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Zaher A, Moura Nascimento Santos MJ, Elsaygh H, Peterson SJ, Colli Cruz C, Thomas AS, Wang Y. Management of refractory checkpoint inhibitor-induced colitis. Expert Opin Drug Saf 2025:1-10. [PMID: 40251944 DOI: 10.1080/14740338.2025.2496431] [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: 01/21/2025] [Revised: 04/06/2025] [Accepted: 04/17/2025] [Indexed: 04/21/2025]
Abstract
INTRODUCTION This review discusses the epidemiology, pathophysiology, and factors associated with refractory immune-mediated diarrhea and colitis (r-IMDC), emphasizing tailored treatment strategies. AREAS COVERED The current literature on r-IMDC was reviewed using PubMed (2015-2025), focusing on clinical trials, meta-analyses, and case reports relevant to its management. EXPERT OPINION Effectively managing r-IMDC is crucial for balancing toxicities and antitumor response. Available second and third-line management options for r-IMDC cases must be carefully evaluated. Future perspectives include development of standardized protocols beyond second-line therapies and predictive biomarkers to enable personalized treatment.
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Affiliation(s)
- Anas Zaher
- Department of Internal Medicine, New York Presbyterian - Brooklyn Methodist/Weill Cornell Medicine, Brooklyn, NY, USA
| | | | - Hassan Elsaygh
- Department of Internal Medicine, University of Debrecen, Debrecen, Hungary
| | - Stephen J Peterson
- Department of Internal Medicine, New York Presbyterian - Brooklyn Methodist/Weill Cornell Medicine, Brooklyn, NY, USA
| | - Carolina Colli Cruz
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anusha Shirwaikar Thomas
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Zeng J, Zhang J, Wang J, Xu L, Wang C, Yin R. Immunotherapy in gestational trophoblastic neoplasia: advances and future directions. Front Immunol 2025; 16:1544585. [PMID: 40292281 PMCID: PMC12021912 DOI: 10.3389/fimmu.2025.1544585] [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: 12/13/2024] [Accepted: 03/26/2025] [Indexed: 04/30/2025] Open
Abstract
Gestational trophoblastic neoplasia (GTN) is a rare but aggressive malignancy that follows normal or aberrant pregnancies. Until the advent of immunotherapy in 2017, surgery and chemotherapy were the standard treatment modalities, with chemotherapy remaining the cornerstone. However, chemoresistance and high-risk disease present significant challenges in managing GTN. Recent advancements in immunotherapy, particularly immune checkpoint inhibitors (ICIs), have offered new hope for managing these difficult cases. This review provides the comprehensive overview of the mechanisms underlying ICIs in GTN, and explores the potential synergy of combining ICIs with targeted therapies, such as vascular endothelial growth factor and epidermal growth factor receptor inhibitors. We also provide an overview of the latest evidence on the use of ICIs in treating GTN, focusing on their effectiveness in both low- and high-risk cases, as well as in chemorefractory settings. In addition, we discuss ongoing clinical trials, immune-related adverse events associated with ICIs, biomarker-driven approaches, immunosuppressive tumor microenvironments, and the challenges posed with ICIs resistance. The review also explores future directions, including the integration of ICIs into standard regimens, the potential for personalized treatment based on tumor biology, and the importance of fertility preservation in young patients with GTN. In conclusion, while challenges remain, immunotherapy represents a promising frontier in GTN treatment, with the potential to improve outcomes and provide a more personalized approach to care.
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Affiliation(s)
- Jing Zeng
- Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Chengdu, Sichuan, China
| | - Jing Zhang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Chengdu, Sichuan, China
- Joint Laboratory of Reproductive Medicine (SCU-CUHK), West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jianzhang Wang
- West China School of Medicine, Sichuan University, Chengdu, Sichuan, China
| | - Lian Xu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Chengdu, Sichuan, China
- Department of Pathology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Cheng Wang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Chengdu, Sichuan, China
- Department of Pathology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Rutie Yin
- Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Chengdu, Sichuan, China
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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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Kondo T, Nakatsugawa M, Okubo M, Nakamura H, Yunaiyama D, Wakiya M, Takeda A, Kikawada N, Kishida T, Someya M, Yoshida S, Ogawa Y, Tsukahara K. Laryngeal Cancer With Lung Metastases Showing Long-Term Complete Response and Delayed Immune-Related Adverse Event After Nivolumab Discontinuation. EAR, NOSE & THROAT JOURNAL 2025; 104:222-227. [PMID: 34281424 DOI: 10.1177/01455613211031025] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
We report a case of laryngeal cancer with multiple lung metastases that maintained a complete response (CR) for 18 months after discontinuing nivolumab treatment, with colitis developing 5 months after drug discontinuation. A 65-year-old man was diagnosed with T3N2cM0 stage IVA right supraglottic squamous cell carcinoma that progressed after 1 course of TPF (cisplatin, docetaxel, and 5-fluorouracil) as induction chemotherapy. He underwent total laryngectomy, bilateral neck dissection, pharyngeal reconstruction with anterolateral thigh flap, and creation of a permanent tracheostoma; extranodal extension was detected in the right cervical lymph node metastasis, and the patient underwent adjuvant radiotherapy. Multiple lung metastases occurred during radiotherapy, and the patient was deemed platinum refractory; nivolumab treatment was thus initiated. The tumor proportion score for programmed death-ligand 1-evaluated via antibody testing of the laryngeal tumor-was <1. The patient received 240 mg/body nivolumab every 2 weeks; a computed tomography performed after course 16 of nivolumab treatment confirmed a CR. He exhibited grade 2 thyroid dysfunction, grade 1 interstitial pneumonia, and grade 2 colitis after 6, 7, and 14 months of receiving nivolumab, respectively; treatment was discontinued as despite maintaining a CR, interstitial pneumonia occurred twice. Colitis appeared 5 months after nivolumab discontinuation; nevertheless, a CR was maintained after 18 months.
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Affiliation(s)
- Takahito Kondo
- Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University Hachioji Medical Center, Tatemachi, Tokyo, Japan
| | - Munehide Nakatsugawa
- Department of Pathology, Tokyo Medical University Hachioji Medical Center, Tatemachi, Tokyo, Japan
| | - Mitsuru Okubo
- Department of Radiology, Tokyo Medical University Hachioji Medical Center, Tatemachi, Tokyo, Japan
| | - Hironori Nakamura
- Department of Gastroenterology and Hepatology, Tokyo Medical University Hachioji Medical Center, Tatemachi, Tokyo, Japan
| | - Daisuke Yunaiyama
- Department of Radiology, Tokyo Medical University Hachioji Medical Center, Tatemachi, Tokyo, Japan
| | - Midori Wakiya
- Department of Pathology, Tokyo Medical University Hachioji Medical Center, Tatemachi, Tokyo, Japan
| | - Atsuo Takeda
- Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University Hachioji Medical Center, Tatemachi, Tokyo, Japan
| | - Naiue Kikawada
- Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University Hachioji Medical Center, Tatemachi, Tokyo, Japan
| | - Takuma Kishida
- Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University Hachioji Medical Center, Tatemachi, Tokyo, Japan
| | - Miwako Someya
- Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University Hachioji Medical Center, Tatemachi, Tokyo, Japan
| | - Shigekazu Yoshida
- Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University Hachioji Medical Center, Tatemachi, Tokyo, Japan
| | - Yasuo Ogawa
- Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University Hachioji Medical Center, Tatemachi, Tokyo, Japan
| | - Kiyoaki Tsukahara
- Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University, Nishishinjuku, Tokyo, Japan
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Chen M, Li Y, Chen P. Restore intestinal steady-state: new advances in the clinical management of chemotherapy-associated diarrhea and constipation. J Mol Histol 2025; 56:101. [PMID: 40056250 PMCID: PMC11890403 DOI: 10.1007/s10735-025-10367-w] [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: 10/15/2024] [Accepted: 02/02/2025] [Indexed: 03/10/2025]
Abstract
Chemotherapy remains the primary therapeutic strategy for most tumors, particularly those at advanced stages with distant metastases and resistance to molecularly targeted therapy or immunotherapy. There are many manifestations of chemotherapy-induced gastrointestinal toxicity (CIGT), including chemotherapy-induced diarrhea (CID) and chemotherapy-induced constipation (CIC). Although the World Health Organisation and the International Association Against Cancer have different grading criteria and strategies for the prevention and treatment of CIGT, there are still many unanswered questions that need to be clarified. This review critically describes pathological mechanisms and clinical research, analyzing the variability in diagnostic criteria and the absence of standardization in grading severity. We identify a critical gap in understanding the molecular underpinnings of CID and CIC and suggest targeted areas for future research, including developing personalized treatment approaches based on genetic profiling. The findings suggest a comprehensive treatment approach combining pharmacological and non-pharmacological strategies to enhance life quality and treatment adherence. This review will offer a comprehensive bird-eye of pathophysiological mechanisms, clinical manifestations, and therapeutic strategies of CIGT, thereby enriching accessible references to clinicians, and helping them to prevent and control CID and CIC.
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Affiliation(s)
| | - Yamao Li
- Ningxia Medical University, Yinchuan, China
| | - Peijun Chen
- Yancheng Sixth People's Hospital, Yancheng, Jiangsu, China
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Colli Cruz C, Moura Nascimento Santos MJ, Wali S, Varatharajalu K, Thomas A, Wang Y. Gastrointestinal toxicities associated with immune checkpoint inhibitors therapy: risks and management. Immunotherapy 2025; 17:293-303. [PMID: 40055892 PMCID: PMC12013428 DOI: 10.1080/1750743x.2025.2473305] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 02/25/2025] [Indexed: 04/22/2025] Open
Abstract
Immune checkpoint inhibitors (ICIs) have greatly improved cancer treatment by boosting the immune system's ability to target tumors. However, they can also cause serious side effects, particularly in the digestive system. These include immune-related diarrhea, inflammation of the intestines and, less commonly, inflammation of the stomach or esophagus. This review underscores the importance of early detection, accurate diagnosis, and timely treatment to improve patient outcomes. It also highlights the need for further research to develop strategies to reduce gastrointestinal toxicities and enhance the overall effectiveness of ICIs in cancer therapy.
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Affiliation(s)
- Carolina Colli Cruz
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Sharada Wali
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Krishnavathana Varatharajalu
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anusha Thomas
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Alwhaibi A, Alenazi MA, Alghadeer S, Mansy W, Alsaif RA, Abualreesh NE, Alanazi RJ, Alroumi A, Alanazi SA. A Real-World Comparison of the Safety Profile for Immune Checkpoint Inhibitors in Oncology Patients. J Clin Med 2025; 14:388. [PMID: 39860394 PMCID: PMC11765622 DOI: 10.3390/jcm14020388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 01/02/2025] [Accepted: 01/05/2025] [Indexed: 01/27/2025] Open
Abstract
Background/Objectives: Owing to the growing use of immune checkpoint inhibitors (ICIs) in the treatment of cancer, a wide spectrum of toxicity has arisen among cancer patients. Yet, limited ICI toxicity-related research is currently conducted in our region. Methods: This is a retrospective observational study conducted on adult cancer patients who received at least one cycle of ICI single therapy. Toxicity profiles of different ICI monotherapies were described and compared, and their association with different risk factors was assessed. SPSS version 28 was used for statistical analyses, and p < 0.05 was considered statistically significant. Results: A total of 428 patients were treated with anti-PD1 (nivolumab [n = 221, 51.6%] and pembrolizumab [n = 126, 29.5%]) or anti-PD-L1 (atezolizumab [n = 78, 18.2%] and durvalumab [n = 3, 0.7%]). Pneumonia was the most common complication (10%), followed by acute kidney injury (AKI; 8.2%) and hepatitis (7.9%). The proportion of hepatitis cases was significantly higher among atezolizumab compared to nivolumab-, pembrolizumab-, and durvalumab-treated patients (17.95% vs. 7.7% vs. 2.4% vs. 0.0%, respectively; p < 0.001). Gastrointestinal complication (colitis) was detected in 3.3% of patients with a significant difference between treatment groups (4.5%, 1.6%, 1.3%, and 33.3% in nivolumab, pembrolizumab, atezolizumab, and durvalumab, respectively; p = 0.008). Cardiac complications occurred in 1.2% of patients with a significant difference between treatment groups (0.5% in the nivolumab, 3.8% in the atezolizumab, 33.3% in the durvalumab, and none in the pembrolizumab groups (p < 0.001)). Musculoskeletal side effects, including both arthralgia and fatigue, were the most-reported side effects by 39.5% of patients, with significantly higher arthralgia complainers only in nivolumab (7.7%) compared to other treatment groups (0%, 2.6%, and 0% in pembrolizumab, atezolizumab, and durvalumab, respectively, p = 0.007). Hepatic, cardiovascular, hematological, respiratory, renal, gastrointestinal complications, thyroid complications, and dermatological side effects were found to occur on weeks 6, 7.5, 8, 8, 10, 10, 10.5, and 12 after treatment initiation, respectively, with no significant difference between treatment groups. Despite that, hepatitis and AKI tended to occur earlier with atezolizumab (week 2, p = 0.084) and pembrolizumab (week 2, p = 0.062), respectively, compared to their comparators. The female gender and a history of hepatitis were found to increase the odds of hepatic complication with anti-PD1 or anti-PD-L1 use [OR = 2.71; 95% CI 1.07-6.85, OR = 11.14; 95% CI 3.46-35.88, respectively]. Previous exposure to cancer therapy only was found to increase the odds of developing pneumonia among the treated patients [OR = 3.08; 95% CI 1.12-8.85]. Having hematological malignancy influenced the odds of hematological complications positively (either neutropenia or thrombocytopenia) compared to solid malignancies when patients were treated with anti-PD1 or anti-PD-L1 [OR = 17.18; 95% CI 4.06-72.71]. Finally, the female gender was found to positively associate with the odds of nausea/vomiting and fatigue secondary to anti-PD1 or anti-PD-L1 administration [OR = 2.08; 95% CI 1.34-3.21, OR = 1.65; 95% CI 1.09-2.51, respectively]. On the other hand, previous exposure to cancer therapy was found to reduce the risk of having arthralgia with anti-PD1 or anti-PD-L1 administration [OR = 0.344; 95% CI 0.121-0.974]. Conclusions: Treatment with anti-PD1 or anti-PD-L1 was associated with a spectrum of complications and side effects. Several risk factors have been identified to impact their occurrence. ICI toxicities and risk factors influencing their odds should be recognized and considered in clinical practice, as this could help in individualizing therapeutics regimens and avoiding treatment interruption.
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Affiliation(s)
- Abdulrahman Alwhaibi
- Department of Clinical Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (S.A.); (W.M.); (N.E.A.)
| | - Miteb A. Alenazi
- Pharmacy Department, King Saud University Medical City, Riyadh 11411, Saudi Arabia;
| | - Sultan Alghadeer
- Department of Clinical Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (S.A.); (W.M.); (N.E.A.)
| | - Wael Mansy
- Department of Clinical Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (S.A.); (W.M.); (N.E.A.)
| | - Reem A. Alsaif
- Pharmacy Department, King Abdulaziz Medical City, National Guard Health Affairs, Riyadh 11426, Saudi Arabia;
| | - Nawaf E. Abualreesh
- Department of Clinical Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (S.A.); (W.M.); (N.E.A.)
| | - Rakan J. Alanazi
- Pharmacy Practice Department, College of Pharmacy, Alfaisal University, Riyadh 11533, Saudi Arabia;
| | - Abdullah Alroumi
- College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Riyadh 11461, Saudi Arabia; (A.A.); (S.A.A.)
| | - Saleh A. Alanazi
- College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Riyadh 11461, Saudi Arabia; (A.A.); (S.A.A.)
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8
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Kim TK, Lee HS, Kim ES. Incidence and risk factors of immune checkpoint inhibitor-induced colitis in Korean patients with cancer. Korean J Intern Med 2025; 40:49-56. [PMID: 39778525 PMCID: PMC11725480 DOI: 10.3904/kjim.2024.135] [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: 04/21/2024] [Revised: 07/25/2024] [Accepted: 08/05/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND/AIMS Immune checkpoint inhibitors (ICIs) are effective in treating cancer. However, various immune-related adverse events (irAEs) have become prevalent, with ICI-induced colitis being the most common gastrointestinal irAE. Thus, we aimed to investigate the incidence and risk factors of ICI-induced colitis in Korean patients with cancer. METHODS This retrospective study included patients treated with ICIs between October 2015 and June 2022 in two tertiary referral centers in Daegu, Korea. The incidence of ICI-induced colitis was determined using electronic medical records. Risk factors for ICI-induced colitis were identified using univariate and multivariate logistic regression analyses. RESULTS We included 1,478 patients with ICI-treated cancer. The incidence of ICI-induced colitis was 3.5% (n = 52/1,478). Multivariate logistic regression analysis showed that the combination of nivolumab and ipilimumab was a risk factor for ICI-induced colitis (p = 0.006; odds ratio, 9.768; 95% confidence interval, 1.93-49.30). CONCLUSION ICI-induced colitis had an incidence rate of 3.5% and was associated with the combination of nivolumab and ipilimumab. Most patients with ICI-induced colitis developed mild symptoms that improved with supportive care alone, making ICI therapy resumption possible.
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Affiliation(s)
- Tae Kyun Kim
- Department of Internal Medicine, Kyungpook National University Chilgok Hospital, Daegu,
Korea
| | - Hyun Seok Lee
- Department of Internal Medicine, Kyungpook National University Chilgok Hospital, Daegu,
Korea
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu,
Korea
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu,
Korea
| | - Eun Soo Kim
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu,
Korea
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu,
Korea
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Gautam M, Jahagirdar V, Mahadevia H, Sanders K, Campbell JP, Sylvestre PB, Chhabra R, Clarkston W, Jonnalagadda SS. Double Whammy: A Case Report of Immune Checkpoint Inhibitor Colitis and Concomitant Cytomegalovirus Colitis in a Patient on Nivolumab. ACG Case Rep J 2025; 12:e01569. [PMID: 39734389 PMCID: PMC11671063 DOI: 10.14309/crj.0000000000001569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 11/07/2024] [Indexed: 12/31/2024] Open
Abstract
Immune checkpoint inhibitors commonly cause gastrointestinal immune-related adverse effects. These patients also carry an increased risk of concomitant infections. This 66-year-old man with immune checkpoint inhibitor colitis was discovered to have concurrent Yersinia and Cytomegalovirus colitis. Such infections may mimic or complicate disease course. Hence, clinicians must monitor patient symptoms, have a low threshold for infectious testing and colonoscopy, and consider treatment strategies to mitigate their risk.
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Affiliation(s)
- Misha Gautam
- Internal Medicine, University of Missouri-Kansas City School of Medicine, Kansas City, MO
| | - Vinay Jahagirdar
- Internal Medicine, University of Missouri-Kansas City School of Medicine, Kansas City, MO
| | - Himil Mahadevia
- Internal Medicine, University of Missouri-Kansas City School of Medicine, Kansas City, MO
| | - Kimberly Sanders
- Gastroenterology and Hepatology, University of Missouri-Kansas City School of Medicine, Kansas City, MO
| | - John P. Campbell
- Gastroenterology, Saint Luke's Hospital of Kansas City, Kansas City, MO
| | | | - Rajiv Chhabra
- Gastroenterology and Hepatology, University of Missouri-Kansas City School of Medicine, Kansas City, MO
- Gastroenterology, Saint Luke's Hospital of Kansas City, Kansas City, MO
| | - Wendell Clarkston
- Gastroenterology and Hepatology, University of Missouri-Kansas City School of Medicine, Kansas City, MO
- Gastroenterology, Saint Luke's Hospital of Kansas City, Kansas City, MO
| | - Sreenivasa S. Jonnalagadda
- Gastroenterology and Hepatology, University of Missouri-Kansas City School of Medicine, Kansas City, MO
- Gastroenterology, Saint Luke's Hospital of Kansas City, Kansas City, MO
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10
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Strouse J, Chan KK, Baccile R, He G, Louden DKN, Giurcanu M, Singh A, Rieth J, Abdel-Wahab N, Katsumoto TR, Singh N, Rouhani S, Reid P. Impact of steroid-sparing immunosuppressive agents on tumor outcome in the context of cancer immunotherapy with highlight on melanoma: a systematic literature review and meta-analysis. Front Immunol 2024; 15:1499478. [PMID: 39737191 PMCID: PMC11682972 DOI: 10.3389/fimmu.2024.1499478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 11/25/2024] [Indexed: 01/01/2025] Open
Abstract
Background The impact of steroid-sparing immunosuppressive agents (SSIAs) for immune-related adverse events (irAEs) on tumor outcome is not well-known. This systematic review evaluates tumor outcomes for corticosteroid (CS) monotherapy versus CS with SSIA (CS-SSIA) for irAE treatment with a focus on melanoma. Methods Search was conducted through 1/5/23 using PubMed, Embase, Cochrane CENTRAL, and Web of Science. We included case series, retrospective/prospective observational studies and interventional clinical trials. Individual-level data was analyzed using KM curves and Cox regression for overall survival (OS) and progression free survival (PFS). Time to SSIA was treated as a time-varying exposure using landmark analysis (landmark timepoint=3 months after irAE) to account for immortal time bias. For group-level data, meta-analysis compared the use of SSIA to No SSIA for irAEs. Results Of twenty-two publications with individual-level data, 147 patients with any cancer (57 CS, 90 CS-SSIA) and 65 with melanoma (18 CS, 47 CS-SSIA) underwent landmark analysis. Twenty-two publications underwent group-level evaluation and four were included in the meta-analysis. CS-SSIA versus CS showed higher risk of all-cause mortality and progression (HR 2.75, 95%CI: 1.44-5.27, p<0.01 and HR 1.75, 95%CI: 1.07-2.85, p=0.03, respectively). Melanoma showed worse OS and PFS for CS-SSIA versus CS (HR 5.68, 95%CI: 1.31-24.67, p=0.02 and HR 2.68, 95%CI: 1.12-6.40, p=0.03, respectively). In the meta-analysis of group-level data (n=2558), we found worse OS and PFS for CS-SSIA versus No SSIA (HR 1.58, 95%CI: 1.25; 2.01, p<0.01 and 1.70, 95%CI: 1.25-2.33, p<0.01). Tumor necrosis factor-alpha inhibitors (TNFi) were the most common SSIA. In the melanoma cohort, TNFi had worse OS and PFS versus CS (HR 6.46, 95%CI: 1.43-29.19, p = 0.02 and HR 7.49, 95%CI: 2.29-24.48, p<0.01, respectively). TNFi versus Other SSIAs showed a trend toward worse OS and worse PFS (HR 6.96, 95%CI: 0.90-53.65, p=0.06 and HR 21.5, 95%CI: 2.63-175.8, p<0.01, respectively). Meta-analysis showed a concern for TNFi compared to Other SSIA (HR 1.56, 95%CI: 1.17-2.09, p<0.01 respectively). Conclusions While our results raise concern about the effects of CS-SSIA and TNFi for irAE therapy on tumor outcomes, prospective randomized controlled trials are needed to definitively assess the effect of SSIAs on tumor outcomes.
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Affiliation(s)
- Jennifer Strouse
- Division of Immunology, University of Iowa, Iowa City, IA, United States
| | - Karmela Kimi Chan
- Division of Rheumatology, Department of Medicine, Hospital for Special Surgery, New York, NY, United States
| | - Rachel Baccile
- Center for Health and The Social Sciences, University of Chicago, Chicago, IL, United States
| | - Gong He
- Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, United States
| | - Diana K. N. Louden
- University Libraries, University of Washington, Seattle, WA, United States
| | - Mihai Giurcanu
- Department of Public Health Sciences, University of Chicago, Chicago, IL, United States
| | - Arohi Singh
- University of Chicago Medicine, Chicago, IL, United States
| | - John Rieth
- Division of Hematology, Oncology, and Blood & Marrow Transplantation, University of Iowa Health Care, Iowa City, IA, United States
| | - Noha Abdel-Wahab
- Section of Rheumatology & Clinical Immunology, Department of General Internal Medicine, and Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Department of Rheumatology & Rehabilitation, Assiut University Hospitals, Assiut University Faculty of Medicine, Asyut, Egypt
| | - Tamiko R. Katsumoto
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, United States
| | - Namrata Singh
- Division of Rheumatology, University of Washington, Seattle, WA, United States
| | - Sherin Rouhani
- Mass General Cancer Center, Massachusetts General Hospital, Boston, MA, United States
| | - Pankti Reid
- Division of Rheumatology, Department of Medicine, University of Chicago, Chicago, IL, United States
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11
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Ababneh O, Nishizaki D, Kato S, Kurzrock R. Tumor necrosis factor superfamily signaling: life and death in cancer. Cancer Metastasis Rev 2024; 43:1137-1163. [PMID: 39363128 PMCID: PMC11554763 DOI: 10.1007/s10555-024-10206-6] [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: 05/10/2024] [Accepted: 08/13/2024] [Indexed: 10/05/2024]
Abstract
Immune checkpoint inhibitors have shaped the landscape of cancer treatment. However, many patients either do not respond or suffer from later progression. Numerous proteins can control immune system activity, including multiple tumor necrosis factor (TNF) superfamily (TNFSF) and TNF receptor superfamily (TNFRSF) members; these proteins play a complex role in regulating cell survival and death, cellular differentiation, and immune system activity. Notably, TNFSF/TNFRSF molecules may display either pro-tumoral or anti-tumoral activity, or even both, depending on tumor type. Therefore, TNF is a prototype of an enigmatic two-faced mediator in oncogenesis. To date, multiple anti-TNF agents have been approved and/or included in guidelines for treating autoimmune disorders and immune-related toxicities after immune checkpoint blockade for cancer. A confirmed role for the TNFSF/TNFRSF members in treating cancer has proven more elusive. In this review, we highlight the cancer-relevant TNFSF/TNFRSF family members, focusing on the death domain-containing and co-stimulation members and their signaling pathways, as well as their complicated role in the life and death of cancer cells.
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Affiliation(s)
- Obada Ababneh
- Faculty of Medicine, Jordan University of Science and Technology, Irbid, 22110, Jordan.
| | - Daisuke Nishizaki
- Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, UC San Diego Moores Cancer Center, La Jolla, CA, USA
| | - Shumei Kato
- Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, UC San Diego Moores Cancer Center, La Jolla, CA, USA
| | - Razelle Kurzrock
- WIN Consortium, Paris, France.
- Department of Medicine, MCW Cancer Center, Milwaukee, WI, USA.
- Department of Oncology, University of Nebraska, Omaha, NE, USA.
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12
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Durán-Pacheco G, Chandler GS, Maiya V, Socinski MA, Sonpavde G, Puente J, Essioux L, Carter C, Cardona JV, Mohindra R, Naidoo J. Correlation of safety and efficacy of atezolizumab therapy across indications. J Immunother Cancer 2024; 12:e010158. [PMID: 39537212 PMCID: PMC11575237 DOI: 10.1136/jitc-2024-010158] [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] [Accepted: 10/18/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND The association between safety and efficacy of immune checkpoint inhibitors is known, but the correlation between severity and impact of specific organ involvement by immune-related adverse events (irAE) and cancer outcomes is poorly understood. Most irAEs are mild-to-moderate but severe irAEs may pose clinical management challenges and affect patient outcomes. METHODS We assessed the association between irAE grade (G) and specific organ involvement with overall survival (OS) in 9,521 patients across 14 studies involving atezolizumab as mono (IO) or with chemo/targeted (C-IO) therapy as compared with chemo/targeted therapy (C) in advanced non-small cell lung, small-cell lung, renal cell, urothelial, and triple-negative breast cancers. We used a mixed-effect Cox proportional hazard model for time-varying covariates to address immortal-time bias; adjusted for baseline factors associated with irAEs and OS to control for confounding bias; and focused on five common irAEs (dermatologic, thyroid dysfunction, hepatitis, pneumonitis, and colitis) to avoid low statistical power for rare events. RESULTS For patients treated with IO or C-IO, G1-2 irAEs were associated with improved OS (HR=0.65, p<0.01) and G3-4 irAEs showed a slight increased risk of death (HR=1.18, p=0.10) versus patients without irAEs. By specific irAE, G1-2 cutaneous irAEs, thyroid dysfunction, or pneumonitis were associated with improved OS (p<0.05), while G3-4 pneumonitis and colitis were associated with worse OS (p<0.01). There was no association between hepatitis and OS by any grade. Findings were consistent across indications. CONCLUSIONS This analysis demonstrates a correlation between irAEs and improved OS with atezolizumab by severity grade and the most common irAEs by organ involvement. Low-grade irAEs are significantly associated with improved OS, while specific high-grade irAEs are associated with poorer OS, underscoring the importance of early recognition and management of toxicity to optimize benefit/risk balance.
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Affiliation(s)
| | - G Scott Chandler
- F Hoffmann-La Roche Ltd, Basel, Switzerland
- Precision Safety, F Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Vidya Maiya
- Genentech Inc, South San Francisco, California, USA
| | | | - Guru Sonpavde
- AdventHealth Cancer Institute, Orlando, Florida, USA
- Medical Oncology, AdventHealth Central Florida, Orlando, Florida, USA
| | - Javier Puente
- Medical Oncology Department, CIBERONC, Madrid, Spain
| | | | - Corey Carter
- Genentech Inc, South San Francisco, California, USA
| | | | - Rajat Mohindra
- Precision Safety, F Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Jarushka Naidoo
- Royal College of Surgeons, Ireland, Cancer Centre, Beaumont Hospital, Dublin, Dublin, Ireland
- Johns Hopkins Medicine, Baltimore, Maryland, USA
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13
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Wang Q, Yu M, Zhang S. Peptic ulcer induced by immune checkpoint inhibitors successfully treated with glucocorticoids: A report of three cases and a literature review. Exp Ther Med 2024; 28:410. [PMID: 39258241 PMCID: PMC11384188 DOI: 10.3892/etm.2024.12699] [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: 02/05/2024] [Accepted: 07/11/2024] [Indexed: 09/12/2024] Open
Abstract
In recent decades, immune checkpoint inhibitors (ICIs) have emerged as safer and less disruptive alternatives to conventional chemotherapy and radiotherapy for certain patients with tumours. ICIs serve a synergistic role alongside conventional therapies by manipulating the immune system to recognise and target tumour cells. However, excessive activation of the immune system can lead to immune-related adverse events including pneumonia, myocarditis and colitis, which pose serious and even fatal risks. In the present case series, three patients with a thoracic tumour with an ICI-induced peptic ulcer triggered by programmed cell death protein 1 antibodies (diagnosed by gastrointestinal endoscopy) are presented. These cases were successfully treated with corticosteroids. The diagnostic and treatment processes undertaken for these patients underscore the requirement to comprehensively understand the mechanism of ICI-induced peptic ulcer. Moreover, the relevant literature was also reviewed in the present study.
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Affiliation(s)
- Qingzhe Wang
- Department of Targeting Therapy and Immunology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Min Yu
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Shuang Zhang
- Department of Targeting Therapy and Immunology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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14
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Deng YF, Cui XS, Wang L. Reconceptualization of immune checkpoint inhibitor-associated gastritis. World J Gastroenterol 2024; 30:4031-4035. [PMID: 39351252 PMCID: PMC11439116 DOI: 10.3748/wjg.v30.i36.4031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 08/28/2024] [Accepted: 09/09/2024] [Indexed: 09/20/2024] Open
Abstract
In recent years, with the extensive application of immunotherapy in clinical practice, it has achieved encouraging therapeutic effects. While enhancing clinical efficacy, however, it can also cause autoimmune damage, triggering immune-related adverse events (irAEs). Reports of immunotherapy-induced gastritis have been increasing annually, but due to its atypical clinical symptoms, early diag-nosis poses a certain challenge. Furthermore, it can lead to severe complications such as gastric bleeding, elevating the risk of adverse outcomes for solid tumor patients if immunotherapy is interrupted. Therefore, gaining a thorough under-standing of the pathogenesis, clinical manifestations, diagnostic criteria, and treatment of immune-related gastritis is of utmost importance for early identification, diagnosis, and treatment. Additionally, the treatment of immune-related gastritis should be personalized according to the specific condition of each patient. For patients with grade 2-3 irAEs, restarting immune checkpoint inhibitors (ICIs) therapy may be considered when symptoms subside to grade 0-1. When restarting ICIs therapy, it is often recommended to use different types of ICIs. For grade 4 irAEs, permanent discontinuation of the medication is necessary.
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Affiliation(s)
- Ying-Fang Deng
- Department of Oncology, Affiliated Hospital of Qinghai University, Xining 810000, Qinghai Province, China
- Ying-Fang Deng and Xian-Shu Cui
| | - Xian-Shu Cui
- Department of Oncology, Affiliated Hospital of Qinghai University, Xining 810000, Qinghai Province, China
- Ying-Fang Deng and Xian-Shu Cui
| | - Liang Wang
- Department of Gastrointestinal Oncology Surgery, Affiliated Hospital of Qinghai University, Xining 810000, Qinghai Province, China
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15
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Zoghbi M, Burk KJ, Haroun E, Saade M, Carreras MTC. Immune checkpoint inhibitor-induced diarrhea and colitis: an overview. Support Care Cancer 2024; 32:680. [PMID: 39311981 PMCID: PMC11420271 DOI: 10.1007/s00520-024-08889-2] [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: 05/13/2024] [Accepted: 09/17/2024] [Indexed: 09/26/2024]
Abstract
Immune checkpoint inhibitors (ICIs) have emerged as an integral component of the management of various cancers and have contributed to significant improvements in overall survival. Most available ICIs target anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4), and anti-programmed cell death 1/programmed cell death ligand 1 (anti-PD1/PDL1). Gastrointestinal immune-related adverse events remain a common complication of ICIs. The predominant manifestations include diarrhea and colitis, which often manifest concurrently as immune-mediated diarrhea and colitis (IMDC). Risk factors for developing these side effects include baseline gut microbiota, preexisting autoimmune disorders, such as inflammatory bowel disease, and type of neoplasm. The hallmark symptom of colitis is diarrhea which may be accompanied by mucus or blood in stools. Patients may also experience abdominal pain, fever, vomiting, and nausea. If not treated rapidly, ICI-induced colitis can lead to serious life-threatening complications. Current management is based on corticosteroids as first-line, and immunosuppressants like infliximab or vedolizumab for refractory cases. Microbiota transplantation and specific cytokines and lymphocyte replication inhibitors are being investigated. Optimal patient care requires maintaining a balance between treatment toxicity and efficacy, hence the aim of this review is to enhance readers' comprehension of the gastrointestinal adverse events associated with ICIs, particularly IMDC. In addition to identifying the risk factors, we discuss the incidence, clinical presentation, workup, and management options of IMDC.
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Affiliation(s)
- Marianne Zoghbi
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Kathryn J Burk
- Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Elio Haroun
- Faculty of Medicine, Saint Joseph University of Beirut, Beirut, 1100, Lebanon
| | - Maria Saade
- Faculty of Medicine, Saint Joseph University of Beirut, Beirut, 1100, Lebanon
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16
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Zhuang Y, Pan B, Zhang Y, Tang Z, Ji X, Zhang S, Yao L, Li T, Ma W, Tan C, Luo Y. Structure-activity relationships of natural and synthetic lathyrane-based diterpenoids for suppression of NLRP3-driven inflammation and gouty arthritis. Bioorg Chem 2024; 150:107558. [PMID: 38878755 DOI: 10.1016/j.bioorg.2024.107558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 06/10/2024] [Accepted: 06/11/2024] [Indexed: 07/21/2024]
Abstract
Lathyrane-based diterpenoid is one of the critical bioactive elements of Euphorbia lathyris L., a widely used traditional Chinese medicine for the treatment of inflammation and infection. In this study, we introduced and evaluated seven synthetic or natural lathyrane-based diterpenoids with the same core structure but notable structural variations at specific positions, for their anti-inflammatory and gout-alleviating properties. There was no significant cytotoxicity below 10 μM among the initial test of the cell counting kit 8 of the seven candidate derivatives (compounds 13 to 19) in this work. Furthermore, maintaining the acyloxy group at 15-C position and the strongly hydrophobic aryl structure at 3-C and 5-C positions, compounds 15 (Euphorbia factor L3, EFL3) and 17 strikingly inhibited the production of IL-1β related to the actuation of the inflammasome in our study. The ELISA assay indicated that the anti-inflammatory effects of EFL3 were better associated with MSU stimulation than other second-line pathways triggered by inflammasome. Further examinations on the acute paw gout model in C57BL/6 mice showed that EFL3 had a significantly inflammatory retarding effect by intraperitoneal injection. It decreased swelling volume as well as the cleavage and activation of local IL-1β and casepas-1 in the paw. To conclude, our findings reveal several potential key structure-activity relationships that govern the anti-inflammatory effects of lathyrane-type diterpenoids, the dispensable acyl group at the 15-C position, the importance of maintaining the spatial structure of the B-ring, and the potential importance of hydrophobic substituents at the 3-C position. These insights may provide guidance for the structural design of lathyrane-type agents in the future; furthermore, we found that the lathyrane-based diterpenoid EFL3 is a potential agent for gout that is expected to provide a novel therapeutic strategy for inflammation intervention.
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Affiliation(s)
- Yuqing Zhuang
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Bin Pan
- Shandong Engineering Research Center of Green and High-value Marine Fine Chemical, Weifang University of Science and Technology, Shouguang, China.
| | - Yuanyuan Zhang
- Sichuan Institute of Food Inspection, Chengdu, Sichuan, China
| | - Zhigang Tang
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xing Ji
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Sijun Zhang
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Lei Yao
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Tao Li
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Wenjing Ma
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chunyu Tan
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
| | - Yubin Luo
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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17
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O'Hare M, Guidon AC. Peripheral nervous system immune-related adverse events due to checkpoint inhibition. Nat Rev Neurol 2024; 20:509-525. [PMID: 39122934 DOI: 10.1038/s41582-024-01001-6] [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] [Accepted: 07/11/2024] [Indexed: 08/12/2024]
Abstract
Immune checkpoint inhibitors have revolutionized cancer therapy and are increasingly used to treat a wide range of oncological conditions, with dramatic benefits for many patients. Unfortunately, the resulting increase in T cell effector function often results in immune-related adverse events (irAEs), which can involve any organ system, including the central nervous system (CNS) and peripheral nervous system (PNS). Neurological irAEs involve the PNS in two-thirds of affected patients. Muscle involvement (immune-related myopathy) is the most common PNS irAE and can be associated with neuromuscular junction involvement. Immune-related peripheral neuropathy most commonly takes the form of polyradiculoneuropathy or cranial neuropathies. Immune-related myopathy (with or without neuromuscular junction involvement) often occurs along with immune-related myocarditis, and this overlap syndrome is associated with substantially increased mortality. This Review focuses on PNS adverse events associated with immune checkpoint inhibition. Underlying pathophysiological mechanisms are discussed, including antigen homology between self and tumour, epitope spreading and activation of pre-existing autoreactive T cells. An overview of current approaches to clinical management is provided, including cytokine-directed therapies that aim to decouple anticancer immunity from autoimmunity and emerging treatments for patients with severe (life-threatening) presentations.
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Affiliation(s)
- Meabh O'Hare
- Brigham and Women's Hospital, Division of Neuromuscular Medicine, Department of Neurology, Boston, MA, USA.
- Massachusetts General Hospital, Division of Neuromuscular Medicine, Department of Neurology, Boston, MA, USA.
| | - Amanda C Guidon
- Massachusetts General Hospital, Division of Neuromuscular Medicine, Department of Neurology, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
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18
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Adiwinata R, Tandarto K, Tanadi C, Waleleng BJ, Haroen H, Rotty L, Gosal F, Rotty L, Hendratta C, Lasut P, Winarta J, Waleleng A, Simadibrata P, Simadibrata M. Immune checkpoint inhibitor colitis, a rising issue in targeted cancer therapy era: A literature review. ROMANIAN JOURNAL OF INTERNAL MEDICINE = REVUE ROUMAINE DE MEDECINE INTERNE 2024; 62:219-230. [PMID: 38595047 DOI: 10.2478/rjim-2024-0015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Indexed: 04/11/2024]
Abstract
Research advances in the oncology treatment field have led to the widespread use of immunotherapy. The usage of immune checkpoint inhibitor (ICI) has improved the survival of cancer patients with metastases. This has also led to the rapidly expanding indications for ICI use. However, ICI usage may lead to toxicity, which may be immune-related, in different organ-specific targets. The immune-related adverse events (irAEs) of ICI may lead to increased morbidity, decreased quality of life, and early termination of ICI. The clinical manifestations of irAEs in the gastrointestinal system are variable, ranging from self-limited to life-threatening or fatal events. In this review article, we would like to focus on discussing ICI-induced colitis, which is one of the most common ICI irAEs in the gastrointestinal tract.
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Affiliation(s)
- Randy Adiwinata
- 1Department of Internal Medicine, Faculty of Medicine, Universitas Sam Ratulangi "Prof. dr. R. D. Kandou" Hospital, Manado, Indonesia
- 2Gastrointestinal Cancer Center, MRCCC Siloam Hospital Semanggi, Jakarta, Indonesia
| | - Kevin Tandarto
- 3Intensive Care Unit, Columbia Asia Hospital, Semarang, Indonesia
| | | | - Bradley Jimmy Waleleng
- 5Division of Gastroenterology-Hepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Sam Ratulangi "Prof. dr. R. D. Kandou" Hospital, Manado, Indonesia
| | - Harlinda Haroen
- 6Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Universitas Sam Ratulangi/Prof. dr. R. D. Kandou Hospital, Manado, Indonesia
| | - Linda Rotty
- 6Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Universitas Sam Ratulangi/Prof. dr. R. D. Kandou Hospital, Manado, Indonesia
| | - Fandy Gosal
- 5Division of Gastroenterology-Hepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Sam Ratulangi "Prof. dr. R. D. Kandou" Hospital, Manado, Indonesia
| | - Luciana Rotty
- 5Division of Gastroenterology-Hepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Sam Ratulangi "Prof. dr. R. D. Kandou" Hospital, Manado, Indonesia
| | - Cecilia Hendratta
- 6Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Universitas Sam Ratulangi/Prof. dr. R. D. Kandou Hospital, Manado, Indonesia
| | - Pearla Lasut
- 6Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Universitas Sam Ratulangi/Prof. dr. R. D. Kandou Hospital, Manado, Indonesia
| | - Jeanne Winarta
- 5Division of Gastroenterology-Hepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Sam Ratulangi "Prof. dr. R. D. Kandou" Hospital, Manado, Indonesia
| | - Andrew Waleleng
- 5Division of Gastroenterology-Hepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Sam Ratulangi "Prof. dr. R. D. Kandou" Hospital, Manado, Indonesia
| | - Paulus Simadibrata
- 2Gastrointestinal Cancer Center, MRCCC Siloam Hospital Semanggi, Jakarta, Indonesia
- 7Abdi Waluyo Hospital, Jakarta, Indonesia
| | - Marcellus Simadibrata
- 8Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
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19
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Brazel D, Larocca C, Shinohara MM. Assessing Health-Related Quality of Life in Mycosis Fungoides and Sézary Syndrome: Unmet Needs. Cancers (Basel) 2024; 16:2757. [PMID: 39123484 PMCID: PMC11312166 DOI: 10.3390/cancers16152757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 07/30/2024] [Accepted: 07/30/2024] [Indexed: 08/12/2024] Open
Abstract
Mycosis fungoides (MF) and Sézary syndrome (SS) can impair multiple dimensions of health-related quality of life (HRQoL). Currently, there is no standardized assessment tool for measuring HRQoL in patients with MF/SS. Here, we describe the existing literature on multiple dimensions of HRQoL in MF/SS with a special focus on the gaps in the current knowledge and identify future directions necessary to assess the HRQoL of patients with this disease.
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Affiliation(s)
- Danielle Brazel
- Department of Hematology/Oncology, Scripps Clinic/Scripps Green Hospital, La Jolla, CA 92037, USA
| | - Cecilia Larocca
- Brigham and Women’s Department of Dermatology, Dana Farber Cancer Center, Boston, MA 02215, USA
| | - Michi M. Shinohara
- Department of Dermatology, University of Washington, 1959 Northeast Pacific Street BB-1353, Box 356524, Seattle, WA 98195, USA
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Hong N, Wang B, Zhou HC, Wu ZX, Fang HY, Song GQ, Yu Y. Multidisciplinary management of ulcerative colitis complicated by immune checkpoint inhibitor-associated colitis with life-threatening gastrointestinal hemorrhage: A case report. World J Gastrointest Surg 2024; 16:2329-2336. [PMID: 39087117 PMCID: PMC11287687 DOI: 10.4240/wjgs.v16.i7.2329] [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: 02/24/2024] [Revised: 05/26/2024] [Accepted: 06/18/2024] [Indexed: 07/22/2024] Open
Abstract
BACKGROUND Programmed cell death 1 (PD-1) inhibitors are immune checkpoint inhibitors (ICI) that have demonstrated significant efficacy in treating various advanced malignant tumors. While most patients tolerate treatment well, several adverse drug reactions, such as fatigue, myelosuppression, and ICI-associated colitis, have been reported. CASE SUMMARY This case involved a 57-year-old male patient with ulcerative colitis complicated by hepatocarcinoma who underwent treatment with tirelizumab (a PD-1 inhibitor) for six months. The treatment led to repeated life-threatening lower gastrointestinal hemorrhage. The patient received infliximab, vedolizumab, and other salvage procedures but ultimately required subtotal colectomy due to uncontrollable massive lower gastrointestinal bleeding. Currently, postoperative gastrointestinal bleeding has stopped, the patient's stool has turned yellow, and his full blood cell count has returned to normal. CONCLUSION This case highlights the necessity of early identification, timely and adequate treatment of ICI-related colitis, and rapid escalation to achieve the goal of improving prognosis.
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Affiliation(s)
- Na Hong
- Department of Gastroenterology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
| | - Bo Wang
- Department of Gastroenterology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
| | - Hang-Cheng Zhou
- Department of Pathology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230036, Anhui Province, China
- Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230036, Anhui Province, China
| | - Zheng-Xiang Wu
- Department of Gastroenterology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
| | - Hua-Ying Fang
- Department of Gastroenterology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
| | - Geng-Qing Song
- Department of Gastroenterology and Hepatology, Metro Health Medical Center, Case Western Reserve University, Cleveland, OH 44109, United States
| | - Yue Yu
- Department of Gastroenterology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
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21
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Malkopoulos A, Mason R, Pillai S, Dzienis M. Immune-related colitis presenting with constipation. BMJ Case Rep 2024; 17:e258940. [PMID: 39038878 DOI: 10.1136/bcr-2023-258940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/24/2024] Open
Abstract
Anticancer immunotherapies modulate the body's immune system to recognise and eradicate cancerous cells. However, stimulation of the body's immune system can also lead to a number of adverse effects when those immune cells target non-cancerous cells in the form of autoimmunity. One relatively common example of this off-target action is colitis.We present three patients who presented atypically with colitis, consequently, leading to a delayed diagnosis. These cases highlight the diverse ways a relatively common immune-related adverse event can present.
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Affiliation(s)
| | - Robert Mason
- Queensland Health, Brisbane, Queensland, Australia
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22
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Magahis PT, Corso T, Livingstone P, Tom E, Srivastava A, Postow M, Faleck D. Open-capsule budesonide for the treatment of immune-related enteritis from checkpoint inhibitors. J Immunother Cancer 2024; 12:e009051. [PMID: 39032941 PMCID: PMC11261704 DOI: 10.1136/jitc-2024-009051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/25/2024] [Indexed: 07/23/2024] Open
Abstract
BACKGROUND Limited data exist for management strategies targeting immunotherapy-related enteritis (irEnteritis). Systemic corticosteroids are commonly used but often are limited by adverse events. Enteric corticosteroids such as budesonide offer an attractive alternative; however, the ileocolonic release of enteric-coated budesonide has limited utility for diffuse enteritis. Open-capsule budesonide (OCB) is a novel therapeutic approach that offers drug delivery throughout the small bowel. We report outcomes in patients treated with OCB for confirmed or suspected irEnteritis. METHODS This retrospective cohort included all individuals treated with OCB for irEnteritis at Memorial Sloan Kettering from July 2018 to August 2023. Primary outcomes included clinical response, clinical remission, and corticosteroid-free remission following OCB. Secondary outcomes were OCB-related adverse events and efficacy by gastrointestinal toxicity location. RESULTS 19 patients (53% female) with irEnteritis were treated with OCB. All patients presented with diarrhea; 15 (79%) reported anorexia with median 6 kg weight loss. 17 patients (89%) underwent esophagogastroduodenoscopy with biopsies revealing enteritis in all; 8 (42%) had concomitant colitis. 15 (79%) patients were treated previously with systemic corticosteroids: 8 (53%) were corticosteroid-dependent while 7 (47%) demonstrated non-response. 18 patients (95%) achieved clinical response, 15 (79%) attained clinical remission, and 11 (58%) had corticosteroid-free remission. Response to OCB was rapid with improvement noted after a median 4 days. 14 (74%) patients restored their pre-irEnteritis weight by OCB cessation. One mild, self-resolving adverse event was reported. CONCLUSIONS OCB is a safe and effective therapy for irEnteritis. OCB avoids systemic immunosuppression and successfully achieves clinical response and remission even in patients previously nonresponsive to systemic corticosteroids. Future studies are needed to optimize indications and duration.
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Affiliation(s)
| | - Tara Corso
- Gastroenterology, Hepatology, and Nutrition Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Pamela Livingstone
- Gastroenterology, Hepatology, and Nutrition Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Erika Tom
- Gastroenterology, Hepatology, and Nutrition Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Amitabh Srivastava
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Michael Postow
- Weill Cornell Medical College, New York, New York, USA
- Melanoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - David Faleck
- Weill Cornell Medical College, New York, New York, USA
- Gastroenterology, Hepatology, and Nutrition Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
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23
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Astašauskaitė S, Kupčinskaitė-Noreikienė R, Zaborienė I, Vaičiūnienė R, Vanagas T, Pranys D, Poškienė L, Juozaitytė E. Multiorgan Toxicity from Dual Checkpoint Inhibitor Therapy, Resulting in a Complete Response-A Case Report. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1129. [PMID: 39064558 PMCID: PMC11278757 DOI: 10.3390/medicina60071129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 06/30/2024] [Accepted: 07/10/2024] [Indexed: 07/28/2024]
Abstract
Immunotherapy treatment with checkpoint inhibitors (ICIs) has led to a breakthrough in the treatment of oncological diseases. Despite its clinical effectiveness, this treatment differs from others, such as cytotoxic chemotherapy, in that it causes immune-related adverse events. This type of toxicity can affect any organ or organ system of the body. We present a literature review and a rare clinical case from our clinical practice, in which a patient with metastatic clear cell renal carcinoma was treated with a single dose of dual checkpoint blockade (cytotoxic T-lymphocyte-4 (CTLA-4) and programmed death-1 (PD-1)) and simultaneously diagnosed with colitis, hepatitis, and nephritis. After early immunosuppressive treatment with the glucocorticoids, complete organ function recovery was achieved. The follow-up revealed a sustained complete response lasting more than a year.
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Affiliation(s)
- Skaistė Astašauskaitė
- Institute of Oncology, Medical Academy, Faculty of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Rita Kupčinskaitė-Noreikienė
- Institute of Oncology, Medical Academy, Faculty of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Inga Zaborienė
- Department of Radiology, Medical Academy, Faculty of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Rūta Vaičiūnienė
- Department of Nephrology, Medical Academy, Faculty of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Tomas Vanagas
- Department of Surgery, Medical Academy, Faculty of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Darius Pranys
- Department of Pathology, Medical Academy, Faculty of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Lina Poškienė
- Department of Pathology, Medical Academy, Faculty of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Elona Juozaitytė
- Institute of Oncology, Medical Academy, Faculty of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
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24
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Lenti MV, Ribaldone DG, Borrelli de Andreis F, Vernero M, Barberio B, De Ruvo M, Savarino EV, Kav T, Blesl A, Franzoi M, Gröchenig HP, Pugliese D, Ianiro G, Porcari S, Cammarota G, Gasbarrini A, Spagnuolo R, Ellul P, Foteinogiannopoulou K, Koutroubakis I, Argyriou K, Cappello M, Jauregui-Amezaga A, Demarzo MG, Silvestris N, Armuzzi A, Sottotetti F, Bertani L, Festa S, Eder P, Pedrazzoli P, Lasagna A, Vanoli A, Gambini G, Santacroce G, Rossi CM, Delliponti M, Klersy C, Corazza GR, Di Sabatino A. A 1-year follow-up study on checkpoint inhibitor-induced colitis: results from a European consortium. ESMO Open 2024; 9:103632. [PMID: 38970840 PMCID: PMC11360400 DOI: 10.1016/j.esmoop.2024.103632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Revised: 05/22/2024] [Accepted: 06/10/2024] [Indexed: 07/08/2024] Open
Abstract
BACKGROUND Data regarding the clinical outcome of patients with immune checkpoint inhibitor (ICI)-induced colitis are scant. We aimed to describe the 12-month clinical outcome of patients with ICI-induced colitis. MATERIALS AND METHODS This was a retrospective, European, multicentre study. Endoscopy/histology-proven ICI-induced colitis patients were enrolled. The 12-month clinical remission rate, defined as a Common Terminology Criteria for Adverse Events diarrhoea grade of 0-1, and the correlates of 12-month remission were assessed. RESULTS Ninety-six patients [male:female ratio 1.5:1; median age 65 years, interquartile range (IQR) 55.5-71.5 years] were included. Lung cancer (41, 42.7%) and melanoma (30, 31.2%) were the most common cancers. ICI-related gastrointestinal symptoms occurred at a median time of 4 months (IQR 2-7 months). An inflammatory bowel disease (IBD)-like pattern was present in 74 patients (77.1%) [35 (47.3%) ulcerative colitis (UC)-like, 11 (14.9%) Crohn's disease (CD)-like, 28 (37.8%) IBD-like unclassified], while microscopic colitis was present in 19 patients (19.8%). As a first line, systemic steroids were the most prescribed drugs (65, 67.7%). The 12-month clinical remission rate was 47.7 per 100 person-years [95% confidence interval (CI) 33.5-67.8). ICI was discontinued due to colitis in 66 patients (79.5%). A CD-like pattern was associated with remission failure (hazard ratio 3.84, 95% CI 1.16-12.69). Having histopathological signs of microscopic colitis (P = 0.049) and microscopic versus UC-/CD-like colitis (P = 0.014) were associated with a better outcome. Discontinuing the ICI was not related to the 12-month remission (P = 0.483). Four patients (3.1%) died from ICI-induced colitis. CONCLUSIONS Patients with IBD-like colitis may need an early and more aggressive treatment. Future studies should focus on how to improve long-term clinical outcomes.
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Affiliation(s)
- M V Lenti
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - D G Ribaldone
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - F Borrelli de Andreis
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; Digestive Endoscopy Unit, Isola Tiberina - Gemelli Isola Hospital, Rome, Italy
| | - M Vernero
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - B Barberio
- Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - M De Ruvo
- Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - E V Savarino
- Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - T Kav
- Department of Gastroenterology, Hacettepe University School of Medicine, Ankara, Türkiye
| | - A Blesl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - M Franzoi
- Department of Internal Medicine and Gastroenterology, Academic Teaching Hospital Brothers of St John of God, St Veit an der Glan, Austria
| | - H P Gröchenig
- Department of Internal Medicine and Gastroenterology, Academic Teaching Hospital Brothers of St John of God, St Veit an der Glan, Austria
| | - D Pugliese
- Department of Medical and Surgical Sciences, CEMAD (Digestive Disease Center), Policlinico Universitario 'A. Gemelli' IRCCS Foundation, Rome, Italy; Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore Roma, Rome, Italy; UOS Gastroenterologia, Ospedale Isola Tiberina Gemelli Isola, Rome, Italy
| | - G Ianiro
- Department of Medical and Surgical Sciences, CEMAD (Digestive Disease Center), Policlinico Universitario 'A. Gemelli' IRCCS Foundation, Rome, Italy; Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore Roma, Rome, Italy
| | - S Porcari
- Department of Medical and Surgical Sciences, CEMAD (Digestive Disease Center), Policlinico Universitario 'A. Gemelli' IRCCS Foundation, Rome, Italy; Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore Roma, Rome, Italy
| | - G Cammarota
- Department of Medical and Surgical Sciences, CEMAD (Digestive Disease Center), Policlinico Universitario 'A. Gemelli' IRCCS Foundation, Rome, Italy; Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore Roma, Rome, Italy
| | - A Gasbarrini
- Department of Medical and Surgical Sciences, CEMAD (Digestive Disease Center), Policlinico Universitario 'A. Gemelli' IRCCS Foundation, Rome, Italy; Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore Roma, Rome, Italy
| | - R Spagnuolo
- Department of Health Sciences, University 'Magna Graecia', Catanzaro, Italy
| | - P Ellul
- Division of Gastroenterology, Department of Medicine, Mater Dei Hospital, Msida, Malta
| | - K Foteinogiannopoulou
- Department of Gastroenterology, University Hospital of Heraklion, Heraklion, Crete, Greece
| | - I Koutroubakis
- Department of Gastroenterology, University Hospital of Heraklion, Heraklion, Crete, Greece
| | - K Argyriou
- Department of Gastroenterology, University Hospital of Larisa, Larisa, Greece
| | - M Cappello
- Gastroenterology & Hepatology Section, PROMISE, University of Palermo, Palermo, Italy
| | - A Jauregui-Amezaga
- Department of Gastroenterology and Hepatology, University Hospital Antwerp, Antwerp, Belgium; Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - M G Demarzo
- Department of Internal Medicine, Ospedale Policlinico San Martino-IRCCS per l'Oncologia, Gastroenterology Unit, University of Genoa, Genoa, Italy
| | - N Silvestris
- Medical Oncology Unit, Department of Human Pathology of Adulthood and Childhood DETEV 'G. Barresi', University of Messina, Messina, Italy
| | - A Armuzzi
- IBD Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - F Sottotetti
- Istituti Clinici Scientifici Maugeri IRCCS, Medical Oncology Unit, Pavia, Italy
| | - L Bertani
- Department of General Surgery and Gastroenterology, Tuscany North West ASL, Pontedera Hospital, Pontedera, Italy
| | - S Festa
- IBD Unit, Ospedale S. Filippo Neri, Rome, Italy
| | - P Eder
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - P Pedrazzoli
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - A Lasagna
- Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - A Vanoli
- Unit of Anatomic Pathology, Department of Molecular Medicine, University of Pavia, and IRCCS San Matteo Hospital Foundation, Pavia, Italy
| | - G Gambini
- Clinical Epidemiology and Biometry Service, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - G Santacroce
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - C M Rossi
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - M Delliponti
- First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - C Klersy
- Clinical Epidemiology and Biometry Service, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - G R Corazza
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - A Di Sabatino
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
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25
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Del Gaudio A, Di Vincenzo F, Petito V, Giustiniani MC, Gasbarrini A, Scaldaferri F, Lopetuso LR. Focus on Immune Checkpoint Inhibitors-related Intestinal Inflammation: From Pathogenesis to Therapeutical Approach. Inflamm Bowel Dis 2024; 30:1018-1031. [PMID: 37801695 PMCID: PMC11144981 DOI: 10.1093/ibd/izad229] [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: 05/25/2023] [Indexed: 10/08/2023]
Abstract
Recently, antitumor immunotherapies have witnessed a breakthrough with the emergence of immune checkpoint inhibitors (ICIs) including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors. Unfortunately, the use of ICIs has also led to the advent of a novel class of adverse events that differ from those of classic chemotherapeutics and are more reminiscent of autoimmune diseases, the immune-related adverse events (IRAEs). Herein, we performed an insight of the main IRAEs associated with ICIs, focusing on gastroenterological IRAEs and specifically on checkpoint inhibitor colitis, which represents the most widely reported IRAE to date. We comprehensively dissected the current evidence regarding pathogenesis, diagnosis, and management of ICIs-induced colitis, touching upon also on innovative therapies.
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Affiliation(s)
- Angelo Del Gaudio
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | - Federica Di Vincenzo
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | - Valentina Petito
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | | | - Antonio Gasbarrini
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | - Franco Scaldaferri
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | - Loris Riccardo Lopetuso
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- Department of Medicine and Ageing Sciences, G. d’Annunzio University of Chieti-Pescara, Chieti, 66100, Italy
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, Chieti, 66100, Italy
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26
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Cariou PL, Pobel C, Michot JM, Danlos FX, Besse B, Carbonnel F, Mariette X, Marabelle A, Messayke S, Robert C, Routier E, Noël N, Lambotte O. Impact of immunosuppressive agents on the management of immune-related adverse events of immune checkpoint blockers. Eur J Cancer 2024; 204:114065. [PMID: 38643707 DOI: 10.1016/j.ejca.2024.114065] [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: 01/20/2024] [Revised: 04/11/2024] [Accepted: 04/11/2024] [Indexed: 04/23/2024]
Abstract
BACKGROUND Immune checkpoint blockers (ICBs) can induce immune-related adverse events (irAEs) whose management is based on expert opinion and may require the prescription of steroids and/or immunosuppressants (ISs). Recent data suggest that these treatments can reduce the effectiveness of ICBs. OBJECTIVE To investigate the relationship between the use of steroids and/or ISs and overall survival (OS) and progression-free survival (PFS) among ICB-treated patients with an irAE. METHODS We prospectively collected data from the medical records of patients with solid tumors or lymphoma in the French REISAMIC cohort and who had been treated with ICBs between June 2014 and June 2020. RESULTS 184 ICB-treated patients experienced at least one Common Terminology Criteria for Adverse Events grade ≥ 2 irAE. 107 (58.2%) were treated with steroids alone, 20 (10.9%) with steroids plus IS, 57 (31.0%) not received steroids or IS. The median OS was significantly shorter for patients treated with steroids alone (25.2 months [95% confidence interval (CI): 22.3-32.4] than for patients treated without steroids or IS (63 months [95%CI: 40.4-NA]) and those receiving an IS with steroids (53.4 months [95%CI: 47.3-NA]) (p < 0.001). The median PFS was significantly shorter for patients treated with steroids alone (17.0 months [95%CI: 11.7-22.9]) than for patients treated without steroids or IS (33.9 months [95%CI: 18.0-NA]) and those receiving an IS with steroids (41.1 months [95%CI: 26.2-NA]) (p = 0.006). There were no significant intergroup differences in the hospital admission and infection rates. CONCLUSION In a prospective cohort of ICB-treated patients, the use of IS was not associated with worse OS or PFS, contrasting with the use of steroids for the management of irAEs.
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Affiliation(s)
- Pierre-Louis Cariou
- Université Paris Saclay, AP-HP, Hôpital de Bicêtre, Department of Internal Medicine, UMR 1184, CEA INSERM, FHU CARE, Le Kremlin Bicêtre, France
| | - Cédric Pobel
- Drug Development Department (DITEP), Gustave Roussy, 94805 Villejuif, France
| | - Jean-Marie Michot
- Drug Development Department (DITEP), Gustave Roussy, 94805 Villejuif, France
| | | | - Benjamin Besse
- Department of Cancer Medicine, Gustave Roussy, Villejuif, France
| | - Franck Carbonnel
- AP-HP, Department of Gastroenterology, University Hospital of Bicêtre, Paris Sud University, FHU CARE, 78 Rue du General Leclerc, 94270 Le Kremlin-Bicetre, France
| | - Xavier Mariette
- Université Paris-Saclay, AP-HP, Hôpital Bicêtre, Rheumatology Department, INSERM UMR 1184, FHU CARE, Paris, Le Kremlin Bicêtre, France
| | - Aurélien Marabelle
- Drug Development Department (DITEP), Gustave Roussy, 94805 Villejuif, France
| | - Sabine Messayke
- Gustave Roussy - Paris-Saclay University, Pharmacovigilance Unit, 94800 Villejuif, France
| | - Caroline Robert
- Dermatology Service, Department of Medicine, Gustave Roussy and Paris-Saclay University, 114 Rue Edouard Vaillant, 94805 Villejuif, France
| | - Emilie Routier
- Dermatology Service, Department of Medicine, Gustave Roussy and Paris-Saclay University, 114 Rue Edouard Vaillant, 94805 Villejuif, France
| | - Nicolas Noël
- Université Paris Saclay, AP-HP, Hôpital de Bicêtre, Department of Internal Medicine, UMR 1184, CEA INSERM, FHU CARE, Le Kremlin Bicêtre, France
| | - Olivier Lambotte
- Université Paris Saclay, AP-HP, Hôpital de Bicêtre, Department of Internal Medicine, UMR 1184, CEA INSERM, FHU CARE, Le Kremlin Bicêtre, France.
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Riveiro-Barciela M, Carballal S, Díaz-González Á, Mañosa M, Gallego-Plazas J, Cubiella J, Jiménez-Fonseca P, Varela M, Menchén L, Sangro B, Fernández-Montes A, Mesonero F, Rodríguez-Gandía MÁ, Rivera F, Londoño MC. Management of liver and gastrointestinal toxicity induced by immune checkpoint inhibitors: Position statement of the AEEH-AEG-SEPD-SEOM-GETECCU. GASTROENTEROLOGIA Y HEPATOLOGIA 2024; 47:401-432. [PMID: 38228461 DOI: 10.1016/j.gastrohep.2023.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 09/28/2023] [Accepted: 10/19/2023] [Indexed: 01/18/2024]
Abstract
The development of the immune checkpoint inhibitors (ICI) is one of the most remarkable achievements in cancer therapy in recent years. However, their exponential use has led to an increase in immune-related adverse events (irAEs). Gastrointestinal and liver events encompass hepatitis, colitis and upper digestive tract symptoms accounting for the most common irAEs, with incidence rates varying from 2% to 40%, the latter in patients undergoing combined ICIs therapy. Based on the current scientific evidence derived from both randomized clinical trials and real-world studies, this statement document provides recommendations on the diagnosis, treatment and prognosis of the gastrointestinal and hepatic ICI-induced adverse events.
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Affiliation(s)
- Mar Riveiro-Barciela
- Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Universitat Autònoma de Barcelona (UAB), Department of Medicine, Spain.
| | - Sabela Carballal
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Gastroenterology Department, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Universitat de Barcelona, Spain
| | - Álvaro Díaz-González
- Gastroenterology Department, Grupo de Investigación Clínica y Traslacional en Enfermedades Digestivas, Instituto de Investigación Valdecilla (IDIVAL), Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | - Míriam Mañosa
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Gastroenterology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | | | - Joaquín Cubiella
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Gastroenterology Department, Hospital Universitario de Ourense, Grupo de Investigación en Oncología Digestiva-Ourense, Spain
| | - Paula Jiménez-Fonseca
- Medical Oncology Department, Hospital Universitario Central de Asturias, ISPA, Oviedo, Spain
| | - María Varela
- Gastroenterology Department, Hospital Universitario Central de Asturias, IUOPA, ISPA, FINBA, University of Oviedo, Oviedo, Spain
| | - Luis Menchén
- Servicio de Aparato Digestivo - CEIMI, Instituto de Investigación Sanitaria Gregorio, Marañón, Spain; Departamento de Medicina, Universidad Complutense, Madrid, Spain
| | - Bruno Sangro
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Liver Unit, Cancer Center Clinica Universidad de Navarra, Pamplona-Madrid, Spain
| | - Ana Fernández-Montes
- Medical Oncology Department, Complexo Hospitalario Universitario de Ourense, Ourense, Spain
| | - Francisco Mesonero
- Gastroenterology and Hepatology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain; Universidad de Alcalá de Henares, Spain
| | - Miguel Ángel Rodríguez-Gandía
- Gastroenterology and Hepatology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRyCIS), Madrid, Spain
| | - Fernando Rivera
- Medical Oncology Department, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain
| | - María-Carlota Londoño
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Universitat de Barcelona, Spain; Liver Unit, Hospital Clínic Barcelona, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Spain
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Lei C, Kong X, Li Y, Yang H, Zhang K, Wang Z, Chang H, Xuan L. PD-1/PD-L1 Inhibitor - Related Adverse Events and Their Management in Breast Cancer. J Cancer 2024; 15:2770-2787. [PMID: 38577606 PMCID: PMC10988294 DOI: 10.7150/jca.85433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 03/03/2024] [Indexed: 04/06/2024] Open
Abstract
As the positive results of multiple clinical trials were released, the Programmed cell death 1 (PD-1) and Programmed cell death ligand 1 (PD-L1) inhibitors emerge as the focus of integrative breast cancer treatment. PD-1/PD-L1 inhibitors are often used as a sequential agent to be combined with other agents such as chemotherapeutic agents, targeted agents, and radiation therapy. As multiple therapies are administered simultaneously or in sequence, they are prone to a variety of adverse effects on patients while achieving efficacy. It is a challenge for clinicians to maintaining the balance between immune-related adverse effects(irAEs) and treatment efficacy. Previous literatures have paid lots of attention on the adverse effects caused by immunosuppressive agents themselves, while there is a dearth of the research on the management of adverse immune effects during the combination of immunotherapy with other treatments. In this review, we discuss the overall incidence of irAEs caused by PD-1/PD-L1 inhibitors in combination with various types of treatments in breast cancer, including chemotherapy, CTLA-4 inhibitors, targeted therapy, and radiotherapy, and systematically summarizes the clinical management to each organ-related adverse immune reaction. It is important to emphasize that in the event of irAEs such as neurological, hematologic, and cardiac toxicity, there is no alternative treatment but to terminate immunotherapy. Thus, seeking more effective strategy of irAEs' management is imminent and clinicians are urged to raise the awareness of the management of adverse immune reactions.
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Affiliation(s)
- Chuqi Lei
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiangyi Kong
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuan Li
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huaiyu Yang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ke Zhang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhongzhao Wang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hu Chang
- Administration Office, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Lixue Xuan
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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29
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Jiang QY, Xue RY. Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio: Markers predicting immune-checkpoint inhibitor efficacy and immune-related adverse events. World J Gastrointest Oncol 2024; 16:577-582. [PMID: 38577447 PMCID: PMC10989358 DOI: 10.4251/wjgo.v16.i3.577] [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: 11/01/2023] [Revised: 12/14/2023] [Accepted: 01/18/2024] [Indexed: 03/12/2024] Open
Abstract
We conducted a comprehensive review of existing prediction models pertaining to the efficacy of immune-checkpoint inhibitor (ICI) and the occurrence of immune-related adverse events (irAEs). The predictive potential of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in determining ICI effectiveness has been extensively investigated, while limited research has been conducted on predicting irAEs. Furthermore, the combined model incorporating NLR and PLR, either with each other or in conjunction with additional markers such as carcinoembryonic antigen, exhibits superior predictive capabilities compared to individual markers alone. NLR and PLR are promising markers for clinical applications. Forthcoming models ought to incorporate established efficacious models and newly identified ones, thereby constituting a multifactor composite model. Furthermore, efforts should be made to explore effective clinical application approaches that enhance the predictive accuracy and efficiency.
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Affiliation(s)
- Qiu-Yu Jiang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai 200032, China
| | - Ru-Yi Xue
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai 200032, China
- Department of Gastroenterology and Hepatology, Shanghai Baoshan District Wusong Central Hospital (Zhongshan Hospital Wusong Branch, Fudan University), Shanghai 200940, China
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Velikova T, Krastev B, Gulinac M, Zashev M, Graklanov V, Peruhova M. New strategies in the diagnosis and treatment of immune-checkpoint inhibitor-mediated colitis. World J Clin Cases 2024; 12:1050-1062. [PMID: 38464930 PMCID: PMC10921308 DOI: 10.12998/wjcc.v12.i6.1050] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/20/2023] [Accepted: 01/19/2024] [Indexed: 02/20/2024] Open
Abstract
Immune-checkpoint inhibitor-mediated colitis (IMC) is an increasingly recognized adverse event in cancer immunotherapy, particularly associated with immune checkpoint inhibitors (ICIs) such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed cell death protein-1 antibodies. As this revolutionary immunotherapy gains prominence in cancer treatment, understanding, diagnosing, and effectively managing IMC becomes paramount. IMC represents a unique challenge due to its immune-mediated nature and potential for severe complications. However, a precise picture of IMC pathophysiology is currently unavailable. Therefore, we aimed to summarize the existing data while acknowledging the need for further research. This comprehensive review explores the mechanisms underlying ICIs, gastrointestinal adverse effects, and, in particular, IMC's incidence, prevalence, and features. Our review also emphasizes the importance of recognizing IMC's distinct clinical and histopathological features to differentiate it from other forms of colitis. Furthermore, this paper highlights the urgent need for evolving diagnostic methods, therapeutic strategies, and a multidisciplinary approach to effectively manage IMC.
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Affiliation(s)
- Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
| | - Boris Krastev
- Medical Center Nadezhda, Medical Center Nadezhda, Sofia 1407, Bulgaria
| | - Milena Gulinac
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
- General and Clinical Pathology, Medical University of Plovdiv, Plovdiv 4002, Bulgaria
| | - Miroslav Zashev
- Department of General Surgery, University Hospital “Heart and Brain”, Burgas 8000, Bulgaria
| | - Vasko Graklanov
- First Department of Internal Diseases, Medical University of Plovdiv, Plovdiv 4000, Bulgaria
- Department of Hematology, University Hospital “St. George”, Plovdiv 4000, Bulgaria
| | - Milena Peruhova
- Division of Gastroenterology, University Hospital “Heart and Brain”, Burgas 1000, Bulgaria
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31
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Yan T, Yu L, Zhang J, Chen Y, Fu Y, Tang J, Liao D. Achilles' Heel of currently approved immune checkpoint inhibitors: immune related adverse events. Front Immunol 2024; 15:1292122. [PMID: 38410506 PMCID: PMC10895024 DOI: 10.3389/fimmu.2024.1292122] [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: 09/11/2023] [Accepted: 01/04/2024] [Indexed: 02/28/2024] Open
Abstract
Immunotherapy has revolutionized the cancer treatment landscape by opening up novel avenues for intervention. As the use of immune checkpoint inhibitors (ICIs) has exponentially increased, so have immune-related adverse events (irAEs). The mechanism of irAEs may involve the direct damage caused by monoclonal antibodies and a sequence of immune responses triggered by T cell activation. Common side effects include dermatologic toxicity, endocrine toxicity, gastrointestinal toxicity, and hepatic toxicity. While relatively rare, neurotoxicity, cardiotoxicity, and pulmonary toxicity can be fatal. These toxicities pose a clinical dilemma regarding treatment discontinuation since they can result in severe complications and necessitate frequent hospitalization. Vigilant monitoring of irAEs is vital in clinical practice, and the principal therapeutic strategy entails the administration of oral or intravenous glucocorticoids (GSCs). It may be necessary to temporarily or permanently discontinue the use of ICIs in severe cases. Given that irAEs can impact multiple organs and require diverse treatment approaches, the involvement of a multidisciplinary team of experts is imperative. This review aims to comprehensively examine the pathogenesis, clinical manifestations, incidence, and treatment options for various irAEs.
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Affiliation(s)
- Ting Yan
- Department of Pharmacy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Lun Yu
- Department of Positron Emission Tomography–Computed Tomography (PET-CT) Center, Chenzhou No. 1 People’s Hospital, Chenzhou, China
| | - Jiwen Zhang
- Department of Pharmacy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- School of Pharmacy, University of South China, Hengyang, China
| | - Yun Chen
- Department of Pharmacy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Yilan Fu
- Department of Pharmacy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Jingyi Tang
- Department of Pharmacy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Dehua Liao
- Department of Pharmacy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
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Riveiro-Barciela M, Carballal S, Díaz-González Á, Mañosa M, Gallgo-Plazas J, Cubiella J, Jiménez-Fonseca P, Varela M, Menchén L, Sangro B, Fernández-Montes A, Mesonero F, Rodríguez-Gandía MÁ, Rivera F, Londoño MC. Management of liver and gastrointestinal toxicity induced by immune checkpoint inhibitors: Position statement of the AEEH-AEG-SEPD-SEOM-GETECCU. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2024; 116:83-113. [PMID: 38226597 DOI: 10.17235/reed.2024.10250/2024] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2024]
Abstract
The development of the immune checkpoint inhibitors (ICI) is one of the most remarkable achievements in cancer therapy in recent years. However, their exponential use has led to an increase in immune-related adverse events (irAEs). Gastrointestinal and liver events encompass hepatitis, colitis and upper digestive tract symptoms accounting for the most common irAEs, with incidence rates varying from 2 % to 40 %, the latter in patients undergoing combined ICIs therapy. Based on the current scientific evidence derived from both randomized clinical trials and real-world studies, this statement document provides recommendations on the diagnosis, treatment and prognosis of the gastrointestinal and hepatic ICI-induced adverse events.
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Affiliation(s)
| | | | | | - Miriam Mañosa
- Gastroenterology, Hospital Universitari Germans Trias i Pujol
| | | | | | | | - María Varela
- Gastroenterology, Hospital Universitario Central de Asturias
| | - Luis Menchén
- Digestive Diseases, Instituto de Investigación Sanitaria Gregorio Marañón
| | | | | | | | | | - Fernando Rivera
- Hospital Universitario Marqués de Valdecilla, Medical Oncology
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Tasaki Y, Sugiyama Y, Hamamoto S, Naiki T, Uemura T, Yokota K, Kawakita D, Nakamura M, Ogawa R, Shimura T, Mimura Y, Hotta Y, Odagiri K, Ito N, Iida M, Kimura Y, Komatsu H, Kataoka H, Takiguchi S, Morita A, Iwasaki S, Okuda K, Niimi A, Yasui T, Furukawa‐Hibi Y. Eosinophil may be a predictor of immune-related adverse events induced by different immune checkpoint inhibitor types: A retrospective multidisciplinary study. Cancer Med 2023; 12:21666-21679. [PMID: 37986680 PMCID: PMC10757154 DOI: 10.1002/cam4.6724] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 11/04/2023] [Accepted: 11/07/2023] [Indexed: 11/22/2023] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) can cause severe immune-related adverse events (irAEs). However, biomarkers for irAEs common to different types of ICIs and cancers have not been reported. This study examined whether eosinophils can be used as a predictor of irAEs. METHODS Six hundred fourteen patients with cancer (esophageal, gastric, head and neck, lung, melanoma, renal cell, urothelial, and other cancer) received anti-PD-1, anti-PD-L1, or anti-CTLA-4 plus anti-PD-1 therapy. The patients were divided into two groups depending on whether they experienced irAEs (irAE group) or not (non-irAE group). Eosinophils were examined before the two-course treatment. RESULTS Patients in the irAE group who received anti-PD-1 or anti-CTLA-4 plus anti-PD-1 therapy had higher eosinophils before the two-course treatment than those in the non-irAE group (p < 0.05). The eosinophils in the anti-PD-L1 therapy group tended to increase in the irAE group. Furthermore, eosinophils in gastric, head and neck, lung, melanoma, renal, and urothelial cancers were significantly higher in the irAE group than in the non-irAE group (p < 0.05). The optimal cutoff value for eosinophils against irAEs was 3.0% (area under the curve = 0.668). In multivariate analyses, eosinophils of ≥3.0% were an independent factor for irAEs (odds ratio: 2.57, 95% CI: 1.79-3.67). CONCLUSION An increased eosinophil before the two-course treatment may be a predictor of irAEs in various cancers treated with different ICIs.
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Affiliation(s)
- Yoshihiko Tasaki
- Department of Clinical PharmaceuticsNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Yosuke Sugiyama
- Department of Clinical PharmaceuticsNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Shuzo Hamamoto
- Department of Nephro‐UrologyNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Taku Naiki
- Department of Nephro‐UrologyNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Takehiro Uemura
- Department of Respiratory Medicine, Allergy, and Clinical ImmunologyNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Keisuke Yokota
- Department of Thoracic and Pediatric SurgeryNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Daisuke Kawakita
- Department of Otorhinolaryngology, Head and Neck SurgeryNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Motoki Nakamura
- Department of Geriatric and Environmental DermatologyNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Ryo Ogawa
- Department of Gastroenterological SurgeryNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Takaya Shimura
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Yoshihisa Mimura
- Department of Clinical PharmaceuticsNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Yuji Hotta
- Department of Clinical PharmaceuticsNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Kunihiro Odagiri
- Department of Clinical PharmaceuticsNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Nanami Ito
- Department of Clinical PharmaceuticsNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Moeko Iida
- Department of Clinical PharmaceuticsNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Yuka Kimura
- Department of Clinical PharmaceuticsNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Hirokazu Komatsu
- Department of Hematology and OncologyNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Hiromi Kataoka
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Shuji Takiguchi
- Department of Gastroenterological SurgeryNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Akimichi Morita
- Department of Geriatric and Environmental DermatologyNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Shinichi Iwasaki
- Department of Otorhinolaryngology, Head and Neck SurgeryNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Katsuhiro Okuda
- Department of Thoracic and Pediatric SurgeryNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Akio Niimi
- Department of Respiratory Medicine, Allergy, and Clinical ImmunologyNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Takahiro Yasui
- Department of Nephro‐UrologyNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Yoko Furukawa‐Hibi
- Department of Clinical PharmaceuticsNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
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Silverstein J, Wright F, Wang M, Young A, Kim D, De Dios K, Brondfield S, Quandt Z. Evaluating Survival After Hospitalization Due to Immune-Related Adverse Events From Checkpoint Inhibitors. Oncologist 2023; 28:e950-e959. [PMID: 37335906 PMCID: PMC10546826 DOI: 10.1093/oncolo/oyad135] [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: 11/18/2022] [Accepted: 04/14/2023] [Indexed: 06/21/2023] Open
Abstract
BACKGROUND As immune checkpoint inhibitors (CPI) are increasingly approved for cancer treatment, hospitalizations related to severe immune-related adverse events (irAE) will increase. Here, we identify patients hospitalized due to irAEs and describe survival outcomes across irAE, CPI, and cancer type. METHODS We identified patients hospitalized at our institution from January 2012 to December 2020 due to irAEs. Survival was analyzed using Kaplan-Meier survival curves with log-rank tests. RESULTS Of 3137 patients treated with CPIs, 114 (3.6%) were hospitalized for irAEs, resulting in 124 hospitalizations. Gastrointestinal (GI)/hepatic, endocrine, and pulmonary irAEs were the most common causes of irAE-related hospitalization. After CPI initiation, the average time to hospitalization was 141 days. Median survival from hospital admission was 980 days. Patients hospitalized due to GI/hepatic and endocrine irAEs had longer median survival than patients with pulmonary irAEs (795 and 949 days vs. 83 days [P < .001]). Patients with melanoma and renal cell carcinoma had longer median survival than patients with lung cancer (2792 days and not reached vs. 159 days [P < .001]). There was longer median survival in the combination group compared to the PD-(L)1 group (1471 vs. 529 days [P = .04]). CONCLUSIONS As CPI use increases, irAE-related hospitalizations will as well. These findings suggest that among patients hospitalized for irAEs, survival differs by irAE and cancer type, with worse survival for patients with irAE pneumonitis or lung cancer. This real-world data contributes to research pertaining to hospitalization due to severe irAEs, which may inform patient counseling and treatment decision-making.
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Affiliation(s)
- Jordyn Silverstein
- Department of Internal Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Francis Wright
- Department of Internal Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Michelle Wang
- Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA
- Graduate Program in Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, San Francisco, CA, USA
| | - Arabella Young
- Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT, USA
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Daniel Kim
- Department of Internal Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Kimberly De Dios
- Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- Diabetes Center, University of California, San Francisco, San Francisco, CA, USA
| | - Sam Brondfield
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
- Department of Medicine, Division of Hematology and Oncology, University of California, San Francisco, San Francisco, CA, USA
| | - Zoe Quandt
- Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- Diabetes Center, University of California, San Francisco, San Francisco, CA, USA
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35
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Tasaki Y, Hamamoto S, Sugiyama Y, Tomiyama N, Naiki T, Etani T, Taguchi K, Matsuyama N, Sue Y, Mimura Y, Kubota H, Noda Y, Aoki M, Moritoki Y, Nozaki S, Kurokawa S, Okada A, Kawai N, Yasui T, Kimura K. Elevated eosinophils proportion as predictor of immune-related adverse events after ipilimumab and nivolumab treatment of advanced and metastatic renal cell carcinoma. Int J Urol 2023; 30:866-874. [PMID: 37278575 DOI: 10.1111/iju.15220] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 05/22/2023] [Indexed: 06/07/2023]
Abstract
OBJECTIVES Ipilimumab and nivolumab treatment against advanced and metastatic renal cell carcinoma (RCC) causes severe and lethal immune-related adverse events (irAEs). Predicting irAEs might improve clinical outcomes, however no practical biomarkers exist. This study examined whether eosinophils could be effective biomarkers for ≥grade 2 irAEs in RCC. METHODS We retrospectively analyzed 75 patients with RCC treated with ipilimumab and nivolumab between August 2018 and March 2021 in a multicenter study. Eosinophils were examined before and 2 weeks after treatment, and immediately after irAEs development. The optimal cut-off value for ≥grade 2 irAEs was determined by a receiver operating characteristic (ROC) curve. Univariate and multivariate analyses were undertaken to identify predictors of ≥grade 2 irAEs. RESULTS Two weeks after treatment, eosinophils were significantly upregulated in patients who had experienced ≥grade 2 irAEs than in those who had not experienced irAEs (mean, 5.7% vs. 3.2%; p < 0.05). The optimal cut-off value for eosinophils against ≥grade 2 irAEs was 3.0% (area under the curve = 0.69). In multivariate analyses, an eosinophil level ≥ 3.0% was a risk factor for ≥grade 2 irAEs (odds ratio 4.18, 95% confidence interval 1.16-15.1). The eosinophil level 2 weeks after treatment was upregulated by the onset of any type of irAEs including endocrine, gastrointestinal, pulmonary and skin disorders. CONCLUSIONS An increased eosinophil level 2 weeks after treatment might be an effective biomarker for ≥grade 2 irAEs in patients with RCC treated with ipilimumab and nivolumab.
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Affiliation(s)
- Yoshihiko Tasaki
- Department of Clinical Pharmaceutics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Shuzo Hamamoto
- Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Aichi, Nagoya, Japan
| | - Yosuke Sugiyama
- Department of Clinical Pharmaceutics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Nami Tomiyama
- Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Aichi, Nagoya, Japan
| | - Taku Naiki
- Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Aichi, Nagoya, Japan
| | - Toshiki Etani
- Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Aichi, Nagoya, Japan
| | - Kazumi Taguchi
- Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Aichi, Nagoya, Japan
| | - Nayuka Matsuyama
- Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Aichi, Nagoya, Japan
| | - Yasuhito Sue
- Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Aichi, Nagoya, Japan
| | - Yoshihisa Mimura
- Department of Clinical Pharmaceutics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Hiroki Kubota
- Department of Urology, Kainan Hospital, Yatomi, Aichi, Japan
| | - Yusuke Noda
- Department of Urology, Toyota Kosei Hospital, Toyota, Aichi, Japan
| | - Maria Aoki
- Department of Urology, Nagoya East Medical Center, Nagoya, Aichi, Japan
| | | | - Satoshi Nozaki
- Department of Urology, Nagoya Tokushukai General Hospital, Kasugai, Aichi, Japan
| | - Satoshi Kurokawa
- Department of Urology, Nagoya Tokushukai General Hospital, Kasugai, Aichi, Japan
| | - Atsushi Okada
- Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Aichi, Nagoya, Japan
| | - Noriyasu Kawai
- Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Aichi, Nagoya, Japan
| | - Takahiro Yasui
- Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Aichi, Nagoya, Japan
| | - Kazunori Kimura
- Department of Clinical Pharmaceutics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
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Machado AP, Ratliff H, Abdelwahab A, Vohra MH, Kuang A, Shatila M, Khan MA, Shafi MA, Thomas AS, Philpott J, Alhalabi O, Wang Y. The Safety of Immunosuppressants Used in the Treatment of Immune-Related Adverse Events due to Immune Checkpoint Inhibitors: a Systematic Review. J Cancer 2023; 14:2956-2963. [PMID: 37859810 PMCID: PMC10583582 DOI: 10.7150/jca.87335] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 08/30/2023] [Indexed: 10/21/2023] Open
Abstract
Purpose: Immune checkpoint inhibitor (ICI) use can lead to immune-related adverse events (irAEs) that require treatment with immunosuppressive medications in moderate to severe cases. Oncology society guidelines recommend systemic steroids and immunosuppressants such as infliximab and vedolizumab for the treatment of refractory cases. Limited information is available about the safety profile and potential adverse effects of these immunosuppressants. We have investigated the safety profile of multiple immunosuppressants which are used in the treatment of ICI-related irAEs. Methods: We performed a systematic review of studies reporting irAEs, from ICI use, and their medical management with immunosuppressants in adult cancer patients. We searched MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov from inception through September 1, 2022, using the following keywords or their equivalents: ICI, immunosuppressant, and irAE. We extracted observational studies and clinical trials that matched our criteria. A random effects model was used to estimate the overall incidence of infections associated with the treatment of irAEs. Results: Among the 11 studies included in this review (1036 total patients), melanoma (548 patients, 52.9%) was the most common primary cancer, followed by lung cancer (139 patients, 13.4%) and genitourinary cancers (131 patients, 12.6%). PD-1/PD-L1 monotherapy (460 patients, 44.4%) was used most, followed by a combination of PD-1/PD-L1 and CTLA-4 therapy (350 patients, 33.8%) and CTLA-4 monotherapy (226 patients, 22%). A total of 1024 (98.8%) patients had their irAEs treated with systemic steroids with majority having colitis and hepatobiliary irAEs; 335 patients (32.3%) were also treated with infliximab (mainly for colitis). Our review found 22.3% of patients treated for irAEs developed infectious adverse events (95% CI: 15.6%-29.1%, p<0.001). Among the 3 studies reporting the types of infections (41 total patients), bacterial (80.5%), followed by fungal (36.6%), infections were most common. Conclusions: Adverse events from irAE treatment occurred in about one-third of patients that received either steroids or a combination of steroids and other immunosuppressants. Clinicians should be aware of these immunosuppressant-related adverse effects, which can negatively impact cancer treatment and patient outcomes, when treating irAEs and consider shortening treatment duration or using alternative strategies when possible to mitigate these complications, future prospective studies should further investigate the safety of immunosuppressants in treating irAEs.
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Affiliation(s)
- Antonio Pizuorno Machado
- Department of Internal Medicine, The University of Texas Health Science Center, Houston, TX, USA
| | - Hunter Ratliff
- Department of Internal Medicine, The University of Texas Health Science Center, Houston, TX, USA
| | - Ahmed Abdelwahab
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Muhammad H. Vohra
- Department of Internal Medicine, The University of Texas Health Science Center, Houston, TX, USA
| | - Andrew Kuang
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Malek Shatila
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Muhammad Ali Khan
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Menhaz A. Shafi
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anusha S. Thomas
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jessica Philpott
- Inflammatory Bowel Disease Center, Cleveland Clinic, Cleveland, OH, USA
| | - Omar Alhalabi
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Gusev A. Germline mechanisms of immunotherapy toxicities in the era of genome-wide association studies. Immunol Rev 2023; 318:138-156. [PMID: 37515388 PMCID: PMC11472697 DOI: 10.1111/imr.13253] [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: 03/14/2023] [Accepted: 06/29/2023] [Indexed: 07/30/2023]
Abstract
Cancer immunotherapy has revolutionized the treatment of advanced cancers and is quickly becoming an option for early-stage disease. By reactivating the host immune system, immunotherapy harnesses patients' innate defenses to eradicate the tumor. By putatively similar mechanisms, immunotherapy can also substantially increase the risk of toxicities or immune-related adverse events (irAEs). Severe irAEs can lead to hospitalization, treatment discontinuation, lifelong immune complications, or even death. Many irAEs present with similar symptoms to heritable autoimmune diseases, suggesting that germline genetics may contribute to their onset. Recently, genome-wide association studies (GWAS) of irAEs have identified common germline associations and putative mechanisms, lending support to this hypothesis. A wide range of well-established GWAS methods can potentially be harnessed to understand the etiology of irAEs specifically and immunotherapy outcomes broadly. This review summarizes current findings regarding germline effects on immunotherapy outcomes and discusses opportunities and challenges for leveraging germline genetics to understand, predict, and treat irAEs.
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Affiliation(s)
- Alexander Gusev
- Division of Population Sciences, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
- Division of Genetics, Brigham & Women's Hospital, Boston, Massachusetts, USA
- The Broad Institute, Cambridge, Massachusetts, USA
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Kuang AG, Sperling G, Liang TZ, Lu Y, Tan D, Bollin K, Johnson DB, Manzano JGM, Shatila M, Thomas AS, Thompson JA, Zhang HC, Wang Y. Sclerosing mesenteritis following immune checkpoint inhibitor therapy. J Cancer Res Clin Oncol 2023; 149:9221-9227. [PMID: 37195298 DOI: 10.1007/s00432-023-04802-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 04/18/2023] [Indexed: 05/18/2023]
Abstract
PURPOSE Sclerosing mesenteritis (SM), a fibroinflammatory process of the mesentery, can rarely occur after immune checkpoint inhibitor (ICI) therapy; however, its clinical significance and optimal management are unclear. We aimed to assess the characteristics and disease course of patients who developed SM following ICI therapy at a single tertiary cancer center. METHODS We retrospectively identified 12 eligible adult cancer patients between 05/2011 and 05/2022. Patients' clinical data were evaluated and summarized. RESULTS The median patient age was 71.5 years. The most common cancer types were gastrointestinal, hematologic, and skin. Eight patients (67%) received anti-PD-1/L1 monotherapy, 2 (17%) received anti-CTLA-4 monotherapy, and 2 (17%) received combination therapy. SM occurred after a median duration of 8.6 months from the first ICI dose. Most patients (75%) were asymptomatic on diagnosis. Three patients (25%) reported abdominal pain, nausea, and fever and received inpatient care and corticosteroid treatment with symptom resolution. No patients experienced SM recurrence after the completion of corticosteroids. Seven patients (58%) experienced resolution of SM on imaging. Seven patients (58%) resumed ICI therapy after the diagnosis of SM. CONCLUSIONS SM represents an immune-related adverse event that may occur after initiation of ICI therapy. The clinical significance and optimal management of SM following ICI therapy remains uncertain. While most cases were asymptomatic and did not require active management or ICI termination, medical intervention was needed in select symptomatic cases. Further large-scale studies are needed to clarify the association of SM with ICI therapy.
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Affiliation(s)
- Andrew G Kuang
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Gabriel Sperling
- The University of Texas Medical Branch John Sealy School of Medicine, Galveston, TX, USA
| | - Tom Z Liang
- Division of Pathology/Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yang Lu
- Department of Nuclear Medicine, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dongfeng Tan
- Division of Pathology/Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kathryn Bollin
- Division of Hematology and Oncology, Scripps MD Anderson Cancer Center, La Jolla, CA, USA
| | - Douglas B Johnson
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Joanna-Grace M Manzano
- Department of Hospital Medicine, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Malek Shatila
- Department of Gastroenterology, Hepatology, & Nutrition, Division of Internal Medicine, Unit 1466, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Anusha S Thomas
- Department of Gastroenterology, Hepatology, & Nutrition, Division of Internal Medicine, Unit 1466, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - John A Thompson
- Divison of Medical Oncology, University of Washington, Seattle, WA, USA
| | - Hao Chi Zhang
- Department of Gastroenterology, Hepatology, & Nutrition, Division of Internal Medicine, Unit 1466, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology, & Nutrition, Division of Internal Medicine, Unit 1466, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
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Machado AP, Shatila M, De Toni EN, Török HP, Philpott J, Zhao D, Zhou Y, Varatharajalu K, Shafi MA, Zhang HC, Thomas AS, Wang Y. Colon Adenoma After Diagnosis of Immune Checkpoint Inhibitor-mediated Colitis. J Cancer 2023; 14:2686-2693. [PMID: 37779873 PMCID: PMC10539391 DOI: 10.7150/jca.86635] [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: 05/30/2023] [Accepted: 07/30/2023] [Indexed: 10/03/2023] Open
Abstract
Purpose: While the occurrence of colitis during immune checkpoint inhibitor (ICI) treatment is recognized as a sign of robust immune activation and correlates with better oncological outcomes, the long-term impact of ICI-mediated colitis on the colonic mucosa has not been studied. We thus aim to describe the colonoscopy and histology findings in patients at a follow-up time of ≥ 6 months post initial colitis event. Methods: This retrospective analysis included adult cancer patients diagnosed with ICI colitis at a tertiary cancer center between October 2013 and June 2020. The study group included patients diagnosed with immune mediated colitis who had also undergone a follow up colonoscopy or flex sigmoidoscopy. The control group was patients exposed to ICI without immune mediated colitis. We reported patients' colitis clinical course, treatment, outcomes, and endoscopic and histologic features at diagnosis and at follow-up time of ≥ 6 months. Results: Total 39 patients met the study criteria, with 82% being male, and 35.8% having melanoma. Most patients received a combination of CTLA-4 and PD-1/L1 inhibitors (82%). On initial endoscopic evaluation, inflammation without ulceration was reported in 76.9% of patients and active inflammation on histologic examination in 79.3% of patients. Most patients (79.4%) received corticosteroids, and 56.4% received add-on selective immunosuppressive therapy. Four patients received fecal microbiota transplantation. On follow-up, new incidence of colonic polyps was reported in 51.2% of patients, including adenomas in 33.3% among the colitis patients with median follow up duration of 12 months. The incidence of adenoma polyps 12 months after the colitis event was significantly higher compared to the control group without colitis based on the time-to-event analysis (p=0.041). Conclusion: At a median follow up of 12 months after their initial colitis diagnosis, 51.2% of the patients had new incidence of colonic polyps, including a third with adenoma, at a significantly higher incidence than the control group without colitis. Studies with larger sample sizes are needed to further define the long-term impact of colitis and its treatments on colon health and to refine recommendations for surveillance of colonic adenomas and colorectal cancer.
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Affiliation(s)
- Antonio Pizuorno Machado
- Department of Internal Medicine, The University of Texas Health Science Center, Houston, TX, USA
| | - Malek Shatila
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Enrico N. De Toni
- Department of Medicine II, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Helga-Paula Török
- Department of Medicine II, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Jessica Philpott
- Inflammatory Bowel Disease Center, Cleveland Clinic, Cleveland, OH, USA
| | - Dan Zhao
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yan Zhou
- Department of Hospital Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Krishnavathana Varatharajalu
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mehnaz A. Shafi
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hao Chi Zhang
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anusha S. Thomas
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Pizuorno Machado A, Shatila M, Liu C, Wang J, Altan M, Zhang HC, Thomas A, Wang Y. Immune-related adverse events after immune checkpoint inhibitor exposure in adult cancer patients with pre-existing autoimmune diseases. J Cancer Res Clin Oncol 2023; 149:6341-6350. [PMID: 36752908 DOI: 10.1007/s00432-023-04582-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 01/10/2023] [Indexed: 02/09/2023]
Abstract
PURPOSE Immune checkpoint inhibitor (ICI) therapy can predispose patients to immune-related adverse events (irAEs) and autoimmune disease (AD) flare-ups, but the characteristics of irAEs among patients with pre-existing ADs are largely unknown. We conducted this study to determine the clinical courses, irAEs, AD flares, treatment, and outcomes of patients with AD on ICIs. METHODS This was a retrospective study of adult cancer patients at a large cancer center who were diagnosed with ADs before undergoing ICI therapy. Patients' clinical courses, complications, treatments, and outcomes related to both ADs flares and irAEs were collected and analyzed. RESULTS The study included 197 patients. Most (55.4%) were women. Melanoma comprised the highest proportion (28.4%) of malignancies, and most (83.8%) patients received PD-1/PD-L1 inhibitors. Fifty (25.3%) patients developed a new irAE after starting ICI therapy, while 29 (14.7%) patients had an AD flare-up. Patients with inflammatory bowel disease had the highest incidence of AD flare-ups (31.7%), while patients with Hashimoto hypothyroidism had the highest incidence of new irAEs (39.2%). Patients with inflammatory bowel disease had more severe adverse events. In our cohort, patients with a new diagnosis of irAE were treated with immunosuppressive therapy. AD flares were managed similarly. With regard to irAE manifestations, the most common presentations were colitis (24 [12.1%] patients), hepatic transaminase elevations (8 [4%] patients), and pneumonitis (7 [3.5%] patients). CONCLUSION Our findings suggest that patients with gastrointestinal and rheumatologic ADs had a higher incidence of AD flare-ups, while patients with Hashimoto hypothyroidism and neurologic ADs had a higher incidence of new irAEs. Patients with prior ADs experiencing flare-ups or new irAEs after ICI therapy tend to require aggressive immunosuppressive treatment. Thorough evaluation of baseline disease status, appropriate medical management before ICI therapy, and early recognition of inflammatory exacerbation may help ensure long-term success in treating and improving outcomes in these patients.
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Affiliation(s)
- Antonio Pizuorno Machado
- Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Malek Shatila
- Department of Gastroenterology, Hepatology and Nutrition, Unit 1466, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Cynthia Liu
- Department of Internal Medicine, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Jianbo Wang
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Mehmet Altan
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Hao Chi Zhang
- Department of Gastroenterology, Hepatology and Nutrition, Unit 1466, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Anusha Thomas
- Department of Gastroenterology, Hepatology and Nutrition, Unit 1466, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology and Nutrition, Unit 1466, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
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Krasnow NA, Chute DF, Falade AS, North CM, Reynolds KL, Dougan ML. Evaluation of appendectomy as a potential risk factor for immune checkpoint inhibitor-associated enterocolitis. Immunotherapy 2023; 15:913-920. [PMID: 37292001 PMCID: PMC10346134 DOI: 10.2217/imt-2022-0245] [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: 09/27/2022] [Accepted: 05/23/2023] [Indexed: 06/10/2023] Open
Abstract
Aims: The relationship between appendectomy and immune checkpoint inhibitor (ICI) enterocolitis was explored. Methods: Patients who began ICIs between July 2010 and September 2020 (n = 10,907) were included. The exposure group included patients with evidence of appendectomy prior to ICIs in operative notes (n = 380). The control group included patients with evidence of normal appendix in radiologic reports (n = 3602). ICI enterocolitis was defined as histopathologic evidence of colitis or enteritis attributed to ICIs. The association between appendectomy and ICI enterocolitis was characterized by multivariate logistic regression. Results: 248 patients (6.2%) developed ICI enterocolitis. The odds of ICI enterocolitis were similar among those with prior appendectomy and those without appendectomy (adjusted odds ratio: 0.82; 95% CI: 0.49-1.36; p = 0.449). Conclusion: No association was found between prior appendectomy and ICI enterocolitis.
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Affiliation(s)
| | - Donald F Chute
- Department of Vascular Surgery, UMass Memorial Medical Center, Worcester, MA 01605, USA
| | - Ayo S Falade
- Department of Medicine, Mass General Brigham Salem Hospital, Salem, MA 01970, USA
| | - Crystal M North
- Harvard Medical School, Boston, MA 02115, USA
- Division of Pulmonology/Critical Care, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Kerry L Reynolds
- Harvard Medical School, Boston, MA 02115, USA
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA
| | - Michael L Dougan
- Harvard Medical School, Boston, MA 02115, USA
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA
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Terrin M, Migliorisi G, Dal Buono A, Gabbiadini R, Mastrorocco E, Quadarella A, Repici A, Santoro A, Armuzzi A. Checkpoint Inhibitor-Induced Colitis: From Pathogenesis to Management. Int J Mol Sci 2023; 24:11504. [PMID: 37511260 PMCID: PMC10380448 DOI: 10.3390/ijms241411504] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 07/06/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023] Open
Abstract
The advent of immunotherapy, specifically of immune checkpoint inhibitors (ICIs), for the treatment of solid tumors has deeply transformed therapeutic algorithms in medical oncology. Approximately one-third of patients treated with ICIs may de velop immune-related adverse events, and the gastrointestinal tract is often affected by different grades of mucosal inflammation. Checkpoint inhibitors colitis (CIC) presents with watery or bloody diarrhea and, in the case of severe symptoms, requires ICIs discontinuation. The pathogenesis of CIC is multifactorial and still partially unknown: anti-tumor activity that collaterally effects the colonic tissue and the upregulation of specific systemic inflammatory pathways (i.e., CD8+ cytotoxic and CD4+ T lymphocytes) are mainly involved. Many questions remain regarding treatment timing and options, and biological treatment, especially with anti-TNF alpha, can be offered to these patients with the aim of rapidly resuming oncological therapies. CIC shares similar pathogenesis and aspects with inflammatory bowel disease (IBD) and the use of ICI in IBD patients is under evaluation. This review aims to summarize the pathogenetic mechanism underlying CIC and to discuss the current evidenced-based management options, including the role of biological therapy, emphasizing the relevant clinical impact on CIC and the need for prompt recognition and treatment.
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Affiliation(s)
- Maria Terrin
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (M.T.); (G.M.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy
| | - Giulia Migliorisi
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (M.T.); (G.M.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy
| | - Arianna Dal Buono
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (M.T.); (G.M.)
| | - Roberto Gabbiadini
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (M.T.); (G.M.)
| | - Elisabetta Mastrorocco
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (M.T.); (G.M.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy
| | - Alessandro Quadarella
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (M.T.); (G.M.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy
| | - Alessandro Repici
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy
- Division of Gastroenterology and Digestive Endoscopy, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy
| | - Armando Santoro
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy
- Medical Oncology and Haematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy
| | - Alessandro Armuzzi
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (M.T.); (G.M.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy
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Mathew A, Shatila M, Lai Z, Tan D, Oliva ICG, Wang J, Alhalabi O, Zhang HC, Thomas A, Wang Y. Characteristics of appendicitis after immune checkpoint inhibitor therapy among cancer patients. J Cancer Res Clin Oncol 2023; 149:4591-4599. [PMID: 36163559 DOI: 10.1007/s00432-022-04367-6] [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: 09/03/2022] [Accepted: 09/16/2022] [Indexed: 10/14/2022]
Abstract
PURPOSE Immune checkpoint inhibitor (ICI) therapy has revolutionized cancer care but is associated with immune-related adverse events (irAEs). Recent case reports raised the concern that acute appendicitis may be an irAE. In this study, we sought to describe the disease course of post-ICI therapy appendicitis and its associated complications. METHODS Adult patients who had an International Classification of Diseases code for appendicitis within the first 2 years after initiating ICI therapy from January 2010 to April 2021 and who had imaging evidence of appendicitis were studied retrospectively. RESULTS 13,991 patients were identified who had ICI exposure during the study period, 44 had codes for appendicitis, 10 of whom met the inclusion criteria. Their median age at the time of diagnosis was 59 years. The median time from ICI therapy initiation to appendicitis onset was 188 days. The most common presenting symptoms were abdominal pain (70%) and fever (40%). Abscesses were present in two patients, and a perforation was present in one. All 10 patients received broad-spectrum antibiotics. Five patients needed surgery or interventional radiology drainage. Nine patients had resolution of appendicitis symptoms after treatment. CONCLUSION Post-ICI therapy appendicitis is rare but presents similarly to and has similar complications rates as conventional appendicitis. Appendectomy remains the mainstay of treatment, but its use can be limited in cancer patients. The decision to continue ICI therapy remains at the discretion of the clinician. Further studies are needed to bring awareness to and advance the understanding of this clinical entity.
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Affiliation(s)
- Antony Mathew
- Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Malek Shatila
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Zongshan Lai
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dongfeng Tan
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Isabella C Glitza Oliva
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jianbo Wang
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Omar Alhalabi
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hao Chi Zhang
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anusha Thomas
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Bass AR, Abdel-Wahab N, Reid PD, Sparks JA, Calabrese C, Jannat-Khah DP, Ghosh N, Rajesh D, Aude CA, Gedmintas L, MacFarlane L, Arabelovic S, Falohun A, Mushtaq K, Haj FA, Diab A, Shah AA, Bingham CO, Chan KK, Cappelli LC. Comparative safety and effectiveness of TNF inhibitors, IL6 inhibitors and methotrexate for the treatment of immune checkpoint inhibitor-associated arthritis. Ann Rheum Dis 2023; 82:920-926. [PMID: 37019614 PMCID: PMC10330686 DOI: 10.1136/ard-2023-223885] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 03/24/2023] [Indexed: 04/07/2023]
Abstract
OBJECTIVES To compare the safety and effectiveness of biologic and conventional disease-modifying antirheumatic drugs (DMARDs) for immune checkpoint inhibitor-associated inflammatory arthritis (ICI-IA). METHODS The retrospective multicentre observational study included patients with a diagnosis of ICI-IA treated with a tumour necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL6Ri) and/or methotrexate (MTX); patients with pre-existing autoimmune disease were excluded. The primary outcome was time to cancer progression from ICI initiation; the secondary outcome was time to arthritis control from DMARD initiation. Cox proportional hazard models were used to compare medication groups, adjusting for confounders. RESULTS 147 patients were included (mean age 60.3 (SD 11.9) years, 66 (45%) women). ICI-IA treatment was TNFi in 33 (22%), IL6Ri 42 (29%) and MTX 72 (49%). After adjustment for time from ICI initiation to DMARD initiation, time to cancer progression was significantly shorter for TNFi compared with MTX (HR 3.27 (95% CI 1.21 to 8.84, p=0.019)) while the result for IL6Ri was HR 2.37 (95% CI 0.94 to 5.98, p=0.055). Time to arthritis control was faster for TNFi compared with MTX (HR 1.91 (95% CI 1.06 to 3.45, p=0.032)) while the result for IL6Ri was HR 1.66 (95% CI 0.93 to 2.97, p=0.089). A subset analysis in patients with melanoma gave similar results for both cancer progression and arthritis control. CONCLUSION The treatment of ICI-IA with a biologic DMARD is associated with more rapid arthritis control than with MTX, but may be associated with a shorter time to cancer progression.
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Affiliation(s)
- Anne R Bass
- Rheumatology, Hospital for Special Surgery, New York, New York, USA
- Medicine, Weill Cornell Medicine, New York, New York, USA
| | - Noha Abdel-Wahab
- Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Pankti D Reid
- Rheumatology, University of Chicago Medical Center, Chicago, Illinois, USA
| | - Jeffrey A Sparks
- Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | | | - Deanna P Jannat-Khah
- Jannat Khah: Medicine; Aude: Rheumatology, Hospital for Special Surgery, New York, New York, USA
- Epidemiology in Medicine, Weill Cornell Medical College, New York, New York, USA
| | - Nilasha Ghosh
- Rheumatology, Hospital for Special Surgery, New York, New York, USA
- Medicine, Weill Cornell Medicine, New York, New York, USA
| | - Divya Rajesh
- Harvard Medical School, Boston, Massachusetts, USA
| | - Carlos Andres Aude
- Jannat Khah: Medicine; Aude: Rheumatology, Hospital for Special Surgery, New York, New York, USA
| | - Lydia Gedmintas
- Rheumatology, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | | | - Senada Arabelovic
- Rheumatology, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Adewunmi Falohun
- Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | | | - Farah Al Haj
- Hematology and Medical Oncology, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
| | - Adi Diab
- Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ami A Shah
- Medicine/Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Clifton O Bingham
- Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Karmela Kim Chan
- Rheumatology, Hospital for Special Surgery, New York, New York, USA
- Medicine, Weill Cornell Medicine, New York, New York, USA
| | - Laura C Cappelli
- Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Thomas AR, Eyada M, Kono M, Varatharajalu K, Lu Y, Xu G, Panneerselvam K, Shatila M, Altan M, Wang J, Thompson JA, Zhang HC, Khan MA, Raju GS, Thomas AS, Wang Y. Characteristics, treatment, and outcome of diverticulitis after immune checkpoint inhibitor treatment in patients with malignancies. J Cancer Res Clin Oncol 2023; 149:4805-4816. [PMID: 36242603 DOI: 10.1007/s00432-022-04405-3] [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: 09/03/2022] [Accepted: 10/05/2022] [Indexed: 10/17/2022]
Abstract
PURPOSE Immune checkpoint inhibitors (ICIs) are efficacious for treating various malignancies. In addition to immune-related adverse events (irAEs), growing evidence suggests that ICIs might also be associated with diverticulitis. We aim to assess the clinical presentations and management of colonic diverticulitis among cancer patients after ICI treatment. METHODS A retrospective study was conducted on ICI-treated adult cancer patients between 01/2010 and 06/2020. Patients were grouped based on when diverticulitis developed relative to ICI treatment, either before (controls) or after (cases). Patient clinical characters, treatment, and outcomes were compared between both groups. RESULTS 77 eligible patients were included: 63 patients developed diverticulitis after ICI exposure (46 had initial episode after ICI exposure, 17 had a history of diverticulitis prior then recurred after ICI exposure), and 14 had diverticulitis before ICI exposure. Diverticulitis occurred after a median of 129 days after ICI initiation. Clinical characteristics overlapped with traditional diverticulitis. 93% of patients had symptom resolution after treatment, while 23.8% experienced complications. These patients exhibited higher rates of hospitalization (87% vs 48%, P = 0.015) and surgery/interventional radiology procedures (27% vs 0, P = 0.002), and worse overall survival (P = 0.022). History of diverticulitis was not associated with a more severe disease course. Immunosuppressants (e.g., corticosteroids) were rarely required unless for concurrent ICI-mediated colitis. CONCLUSION Colonic diverticulitis can occur after ICI therapy at very low incidence (0.5%). Its clinical presentation, evaluation, and management are similar to traditional diverticulitis, but associated with higher complication rates requiring surgical intervention and has lower overall survival.
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Affiliation(s)
- Austin R Thomas
- Department of Internal Medicine, The University of Texas Health Science Center, Houston, TX, USA
| | - Mostafa Eyada
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Miho Kono
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Krishnavathana Varatharajalu
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yang Lu
- Division of Diagnostic Imaging, Department of Nuclear Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Guofan Xu
- Division of Diagnostic Imaging, Department of Nuclear Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kavea Panneerselvam
- Department of Internal Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Malek Shatila
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mehmet Altan
- Department of Thoracic-Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jennifer Wang
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - John A Thompson
- Department of Medicine, University of Washington Member, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Hao Chi Zhang
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Muhammad Ali Khan
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Gottumukkala S Raju
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anusha S Thomas
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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46
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Desmedt V, Jauregui-Amezaga A, Fierens L, Aspeslagh S, Dekervel J, Wauters E, Peeters M, Sabino J, Crapé L, Somers M, Hoorens A, Dutré J, Lobatón T. Position statement on the management of the immune checkpoint inhibitor-induced colitis via multidisciplinary modified Delphi consensus. Eur J Cancer 2023; 187:36-57. [PMID: 37116287 DOI: 10.1016/j.ejca.2023.03.025] [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: 07/20/2022] [Revised: 02/10/2023] [Accepted: 03/23/2023] [Indexed: 04/30/2023]
Abstract
INTRODUCTION The use of immune checkpoint inhibitors (ICIs) in cancer immunotherapy has shown increased overall survival in a wide range of cancer types with the associated risk of developing severe immune-mediated adverse events, commonly involving the gastrointestinal tract. AIM The aim of this position statement is to provide an updated practice advice to the gastroenterologists and oncologists on the diagnosis and management of ICI-induced gastrointestinal toxicity. METHODOLOGY The evidence reviewed in this paper includes a comprehensive search strategy of English language publications. Consensus was reached using a three-round modified Delphi methodology and approved by the members of the Belgian Inflammatory Bowel Disease Research and Development Group (BIRD), Belgian Society of Medical Oncology (BSMO), Belgian group of Digestive Oncology (BGDO), and Belgian Respiratory Society (BeRS). CONCLUSIONS The management of ICI-induced colitis requires an early multidisciplinary approach. A broad initial assessment is necessary (clinical presentation, laboratory markers, endoscopic and histologic examination) to confirm the diagnosis. Criteria for hospitalisation, management of ICIs, and initial endoscopic assessment are proposed. Even if corticosteroids are still considered the first-line therapy, biologics are recommended as an escalation therapy and as early treatment in patients with high-risk endoscopic findings.
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Affiliation(s)
- Valérie Desmedt
- Department of Gastroenterology and Hepatology, University Hospital Ghent, Belgium
| | - Aranzazu Jauregui-Amezaga
- Department of Gastroenterology and Hepatology, University Hospital Antwerp, Belgium; Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Belgium.
| | - Liselotte Fierens
- Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), Catholic University of Leuven, Belgium
| | | | - Jeroen Dekervel
- Department of Gastroenterology and Hepatology, University Hospital Leuven, Belgium
| | - Els Wauters
- Respiratory Oncology Unit (Pulmonology), University Hospitals KU Leuven, Leuven, Belgium; Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Marc Peeters
- Department of Digestive Oncology, University Hospital Antwerp, Belgium
| | - Joao Sabino
- Department of Gastroenterology and Hepatology, University Hospital Leuven, Belgium
| | - Lara Crapé
- Department of Gastroenterology, Algemeen Stedelijk Ziekenhuis Aalst, Belgium
| | - Michael Somers
- Department of Gastroenterology and Hepatology, University Hospital Antwerp, Belgium
| | - Anne Hoorens
- Department of Pathology, University Hospital Ghent, Belgium
| | - Joris Dutré
- Department of Gastroenterology, Ziekenhuis Netwerk Antwerpen Jan Palfijn, Belgium
| | - Triana Lobatón
- Department of Gastroenterology and Hepatology, University Hospital Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
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47
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Ferrándiz-Pulido C, Leiter U, Harwood C, Proby CM, Guthoff M, Scheel CH, Westhoff TH, Bouwes Bavinck JN, Meyer T, Nägeli MC, Del Marmol V, Lebbé C, Geusau A. Immune Checkpoint Inhibitors in Solid Organ Transplant Recipients With Advanced Skin Cancers-Emerging Strategies for Clinical Management. Transplantation 2023; 107:1452-1462. [PMID: 36706163 DOI: 10.1097/tp.0000000000004459] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Use of immune checkpoint inhibitors (ICIs) in solid organ transplant recipients (SOTRs) with advanced skin cancers presents a significant clinical management dilemma. SOTRs and other immunosuppressed patients have been routinely excluded from ICI clinical trials with good reason: immune checkpoints play an important role in self- and allograft-tolerance and risk of acute allograft rejection reported in retrospective studies affects 10% to 65% of cases. These reports also confirm that cutaneous squamous cell carcinoma and melanoma respond to ICI therapy, although response rates are generally lower than those observed in immunocompetent populations. Prospective trials are now of critical importance in further establishing ICI efficacy and safety. However, based on current knowledge, we recommend that ICIs should be offered to kidney transplant recipients with advanced cutaneous squamous cell carcinoma, melanoma, or Merkel cell carcinoma if surgery and/or radiotherapy have failed. For kidney transplant recipients, this should be first line ahead of chemotherapy and targeted therapies. In SOTRs, the use of ICIs should be carefully considered with the benefits of ICIs versus risks of allograft rejection weighed up on a case-by-case basis as part of shared decision-making with patients. In all cases, parallel management of immunosuppression may be key to ICI responsiveness. We recommend maintaining immunosuppression before ICI initiation with a dual immunosuppressive regimen combining mammalian target of rapamycin inhibitors and either corticosteroids or calcineurin inhibitors. Such modification of immunosuppression must be considered in the context of allograft risk (both rejection and also its subsequent treatment) and risk of tumor progression. Ultimately, a multidisciplinary approach should underpin all clinical decision-making in this challenging scenario.
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Affiliation(s)
- Carla Ferrándiz-Pulido
- Department of Dermatology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Ulrike Leiter
- Department of Dermatology, Eberhard-Karls University of Tuebingen, Tuebingen, Germany
| | - Catherine Harwood
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Charlotte M Proby
- Department of Dermatology, Ninewells Hospital and Medical School, Dundee, United Kingdom
| | - Martina Guthoff
- Department of Diabetology, Endocrinology, Nephrology, Section of Nephrology and Hypertension, Eberhard-Karls-University, Tuebingen, Germany
| | - Christina H Scheel
- Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, Germany
| | - Timm H Westhoff
- Medical Department I, University Hospital Marien Hospital Herne, Ruhr-University Bochum, Bochum, Germany
| | | | - Thomas Meyer
- Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, Germany
| | - Mirjam C Nägeli
- Department of Dermatology, University Hospital of Zurich, Switzerland
| | - Veronique Del Marmol
- Service de Dermatologie, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Celeste Lebbé
- Dermato-Oncology Department, Université Paris Cite, AP-HP Hôpital Saint Louis, Cancer Institute APHP. Nord-Université Paris CiteINSERM U976, HIPI, Paris, France
| | - Alexandra Geusau
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
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Faleck DM, Dougan M, Tello M, Grossman JE, Moss AC, Postow MA. Accelerating the Evolution of Immune-Related Enterocolitis Management. J Clin Oncol 2023; 41:3110-3115. [PMID: 37040601 PMCID: PMC10256374 DOI: 10.1200/jco.22.02914] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/14/2023] [Accepted: 03/09/2023] [Indexed: 04/13/2023] Open
Affiliation(s)
- David M. Faleck
- Gastroenterology, Hepatology & Nutrition Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | - Michael Dougan
- Division of Gastroenterology and Department of Medicine, Massachusetts General Hospital, and Harvard Medical School, Boston, MA
| | | | | | - Alan C. Moss
- Division of Gastroenterology, Department of Medicine, Boston Medical Center, Boston, MA
| | - Michael A. Postow
- Department of Medicine, Weill Cornell Medical College, New York, NY
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
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49
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Wu X, Srinivasan P, Basu M, Zimmerman T, Li S, Wang Y, Zheng P, Liu Y, Sandler AD. CD24-Fc suppression of immune related adverse events in a therapeutic cancer vaccine model of murine neuroblastoma. Front Immunol 2023; 14:1176370. [PMID: 37346042 PMCID: PMC10279976 DOI: 10.3389/fimmu.2023.1176370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 05/25/2023] [Indexed: 06/23/2023] Open
Abstract
Introduction The combination of Myc-suppressed whole tumor cells with checkpoint inhibitors targeting CTLA-4 and PD-L1 generates a potent therapeutic cancer vaccine in a mouse neuroblastoma model. As immunotherapies translate from pre-clinical to clinical trials, the potential immune-related adverse events (irAEs) associated with induction of potent immunity must be addressed. The CD24-Siglec 10/G interaction is an innate checkpoint that abrogates inflammatory responses to molecules released by damaged cells, but its role in cancer immunology is not well defined. We investigate irAEs of an effective whole cell neuroblastoma vaccine and subsequently the effect of CD24-Fc, a CD24 and Fc fusion protein, on both the vaccine efficacy and induced irAEs in a mouse neuroblastoma model. Methods To test whether the whole tumor cell vaccination leads to autoimmune responses in other organ systems we harvested lung, heart, kidney and colon from naïve mice (n=3), unvaccinated tumor only mice (n=3), and vaccinated mice with CD24 Fc (n=12) or human IgG-Fc control (n=12) after tumor inoculation and vaccination therapy at day 30. The Immune cell infiltrates and immunogenic pathway signatures in different organ systems were investigated using NanoString Autoimmune Profiling arrays. Nanostring RNA transcript results were validated with immunohistochemistry staining. Results The whole tumor cell vaccine combined with immune checkpoint therapy triggers occult organ specific immune cell infiltrates, primarily in cardiac tissue and to a lesser extent in the renal and lung tissue, but not in the colon. CD24-Fc administration with vaccination partially impedes anti-tumor immunity but delaying CD24-Fc administration after initial vaccination reverses this effect. CD24-Fc treatment also ameliorates the autoimmune response induced by effective tumor vaccination in the heart. Discussion This study illustrates that the combination of Myc suppressed whole tumor cell vaccination with checkpoint inhibitors is an effective therapy, but occult immune infiltrates are induced in several organ systems in a mouse neuroblastoma model. The systemic administration of CD24-Fc suppresses autoimmune tissue responses, but appropriate timing of administration is critical for maintaining efficacy of the therapeutic vaccine.
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Affiliation(s)
- Xiaofang Wu
- The Joseph E. Robert Jr. Center for Surgical Care and The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children’s National Hospital, George Washington University, Washington, DC, United States
| | - Priya Srinivasan
- The Joseph E. Robert Jr. Center for Surgical Care and The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children’s National Hospital, George Washington University, Washington, DC, United States
| | - Mousumi Basu
- The Joseph E. Robert Jr. Center for Surgical Care and The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children’s National Hospital, George Washington University, Washington, DC, United States
| | - Talia Zimmerman
- The Joseph E. Robert Jr. Center for Surgical Care and The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children’s National Hospital, George Washington University, Washington, DC, United States
| | - Samuel Li
- The Joseph E. Robert Jr. Center for Surgical Care and The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children’s National Hospital, George Washington University, Washington, DC, United States
| | - Yin Wang
- University of Maryland Medical Center, University of Maryland, Baltimore, MD, United States
| | - Pan Zheng
- OncoC4. Inc, Rockville, MD, United States
| | - Yang Liu
- OncoC4. Inc, Rockville, MD, United States
| | - Anthony David Sandler
- The Joseph E. Robert Jr. Center for Surgical Care and The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children’s National Hospital, George Washington University, Washington, DC, United States
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50
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Badran YR, Zou F, Durbin SM, Dutra BE, Abu-Sbeih H, Thomas AS, Altan M, Thompson JA, Qiao W, Leet DE, Lai PY, Horick NK, Postow MA, Faleck DM, Wang Y, Dougan M. Concurrent immune checkpoint inhibition and selective immunosuppressive therapy in patients with immune-related enterocolitis. J Immunother Cancer 2023; 11:e007195. [PMID: 37349130 PMCID: PMC10314704 DOI: 10.1136/jitc-2023-007195] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/07/2023] [Indexed: 06/24/2023] Open
Abstract
PURPOSE Immune checkpoint inhibitor (ICI) therapy is often suspended because of immune-related enterocolitis (irEC). We examined the effect of resumption of ICIs with or without concurrent selective immunosuppressive therapy (SIT) on rates of symptom recurrence and survival outcomes. METHODS This retrospective, multicenter study examined patients who were treated with ICI and developed irEC requiring SIT (infliximab or vedolizumab) for initial symptom control or to facilitate steroid tapering between May 2015 and June 2020. After symptom resolution, patients were restarted either on ICI alone or on concurrent ICI and SIT at the discretion of the treating physicians. The associations between irEC recurrence and treatment group were assessed via univariate analyses and multivariate logistic regression. Cox proportional hazards model was used for survival analysis. RESULTS Of the 138 included patients who required SIT for initial irEC symptom control, 61 (44.2%) patients resumed ICI without concurrent SIT (control group) and 77 (55.8%) patients resumed ICI therapy with concurrent SIT: 33 with infliximab and 44 with vedolizumab. After symptom resolution, patients in the control group were more commonly restarted on a different ICI regimen (65.6%) compared with those receiving SIT (31.2%) (p<0.001). The total number of ICI doses administered after irEC resolution and ICI resumption was similar in both groups (four to five doses). Recurrence of severe colitis or diarrhea after ICI resumption was seen in 34.4% of controls compared with 20.8% of patients receiving concurrent SIT. Concurrent SIT was associated with reduced risk of severe irEC recurrence after ICI resumption in a multivariate logistic regression model (OR 0.34; 95% CI 0.13 to 0.92; p=0.034). There was no difference in survival outcomes between patients in the control group and patients concurrently treated with SIT. CONCLUSION After resolution of irEC symptoms, reinitiation of ICI with concurrent SIT is safe, reduces severe irEC recurrence, and has no negative impact on survival outcomes.
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Affiliation(s)
- Yousef R Badran
- Division of Gastroenterology, Department of Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, MA, USA
| | - Fangwen Zou
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China
| | - Sienna M Durbin
- Harvard Medical School, Boston, MA, USA
- Department of Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Barbara E Dutra
- Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Hamzah Abu-Sbeih
- Department of Internal Medicine, University of Missouri Kansas City, Kansas City, Missouri, USA
| | - Anusha S Thomas
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Mehmet Altan
- Department of Thoracic, Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - John A Thompson
- Department of Medicine, Division of Oncology, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, University of Washington, Seattle, Washington, USA
| | - Wei Qiao
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Donna E Leet
- Harvard Medical School, Boston, MA, USA
- Department of Internal Medicine, University of California San Francisco, San Francisco, California, USA
| | - Po-Ying Lai
- Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA
| | - Nora K Horick
- Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA
| | - Michael A Postow
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Department of Medicine, Weill Cornell Medical Center, New York, New York, USA
| | - David M Faleck
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Department of Medicine, Weill Cornell Medical Center, New York, New York, USA
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Michael Dougan
- Division of Gastroenterology, Department of Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, MA, USA
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