Akazawa Yu, Nosaka Takuto, Murata Yosuke, Tanaka Tomoko, Takahashi Kazuto, Naito Tatsushi, Ohtani Masahiro, Nakamoto Yasunari
Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
Front Immunol. 2025 Jul 29;16:1590992. doi: 10.3389/fimmu.2025.1590992. eCollection 2025.
With the widespread use of immune checkpoint inhibitors (ICIs), the management of immune-related adverse events (irAEs) has become increasingly important. ICI-induced pancreatic injury (ICI-PI) is rare, and its clinical characteristics remain unclear. This study aimed to clarify the risk factors for the development of ICI-PI and prognostic impact of ICI-PI.
A total of 1039 patients with malignant tumors who received ICI therapy were recruited from September 2014 to December 2024 for this retrospective study. The clinical and pathological characteristics of ICI-PI, including risk factors and prognostic impact, were analyzed. The onset of ICI-PI and irAEs of other organs were defined according to CTCAE ver5.0. The pathological characteristics were evaluated using pancreatic tissue specimens obtained by endoscopic ultrasound-guided fine-needle biopsy.
Of the 982 patients (703 males, 279 females; median age, 71.1 years) included in the study, 48 (4.9%) developed ICI-PI (Grades 2, 3, and 4 in 41, 3, and 4 cases, respectively), and 6 patients (0.6%) developed pancreatitis. Multivariate analysis revealed that the high serum amylase levels before ICI administration (odds ratio, 6.10; 95%CI, 2.55-14.6; < 0.001) and the onset of irAE in other organs (odds ratio, 3.49; 95%CI, 1.88-6.49; < 0.001) were independent risk factors for ICI-PI development. The incidence of other organ irAEs was significantly higher in the ICI-PI onset group than in the ICI-PI non-onset group ( < 0.001). Additionally, there was significantly better overall survival in the ICI-PI onset group than in the ICI-PI non-onset group ( < 0.001), which was corroborated by a landmark analysis. Also, pathological examination of ICI-related pancreatitis using multiplex fluorescence immunohistochemistry demonstrated infiltration of predominantly CD8 positive T lymphocytes contained abundant granzyme B into the pancreatic parenchyma.
High serum amylase levels before ICI administration and development of other organ irAEs were identified as novel risk factors for ICI-PI onset, and the long-term prognosis was better in patients with ICI-PI. This finding suggests that thorough systemic management, including proactive evaluation of serum amylase levels and comprehensive monitoring for various irAEs, can contribute to early detection of ICI-PI, potentially leading to improved patient outcomes.
随着免疫检查点抑制剂（ICI）的广泛应用，免疫相关不良事件（irAE）的管理变得越来越重要。ICI诱导的胰腺损伤（ICI-PI）较为罕见，其临床特征仍不明确。本研究旨在阐明ICI-PI发生的危险因素及ICI-PI的预后影响。
本回顾性研究纳入了2014年9月至2024年12月期间接受ICI治疗的1039例恶性肿瘤患者。分析了ICI-PI的临床和病理特征，包括危险因素和预后影响。根据CTCAE ver5.0定义ICI-PI的发病情况以及其他器官的irAE。使用内镜超声引导下细针穿刺活检获取的胰腺组织标本评估病理特征。
在纳入研究的982例患者（703例男性，279例女性；中位年龄71.1岁）中，48例（4.9%）发生了ICI-PI（分别为41例2级、3例3级和4例4级），6例（0.6%）发生了胰腺炎。多因素分析显示，ICI给药前血清淀粉酶水平升高（比值比，6.10；95%置信区间，2.55-14.6；P<0.001）和其他器官发生irAE（比值比，3.49；95%置信区间，1.88-6.49；P<0.001）是ICI-PI发生的独立危险因素。ICI-PI发病组其他器官irAE的发生率显著高于未发病组（P<0.001）。此外，ICI-PI发病组的总生存期显著优于未发病组（P<0.001），这一结果得到了倾向性分析的证实。此外，使用多重荧光免疫组化对ICI相关胰腺炎进行病理检查显示，主要为CD8阳性T淋巴细胞浸润，这些细胞含有丰富的颗粒酶B，浸润至胰腺实质。
ICI给药前血清淀粉酶水平升高和其他器官发生irAE被确定为ICI-PI发病的新危险因素，ICI-PI患者的长期预后较好。这一发现表明，全面的系统管理，包括主动评估血清淀粉酶水平和对各种irAE进行综合监测，有助于早期发现ICI-PI，可能改善患者预后。
