Association between programmed death protein 1-related single-nucleotide polymorphisms and immune-related adverse events induced by programmed death protein 1 inhibitors-a pilot study.

Programmed death protein 1 (PD-1) inhibitors have potent anti-tumor activities. However, they often result in immune-related adverse events (irAEs) of varying severity. Therefore, the factors affecting the incidence of irAEs warrant urgent investigation. This study aimed to identify specific and sensitive predictors of irAEs in a Chinese population. We conducted a genome-wide association study (GWAS) comprising 80 patients with malignant tumors to evaluate single-nucleotide polymorphism (SNP) loci associated with the incidence of irAEs. The SNP rs2157775 on the LOC339166 gene had the lowest P value but did not reach the significance threshold after Bonferroni correction. Therefore, potentially associated SNPs were further investigated through the mechanism-related PD-1 pathway using the ImmPort and PathCards Human Gene Databases. A binary logistic regression model revealed that CD3E (rs3782040) A/A was associated with a lower incidence of irAEs in patients with malignant tumors who received PD-1 inhibitors. In contrast, PTPN11 (rs143894582) C/CA was associated with a higher incidence of irAEs. These findings provide a basis for the verification and identification of new loci to provide insight into the etiology of irAEs.

A case of immune checkpoint inhibitor-associated hemophagocytosis after initiation of atezolizumab plus bevacizumab therapy for advanced hepatocellular carcinoma.

A woman in the 70s with a decreased appetite and weight loss (4 kg) in the last 3 months was referred to our hospital. An enhanced CT scan of the abdomen showed a hepatocellular carcinoma (HCC) of 83 mm in diameter of the liver with metastasis to the para-aortic lymph nodes, the left adrenal gland, and the right lower lung lobe (cStage IVb). She was started on atezolizumab + bevacizumab (Atezo-Bev) therapy. A week after the treatment, she began to have a decreased appetite, fever in the 39 °C range, subcutaneous bleeding, and a slight headache when walking. So she was urgently admitted to our hospital. We diagnosed her as having a hemophagocytic syndrome and administered 1 g steroid pulse therapy for 3 days followed by 1 mg/kg of prednisone. Her condition began to improve. This is the first case report of a hemophagocytic syndrome in a patient with HCC treated with Atezo-Bev.

Pembrolizumab-Induced Myasthenia Gravis With Myocarditis in the Setting of Metastatic Renal Cell Carcinoma.

Immune checkpoint inhibitors (ICIs) like pembrolizumab are increasingly used for treating renal cell carcinoma (RCC), offering benefits such as enhanced specificity and activation of immunological memory. However, ICIs can lead to immune-related adverse events (irAEs), including rare but serious neurologic consequences such as myasthenia gravis (MG). We present a case of pembrolizumab-induced MG with concurrent orbital myositis and myocarditis. A 69-year-old male with a history of pT3aN1 kidney cancer presented with abdominal pain, night sweats, and weight loss. Initial imaging revealed a retroperitoneal mass and a thyroid mass, and a biopsy confirmed papillary RCC. The patient began neoadjuvant therapy with pembrolizumab and axitinib. Three weeks post-initiation, he developed dysphagia, ptosis, and proptosis, which progressed with each pembrolizumab infusion. Hospitalization was required after the third cycle due to bilateral ptosis, heart block, and elevated troponins. Despite initial steroid treatment, symptoms persisted. Diagnoses of ICI-related MG (irMG) and myocarditis were established, and treatment included cessation of pembrolizumab, high-dose steroids, IVIGs, and a pacemaker for heart block. Post-discharge, the patient showed a slight improvement in ptosis but persistent dysphagia. MG induced by ICIs is a rare but severe complication with rapid onset and progression, often presenting with bulbar involvement and a significant risk of respiratory failure. The therapeutic regimen for our patient, including high-dose methylprednisolone and IVIG, aligns with current recommendations. This case underscores the importance of recognizing cardiac irAEs like myocarditis in patients on ICIs, as early intervention can significantly affect outcomes. Despite therapeutic interventions, complete resolution of irMG symptoms is rare, and persistent sequelae are common. This case highlights the critical need for vigilant monitoring and prompt management of neurologic and cardiac irAEs in patients undergoing ICI therapy. Clinicians should maintain a high index of suspicion for MG and myocarditis to improve diagnostic accuracy and patient outcomes.

Reconceptualization of immune checkpoint inhibitor-associated gastritis.

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.

Medical dilemma: Programmed death 1 blockade (sintilimab) therapy in patients suffering from tumours combined with psoriasis.

Tumour immunotherapy represented by immune checkpoint inhibitors (ICIs) has greatly improved the overall prognosis of patients with malignant tumours, and is regarded as an important breakthrough in the field of medicine in recent years. ICIs have gradually become the core of tumour therapy and are increasingly used in the clinic. In order to achieve early clinical prediction and management of immune-related adverse events (irAEs), it is still necessary to perform further research on the mechanisms, risk factors, and predictors of irAE occurrence in the future. Zhou et al describe the consultation of a patient with advanced gastric cancer combined with chronic plaque psoriasis. This case provides an important reference for the use of programmed cell death protein-1 (PD-1) inhibitors in patients of tumours combined with chronic plaque psoriasis. This case also highlights that screening of high-risk groups for irAEs is critical before applying PD-1 inhibitors to patients with chronic psoriasis combined with tumours. PD-1 inhibitors are new and potent antineoplastic agents that can cause serious immune-related adverse events such as toxic epidermal necrolysis release and psoriasis. Glucocorticosteroids are the first-line agents for irAEs. The incidence of rheumatic irAEs may be higher in reality, which will inevitably become a new challenge for rheumatologists and dermatologists.

Sintilimab-induced myocarditis suspected in a patient with esophageal cancer and followed septic shock: case report and literature review.

Background: Immune checkpoint inhibitors (ICIs) have become a prevalent tool in anti-tumor therapy in recent years. They may cause immune-related adverse events (irAEs) including potentially life-threatening cardiovascular toxicities such as myocarditis. Case presentation: In this report, we describe a 69-year-old man with recurrent esophageal cancer who developed myocarditis after receiving three cycles of sintilimab combined with nab-paclitaxel. Despite a rising cardiac troponin I (cTnI), he initially reported no discomfort. He was later suspected of having with sintilimab-induced myocarditis. Although treatment with methylprednisolone reduced his cTnI levels, he still experienced significant discomfort. Moreover, he developed pneumonia and septic shock. Conclusion: In our literature search to identify all reported cases of sintilimab-associated adverse events involving myocarditis, we found 14 patients, including those with esophageal cancer, thymoma, lung cancer, gastric cancer, hepatobiliary carcinoma, and chordoma. The primary treatment for ICI-induced cardiotoxicity is methylprednisolone. However, the long-term or high-dose use of steroids can also induce side effects, which have not been the focus of these case reports. This is the first reported case of asymptomatic immune-mediated myocarditis occurring during the treatment of esophageal cancer with sintilimab. It is also the first to address the side effects of methylprednisolone used in the treatment of sintilimab-related myocarditis. To facilitate an early diagnosis, regular monitoring is required during sintilimab treatment. We should also focus on the prevention and management of adverse effects related to steroid use.

Impact of immune-related adverse events on survival among patients with head-and-neck squamous cell carcinoma.

Aim: Immune-checkpoint inhibitors (ICIs) have revolutionized treatment of metastatic head and neck squamous cell carcinomas (HNSCCs). Our goal was to assess for an association between immune-related adverse events (irAEs) and clinical outcomes for patients on ICIs.Methods: We analyzed a cohort of 110 HNSCC patients who received ICI therapy at the University of Virginia.Results: On review, 48% of our patients experienced an irAE with the most common events being hypothyroidism (30%), dermatitis (14%) and hepatitis (11%). Women were more likely to experience irAEs. Treatment interruption/discontinuation occurred in 43% patients with irAEs. Development of irAEs was associated with superior objective response rate (68 vs. 39%, p = 0.009), with a greater rate of CR (17 vs. 5%) and PR (32 vs. 16%). Twelve patients underwent ICI re-treatment following irAE, with 17% attaining a complete disease response, 25% attaining a partial response, 33% achieving stable disease and 25% experiencing disease progression with ICI resumption.Conclusion: Development of irAE was associated with superior objective response rate, with a greater rate of CR and PR. ICI re-treatment following irAE was feasible in a significant proportion of patients and can be attempted in carefully selected patients, given the dearth of second-line therapies for these patients.

While outcomes for patients who receive immunotherapy for advanced head and neck cancer are greatly improved compared with traditional chemotherapy, a feared complication of this treatment is immune-related side effects. The exact incidence of these side effects is not known in head and neck cancer but are well described in other cancers. In this study, about half of head and neck cancer patients who received immunotherapy developed side effects due to immune over-activation. Women and patients who did not receive radiation were more likely to develop these side effects. Patient who developed immune side effects were more likely to see shrinkage in their tumors, and may have a higher likelihood of longer survival, although the findings were not statistically significant.

Sarcopenia predicts immune-related adverse events due to anti-PD-1/PD-L1 therapy in patients with advanced lung cancer.

Introduction: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of a number of patients with advanced cancer, and while this has resulted in increased survival times, it has also led to the emergence of novel immune-related adverse events (irAEs). In individuals with advanced cancer, sarcopenia is a significant symptom of cachexia and is linked to poor nutritional status and increased mortality. The present study aimed to evaluate sarcopenia and other risk variables that can affect the emergence of irAEs in patients with lung cancer. Methods: A single-center retrospective analysis of 129 patients with advanced lung cancer treated with programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) checkpoint inhibitors was conducted from August 2020 to August 2022. Data on baseline characteristics and adverse events of participants were collected. Computed tomography was used to determine the skeletal muscle index at the third lumbar vertebra (L3-SMI) and whether sarcopenia is present. Results: The median age of all participants was 60 years old (range, 52-66 years), with men accounting for 68.9% of the total patient cohort. The present study showed that 44 (34%) participants presented with any degree of irAEs, and 79 (61.2%) patients presented with sarcopenia. There were no statistically significant differences in baseline characteristics, such as age and sex, between patients who presented with irAEs and those without irAEs. Using logistic regression analysis, individuals with sarcopenia were 2.635-times more likely to experience any grade of irAEs than those without sarcopenia. Discussion: irAEs are prevalent side effects of PD-1/PD-L1 inhibitor therapy for patients with cancer. By diagnosing and treating sarcopenia early, it is possible to lower the potential risk of irAEs in patients with advanced cancer. Furthermore, sarcopenia can be utilized as a predictor of irAEs.

Analysis of the association between immune-related adverse events and the effectiveness in patients with advanced non-small-cell-lung cancer.

PURPOSE: Immune checkpoint inhibitors (ICIs) have improved lung cancer treatment but are associated with immune-related adverse events (irAEs). This study analyzes the relationship between irAEs and treatment effectiveness in advanced non-small cell lung cancer (NSCLC) patients. METHODS: We conducted a retrospective study of NSCLC patients treated with ICIs from March 2019 to October 2022 at Zhongshan Hospital (Xiamen). Patients were divided into irAE and non-irAE groups, and treatment outcomes were compared. RESULTS: A total of 154 patients were included, with 36.4% in the irAE group and 63.6% in the non-irAE group. Most irAEs were Grade 1-2 (86.4%), with 13.6% being Grade 3 or higher. The irAE group had higher disease control rates (DCR: 94.6% vs. 76.5%, P = 0.004) and objective response rates (ORR: 42.9% vs. 26.5%, P = 0.037). Median progression-free survival (PFS) was longer in the irAE group (18 vs. 9 months, HR: 0.53, P = 0.001), as was overall survival (OS: 39.5 vs. 16 months, HR: 0.46, P = 0.001). Landmark analysis at 6 and 12 weeks confirmed that irAEs were associated with improved outcomes. Moreover, patients who experienced two or more adverse events during treatment had significantly longer OS compared to those who had only one or no adverse events (41.6 months vs. 34.0 vs. 23.6, P = 0.003). CONCLUSION: Patients with irAEs demonstrated better outcomes, including ORR, DCR, PFS, and OS. Further studies on biomarkers and irAE incidence are warranted to improve lung cancer management.

Association Between the Immune Checkpoint Inhibitor Durvalumab and Myasthenia Gravis: A Comprehensive Review.

Immune checkpoint inhibitors (ICIs), including Imfinzi (durvalumab), have revolutionized cancer treatment by stimulating the body's immune system to target cancerous cells. Although pharmaceuticals offer therapeutic benefits, several drugs have been associated with immune-related adverse events (irAEs), including the uncommon but serious condition known as myasthenia gravis (MG). This review synthesizes data from pertinent research to offer a thorough evaluation of the literature on the underlying mechanisms, clinical manifestations, and therapeutic approaches for durvalumab-induced MG. The incidence of MG in patients on durvalumab and other ICIs is typically low, with less than 1% documented, despite the potential for severe problems associated with the disease. Durvalumab disrupts immunological tolerance by stimulating autoreactive T-cells and inducing the production of autoantibodies. The clinical consequences of MG need meticulous monitoring, prompt identification, and suitable management to efficiently control the condition. Medical practitioners must carefully weigh the positive effects of ICIs against the possible hazards, emphasizing the necessity for more extensive investigation to improve patient results and establish uniform treatment protocols.

Adjuvant immunotherapy in older patients with stage III and resected stage IV melanoma: Toxicity and recurrence-free survival outcomes from the Dutch melanoma treatment registry.

BACKGROUND: Adjuvant anti-PD-1 therapy improves relapse free survival in stage III melanoma, but also leads to immune-related adverse events (irAEs). Older patients are of particular interest due to comorbidities and frailty, which may impact their ability to tolerate irAEs and benefit from anti-PD-1 therapy. This study aimed to explore associations between clinical parameters and the occurrence of grade ≥ 3 irAEs and recurrence-free survival (RFS) in older patients with radically resected stage III/IV cutaneous melanoma treated with adjuvant anti-PD-1 therapy. METHODS: Patients aged ≥ 65 with resected stage III/IV cutaneous melanoma treated with adjuvant anti-PD-1 therapy between 2018 and 2022 were selected using real-world data from the nationwide Dutch Melanoma Treatment Registry (DMTR). A univariate and multivariable logistic regression was used to compare determinants of grade ≥ 3 irAEs, and univariate and multivariable Cox-proportional hazard models were fitted to identify factors influencing RFS. RESULTS: The study included 885 patients, with 280 aged 75 and older. The incidence of grade ≥ 3 irAEs was 15.5 % in the 65-74 age group and 13.9 % in the ≥ 75 age group. No significant correlation was found between age and grade ≥ 3 irAEs. However, an increasing number of comorbidities was associated with a higher risk of grade ≥ 3 irAEs (multivariable analyses: OR 1.83, 95 % C.I. 0.99-3.40). The 1-year RFS rate of 80.0 % of this study was comparable to those reported in previous registration trials and real-world data. Having ≥ 3 comorbidities was significantly associated with a decrease in RFS (HR: 1.68, 95 % C.I. 1.15-2.44). CONCLUSION: Older patients had similar benefit of adjuvant immunotherapy compared to older subgroups in previous trials. However, patients with multiple comorbidities were at increased risk of grade ≥ 3 irAEs and had a lower RFS. This should be considered when deciding upon adjuvant treatment.

Immune-related adverse events in a nationwide cohort of real-world melanoma patients treated with adjuvant anti-PD1 - Seasonal variation and association with outcome.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) carry the risk of immune-related adverse events (irAEs), a significant concern as therapy has transitioned to the adjuvant setting. Balancing therapeutic benefits against potential risks is crucial, necessitating real-world data from an unselected patient population in addition to clinical trial data to ensure optimal clinical decision-making. METHODS: This nationwide real-world study assessed irAEs in patients receiving adjuvant anti-PD1 therapy, primarily nivolumab, for resected stage III-IV melanoma between 2018-2022. Data were retrieved from two national databases: the IMMUNOTOX database and the Danish Metastatic Melanoma Database (DAMMED). IrAEs were sub-grouped according to organ systems graded using CTCAE ver. 5.0 ranging from mild toxicities (grade 1-2) to severe (grade 3-4) and fatal (grade 5). RESULTS: Among 792 included patients, (55 % male, median age 62 years (range 16-88)), 697 patients (88 %) experienced an irAE. Severe irAEs occurred in 116 patients (15 %) and five (0.6 %) died due to toxicity. A landmark analysis showed that patients who experienced at least one irAE before the 1st evaluation at 90 days had an increased progression free survival (PFS) (p = 0.032) and overall survival (OS) (p = 0.0071). Additionally, a seasonal pattern was noted with higher incidence of irAEs during summer. CONCLUSION: The prevalence of irAEs in real-world patients is comparable to the observed risk in clinical trials. Patients experiencing irAEs demonstrate a lower risk of melanoma relapse. Further, gender, age and seasonal variation may impact the incidence of irAEs.

Evaluation of the safety of PD-1/PD-L1 inhibitors for immunotherapy in patients with malignant tumors after COVID-19 infection: A single-center cohort study.

INTRODUCTION: An increasing body of evidence suggests a close association between COVID-19 infection and the safety of PD-1/PD-L1 inhibitor therapy in cancer patients. However, the available data concerning these impacts remain limited and occasionally contradictory. MATERIAL AND METHODS: We conducted a retrospective analysis of cancer patients who received PD-1/PD-L1 inhibitor therapy at the same institution from November 2022 to May 2023. After excluding patients with missing information, a total of 224 cases were included. In our study, immune-related adverse events (irAEs) that occurred during the hospitalization of patients were included in the analysis. Further analysis of inter-subgroup differences was conducted following a 1:2 propensity score matching. Statistical analyses were performed using the Fisher's exact, chi-squared, and Mann-Whitney U-tests. RESULT: The results showed that no statistically significant differences between the two subgroups in the incidence of irAEs, changes in immune function before and after using PD-1/PD-L1 inhibitors, and alterations in hepatic and renal function (p > 0.05). CONCLUSION: Our findings suggest that infection with COVID-19 does not significantly impact the safety of PD-1/PD-L1 inhibitors in cancer patients. Most cancer patients used PD-1/PD-L1 inhibitors during COVID-19 infection (asymptomatic or mild infection) did not experience exacerbation of their underlying condition, nor did they exhibit a substantial increase in toxic side effects.

A case report of the diagnosis and treatment of immune checkpoint inhibitor-related encephalitis induced by camrelizumab.

Background: Camrelizumab has been widely used in the treatment of various cancers, it is important to determine the side-effect of this drug and the corresponding treatment strategy. Case Description: The current case report describes the clinic, diagnosis, treatment and prognosis of camrelizumab-related encephalitis. Camrelizumab was administrated to a 67-year-old man with squamous cell carcinoma (SCC), a form of non-small cell lung cancer (NSCLC). One month after the treatment, the patient showed typical encephalitis symptoms including systemic fatigue, numbness of extremities and walking instability. Furthermore, the total protein in cerebrospinal fluid (CSF) was significantly elevated (1,399 vs. normal range 120-600 mg/L). Importantly, magnetic resonance imaging showed there was no brain metastasis. The patient did not get better after two days of intravenous injection of thioctic acid (1.2 g) and cobamamide (1.5 mg) once daily. Therefore, this patient was diagnosed as camrelizumab-related encephalitis. Then, we put him on one-month regimen: oral taper corticoids (methylprednisolone, MP) at 500 mg (days 1-4), 120 mg (days 5-10) and 60 mg (days 11-15); MP was replaced with oral prednisone acetate at 30 mg (days 16-30). After the treatment, the total protein in CSF was decreased to 873 mg/L, and all of encephalitis-related symptom was completely lost. About one year after the onset of encephalitis, the patient showed no recurrence of neurological symptoms. Conclusions: The present case proves the efficacy and safety of corticoids in the treatment of camrelizumab-related adverse effects.

Severe Guillain-Barre syndrome induced by intravitreal injection of ranibizumab for branch retinal vein occlusion: a case report.

Background: Guillain-Barré syndrome (GBS) is an acute/subacute immune-mediated polyneuropathy characterized by varying degrees of limb or cranial nerve involvement, manifested as limb weakness, absent tendon reflexes, and sensory and autonomic dysfunction caused by demyelination and/or axonal damage of peripheral nerves and nerve roots. Upper respiratory tract infections and gastroenteritis are the most important triggering factors, but the occurrence of explosive GBS after injection of ranibizumab is very rare. Case Description: A 53-year-old female was diagnosed with left branch retinal vein occlusion (RVO) and underwent three intravitreal injections of ranibizumab (0.5 mg) in the left eye. After the third injection, she developed weakness, numbness, and tingling in the limbs, which worsened to respiratory muscle paralysis requiring mechanical ventilation and tracheostomy. Cerebrospinal fluid showed protein-cell dissociation, a positive anti-ganglioside antibody spectrum, and electromyography revealed multiple demyelinating changes in peripheral nerves. The diagnosis was GBS. After treatment with immunoglobulin (25 g) therapy, the patient improved. After two months of treatment, the tracheotomy site healed well, and the patient was able to walk independently and perform basic activities of daily living. After one year of follow-up, the patient did not experience a relapse and was basically cured. This successful outcome highlights the importance of promptly recognizing and treating GBS induced by ranibizumab, which is crucial for optimizing patient outcomes and preventing potential life-threatening consequences in patients with RVO. Conclusions: This case underscores the potential occurrence of GBS in patients undergoing ranibizumab treatment for RVO. It highlights the importance for clinicians to promptly recognize and diagnose GBS, initiate appropriate interventions, optimize patient outcomes, and prevent potential life-threatening consequences.

Extracorporeal photopheresis vs. systemic immunosuppression for immune-related adverse events: Interim analysis of a prospective two-arm study.

BACKGROUND: Checkpoint inhibitor-induced steroid-refractory (sr) and steroid-dependent (sd) immune-related adverse events (irAE) account for about 11 % of irAE. Although these patients face worse outcomes due to irAE mortality and/or sustained immunosuppression, which impairs anti-tumor response, there is no established second-line treatment based on prospective trial data. METHODS: This prospective comparative study investigates outcomes of extracorporeal photopheresis (ECP), an immunomodulating therapy, versus second-line immunosuppressants (SLI) in sr/sd-irAE. The primary endpoint was longitudinal change in immunophenotype; secondary endpoints were outcome of irAE and tumor response. Patient demographics, quality of life (EORTC QLQ-C30; global health status (GHS/QoL)) and longitudinal blood samples were analyzed at baseline; in weeks 1, 4, 8, and 12. RESULTS: At interim analysis, 21 patients (11 ECP, 10 SLI) with 7 different sr/sd-irAE were included. Compared with the SLI group, the ECP group demonstrated a higher clinical response rate of irAE (93 % vs. 80 %; 95 % CI 0.83-1.92; P = 0.54) and a better GHS/QoL score throughout all follow-up visits. ECP patients showed a numerically higher overall survival (23 vs. 12 months; 95 % CI 0.02-3.02; P = 0.27) and lower cancer progression rates (33 % vs. 67 %; 95 % CI 0.09-1.60; P = 0.52). Immunophenotyping revealed changes in immune cell populations and the regulation of immune checkpoints. There were no significant safety issues in either treatment group. CONCLUSION: This prospective comparative study supports the clinical efficacy of ECP in the treatment of sr/sd-irAE in comparison to the SLI cohort. Thus, ECP represents a potential treatment option for this indication, given its good safety profile while maintaining anti-tumor response. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05700565, https://classic. CLINICALTRIALS: gov/ct2/show/NCT05700565.

Immune checkpoint inhibitor-associated sick sinus syndrome and cardiogenic shock.

Immune checkpoint inhibitors (ICI) represent a major advance in the treatment of cancer. Most studies of ICI have underestimated their cardiotoxicity; however, an increasing number of cases of cardiotoxicity are being reported. Herein we discussed a 67-year-old, male, Japanese patient who presented with cardiogenic shock accompanied by sick sinus syndrome 4 days into his second course of ipilimumab plus nivolumab combination therapy. A temporary transvenous pacemaker was subsequently placed, and a permanent pacemaker was implanted for persistent, symptomatic, intermittent bradycardia. The permanent implantation of the pacemaker improved his symptoms and allowed him to continue his ICI therapy.

A case of gastritis caused by immune checkpoint inhibitor treated with infliximab.

Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs) in various organs. Herein, we present a rare case involving a patient with immunotherapy-related gastritis who developed refractory vomiting and anorexia after treatment with nivolumab for cutaneous malignant melanoma. The patient was treated with oral corticosteroids, but the efficacy was limited. The symptoms improved markedly after treatment with infliximab. With the increasing use of ICIs, the number of reports of gastritis due to irAEs has also increased. Health care providers treating malignancies should be aware of this side effect and know how to diagnose and treat it.

Risk of severe immune-related adverse events in cancer patients with pre-existing autoimmunity receiving immune checkpoint inhibitor therapy.

Purpose: To evaluate the frequency and severity of irAEs in patients with pre-existing autoimmunity, including irAE-related morbidity and mortality, irAE-related management and resolution, and outcome of ICI rechallenge, to better understand the treatment options for this vulnerable patient population. Methods: We designed a retrospective, single-center, case-control study at a large, academic medical center to evaluate the incidence and severity of irAEs in patients with pre-existing autoimmunity compared to controls. Controls were matched 2:1 for age, sex, cancer histology, and ICI class. Patients were identified with ICD 9 and 10 codes followed by manual chart extraction. Cases were defined as patients with pre-existing, systemic autoimmunity. The primary outcome was severe irAE (Grade 3 or higher by Common Terminology Criteria for Adverse Events) within 6 months of ICI therapy. Secondary outcomes included response to ICIs, resolution of the irAE, ICI rechallenge success, and survival. Statistical analyses were performed by Chi-square, Fishers exact, Mann-Whitney, and Log-rank tests. Results: Of 3,130 patients treated with ICIs from 2015-2021, 28 cases with pre-existing autoimmune disease were identified and were matched with 56 controls. Pre-existing autoimmune conditions included antiphospholipid syndrome, inflammatory polyarthritis, juvenile rheumatoid arthritis, multiple sclerosis, psoriatic arthritis, rheumatoid arthritis, and type I diabetes. Multiple cancer histologies, including genitourinary, gynecologic, head & neck, hepatobiliary, lung, melanoma, and pancreatic, were represented. Six of 28 cases (21.4%) experienced severe irAEs compared to 9/56 (16.1%) controls; the odds of developing a severe irAE were not significantly different (OR 0.43, 95% CI 0.083-2.33, p = 0.627, ns). Moreover, there were no significant differences in overall survival or tumor response between the two groups. The majority of irAEs resolved without long-term sequelae (66.7% of cases, 55.6% of controls). The majority of patients who were rechallenged with ICIs were successful in continuing therapy (66.7% of cases, 100% of controls). Conclusion: Our study suggests that patients with pre-existing autoimmune disease can be treated with ICI cancer therapies and experience rates of severe irAEs and overall survival that are similar to those of the general population. These data can aid oncologists in discussing risks and benefits of ICIs when treating patients with pre-existing autoimmunity and solid tumors.