02), pre-ICI white-cell (WBC) count (OR 0.94, 95% CI (0.89-0.99), P = 0.04), pembrolizumab (OR 2.6, 95% CI (1.05-6.3), P = 0.04), and nivolumab use (OR 2.6, 95% CI (1.04-6.6), P = 0.04) as significant predictors of IREs. After MVR, factors influencing mortality in the subgroup with IREs included a higher age (OR 1.1, 95% CI 1.04-1.2, P = 0.001) and platelet-to-lymphocyte ratio (OR 1.004, 95% CI 0.7-1.4, P = 0.006). CONCLUSIONS This first extensive Middle Eastern and South Asian cohort reported a higher-than-previously known incidence of IREs. Hypothyroidism, insulin deficiency, and hyperthyroidism were the commonest IREs, with pembrolizumab being the commonest ICI. IRE development was associated with higher age, a low WBC count, pembrolizumab, and nivolumab use. The development of IREs did not seem to influence mortality. Further research on IREs is imperative to optimize management guidelines in the era of precision medicine.
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Affiliation(s)
- Fateen Ata
- Department of Endocrinology, Hamad General Hospital, Hamad Medical Corporation, PO BOX 3050, Doha, Qatar.
| | - Adeel Ahmad Khan
- Department of Endocrinology, Hamad General Hospital, Hamad Medical Corporation, PO BOX 3050, Doha, Qatar
| | - Emad Algorani
- Department of Internal Medicine, Hamad Medical Corporation, Doha, Qatar
| | | | - Reham Abo Shdid
- Department of Geriatric Medicine, Hamad Medical Corporation, Doha, Qatar
| | - Mohammad Nofal
- Department of Internal Medicine, Hamad Medical Corporation, Doha, Qatar
| | - Ayman R Ibrahim
- Department of Internal Medicine, Hamad Medical Corporation, Doha, Qatar
| | - Loai Abdullah
- Department of Internal Medicine, Hamad Medical Corporation, Doha, Qatar
| | | | | | - Kakil Ibrahim Rasul
- Department of Oncology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Tarik Elhadd
- Department of Endocrinology, Hamad General Hospital, Hamad Medical Corporation, PO BOX 3050, Doha, Qatar
| | - Haval Surchi
- Department of Endocrinology, Hamad General Hospital, Hamad Medical Corporation, PO BOX 3050, Doha, Qatar
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Sui X, Danzeng D, Ni P, Geng J, Gesang P, Zhaxi R, Wei Y. Neoadjuvant immunotherapy plus chemotherapy in high altitude natives with resectable esophageal squamous cell carcinoma in Tibet. Asian J Surg 2024:S1015-9584(24)02761-1. [PMID: 39645490 DOI: 10.1016/j.asjsur.2024.11.134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 11/09/2024] [Accepted: 11/18/2024] [Indexed: 12/09/2024] Open
Abstract
BACKGROUD Neoadjuvant therapy followed by surgery has been proved to improve the survival of patients with ESCC, and neoadjuvant chemoradiotherapy (nCRT) is the standard of care in most areas of the world. However, multimodality therapy including radiation therapy is actually limited in the current treatment of esophageal cancer in Tibet. The role of neoadjuvant immunotherapy in resectable esophageal cancer has been assessed in multiple phase II clinical trials, but there's lack of evidence of applying neoadjuvant immunotherapy plus chemotherapy in Tibetan residents. METHODS Patients with previously treatment-naïve, resectable ESCC were included in this study. The preoperative treatment regimen included Tislelizumab, nab-paclitaxel and carboplatin. Surgery was planned for every patient who completed neoadjuvant treatment. Surgical approaches and extent of esophageal resection was chosen depended on tumor location. RESULTS 23 patients with resectable ESCC were included from January 2022 to May 2024 in this study. Among all patients, 5 (21.7 %) had thyroid nodules or dysfunction. 19 of 23 (82.6 %) patients finished 2-3 cycles of treatment. 19 (82.6 %) patients experienced treatment-related adverse events (TRAEs), with 11 (47.8 %) patients experiencing grade 3-4 TRAEs. Thyroid toxicity of grade 1-2 was observed in 12 (52.2 %) patients. The objective response rate (ORR) was 69.6 %, and the disease control rate (DCR) was 100 %.。14 (60.9 %) of 23 patients underwent surgery. All patients underwent R0 resection. The pCR rate was 21.4 %. The median follow-up was 22.4 months. During the follow-up period, there were no recurrences, but 3 patients died due to non-tumor-related causes. CONCLUSION Esophagectomy following neoadjuvant immunotherapy plus chemotherapy appears to be safe and feasible in high altitude natives with resectable esophageal squamous cell carcinoma in Tibet.
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Affiliation(s)
- Xizhao Sui
- Department of Thoracic Surgery, Peking University People's Hospital, China.
| | - Duoji Danzeng
- Department of Cardio-thoracic Surgery, The Tibet Autonomous Region People's Hospital, China
| | - Ping Ni
- Department of Cardio-thoracic Surgery, The Tibet Autonomous Region People's Hospital, China
| | - Jiayi Geng
- Department of Thoracic Surgery, Peking University People's Hospital, China
| | - Pingcuo Gesang
- Department of Cardio-thoracic Surgery, The Tibet Autonomous Region People's Hospital, China
| | - Renqing Zhaxi
- Department of Cardio-thoracic Surgery, The Tibet Autonomous Region People's Hospital, China
| | - Yuling Wei
- Department of Cardio-thoracic Surgery, The Tibet Autonomous Region People's Hospital, China
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Li L, Ding X, Zhang X, Kong S, Chen M. Clinical Significance of Thyroid Autoantibodies in Differential Diagnosis and Predicting the Course of Programmed Cell Death Protein-1 Inhibitor-Induced Thyroid Dysfunction. Endocr Pract 2024; 30:1166-1170. [PMID: 39216687 DOI: 10.1016/j.eprac.2024.08.012] [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: 07/01/2024] [Revised: 08/15/2024] [Accepted: 08/23/2024] [Indexed: 09/04/2024]
Abstract
OBJECTIVE Thyroid immune-related thyrotoxicosis is one of the most common adverse effects in patients treated with programmed cell death protein-1 (PD-1) inhibitors. We investigated the significance of levels of serum anti-thyroglobulin antibodies (TgAbs), anti-thyroid peroxidase antibodies (TPOAbs), and thyroid-stimulating hormone receptor antibodies (TRAbs) in the identification of anti-PD-1-induced thyroid thyrotoxicosis. METHODS We divided 161 patients with thyroid dysfunction who received PD-1 inhibitors at our hospital between January 2022 and June 2024 into 3 groups: primary hypothyroidism group, primary hyperthyroidism group, and destructive thyroiditis group. The characteristics of the 3 groups were determined, and the positivity rates of serum TgAbs, TPOAbs, and TRAbs were assessed. An additional 42 patients diagnosed with Hashimoto's thyroiditis were selected as the control group for PD-1 inhibition-induced destructive thyroiditis. Age, sex, and time of transition from thyrotoxicosis to hypothyroidism in the 2 groups were compared. RESULTS In the primary hypothyroidism group, only 1 case was TPOAbs-positive (1/1%). In the destructive thyroiditis group, the positivity rate for TPOAbs or TgAbs was 92.9%, and TPOAbs and TgAbs were negative in the primary hyperthyroidism group. TRAbs were undetectable in all 3 groups. There were statistically significant differences in age, sex, and time from thyrotoxicosis to hypothyroidism in the PD-1 induced destructive thyroiditis and Hashimoto's thyroiditis groups. CONCLUSIONS In patients with thyrotoxicosis caused by PD-1 inhibitors, serum TgAb, and TPOAb levels can be used to distinguish between primary hyperthyroidism and destructive thyroiditis. This study provides insights into novel treatment targets and effective management strategies for PD-1-induced thyrotoxicosis.
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Affiliation(s)
- Li Li
- Department of Clinical Laboratory, Taixing City People's Hospital, Taixing, China
| | - Xiaoxia Ding
- Department of Clinical Laboratory, Taixing City People's Hospital, Taixing, China
| | - Xihui Zhang
- Department of Clinical Laboratory, Taixing City People's Hospital, Taixing, China
| | - Shuangming Kong
- Anaesthesiology Department, Taixing City People's Hospital, Taixing, China.
| | - Ming Chen
- Department of Clinical Laboratory, Taixing City People's Hospital, Taixing, China.
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Fischer A, Martínez-Gómez JM, Mangana J, Dummer R, Erlic Z, Nölting S, Beuschlein F, Maurer A, Messerli M, Huellner MW, Skawran S. 18 F-FDG PET/CT for Detection of Immunotherapy-Induced Hypophysitis-A Case-Control Study. Clin Nucl Med 2024; 49:e656-e663. [PMID: 39325145 DOI: 10.1097/rlu.0000000000005440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/27/2024]
Abstract
PURPOSE Hypophysitis occurs in up to 10% of patients treated with immune-checkpoint inhibitors (ICIs). MRI shows no abnormalities of the pituitary gland in one third of patients. A delayed diagnosis increases the risk for life-threatening adrenal crisis, underscoring the need for early detection. This study evaluates the diagnostic accuracy FDG PET/CT in detecting ICI-induced hypophysitis in a cohort of melanoma patients. MATERIALS AND METHODS Patients with metastatic melanoma and ICI-induced hypophysitis, who underwent FDG PET/CT 90 days before to 10 days after diagnosis, were compared with an age- and sex-matched control group of patients undergoing ICI treatment without signs of hypophysitis. The ratio of SUV max of the pituitary gland to the SUV mean of the blood pool (target-to-background ratio [TBR]) was calculated. Diagnostic accuracy of the TBR was assessed using area under the receiver operating characteristics curve analysis. RESULTS A total of 28 patients was included. The majority of patients with hypophysitis received ipilimumab/nivolumab (64.3%, 9/14). Visual assessment of the TBR distribution demonstrated a positive correlation with decreasing time to diagnosis. To evaluate diagnostic performance, only patients with FDG PET/CT 50 days before to 8 days after diagnosis (11/14) were included. TBR was significantly higher in these compared with the control group (median [interquartile range], 2.78 [2.41] vs 1.59 [0.70], respectively; P = 0.034). A sensitivity of 72.7% and a specificity of 90.9% were achieved at a TBR threshold of 2.41 (area under the receiver operating characteristics curve = 0.769). CONCLUSIONS Our findings suggest that, in patients undergoing ICI treatment for metastatic melanoma, a pituitary TBR of approximately 2.4 may indicate impending ICI-induced hypophysitis.
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Wei XC, Guo YY, Zhang Y, Bu YS, Zhang FY. Factors associated with immune-related thyroid dysfunction induced by PD-1/PD-L1 inhibitors in cancer patients: an observational study. J Chemother 2024; 36:654-661. [PMID: 38240051 DOI: 10.1080/1120009x.2024.2305065] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 12/26/2023] [Accepted: 01/09/2024] [Indexed: 11/22/2024]
Abstract
This study aimed to identify the potential factors associated with immune thyroid dysfunction caused by programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors in cancer patients. We conducted a retrospective study of thyroid immune-related adverse events (irAEs) in cancer patients treated with PD-1/PD-L1 inhibitors at Tianjin First Central Hospital from January 2020 to March 2023. Thyroid irAEs were characterized as hypothyroidism, hyperthyroidism and thyrotoxicosis followed by hypothyroidism. A total of 175 patients were screened in the study, of whom 48 patients (27%) developed thyroid irAEs (including 24 hypothyroidism, 11 hyperthyroidism and 13 thyrotoxicosis followed by hypothyroidism) following PD-1/PD-L1 inhibitors treatment. Multivariate logistic regression analysis showed that combination therapy with PD-1/PD-L1 inhibitors and tyrosine kinase inhibitors (lenvatinib/regorafenib) and high baseline anti-TPO level were associated with the development of thyroid irAEs caused by PD-1/PD-L1 inhibitors. The nomogram models showed good discriminant ability and could bring net benefits for more patients according to the decision curve analysis. However, the model needs to be further validated in other large cohorts.
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Affiliation(s)
- Xiao-Chen Wei
- Department of Pharmacy, Tianjin First Central Hospital, Tianjin, P.R. China
| | - Yuan-Yuan Guo
- Department of Pharmacy, Tianjin First Central Hospital, Tianjin, P.R. China
| | - Yi Zhang
- Department of Pharmacy, Tianjin First Central Hospital, Tianjin, P.R. China
| | - Yi-Shan Bu
- Department of Pharmacy, Tianjin First Central Hospital, Tianjin, P.R. China
| | - Feng-Ying Zhang
- Department of Pharmacy, Tianjin First Central Hospital, Tianjin, P.R. China
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Justice J, Kankaria RA, Johnson DB. Immune checkpoint inhibition of metastatic melanoma: achieving high efficacy in the face of high toxicity. Expert Rev Clin Pharmacol 2024; 17:1115-1125. [PMID: 39570086 DOI: 10.1080/17512433.2024.2431513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 11/15/2024] [Indexed: 11/22/2024]
Abstract
INTRODUCTION Immune checkpoint inhibitors (ICIs) have advanced the treatment of metastatic melanoma by blocking immune system down-regulators enhancing T-cell-mediated anti-tumor responses. However, many ICIs induce immune-related adverse effects (irAEs) that can impact many organ systems. AREAS COVERED Strategies used to manage irAEs include corticosteroids, anti-tumor necrosis factor alpha (TNF-α) agents, other biological therapies, fecal microbiota transplantation (FMT), and emerging regimens. In this review, we describe current evidence for the efficacy of ICIs, acute and chronic immune toxicities, and strategies to manage toxicities for patients treated with ICIs. EXPERT OPINION IrAE management will likely evolve by developing more tailored approaches to prevent toxicities, improving non-steroidal management strategies and tailoring the dose of steroids, and identifying biomarkers of severe toxicities.
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Affiliation(s)
- Joy Justice
- Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Roma A Kankaria
- Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Douglas B Johnson
- Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
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Podder V, Ranjan T, Margolin K, Maharaj A, Ahluwalia MS. Evaluating the Safety of Immune Checkpoint Inhibitors and Combination Therapies in the Management of Brain Metastases: A Comprehensive Review. Cancers (Basel) 2024; 16:3929. [PMID: 39682118 DOI: 10.3390/cancers16233929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 10/31/2024] [Accepted: 11/21/2024] [Indexed: 12/18/2024] Open
Abstract
Brain metastases (BM) are a frequent and severe complication in patients with lung cancer, breast cancer, and melanoma. Immune checkpoint inhibitors (ICIs) have become a crucial treatment option for BM, whether used alone or in combination with chemotherapy and stereotactic radiosurgery (SRS). However, ICIs are associated with immune-related adverse events (irAEs) that can affect multiple organ systems, complicating their use in BM patients. This review examines the mechanisms of irAEs and their effects on different organs and evaluates the safety of ICIs across various treatment strategies for BM. Our analysis indicates that ICIs significantly improve survival and disease control in BM patients, but their use increases the risk of irAEs, including dermatologic, gastrointestinal, endocrine, pulmonary, and neurologic toxicities. Neurotoxic events, particularly treatment-associated brain necrosis (TABN) and encephalitis, are more common in BM patients. While the overall incidence of irAEs is similar between patients with and without BM, the neurotoxicity risk is higher in the BM population. Combining ICIs with chemotherapy and SRS enhances efficacy but also heightens the risk of adverse events across organ systems. ICIs offer substantial benefits for BM patients but require careful management to mitigate the risks of irAEs. Close patient monitoring, individualized treatment protocols, and prompt intervention are essential for optimizing the outcomes. Future research should focus on refining combination strategies and improving the management of irAEs, particularly neurotoxicity, to maximize therapeutic benefits for BM patients.
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Affiliation(s)
- Vivek Podder
- Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33186, USA
| | - Tulika Ranjan
- Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33186, USA
| | - Kim Margolin
- Saint John's Cancer Institute, Santa Monica, CA 90404, USA
| | - Arun Maharaj
- Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33186, USA
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Zhu S, Yang T, Zhao Y, Sun Y, Zheng X, Xu H. Interpretable machine learning model predicting immune checkpoint inhibitor-induced hypothyroidism: A retrospective cohort study. Cancer Sci 2024; 115:3767-3775. [PMID: 39313863 PMCID: PMC11531944 DOI: 10.1111/cas.16352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 08/22/2024] [Accepted: 09/08/2024] [Indexed: 09/25/2024] Open
Abstract
Hypothyroidism is a known adverse event associated with the use of immune checkpoint inhibitors (ICIs) in cancer treatment. This study aimed to develop an interpretable machine learning (ML) model for individualized prediction of hypothyroidism in patients treated with ICIs. The retrospective cohort of patients treated with ICIs was from the First Affiliated Hospital of Ningbo University. ML methods applied include logistic regression (LR), random forest classifier (RFC), support vector machine (SVM), and extreme gradient boosting (XGBoost). The area under the receiver-operating characteristic curve (AUC) was the main evaluation metric used. Furthermore, the Shapley additive explanation (SHAP) was utilized to interpret the outcomes of the prediction model. A total of 458 patients were included in the study, with 59 patients (12.88%) observed to have developed hypothyroidism. Among the models utilized, XGBoost exhibited the highest predictive capability (AUC = 0.833). The Delong test and calibration curve indicated that XGBoost significantly outperformed the other models in prediction. The SHAP method revealed that thyroid-stimulating hormone (TSH) was the most influential predictor variable. The developed interpretable ML model holds potential for predicting the likelihood of hypothyroidism following ICI treatment in patients. ML technology offers new possibilities for predicting ICI-induced hypothyroidism, potentially providing more precise support for personalized treatment and risk management.
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Affiliation(s)
- Su‐Yan Zhu
- Department of PharmacyThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
| | - Tong‐Tong Yang
- Department of PharmacyThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
| | - Yi‐Zhuo Zhao
- Department of Evaluation and InspectionCenter of Drug Evaluation and Inspection and Adverse Drug Reaction Monitoring of Ningxia Hui Autonomous RegionYinchuan CityNingxia Hui Autonomous RegionChina
| | - Yu Sun
- Department of PharmacyThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
| | - Xiao‐Meng Zheng
- Department of PharmacyThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
| | - Hong‐Bin Xu
- Department of PharmacyThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
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Wang C, Feng Q, Shi S, Qin Y, Lu H, Zhang P, Liu J, Chen B. The Rational Engineered Bacteria Based Biohybrid Living System for Tumor Therapy. Adv Healthc Mater 2024; 13:e2401538. [PMID: 39051784 DOI: 10.1002/adhm.202401538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 07/16/2024] [Indexed: 07/27/2024]
Abstract
Living therapy based on bacterial cells has gained increasing attention for their applications in tumor treatments. Bacterial cells can naturally target to tumor sites and active the innate immunological responses. The intrinsic advantages of bacteria attribute to the development of biohybrid living carriers for targeting delivery toward hypoxic environments. The rationally engineered bacterial cells integrate various functions to enhance the tumor therapy and reduce toxic side effects. In this review, the antitumor effects of bacteria and their application are discussed as living therapeutic agents across multiple antitumor platforms. The various kinds of bacteria used for cancer therapy are first introduced and demonstrated the mechanism of antitumor effects as well as the immunological effects. Additionally, this study focused on the genetically modified bacteria for the production of antitumor agents as living delivery system to treat cancer. The combination of living bacterial cells with functional nanomaterials is then discussed in the cancer treatments. In brief, the rational design of living therapy based on bacterial cells highlighted a rapid development in tumor therapy and pointed out the potentials in clinical applications.
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Affiliation(s)
- Chen Wang
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-Sen University, No. 66, Gongchang Road, Guangming District, Shenzhen, Guangdong, 518107, China
| | - Qiliner Feng
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-Sen University, No. 66, Gongchang Road, Guangming District, Shenzhen, Guangdong, 518107, China
| | - Si Shi
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-Sen University, No. 66, Gongchang Road, Guangming District, Shenzhen, Guangdong, 518107, China
| | - Yuxuan Qin
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-Sen University, No. 66, Gongchang Road, Guangming District, Shenzhen, Guangdong, 518107, China
| | - Hongli Lu
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-Sen University, No. 66, Gongchang Road, Guangming District, Shenzhen, Guangdong, 518107, China
| | - Peng Zhang
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-Sen University, No. 66, Gongchang Road, Guangming District, Shenzhen, Guangdong, 518107, China
| | - Jie Liu
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-Sen University, No. 66, Gongchang Road, Guangming District, Shenzhen, Guangdong, 518107, China
| | - Baizhu Chen
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-Sen University, No. 66, Gongchang Road, Guangming District, Shenzhen, Guangdong, 518107, China
- Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument, Sun Yat-Sen University, Shenzhen, Guangdong, 518107, China
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Rossi S, Silvetti F, Bordoni M, Ciarloni A, Salvio G, Balercia G. Pembrolizumab-induced Thyroiditis, Hypophysitis and Adrenalitis: A Case of Triple Endocrine Dysfunction. JCEM CASE REPORTS 2024; 2:luae200. [PMID: 39498471 PMCID: PMC11532647 DOI: 10.1210/jcemcr/luae200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Indexed: 11/07/2024]
Abstract
Immune checkpoint inhibitor drugs can trigger autoimmune endocrine reactions as a known side effect. Several cases of immunotherapy-induced autoimmune endocrinopathies have been described, but multiple sequential endocrine toxicities are a rare occurrence. A 39-year-old patient with metastatic melanoma started adjuvant therapy with pembrolizumab. One month later he presented with asymptomatic thyrotoxicosis and, within several weeks, overt hypothyroidism, for which he started levothyroxine therapy. Subsequently the patient developed central adrenal insufficiency due to probable hypophysitis, and steroid replacement therapy was started. Pembrolizumab therapy was then discontinued. After a few months, a full recovery of pituitary function was observed, but primary adrenal insufficiency occurred, requiring additional fludrocortisone therapy. The described clinical case is a very uncommon case of triple endocrinological toxicity from immunotherapy. The clinical and biochemical manifestations of immunotherapy-induced endocrinopathies can be variable and atypical; therefore, it is necessary to pay special attention to any clue of hormonal dysfunction.
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Affiliation(s)
- Silvia Rossi
- Endocrinology Clinic, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona 60126, Italy
| | - Francesca Silvetti
- Endocrinology Clinic, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona 60126, Italy
| | - Monia Bordoni
- Endocrinology Clinic, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona 60126, Italy
| | - Alessandro Ciarloni
- Endocrinology Clinic, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona 60126, Italy
| | - Gianmaria Salvio
- Endocrinology Clinic, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona 60126, Italy
| | - Giancarlo Balercia
- Endocrinology Clinic, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona 60126, Italy
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Martín-Escolano R, Virseda-Berdices A, Berenguer J, González-García J, Brochado-Kith O, Fernández-Rodríguez A, Díez C, Hontañon V, Resino S, Jiménez-Sousa MÁ. Low plasma levels of BTLA and LAG-3 before HCV therapy are associated with metabolic disorders after HCV eradication in persons with HIV/HCV coinfection: a retrospective study. Front Pharmacol 2024; 15:1341612. [PMID: 39530457 PMCID: PMC11551606 DOI: 10.3389/fphar.2024.1341612] [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: 11/20/2023] [Accepted: 10/04/2024] [Indexed: 11/16/2024] Open
Abstract
Background Understanding the predictors of metabolic disorders in persons with HIV/HCV coinfection post-HCV therapy is crucial for improving patient outcomes. Since immune checkpoint proteins are usually upregulated in these persons with HIV/HCV coinfection, we aimed to evaluate the association between plasma immune checkpoint proteins at baseline (before HCV therapy) and metabolic disturbances during the follow-up (about 5 years after successful HCV treatment) in persons with HIV/HCV coinfection. Methods We performed a retrospective study on 80 persons with HIV/HCV coinfection with advanced fibrosis or cirrhosis who cleared HCV infection after successful HCV therapy and were followed for about 5 years after completion of HCV treatment. Plasma samples were collected at baseline. Immune checkpoint proteins were analyzed using a Luminex 200™ analyzer. Outcomes were the development of a metabolic event (type 2 diabetes mellitus and/or dyslipidemia) and the change in Triglycerides and glucose (TyG) index. Results During follow-up, 21 (26%) patients developed metabolic events (type 2 diabetes mellitus/dyslipidemia), and 29 (46.0%) patients had an increase in TyG during the follow-up. Low baseline values of BTLA and LAG-3, two immune checkpoint proteins, were associated with the development of metabolic events (aAMR = 0.69 and aAMR = 0.71, respectively) and with increases in TyG values (aAMR = 0.72 and aAMR = 0.70, respectively). In addition, other immune checkpoint proteins were also inversely associated with increases in TyG. Conclusion We discovered that low plasma levels of BTLA and LAG-3 before HCV therapy significantly correlate with an increased risk of developing metabolic disorders after treatment.
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Affiliation(s)
- Rubén Martín-Escolano
- Centro Nacional de Microbiología (CNM), Unidad de Infección Viral e Inmunidad, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Ana Virseda-Berdices
- Centro Nacional de Microbiología (CNM), Unidad de Infección Viral e Inmunidad, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Juan Berenguer
- Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Unidad de Enfermedades Infecciosas/VIH, Hospital General Universitario “Gregorio Marañón”, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Juan González-García
- Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Servicio de Medicina Interna-Unidad de VIH, Hospital Universitario La Paz, Madrid, Spain
- Instituto de Investigación Sanitaria La Paz (IdiPAZ), Madrid, Spain
| | - Oscar Brochado-Kith
- Centro Nacional de Microbiología (CNM), Unidad de Infección Viral e Inmunidad, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Amanda Fernández-Rodríguez
- Centro Nacional de Microbiología (CNM), Unidad de Infección Viral e Inmunidad, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Cristina Díez
- Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Unidad de Enfermedades Infecciosas/VIH, Hospital General Universitario “Gregorio Marañón”, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Victor Hontañon
- Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Servicio de Medicina Interna-Unidad de VIH, Hospital Universitario La Paz, Madrid, Spain
- Instituto de Investigación Sanitaria La Paz (IdiPAZ), Madrid, Spain
| | - Salvador Resino
- Centro Nacional de Microbiología (CNM), Unidad de Infección Viral e Inmunidad, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - María Ángeles Jiménez-Sousa
- Centro Nacional de Microbiología (CNM), Unidad de Infección Viral e Inmunidad, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
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Wang C, Cai Y, Feng P. Case report: A case of sintilimab-induced recurrent diabetic ketoacidosis and thyroid dysfunction in a patient with advanced cervical carcinoma. Front Immunol 2024; 15:1405856. [PMID: 39450164 PMCID: PMC11499202 DOI: 10.3389/fimmu.2024.1405856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Accepted: 09/25/2024] [Indexed: 10/26/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) have radically altered cancer treatment, but immune toxicities called immune-related adverse events (irAEs), particularly endocrine toxicities, such as acute-onset diabetes and thyroid dysfunction, pose challenges. Although most irAEs have mild-to-moderate severity, failure to diagnose and treat them promptly can result in life-threatening complications. This report presents the case of a 50-year-old woman who developed ICI-induced diabetes mellitus (ICI-DM) during sintilimab treatment for advanced cervical carcinoma. The patient experienced repeated episodes of diabetic ketoacidosis (DKA) and subclinical hypothyroidism. Unlike the case of patients with typical type 1 diabetes mellitus (T1DM), our patient tested negative for β cell autoantibodies and progressed rapidly. Prompt recognition and insulin treatment are crucial for helping patients overcome such crises. Eventually, sintilimab was discontinued, and chemotherapy was initiated. This case report contributes to our understanding of ICI-DM. The significance of monitoring thyroid function and blood glucose levels before initiating ICI treatment to identify irAEs early and effectively manage them are important considerations.
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Affiliation(s)
- Chunliang Wang
- Department of Endocrinology, The Affiliated People’s Hospital of Ningbo University, Ningbo, China
| | - Ye Cai
- Department of Endocrinology, The Affiliated People’s Hospital of Ningbo University, Ningbo, China
| | - Pei Feng
- Department of Information, The Affiliated People’s Hospital of Ningbo University, Ningbo, China
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Kim HI, Kim WG, Kim M, Ko NG, Jin M, Jung HA, Sun JM, Ahn JS, Ahn MJ, Choi YL, Jeon MJ, Kim TY, Kim WB, Kim SW, Lee DH, Jang SJ, Kim SW, Chung JH, Kim TH, Lee SH. Biomarker role of thyroid irAE and PD-L1 positivity in predicting PD-1 blockade efficacy in patients with non-small cell lung cancer. Cancer Immunol Immunother 2024; 73:260. [PMID: 39382668 PMCID: PMC11479622 DOI: 10.1007/s00262-024-03852-w] [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: 06/24/2024] [Accepted: 09/28/2024] [Indexed: 10/10/2024]
Abstract
Thyroid immune-related adverse events (irAEs) are associated with programmed cell death protein 1 (PD-1) blockade efficacy in non-small cell lung cancer (NSCLC). However, their independence from PD-L1 expression and quantitative impact on predicting PD-1 blockade efficacy remain unexplored. This multicenter, retrospective, longitudinal study from Korea included 71 metastatic NSCLC patients who underwent PD-L1 expression and thyroid function testing during PD-1 blockade. Disease progression by the Response Evaluation Criteria for Solid Tumors was the main outcome. Three-stage analyses were performed: (1) multivariate Cox regression models adjusted for PD-L1 expression according to thyroid irAEs; (2) subgroup analyses; (3) regrouping and comparing predictivity of current and alternative staging. Patients with thyroid irAE + exhibited a longer progression-free survival [7/20 vs. 34/51, adjusted HR 0.19 (0.07-0.47); P < 0.001] than those with thyroid irAE-, independent of PD-L1 expression; the results remained across most subgroups without interaction. The three groups showed different adjusted HR for disease progression (Group 1: PD L1 + and thyroid irAE + ; Group 2: PD-L1 + or thyroid irAE + : 5.08 [1.48-17.34]; Group 3: PD-L1- and thyroid irAE- : 30.49 [6.60-140.78]). Alternative staging (Group 1 in stage IVB → stage IVA; Group 3 in stage IVA → stage IVB) improved the prognostic value (PVE: 21.7% vs. 6.44%; C-index: 0.706 vs. 0.617) compared with the 8th Tumor-Node-Metastasis staging. Our study suggests thyroid irAEs and PD-L1 expression are independent biomarkers that improve predicting PD-1 blockade efficacy in NSCLC. Thyroid irAEs would be helpful to identify NSCLC patients who benefit from PD-1 blockade in early course of treatment.
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Affiliation(s)
- Hye In Kim
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Won Gu Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Mijin Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Nak Gyeong Ko
- Department of Research and Support, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Mihyeon Jin
- Department of Research and Support, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Hyun Ae Jung
- Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-Ro, Gangnam-Gu, Seoul, Korea
| | - Jong-Mu Sun
- Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-Ro, Gangnam-Gu, Seoul, Korea
| | - Jin Seok Ahn
- Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-Ro, Gangnam-Gu, Seoul, Korea
| | - Myung-Ju Ahn
- Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-Ro, Gangnam-Gu, Seoul, Korea
| | - Yoon-La Choi
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Min Ji Jeon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Tae Yong Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Won Bae Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sang-We Kim
- Division of Oncology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Dae Ho Lee
- Division of Oncology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Se Jin Jang
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sun Wook Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-Ro, Gangnam-Gu, Seoul, 06351, Korea
| | - Jae Hoon Chung
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-Ro, Gangnam-Gu, Seoul, 06351, Korea
| | - Tae Hyuk Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-Ro, Gangnam-Gu, Seoul, 06351, Korea.
| | - Se-Hoon Lee
- Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-Ro, Gangnam-Gu, Seoul, Korea.
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Chiriac R, Baseggio L, Golfier C. Central nervous system relapse of an extranodal natural killer/T-cell lymphoma. EJHAEM 2024; 5:1084-1085. [PMID: 39415911 PMCID: PMC11474378 DOI: 10.1002/jha2.1025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 09/16/2024] [Accepted: 09/17/2024] [Indexed: 10/19/2024]
Affiliation(s)
- Radu Chiriac
- Hospices Civils de LyonCentre Hospitalier Lyon SudLaboratoire d'hématologiePierre‐BeniteFrance
| | - Lucile Baseggio
- Hospices Civils de LyonCentre Hospitalier Lyon SudLaboratoire d'hématologiePierre‐BeniteFrance
| | - Camille Golfier
- Hospices Civils de LyonCentre Hospitalier Lyon SudHématologie cliniquePierre‐BeniteFrance
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Ruiz-Esteves KN, Shank KR, Deutsch AJ, Gunturi A, Chamorro-Pareja N, Colling CA, Zubiri L, Perlman K, Ouyang T, Villani AC, Florez JC, Gusev A, Reynolds KL, Miller KK, Udler MS, Sise ME, Rengarajan M. Identification of Immune Checkpoint Inhibitor-Induced Diabetes. JAMA Oncol 2024; 10:1409-1416. [PMID: 39207773 PMCID: PMC11362970 DOI: 10.1001/jamaoncol.2024.3104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 05/15/2024] [Indexed: 09/04/2024]
Abstract
Importance Immune checkpoint inhibitors (ICIs) have revolutionized cancer care; however, accompanying immune-related adverse events (irAEs) confer substantial morbidity and occasional mortality. Life-threatening irAEs may require permanent cessation of ICI, even in patients with positive tumor response. Therefore, it is imperative to comprehensively define the spectrum of irAEs to aid individualized decision-making around the initiation of ICI therapy. Objective To define incidence, risk factors, and clinical spectrum of an irreversible and life-threatening irAE: ICI-induced diabetes. Design, Setting, and Participants This cohort study, conducted at an academic integrated health care system examined 14 328 adult patients treated with ICIs, including 64 patients who developed ICI-induced diabetes, from July 2010 to January 2022. The data were analyzed from 2022 to 2023. Cases of ICI-induced diabetes were manually confirmed; detailed clinical phenotyping was performed at diagnosis and 1-year follow-up. For 862 patients, genotyping data were available, and polygenic risk for type 1 diabetes was determined. Main Outcomes and Measures For ICI-induced diabetes cases and controls, demographic characteristics, comorbidities, tumor category, and ICI category were compared. Among ICI-induced diabetes cases, markers of glycemic physiology were examined at diagnosis and 1-year follow-up. For patients with available genotyping, a published type 1 diabetes polygenic score (T1D GRS2) was calculated. Results Of 14 328 participants, 6571 (45.9%) were women, and the median (range) age was 66 (8-106) years. The prevalence of ICI-induced diabetes among ICI-treated patients was 0.45% (64 of 14 328), with an incidence of 124.8 per 100 000 person-years. Preexisting type 2 diabetes (odds ratio [OR], 5.91; 95% CI, 3.34-10.45) and treatment with combination ICI (OR, 2.57; 95% CI, 1.44-4.59) were significant clinical risk factors of ICI-induced diabetes. T1D GRS2 was associated with ICI-induced diabetes risk, with an OR of 4.4 (95% CI, 1.8-10.5) for patients in the top decile of T1D GRS2, demonstrating a genetic association between spontaneous autoimmunity and irAEs. Patients with ICI-induced diabetes were in 3 distinct phenotypic categories based on autoantibodies and residual pancreatic function, with varying severity of initial presentation. Conclusions and Relevance The results of this analysis of 14 328 ICI-treated patients followed up from ICI initiation determined the incidence, risk factors and clinical spectrum of ICI-induced diabetes. Widespread implementation of this approach across organ-specific irAEs may enhance diagnosis and management of these conditions, and this becomes especially pertinent as ICI treatment rapidly expands to treat a wide spectrum of cancers and is used at earlier stages of treatment.
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Affiliation(s)
- Karina N. Ruiz-Esteves
- Department of Medicine, Massachusetts General Hospital, Boston, MA and Harvard Medical School, Boston
| | - Kaitlyn R. Shank
- Department of Medicine, Massachusetts General Hospital and Department of Medicine, Brigham and Women’s Hospital, Boston
| | - Aaron J. Deutsch
- Department of Medicine and Center for Genomic Medicine, Massachusetts General Hospital, Programs in Metabolism and Medical and Population Genetics, Broad Institute, Cambridge
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Alekhya Gunturi
- Department of Medicine, Massachusetts General Hospital and Boston University School of Medicine, Boston
| | - Natalia Chamorro-Pareja
- Department of Medicine, Massachusetts General Hospital, Boston, MA and Harvard Medical School, Boston
| | - Caitlin A. Colling
- Department of Medicine, Massachusetts General Hospital, Boston, MA and Harvard Medical School, Boston
| | - Leyre Zubiri
- Department of Medicine, Massachusetts General Hospital, Boston, MA and Harvard Medical School, Boston
| | | | - Tianqi Ouyang
- Department of Medicine, Massachusetts General Hospital, Boston
| | - Alexandra-Chloé Villani
- Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Jose C. Florez
- Department of Medicine and Center for Genomic Medicine, Massachusetts General Hospital, Programs in Metabolism and Medical and Population Genetics, Broad Institute, Cambridge
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Alexander Gusev
- Division of Population Sciences, Dana-Farber Cancer Institute and Harvard Medical School, Broad Institute, Cambridge, Massachusetts
- Division of Genetics, Brigham and Women’s Hospital and Harvard Medical School, Boston
| | - Kerry L. Reynolds
- Department of Medicine, Mass General Cancer Center, Massachusetts General Hospital, Boston
| | - Karen K. Miller
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston
| | - Miriam S. Udler
- Department of Medicine and Center for Genomic Medicine, Massachusetts General Hospital, Programs in Metabolism and Medical and Population Genetics, Broad Institute, Cambridge
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Meghan E. Sise
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston
| | - Michelle Rengarajan
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Broad Institute of Massachusetts Institute of Technology and Harvard University, Boston
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Chen Y, Zhou Q, Jia Z, Cheng N, Zhang S, Chen W, Wang L. Enhancing cancer immunotherapy: Nanotechnology-mediated immunotherapy overcoming immunosuppression. Acta Pharm Sin B 2024; 14:3834-3854. [PMID: 39309502 PMCID: PMC11413684 DOI: 10.1016/j.apsb.2024.05.032] [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: 03/22/2024] [Revised: 05/12/2024] [Accepted: 05/24/2024] [Indexed: 09/25/2024] Open
Abstract
Immunotherapy is an important cancer treatment method that offers hope for curing cancer patients. While immunotherapy has achieved initial success, a major obstacle to its widespread adoption is the inability to benefit the majority of patients. The success or failure of immunotherapy is closely linked to the tumor's immune microenvironment. Recently, there has been significant attention on strategies to regulate the tumor immune microenvironment in order to stimulate anti-tumor immune responses in cancer immunotherapy. The distinctive physical properties and design flexibility of nanomedicines have been extensively utilized to target immune cells (including tumor-associated macrophages (TAMs), T cells, myeloid-derived suppressor cells (MDSCs), and tumor-associated fibroblasts (TAFs)), offering promising advancements in cancer immunotherapy. In this article, we have reviewed treatment strategies aimed at targeting various immune cells to regulate the tumor immune microenvironment. The focus is on cancer immunotherapy models that are based on nanomedicines, with the goal of inducing or enhancing anti-tumor immune responses to improve immunotherapy. It is worth noting that combining cancer immunotherapy with other treatments, such as chemotherapy, radiotherapy, and photodynamic therapy, can maximize the therapeutic effects. Finally, we have identified the challenges that nanotechnology-mediated immunotherapy needs to overcome in order to design more effective nanosystems.
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Affiliation(s)
- Yunna Chen
- Key Laboratory of Molecular Biology (Brain diseases), Anhui University of Chinese Medicine, Hefei 230012, China
| | - Qianqian Zhou
- MOE-Anhui Joint Collaborative Innovation Center for Quality Improvement of Anhui Genuine Chinese Medicinal Materials, Hefei 230012, China
- Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei 230012, China
| | - Zongfang Jia
- MOE-Anhui Joint Collaborative Innovation Center for Quality Improvement of Anhui Genuine Chinese Medicinal Materials, Hefei 230012, China
- Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei 230012, China
| | - Nuo Cheng
- MOE-Anhui Joint Collaborative Innovation Center for Quality Improvement of Anhui Genuine Chinese Medicinal Materials, Hefei 230012, China
- Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei 230012, China
| | - Sheng Zhang
- Key Laboratory of Molecular Biology (Brain diseases), Anhui University of Chinese Medicine, Hefei 230012, China
| | - Weidong Chen
- MOE-Anhui Joint Collaborative Innovation Center for Quality Improvement of Anhui Genuine Chinese Medicinal Materials, Hefei 230012, China
- Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei 230012, China
| | - Lei Wang
- MOE-Anhui Joint Collaborative Innovation Center for Quality Improvement of Anhui Genuine Chinese Medicinal Materials, Hefei 230012, China
- Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei 230012, China
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Cao W, Xie Y, Cai L, Wang M, Chen Z, Wang Z, Xv J, Wang Y, Li R, Liu X, Wang W. Pan‑cancer analysis on the role of KMT2C expression in tumor progression and immunotherapy. Oncol Lett 2024; 28:444. [PMID: 39091583 PMCID: PMC11292467 DOI: 10.3892/ol.2024.14577] [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: 12/04/2023] [Accepted: 05/10/2024] [Indexed: 08/04/2024] Open
Abstract
Histone lysine N-methyltransferase 2C (KMT2C) is involved in transcriptional regulation and DNA damage repair. Mutations in KMT2C have been implicated in the progression, metastasis, and drug resistance of multiple cancer types. However, the roles of KMT2C in the regulation of tumor prognosis, immune cell infiltration and the immune microenvironment in these multiple cancer types remain unclear. Therefore, in the present study, data from The Cancer Genome Atlas and Genotype-Tissue Expression databases were used for KMT2C expression analyses. Kaplan-Meier and univariate Cox regression analyses were also performed to investigate the prognostic role of KMT2C. In addition, Gene Set Enrichment Analysis (GSEA) was conducted to study the KMT2C-related signaling pathways. Tumor immune estimation resource 2 and single-sample GSEA were conducted to investigate the correlation between KMT2C expression and immune cell infiltrations, and Spearman's analysis was conducted to study the correlations among KMT2C, tumor mutational burden, microsatellite instability, immune regulators, chemokines and immune receptors. Immunohistochemistry of patient kidney tumor samples was performed to verify the correlation between KMT2C and programmed death-ligand 1 (PD-L1) expression. Finally, RNA interference, wound healing and colony formation assays were conducted to evaluate the effects of KMT2C expression on cell proliferation and metastasis. The results of the present study demonstrated that KMT2C was highly expressed in multiple cancer types, was a protective factor in kidney renal clear cell carcinoma and ovarian serous cystadenocarcinoma, and a risk factor for lung squamous cell carcinoma and uveal melanoma. In addition, KMT2C levels were negatively correlated with immune-activated pathways and the infiltration of immune cells, and positively correlated with inhibitory immune factors and tumor angiogenesis. Patients with low KMT2C expression had higher objective response rates to immunotherapy, and drug sensitivity analysis indicated that topoisomerase, histone deacetylase, DOT1-like histone H3K79 methyltransferase and G9A nuclear histone lysine methyltransferase inhibitors could potentially be used to treat tumors with high KMT2C expression levels. Finally, the KMT2C and PD-L1 expression levels were shown to be positively correlated, and KMT2C knockdown markedly promoted the proliferation and invasion capacities of A549 cells. In conclusion, the present study revealed that low KMT2C expression may be a promising biomarker for predicting the response of patients with cancer to immunotherapy. Conversely, high KMT2C expression was shown to promote tumor angiogenesis, which may contribute to the formation of the immunosuppressive tumor microenvironment.
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Affiliation(s)
- Wei Cao
- Department of Thoracic Surgery, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
| | - Yawen Xie
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Li Cai
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, P.R. China
- Department of Pathology, School of Basic Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Mengqing Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Zhuoying Chen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Ziteng Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Jiajia Xv
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Yuqing Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Rong Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Xuesong Liu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Wenliang Wang
- Institute of Clinical Immunology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
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Kang K, Lin X, Chen P, Liu H, Liu F, Xiong W, Li G, Yi M, Li X, Wang H, Xiang B. T cell exhaustion in human cancers. Biochim Biophys Acta Rev Cancer 2024; 1879:189162. [PMID: 39089484 DOI: 10.1016/j.bbcan.2024.189162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 07/23/2024] [Accepted: 07/24/2024] [Indexed: 08/04/2024]
Abstract
T cell exhaustion refers to a progressive state in which T cells become functionally impaired due to sustained antigenic stimulation, which is characterized by increased expression of immune inhibitory receptors, but weakened effector functions, reduced self-renewal capacity, altered epigenetics, transcriptional programme and metabolism. T cell exhaustion is one of the major causes leading to immune escape of cancer, creating an environment that supports tumor development and metastatic spread. In addition, T cell exhaustion plays a pivotal role to the efficacy of current immunotherapies for cancer. This review aims to provide a comprehensive view of roles of T cell exhaustion in cancer development and progression. We summerized the regulatory mechanisms that involved in T cell exhaustion, including transcription factors, epigenetic and metabolic reprogramming events, and various microenvironmental factors such as cytokines, microorganisms, and tumor autocrine substances. The paper also discussed the challenges posed by T cell exhaustion to cancer immunotherapies, including immune checkpoint blockade (ICB) therapies and chimeric antigen receptor T cell (CAR-T) therapy, highlightsing the obstacles encountered in ICB therapies and CAR-T therapies due to T cell exhaustion. Finally, the article provides an overview of current therapeutic options aimed to reversing or alleviating T cell exhaustion in ICB and CAR-T therapies. These therapeutic approaches seek to overcome T cell exhaustion and enhance the effectiveness of immunotherapies in treating tumors.
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Affiliation(s)
- Kuan Kang
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078, Hunan, China
| | - Xin Lin
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078, Hunan, China
| | - Pan Chen
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China
| | - Huai Liu
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; Department of Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Feng Liu
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; Department of Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Wei Xiong
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078, Hunan, China
| | - Guiyuan Li
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078, Hunan, China
| | - Mei Yi
- Department of Dermatology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Xiayu Li
- Hunan Key Laboratory of Nonresolving Infammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China.
| | - Hui Wang
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; Department of Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China.
| | - Bo Xiang
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078, Hunan, China; FuRong Laboratory, Changsha 410078, Hunan, China.
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