
==== Front
Immunotherapy
Immunotherapy
Immunotherapy
1750-743X
1750-7448
Taylor & Francis

38888461
10.1080/1750743X.2024.2354108
2354108
Version of Record
Case Report
Case Series
Pancreas-specific immune-related adverse events in patients with lung cancer: a case series study
https://orcid.org/0000-0003-0490-5109
Jia Liu ‡ a
Yuequan Shi ‡ a
Jian Fang b
Hongmin Lu c
Yongjie Shui d
Xiaoyan Liu a
Minjiang Chen a
Yan Xu a
Mengzhao Wang * a
a Department of Respiratory & Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
b Department of Thoracic Oncology II, Key Laboratory of Carcinogenesis & Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, China
c Department of Oncology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
d Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
* CONTACT: mengzhaowang@sina.com
‡ Authors contributed equally

18 6 2024
2024
18 6 2024
16 11 715722
Aptara10 5 2024
17 6 2024
10 7 2023
03 5 2024
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

ABSTRACT

Immune-related adverse events (irAEs) are one of the key concerns in cancer patients treated with immune checkpoint inhibitors (ICIs). Among the various irAEs, pancreas-specific irAE is a rare but special one with a variety of manifestations, such as pancreatic enzymes elevation, pancreatitis as well as diabetes. The current study reported 22 pancreas-specific irAEs in 21 patients with lung cancer, including pancreatic injury in 13 patients, pancreatitis in four patients and diabetes mellitus in five patients.

Article highlights

A case series of 21 patients who had developed pancreas-specific immune-related adverse events (irAEs)

Among these patients, 13 presented with pancreatic injury, four developed immune-related pancreatitis and five were diagnosed with grade immune checkpoint inhibitor (ICI)-related diabetes.

Three types of pancreas-specific irAEs: pancreatic injury, pancreatitis & diabetes

In this study, pancreas-specific irAEs were divided into three types: pancreatic injury, pancreatitis and diabetes. The manifestations, managements and evolutions were presented.

Immune-related pancreatic injury

Most immune-related pancreatic injury can recover without intervention or discontinuation of ICIs, even in recurrent lipase/amylase elevation cases.

Immune-related pancreatitis

Immune-related pancreatitis presents with similar features to acute pancreatitis in symptoms and imaging, and it responds well to corticosteroids.

Immune-related diabetes mellitus

ICI-DM is usually a severe adverse event since DKA is often the first presentation. And it is insulin dependent.

Keywords: 

immune-related adverse events
immune-related diabetes
immune-related pancreatic injury
immune-related pancreatitis
immunotherapy
The National High Level Hospital Clinical Research Funding of China 2022-PUMCH-B-106 We acknowledge and appreciate Shanghai General Hospital for providing the case of patient number 21. And this study was supported by the National High Level Hospital Clinical Research Funding to M Wang (Grant No. 2022-PUMCH-B-106) and the National High Level Hospital Clinical Research Funding to Y Xu (Grant No. 2022-PUMCH-C-054).
==== Body
pmc1. Background

Immune checkpoint inhibitors (ICIs), including cytotoxic T-cell lymphocyte-4 (CTLA-4) and programmed death-1 (PD-1)/ligand-1 (PD-L1) inhibitors, have revolutionized the treatment of various advanced cancers. By binding and blocking CTLA-4 or PD-1/PD-L1, ICIs cause upregulated antitumor immune activity and significantly improve the prognosis of patients with malignancies [1–4]. Nonetheless, the effects of this immunotherapy are not limited to an antitumor response but also unexpected toxicities, known as immune-related adverse events (irAEs).

IrAEs can affect almost any organs and systems, commonly the dermatologic, digestive, pulmonary and endocrine systems [5]. Among all these organs and systems, the pancreas is a special organ because it serves not only exocrine but also endocrine functions. Both exocrine and endocrine functions can be affected in ICI-related pancreatic injury (pancreas-specific irAE). Some patients mainly present with serum lipase/amylase elevation, acute pancreatitis or exocrine pancreatic insufficiency [6,7] while others develop autoimmune diabetes similar to Type I diabetes mellitus (T1DM), even leading to life-threatening diabetic ketoacidosis (DKA) [8].

Pancreas-specific irAE is a relatively uncommon irAE with few studies available. Current guidelines for the management of pancreas-specific irAE are based on limited evidence [9–11]. Given the widespread use of ICIs in clinical practice, it is essential for clinicians to better understand the clinical characteristics and management of pancreas-specific irAE. Therefore, we aimed to describe the manifestations, treatment and outcomes of pancreas-specific irAE in patients with advanced lung cancer in this case series.

2. Methods

2.1. Study design

Advanced lung cancer patients treated with ICI at Peking Union Medical College Hospital, Beijing Cancer Hospital, The Second Affiliated Hospital of Zhejiang University School of Medicine, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Shanghai General Hospital from July 2017 to January 2021 were reviewed through the electronic medical record systems. Patients who were diagnosed with pancreas-specific irAE (defined in Table 1) were included. For the patients with multiple types of pancreatic injuries related to immunotherapy, each event was included separately. The Common Terminology Criteria for Adverse Events (CTCAE) 5.0 was used to assess ICI-DM while a novel classification [12] was hired to better categorize and quantify the degree of pancreatic injury (Table 1). The study was approved by Peking Union Medical College Hospital ethics committee on human experimentation.

Table 1. Different pancreas-specific immune-related adverse events and the definitions.

 	Definition	
Pancreatitis	Amylase or lipase elevation (≥three-times UNL) with clinical or radiologic pancreatitis	
Type I pancreatic injury	Amylase or lipase elevation (≥three-times UNL) with no clinical or radiologic pancreatitis	
Type II pancreatic injury	Amylase or lipase elevation (<three-times UNL) with either clinical nor radiologic pancreatitis	
Type III pancreatic injury	Amylase or lipase elevation (<three-times UNL) with no clinical or radiologic pancreatitis	
ICI-DM	New onset hyperglycemia with evidence of insulin deficiency	
Pancreas-specific immune-related adverse events were varied. Some patients mainly present with serum lipase/amylase elevation, acute pancreatitis while others develop autoimmune diabetes similar to Type I diabetes mellitus (T1DM). This table shows the definitions of different pancreas-specific immune-related adverse events including a novel classification to better categorize and quantify the degree of pancreatic injury.

ICI-DM: Immune checkpoint inhibitor-related diabetes mellitus; UNL: Upper limit of normal.

Included pancreas-specific irAEs and the definitions are shown in Table 1.

The exclusion criteria included having pre-existing lipase elevation before ICI initiation, developing pancreatitis from other causes, such as biliary tract disease, pancreatic metastases, alcohol, etc., blood glucose fluctuations that can be explained by a pre-existing diabetes history and developing hyperglycemia due to other reasons, such as Cushing syndrome, steroid diabetes, hyperthyroidism, etc.

2.2. Patient characteristics

For the included patients, information about demographic characteristics, prior history of pancreatitis/cholelithiasis or diabetes, comorbidities, disease stage, pancreatic metastasis, ICI type, treatment response, irAEs, peak value of serum lipase and amylase, radiology presentations including computed tomography (CT) and/or magnetic resonance (MR) findings of the pancreas, treatment of pancreas-specific irAE, progression-free survival (PFS) and overall survival (OS) were collected. Cancer staging was assessed in accordance with the American Joint Committee on Cancer's Cancer Staging Manual, 7th edition.

The onset time of pancreas-specific irAE was calculated from ICI initiation to the first clinical evidence of pancreas-specific irAE, based on either elevated lipase/amylase or blood glucose. For asymptomatic recurrent lipase/amylase elevation, only the first time was recorded. For concurrent pancreatitis and diabetes in the same patient, the onset times were recorded respectively. At the initiation of ICI-DM, elevated pancreatic enzymes without clinical or radiologic pancreatitis were identified as concomitant symptoms rather than independent adverse events. The duration of pancreas-specific irAE was measured from any lipase/amylase elevation onset to completely normal serum lipase and amylase.

Statistical analysis was carried out by the SPSS 24.0.

3. Results

3.1. Patient characteristics

A total of 21 patients and 22 pancreas-specific irAEs were identified, and the pre-ICI-treatment clinical characteristics of these patients are summarized in Table 2.

Table 2. Baseline characteristics of pancreas-specific immune-related adverse event patients (N = 21).

Characteristics	Values	
Age, years, median (range)	67 (34–83)	
BMI, kg/mm2, median (range)	23.2 (15.4–36.1)	
Male, n (%)	16 (76.2)	
Ever smoker, n (%)	13 (61.9)	
Comorbidities, n (%)	
Type 2 diabetes mellitus	5 (23.8)	
Hypertension	6 (28.6)	
Ischemic heart disease	1 (4.8)	
Cancer type, n (%)	
LUAD	11 (52.4)	
LUSC	6 (28.6)	
SCLC	3 (14.3)	
LCLC	1 (4.8)	
Stage	
III	2 (9.5)	
IV	19 (90.5)	
Line of ICI treatment	
1st line	14(66.7)	
2nd line	3(14.3)	
≥3rd line	4(19.0)	
Therapy, n (%)	
Anti-PD-1 + chemotherapy	10(47.6)	
Anti-PD-L1 + chemotherapy	1(4.8)	
Anti-PD-(L)1 monotherapy	6(28.6)	
Anti-PD-1 + anti-CTLA-4	4(19.0)	
Best objective response of ICI	
Complete/partial response	12(57.1)	
Stable disease	7(33.3)	
Progression of disease	1(4.8)	
NA	1(4.8)	
In this case series study, a total of 21 patients and 22 pancreas-specific immune-related adverse events were identified and the pre-ICI-treatment clinical characteristics of these patients are summarized in this table.

BMI: Body mass index; CTLA-4: Cytotoxic T-lymphocyte antigen-4; ICI: immune checkpoint inhibitor; LCLC: Large cell lung cancer; LUAD: Lung adenocarcinoma. LUSC: Lung squamous carcinoma; NA: Not available; PD-1: Programmed cell death-1; PD-L1: Programmed cell death ligand-1; SCLC: Small-cell lung cancer.

In this cohort, the median age of the patients was 67 years old, and 76.2% (n = 16) were male. The median body mass index (BMI) was 23.2 kg/mm2. Non-small-cell lung cancer (NSCLC) was the most common malignancy, with 11 cases of lung adenocarcinomas, 6 cases of squamous lung carcinomas and 1 case of large cell carcinoma. A total of 19 patients had advanced tumors in stage IV. One patient had pancreatic metastasis. The antitumor therapy included chemoimmunotherapy, anti-PD-(L)1 monotherapy and anti-PD-1 plus anti-CTLA-4 combination therapy. Pembrolizumab, which was administered to 11 patients, was the most commonly used ICI, whether alone or in combination. Apart from pancreas-specific irAE, 6 patients developed multi-irAEs, including dermatitis (2), thyroiditis (3), pneumonia (1), liver enzyme elevation (1) and colitis (1).

The median time from ICI initiation to pancreas-specific irAE was 12 weeks (range 3–90 weeks). Among these patients, 13 patients presented with pancreatic injury, four developed acute pancreatitis and five were diagnosed with ICI-related diabetes, with one patient developing pancreatitis and ICI-related diabetes sequentially.

3.2. Pancreatic injury

Five patients (patient numbers 3, 8, 11, 12, 13) developed Type I pancreatic injury (amylase or lipase elevation >= three-times UNL with no clinical or radiologic pancreatitis). Patient No. 13 had asymptomatic grade 3 serum lipase elevation (peak level of 5231 U/L, UNL 393 U/L) and grade 2 serum amylase elevation. His CT scans showed dilatation of the pancreatic duct 8 months after the initiation of ICI and 6 months before the lipase/amylase elevation. The pancreatic duct remained expanded during the last follow-up. He discontinued ICI and was treated with intravenous fluids and corticosteroids due to concurrent grade 3 immune-related colitis. His lipase and amylase levels decreased to the normal range within 10 days.

Patient No. 12 had asymptomatic grade 3 serum amylase elevation (peak level of 1003 U/l, UNL 115 U/l) and grade 1 serum lipase elevation. CT scans suggested pancreatic atrophy and thinning before the initiation of immunotherapy, and no new findings were reported after the amylase elevation. He recovered to light amylase elevation (<2 UNL) after intravenous fluid therapy and acid suppression therapy for 10 days. Immunotherapy was omitted for 1 cycle.

Among the other three patients, no specific treatment was applied for pancreatic injury. One (No. 11) developed recurrent lipase elevation (<3 UNL) without related symptoms, and for each episode, the levels could resolve without the suspension of ICI or any further intervention.

Eight patients (patient numbers 1, 2, 4, 5, 6, 7, 9, 10) had type III pancreatic injury (completely asymptomatic lipase/amylase elevation <3 UNL). CT or MR scans were performed in three of them and suggested nothing abnormal on pancreas imaging. Immunotherapy was suspended for one cycle in patient No. 6 due to elevated amylase. Patient No.7 discontinued immunotherapy since progressed disease before the development of pancreatic injury. No specific treatment was applied to the other six patients. The elevated serum enzymes of four patients decreased to normal levels with a median duration time of 16 days (follow-up data were not available in the other 4 patients). Among these four patients, one developed recurrent type III pancreatic injury and resolved without the suspension of ICI or any further intervention.

No type II pancreatic injury was identified among these patients.

3.3. Immune-related pancreatitis

Four patients (patient numbers 14–17) were diagnosed with immune-related pancreatitis according to our diagnostic criteria mentioned in the Methods section.

Symptoms and radiologic findings of immune-related pancreatitis: Epigastric pain was the most common symptom and occurred in 3 patients (patient numbers 14, 15, 17). Patient No. 16 presented with vomiting at the initiation of pancreatitis. CT scans of patient No. 14 suggested decreased density of the pancreatic neck and increased density of the peripancreatic fat. Magnetic resonance cholangiopancreatography (MRCP) of patient No. 15 suggested pancreatic duct stenosis and pancreatic enlargement with diffuse abnormal signals (Figure 1), which was in accordance with pancreatitis. CT imaging of patient No. 16 showed low density lesions in the pancreatic body and tail, suggesting inflammation. No abnormal signs on the pancreas were found by CT scan or MRCP on patient No. 17.

Figure 1. Magnetic resonance cholangiopancreatography of patient No. 15, who was diagnosed with immune-related pancreatitis. The T1 fat-suppressed signal was unevenly decreased, and the T2 signal was slightly increased. MRCP showed multisegmental stenosis of the main pancreatic duct.

Management and evolution (summarized in Table 3): ICIs were discontinued, intravenous fluids and corticosteroids were prescribed in patients No. 14 and No. 15, and the elevated enzymes recovered after 12 weeks and 24 weeks, respectively. ICI was discontinued in patients No. 16, and intravenous fluids were given. He recovered from the pancreatitis within 2 weeks, but the cancer progressed. Intravenous fluids were given to patient No. 17 for 5 days, his symptoms improved and the lipase level returned to the normal range. During the lipase elevation, his fasting blood glucose was normal. Unexpectedly, he developed DKA and was diagnosed with ICI-related diabetes later, which has been reported in detail by a case report [8].

Table 3. Treatment and disease evolution of patients with immune-related pancreatitis.

Patient no.	Clinical symptoms	Treatment	ICI suspension	ICI rechallenge	Note	
Fasting, IV fluids	Acid-suppressing drugs	Octreotide	Steroids	
14	Epigastric pain	√	√	√	√	√	Yes	–	
15	Epigastric pain	√	√	–	√	√	Yes	Recurrent lipase elevation	
16	Vomiting	√	–	√	–	√	No	Progression disease	
17	Epigastric pain	√	√	√	–	No	–	Developed ICI-DM after pancreatitis	
Four patients (patient numbers 14–17) were diagnosed with immune-related pancreatitis. ICIs were discontinued, intravenous fluids and corticosteroids were prescribed in patients No. 14 and No. 15 and the elevated enzymes recovered after 12 weeks and 24 weeks, respectively. ICI was discontinued in patients No. 16, and intravenous fluids were given. He recovered from the pancreatitis within 2 weeks, but the cancer progressed. Intravenous fluids were given to patient No.17 for 5 days, his symptoms improved and the lipase level returned to the normal range. During the lipase elevation, his fasting blood glucose was normal. Unexpectedly, he developed DKA and was diagnosed with ICI-related diabetes later.

ICI: Immune checkpoint inhibitor; ICI-DM: ICI-related diabetes mellitus; IV: Intravenous.

3.4. Immune-related diabetes mellitus

ICI-related DM was diagnosed in five patients (patient numbers 17–21), with a median onset time of 11 weeks (range 10–26 weeks). Patient 17 developed concurrent pancreatitis, as mentioned above. Three patients (patient numbers 17, 20 and 21) initially presented with DKA. Patients 17 and 18 developed elevated serum lipase or amylase levels at the onset of ICI-DM. All five patients were insulin dependent. ICI therapy was reserved in four patients but was discontinued in patient 18 due to multiple irAEs.

3.5. Follow-up of patients with pancreas-specific irAE

The median follow-up time of the current study was 16.5 months. One patient (patient No. 15) developed pancreatic atrophy, 10 months after pancreatitis, without exocrine pancreatic insufficiency. The median PFS was 11.1 months, and the median OS was not available.

4. Discussion

Immune-related pancreatic injury is an uncommon adverse event that can present as serum lipase/amylase elevation, pancreatitis or diabetes mellitus. Pancreatic enzyme elevation or pancreatitis was reported in 0.5–3% of patients with cancer receiving ICI monotherapy or combination therapy [6,13]. ICI-DM is even rarer, with an incidence of less than 1% [14,15]. ICI-DM was mostly reported in patients treated with anti-PD-(L)1 monotherapy or combination therapy, and very rarely reported in patients receiving CTLA-4 monotherapy [8]. The current study provided a detailed description of the clinical characteristics and outcomes of pancreas-specific irAE in patients with lung cancer. Pancreatitis and diabetes induced by ICI can develop either independently or sequentially. The median time from ICI initiation to pancreas-specific irAE was 12 weeks, which correlated to four cycles. This result is consistent with previous studies showing that the onset of immune-related pancreatitis varied widely from 2–16 weeks [16–19] and the median time to onset of ICI-DM was 7–17 weeks [20]. Studies have shown that combination therapy of anti-CTLA-4 and anti-PD-1 has a higher incidence of immune-related lipase elevation [13], but no research has examined the difference in onset times. The severity of pancreas-specific irAE ranges from mild to life-threatening. Most pancreas-specific irAE patients present with type III pancreatic injury, while some develop pancreatitis and/or ICI-DM. ICI-DM could be life threatening when patients present with DKA.

Clinical presentation of immune-related pancreatitis was epigastric pain, nausea, vomiting and fever according to a previous report [21], which is similar to traditional acute pancreatitis. In the current case series, patient No. 16 presented with vomiting and advanced age (83 years old) may have contributed to the nontypical symptoms. Elevated lipase values usually indicate an increased risk of pancreatitis [22]. On contrast-enhanced CT, ICI-induced pancreatitis generally appears as enlargement of part or whole of the pancreas, decreased enhancement and surrounding fat stranding. These features are not specific and are similar to interstitial edematous pancreatitis in acute pancreatitis [23]. In the diagnosis of immune-related pancreatitis, clinicians need to pay attention to clinical symptoms because some patients have no positive findings on imaging tests in the early stage of the disease.

Immune-related pancreatitis and ICI-DM are closely associated with each other. First, there might be similar pathological mechanisms, including enhanced T-cell activity against antigens present on tumor and normal tissues [24]. Second, elevated amylase and lipase were present in approximately a third of ICI-DM patients [14]. According to our case series, patients with ICI-DM were all insulin-dependent permanently, while patients with pancreatitis recovered. DM is presumed to be permanent, irreversible endocrine dysfunction, while pancreatitis is usually associated with transient inflammation (though recurrent). A possible explanation for this difference is that immune activity almost destroys the whole pancreas islet since the number of beta-cells is small, thus eliminates the possibility to resume insulin production [24]. Undetectable C-peptide levels serve as evidence for this hypothesis, although histologic confirmation is lacking. Furthermore, the initial phase of beta-cell damage is often asymptomatic and imperceptible, obvious symptoms, such as DKA, usually appear when the islet has been destroyed [24]. At this time, anti-inflammatory therapy is unable to be beneficial [24]. It is possible, although, that less severe cases of diabetes have been underrecognized.

Regarding management, patients with ICI-DM almost certainly require permanently insulin replacement therapy, while guidelines on the treatment of immune-related pancreatitis are limited [25]. ICI discontinuation and supportive management are the foundation of treatment of immune-related pancreatitis [10]. According to the current study, one patient who did not receive corticosteroid therapy for pancreatitis developed DKA 4 days after the onset of pancreatitis, suggesting persistent inflammation in the pancreas that was not relieved by supportive treatments. However, the use of glucocorticoids remains controversial. It is generally believed that steroids could improve clinical symptoms, but a retrospective study observed no benefit of steroids in preventing long-term adverse outcomes (chronic pancreatitis and diabetes) of immune-related pancreatic injury or improving overall survival [21]. Apart from chronic pancreatitis and diabetes, some other possible long-term adverse outcomes are pancreatic atrophy and exocrine pancreatic insufficiency [26]. ICI rechallenge should be done with caution since it has been reported that the duration of ICI therapy is significantly related to pancreatic atrophy [12,27].

For classical acute pancreatitis, there are many confirmed risk factors, such as alcohol, tobacco, gallstones and cannabis [28]. However, the relationship between these risk factors and pancreas-specific irAE has not been proven. Predicting the occurrence of irAE remains difficult, as well as a research hotspot. Current studies have found some possible biomarkers, such as the Eastern Cooperative Oncology Group performance status and neutrophil-to-lymphocyte ratio [29,30]. It is generally believed that the onset of irAEs indicates a better prognosis in patients receiving ICIs. This area needs further exploration of biomarkers to predict ICI efficacy and irAEs more accurately.

The current study does have some limitations. First, there was probable bias in the current data analysis. For example, the duration of pancreas-specific irAE may be biased because the patients may have recurrent lipase/amylase elevations which have not been recorded. Second, the sample size and limited follow-up time were not adequate for further survival analysis. Third, the necessity of steroids in pancreatitis treatment was not clear due to a lack of a control group. Finally, although fasting blood glucose was recorded, more detailed data related to diabetes were not available. Hence, the relationship between pancreatic injury and immune-related diabetes could not be further explored.

5. Conclusion

In this case series study, pancreas-specific irAEs were divided into three types: pancreatic injury, pancreatitis and diabetes. The manifestations, managements and evolutions of a total of 22 pancreas-specific irAEs were presented. Immune-related pancreatic injury/pancreatitis and ICI-DM can occur independently or sequentially. Most immune-related pancreatic injury can recover without intervention or discontinuation of ICIs, even in recurrent lipase/amylase elevation cases. Immune-related pancreatitis presents with similar features to acute pancreatitis in symptoms and imaging but has a longer duration time, and it responds well to corticosteroids. ICI-DM is usually a severe adverse event since DKA is often the first presentation. Long-term insulin replacement therapy should be given if necessary.

Financial disclosure

We acknowledge and appreciate Shanghai General Hospital for providing the case of patient number 21. And this study was supported by the National High Level Hospital Clinical Research Funding to M Wang (Grant No. 2022-PUMCH-B-106) and the National High Level Hospital Clinical Research Funding to Y Xu (Grant No. 2022-PUMCH-C-054).

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, stock ownership or options and expert testimony.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

This study was approved by Peking Union Medical College Hospital ethics committee on human experimentation (the study approval number S-K1315).

The authors state that they have obtained verbal and written informed consent from the patient/patients for the inclusion of their medical and treatment history within this case report.
==== Refs
References

Papers of special note have been highlighted as: • of interest; •• of considerable interest

1. Azoury SC, Straughan DM, Shukla V. Immune checkpoint inhibitors for cancer therapy: clinical efficacy and safety. Curr Cancer Drug Targets. 2015;15 (6 ):452–462. doi:10.2174/156800961506150805145120 26282545
2. Shen X, Zhao B. Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis. BMJ. 2018;362 :k3529. doi:10.1136/bmj.k3529 30201790
3. Hodi FS, Chesney J, Pavlick AC, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, Phase II trial. Lancet Oncol. 2016;17 (11 ):1558–1568. doi:10.1016/s1470-2045(16)30366-7 27622997
4. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375 (19 ):1845–1855. doi:10.1056/NEJMoa1611299 27717298
5. Shi Y, Fang J, Zhou C, et al. Immune checkpoint inhibitor-related adverse events in lung cancer: real-world incidence and management practices of 1905 patients in China. Thorac Cancer. 2022;13 (3 ):412–422. doi:10.1111/1759-7714.14274 34935288
6. Zhao Z, Zhang W, Pang L, et al. Pancreatic adverse events of immune checkpoint inhibitors therapy for solid cancer patients: a systematic review and meta-analysis. Front Immunol. 2023;14 :1166299. doi:10.3389/fimmu.2023.1166299 37359551
7. Satish D, Lin I-H, Flory J, et al. Exocrine pancreatic insufficiency induced by immune checkpoint inhibitors. Oncologist. 2023;28 (12 ):1085–1093. doi:10.1093/oncolo/oyad150 37285223
8. Liu J, Shi Y, Liu X, et al. Clinical characteristics and outcomes of immune checkpoint inhibitor-induced diabetes mellitus. Transl Oncol. 2022;24 :101473. doi:10.1016/j.tranon.2022.101473 35905639
9. Rapoport BL, Anderson R, Cooksley T, et al. MASCC 2020 recommendations for the management of immune-related adverse events of patients undergoing treatment with immune checkpoint inhibitors. Support Care Cancer. 2020;28 (12 ):6107–6110. doi:10.1007/s00520-020-05727-z 32886228
10. Schneider BJ, Naidoo J, Santomasso BD, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO Guideline Update. J Clin Oncol. 2021;39 (36 ):4073–4126. doi:10.1200/jco.21.01440 34724392
11. Cooksley T, Girotra M, Ginex P, et al. Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of immune checkpoint inhibitor endocrinopathies and the role of advanced practice providers in the management of immune-mediated toxicities. Support Care Cancer. 2020;28 (12 ):6175–6181. doi:10.1007/s00520-020-05709-1 32856213
12. Ashkar M, Chandra S, Vege SS, et al. Pancreatic involvement due to immune checkpoint inhibitors: a proposed classification. Cancer Immunol Immunother. 2023;72 (4 ):895–901. doi:10.1007/s00262-022-03295-1 36161510
• Proposed a novel classification to better categorize and quantify the degree of pancreatic injury.

13. Su Q, Zhang XC, Zhang CG, et al. Risk of immune-related pancreatitis in patients with solid tumors treated with immune checkpoint inhibitors: systematic assessment with meta-analysis. J Immunol Res. 2018;2018 :1027323. doi:10.1155/2018/1027323 29971244
• A systematic assessment of immune-related pancreatitis.

14. Stamatouli AM, Quandt Z, Perdigoto AL, et al. Collateral damage: insulin-dependent diabetes induced with checkpoint inhibitors. Diabetes. 2018;67 (8 ):1471–1480. doi:10.2337/dbi18-0002 29937434
• A clinical study of immune-checkpoint inhibitor-induced diabetes.

15. Baden MY, Imagawa A, Abiru N, et al. Characteristics and clinical course of Type I diabetes mellitus related to anti-programmed cell death-1 therapy. Diabetology Inter. 2019;10 (1 ):58–66. doi:10.1007/s13340-018-0362-2
• A national survey to clarify the characteristics and clinical course of immune-checkpoint inhibitor-induced diabetes.

16. Uchikoshi F, Yang ZD, Rostami S, et al. Prevention of autoimmune recurrence and rejection by adenovirus-mediated CTLA4Ig gene transfer to the pancreatic graft in BB rat. Diabetes. 1999;48 (3 ):652–657. doi:10.2337/diabetes.48.3.652 10078573
17. Di Giacomo AM, Danielli R, Guidoboni M, et al. Therapeutic efficacy of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with metastatic melanoma unresponsive to prior systemic treatments: clinical and immunological evidence from three patient cases. Cancer Immunol Immunother. 2009;58 (8 ):1297–1306. doi:10.1007/s00262-008-0642-y 19139884
18. Alabed YZ, Aghayev A, Sakellis C, et al. Pancreatitis secondary to anti-programmed death receptor 1 immunotherapy diagnosed by FDG PET/CT. Clin Nucl Med. 2015;40 (11 ):e528–529. doi:10.1097/rlu.0000000000000940 26284765
19. Hofmann L, Forschner A, Loquai C, et al. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer. 2016;60 :190–209. doi:10.1016/j.ejca.2016.02.025 27085692
20. Quandt Z, Young A, Anderson M. Immune checkpoint inhibitor diabetes mellitus: a novel form of autoimmune diabetes. Clin Exp Immunol. 2020;200 (2 ):131–140. doi:10.1111/cei.13424 32027018
21. Abu-Sbeih H, Tang T, Lu Y, et al. Clinical characteristics and outcomes of immune checkpoint inhibitor-induced pancreatic injury. J Immunother Cancer. 2019;7 (1 ):31. doi:10.1186/s40425-019-0502-7 30728076
•• Reported and summarized the clinical characteristics and outcomes of immune-related pancreatic injury.

22. Ismail OZ, Bhayana V. Lipase or amylase for the diagnosis of acute pancreatitis? Clin Biochem. 2017;50 (18 ):1275–1280. doi:10.1016/j.clinbiochem.2017.07.003 28720341
23. Porcu M, Solinas C, Migali C, et al. Immune checkpoint inhibitor-induced pancreatic injury: imaging findings and literature review. Target Oncol. 2020;15 (1 ):25–35. doi:10.1007/s11523-019-00694-w 31925647
24. Liao D, Liu C, Chen S, et al. Recent advances in immune checkpoint inhibitor-induced Type I diabetes mellitus. InterImmunopharmacol. 2023;122 :110414. doi:10.1016/j.intimp.2023.110414
25. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36 (17 ):1714–1768. doi:10.1200/jco.2017.77.6385 29442540
26. Hoadley A, Sandanayake N, Long GV. Atrophic exocrine pancreatic insufficiency associated with anti-PD1 therapy. Ann Oncol. 2017;28 (2 ):434–435. doi:10.1093/annonc/mdw626 27864215
27. Ashkar M, Chandra S, Vege SS, et al. Pancreatic involvement due to immune checkpoint inhibitors: a proposed classification. Cancer Immunol Immunother. 2022;72 (4 ):895–901. doi:10.1007/s00262-022-03295-1 36161510
28. Mandalia A, Wamsteker EJ, DiMagno MJ. Recent advances in understanding and managing acute pancreatitis. F1000Res. 2018;7 :959. doi:10.12688/f1000research.14244.2
29. Matsukane R, Watanabe H, Minami H, et al. Continuous monitoring of neutrophils to lymphocytes ratio for estimating the onset, severity, and subsequent prognosis of immune related adverse events. Sci Rep. 2021;11 (1 ):1324. doi:10.1038/s41598-020-79397-6 33446685
30. Ksienski D, Wai ES, Alex D, et al. Prognostic significance of the neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio for advanced non-small cell lung cancer patients with high PD-L1 tumor expression receiving pembrolizumab. Transl Lung Cancer Res. 2021;10 (1 ):355–367. doi:10.21037/tlcr-20-541 33569318
