Combination immune checkpoint inhibitor therapy (ICI) with ipilimumab (anti-cytotoxic T-lymphocyte-associated protein 4) + nivolumab (anti-PD-1) in untreated, metastatic melanoma has achieved a ten-year melanoma-specific survival of 52%. However, approximately 40%-55% of patients with metastatic melanoma have primary resistance and do not initially respond to anti-PD-1, and an additional 25% of patients develop secondary resistance, exhibiting an initial response followed by disease progression. In PD-1-refractory melanoma, treatment options are limited. Addition of ipilimumab, relatlimab (anti-LAG3), or lenvatinib (VEGFR TKI) has minimal to modest efficacy. Switching to targeted BRAF/MEK inhibition improves survival for BRAF-mutant disease. MEK and KIT inhibitors have limited activity in NRAS- and KIT-mutant metastatic melanoma, respectively. Recently, personalized, autologous tumor-infiltrating lymphocyte therapy has become a US Food and Drug Administration-approved second-line option; lifileucel demonstrates durable response (approximately 30%) in heavily pretreated, metastatic melanoma. Emerging therapeutics that show promising clinical benefit in ongoing clinical trials include novel engineered oncolytic viral and human leukocyte antigen (HLA)-restricted immune-mediated T-cell therapies. As a therapy which is limited to patients who are HLA-A*02:01, T-cell receptor (TCR) engineered T cells (TCR-T) iterates on personalized adoptive cell transfer, and immune mobilizing monoclonal TCRs against cancer are CD3 bispecifics that bind glycoprotein 100 (tebentafusp, approved for metastatic uveal melanoma) or PRAME to activate T cells. Finally, in patients at high risk for immune-related adverse events (irAEs), ICI should still be considered. ICI may be given with modified immunosuppression in patients with autoimmune disease or previous organ transplantation. Cumulative data support safe administration in older patients and in ICI rechallenge for patients with previous irAE.

Immune checkpoint inhibitor-induced type 1 diabetes mellitus (ICI-T1DM) is a rare adverse reaction associated with durvalumab. Among the adverse reactions to durvalumab, the incidence of new-onset diabetes is relatively rare, occurring in ~0.2% of cases. The present study reports the case of a 62-year-old woman who developed ICI-T1DM following two cycles of durvalumab, presenting with thirst, polydipsia and polyuria. Laboratory examinations (glycated hemoglobin and glutamic acid decarboxylase antibody), along with consultations from an endocrinologist, led to the patient being diagnosed with ICI-T1DM. Immunotherapy was discontinued, and insulin replacement therapy was initiated. Blood glucose levels were closely monitored using a subcutaneous meter. The onset of diabetic ketoacidosis (DKA) was prevented due to timely treatment. In conclusion, medical oncologists need to be aware that durvalumab, an immunotherapy agent, can induce ICI-T1DM. Therefore, regular monitoring of blood glucose levels and collaborative consultations with endocrinologists are essential for an accurate diagnosis when elevated blood sugar levels are detected. The prompt diagnosis of ICI-T1DM is crucial to prevent the occurrence of DKA.

This study aimed to investigate the safety and efficacy of programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) antibody-based therapy in treating patients with advanced non-small cell lung cancer (NSCLC) according to different PD-L1 expression statuses in a real-world setting.

This retrospective, multicenter, observational study enrolled adult patients who received PD-1/PD-L1 antibody-based therapy in China and met the following criteria: (1) had pathologically confirmed, unresectable stage III-IV NSCLC; (2) had a baseline PD-L1 tumor proportion score (TPS); and (3) had confirmed efficacy evaluation results after PD-1/PD-L1 treatment. Logistic regression, Kaplan-Meier analysis, and Cox regression were used to assess the progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) as appropriate.

A total of 409 patients, 65.0% (n = 266) with a positive PD-L1 TPS (≥1%) and 32.8% (n = 134) with PD-L1 TPS ≥50%, were included in this study. Cox regression confirmed that patients with a PD-L1 TPS ≥1% had significantly improved PFS (hazard ratio [HR] 0.747, 95% confidence interval [CI] 0.573-0.975, P = 0.032). A total of 160 (39.1%) patients experienced 206 irAEs, and 27 (6.6%) patients experienced 31 grade 3-5 irAEs. The organs most frequently associated with irAEs were the skin (52/409, 12.7%), thyroid (40/409, 9.8%), and lung (34/409, 8.3%). Multivariate logistic regression revealed that a PD-L1 TPS ≥1% (odds ratio [OR] 1.713, 95% CI 1.054-2.784, P = 0.030) was an independent risk factor for irAEs. Other risk factors for irAEs included pretreatment absolute lymphocyte count >2.5 × 109/L (OR 3.772, 95% CI 1.377-10.329, P = 0.010) and pretreatment absolute eosinophil count >0.2 × 109/L (OR 2.006, 95% CI 1.219-3.302, P = 0.006). Moreover, patients who developed irAEs demonstrated improved PFS (13.7 months vs. 8.4 months, P <0.001) and OS (28.0 months vs. 18.0 months, P = 0.007) compared with patients without irAEs.

A positive PD-L1 TPS (≥1%) was associated with improved PFS and an increased risk of irAEs in a real-world setting. The onset of irAEs was associated with improved PFS and OS in patients with advanced NSCLC receiving PD-1/PD-L1-based therapy.

Immune checkpoint inhibitors (ICIs) constitute a major breakthrough in the field of cancer therapy; their use has resulted in improved outcomes across various tumour types. However, ICIs can cause a diverse range of immune-related adverse events (irAEs) that present a considerable challenge to the efficacy and safety of these treatments. The gut microbiota has been demonstrated to have a crucial role in modulating the tumour immune microenvironment and thus influences the effectiveness of ICIs. Accumulating evidence indicates that alterations in the composition and function of the gut microbiota are also associated with an increased risk of irAEs, particularly ICI-induced colitis. Indeed, these changes in the gut microbiota can contribute to the pathogenesis of irAEs. In this Review, we first summarize the current clinical challenges posed by irAEs. We then focus on reported correlations between alterations in the gut microbiota and irAEs, especially ICI-induced colitis, and postulate mechanisms by which these microbial changes influence the occurrence of irAEs. Finally, we highlight the potential value of gut microbial changes as biomarkers for predicting irAEs and discuss gut microbial interventions that might serve as new strategies for the management of irAEs, including faecal microbiota transplantation, probiotic, prebiotic and/or postbiotic supplements, and dietary modulations.

Immunotherapy has become a significant research focus for cancer treatment in recent years because it can generate enduring immunological responses and has promising therapeutic potential. Nevertheless, excessive stimulation of the immune system may adversely affect healthy organs, which can lead to immune-related toxicities, including gastrointestinal, pulmonary, hepatic, and dermatological toxicities. Among them, gastrointestinal toxicity induced by the immune response is the most common. Immune-associated enteritis has an incidence rate of 8%-27% and is one of the most prevalent forms of gastrointestinal toxicity. Tislelizumab is an approved first-line treatment for individuals with recurrent or metastatic nasopharyngeal cancer functioning as an inhibitor of PD-1. Here, we report a patient with nasopharyngeal carcinoma who developed bloody stools and diarrhea after two cycles of tislelizumab. Abdominal CT revealed intestinal wall thickening with inflammatory exudation. Congestion, edema, and mucosal punctate ulcers were discovered during the colonoscopy. Histopathology confirmed active mucosal inflammation. The initial treatment with loperamide, bifidobacterium tetrad, and norfloxacin failed, but the symptoms improved significantly after switching to metronidazole, mesalazine, and methylprednisolone. This article reviewed a case of immunological enteritis triggered by tislelizumab, demonstrating that mesalazine can markedly alleviate the symptoms of immune-associated enteritis, aiming to enhance future clinical efforts regarding tislelizumab-induced immunological enteritis.

The incidence of and risk factors for arterial thromboembolism (ATE) in patients with cancer, particularly in those with low socioeconomic status, remains understudied.

We aimed to report the association between cancer-related and cardiovascular (CV) risk factors and the development of ATE.

We performed a retrospective cohort study of patients with newly diagnosed invasive cancer from 2011 to 2021 at a safety-net hospital system. We ascertained ATE outcomes using validated inpatient billing diagnosis codes for myocardial infarction and ischemic stroke. We examined the incidence of ATE after cancer diagnosis using the cumulative incidence competing risk method to account for early mortality and estimated subdistribution hazard ratios for ATE using multivariable Fine-Gray models.

Among 17 236 patients (45.4% male, median 56 years), the ATE incidence was 1.5% (95% CI, 1.3%-1.6%) at 1 year and 2.8% (95% CI, 2.5%-3%) at 5 years after cancer diagnosis. In unadjusted analysis, the 5-year ATE incidence was highest in hematologic malignancies, such as multiple myeloma (8.6%) and acute leukemia (7.8%), among patients receiving immune checkpoint inhibitors (8.3% vs 2.7%), those with poor Eastern Cooperative Oncology Group performance status (5.4% performance status 4 vs 2.2% performance status 0), and advanced stage (3.1% IV vs 1.9% I). After multivariable adjustment, only cancer type remained significantly associated with ATE along with known CV risk factors, including advanced age, smoking, diabetes, hypertension, history of myocardial infarction, and history of ischemic stroke.

Both cancer type and traditional CV risk factors are independently associated with the development of ATE in patients with cancer.

The objective of this study was to identify symptom clusters in lung cancer patients receiving immunotherapy and explore their impact on the quality of life of patients.

Immunotherapy is widely used in lung cancer; however, there is little understanding of symptom clusters and their impacts on the quality of life of this population.

Cross-sectional study.

The survey contained the Memorial Symptom Assessment Scale (MSAS), Quality of Life Questionnaire-Lung Cancer 43 and a self-designed General Information Evaluation Form. Symptom clusters were identified using exploratory factor analysis (EFA) based on the symptom scores. Spearman correlation analysis was performed to evaluate the associations between each symptom cluster and the patients' quality of life. Multiple linear regression analysis was employed to examine the impact of the symptom clusters on quality of life. This study adhered to the STROBE guidelines.

In total, 240 participants completed the survey. Five symptom clusters were identified and named according to their characteristics: emotional-related symptom cluster, lung cancer-related symptom cluster, physical symptom cluster, skin symptom cluster and neural symptom cluster. All symptom clusters, except for the neural symptom cluster, had a significantly detrimental impact on patient quality of life.

Lung cancer patients undergoing immunotherapy experience a range of symptoms, which can be categorized into five clusters. These symptom clusters have a negative impact on patients' quality of life. Future research should focus on developing interventions for each symptom cluster and their influencing factors.

In the data collection phase, lung cancer patients undergoing immunotherapy were recruited to participate in the survey.

Morbilliform eruptions, which are a clinical reaction pattern characterized by erythematous macules and papules coalescing into patches that cover most of the skin surface, are one of the most common cutaneous findings in the inpatient setting. In the hospital setting, most causes are benign and due to low-risk drug exanthems; however, morbilliform eruptions may also be a sign of high-risk diseases, including Stevens-Johnson syndrome/toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome, acute generalized exanthematous pustulosis, and graft-versus-host disease. Proper identification of the etiology and risk stratification of a morbilliform eruption is critical to ensure proper management and optimize patient outcomes. In this review, we discuss the key features that differentiate high-risk from low-risk morbilliform eruptions, as well as specific characteristics that differentiate the different high-risk eruptions. Additionally, we offer a clinical algorithm that may be applied in the management of a patient who presents with a morbilliform rash.

Immune checkpoint inhibitors (ICIs) have demonstrated favorable outcomes in various cancers. However, it has been observed that ICIs may induce life-threatening cardiovascular toxicity. In this study, a meta-analysis was conducted to determine the risk of cardiovascular toxicities in patients exposed to ICIs or in combination with chemotherapy. PubMed, Cochrane Library, and Embase databases were searched from inception to September 24, 2023. This study was conducted in accordance with the PRISMA guidelines. A meta-analysis was conducted on the risk of cardiotoxicity in cancer patients. Data were pooled with a random-effect model. This protocol was registered prospectively in PROSPERO (CRD42023467319). The primary outcome was cardiotoxicity risk in observational studies with ICIs or combined with chemotherapy. The risk factors that affected the occurrence of cardiovascular toxicities were also examined. ICIs or combined with chemotherapy increased the cardiotoxicity risk compared with mono-chemotherapy (OR 1.47; 95% CI 1.05-2.06, p = 0.024). The risk of pericardial disease in cardiotoxic events (OR 1.99; 95% CI 1.23-3.22, p = 0.005) and thromboembolic events (OR 1.34; 95% CI 1.04-1.72, p = 0.025) was significantly increased. Smoking (OR 1.25; 95% CI 1.12-1.39, p < 0.001), previous heart disease (OR 2.01; 95% CI 1.64-2.46, p < 0.001), and lung cancer (OR 1.46; 95% CI 1.26-1.69, p < 0.001) were risk factors worthy of attention. ICIs or combined with chemotherapy show an elevated risk of cardiovascular toxicities. Patients who are smoking, diagnosed lung cancer, and having prior medical history of heart diseases need more attention.

The clinical characteristics of immune checkpoint inhibitors (ICIs)-related myocarditis in lung cancer remains uncertain. The purpose of this study was to evaluate the incidence, clinical characteristics, risk factors, and prognosis of myocarditis in lung cancer patients treated with ICIs. Therefore, this study would enhance the understanding of immune related myocarditis in lung cancer population.

A total of 1004 patients were analyzed, among those who developed elevated serum creatine kinase isoenzyme, MB form (CK-MB) and/or high-sensitivity troponin I (hs-cTnI) with electrocardiographic or clinical symptoms after immunotherapy were enrolled in the myocarditis group. The same number of patients who had received immunotherapy but didn't develop myocarditis was randomly selected as the control group. Clinicopathologic features, risk factors, and prognostic factors were evaluated in this study.

66 patients (6.6%) developed ICIs-related myocarditis. In these patients, there were 60 case of possible myocarditis (90.9%), 5 probable myocarditis (7.6%), and 1 definite myocarditis (1.5%). The median time to the occurrence of myocarditis was 3.8 months. The median progression-free survival (PFS) for NSCLC and SCLC patients were 24.4 months and 13.0 months, while the median overall survival (OS) for NSCLC and SCLC patients were 43.3 months and 44.6 months. The grade of myocarditis (OR: 5.79; 95%CI: 1.14-29.41, P = 0.034), immunotherapy cycle (OR: 0.38; 95% CI: 0.16-0.92, P = 0.032), and combination of immune-related adverse events (irAEs) (OR: 3.63; 95% CI: 1.55-8.48, P = 0.003) were the influencing factors of PFS in NSCLC patients. In SCLC patients, the immunotherapy cycle was the influential factor for PFS (OR: 0.16; 95%CI: 0.04-0.61, P = 0.007) and OS (OS: 0.12; 95% CI: 0.03-0.48, P = 0.002). Anti-PD1 therapy (OR: 0.4, 95% CI: 0.13-0.97, P = 0.043) and age (OR: 0.36, 95% CI: 0.16-0.84, P = 0.018) might be the protective factors of myocarditis patients compared with the control group.

The presentations of ICIs-related myocarditis in lung cancer are mainly possible myocarditis and probable myocarditis, which have a mild impact on the prognosis. More cycles of ICI treatment accompany the longer the PFS and OS, as a protective factor. Anti-PD1 therapy and older age may be protective factors for ICI-related myocarditis.

Immune Checkpoint Inhibitor (ICI)-related cardiotoxicity has a high mortality rate, making early prediction crucial for improving patient prognosis. However, early prediction models are currently lacking in clinical practice. This study aims to develop an early prediction model for ICI-related cardiotoxicity using the eXtreme Gradient Boosting (XGBoost) algorithm. Retrospective analysis was conducted on patients who received ICI therapy between January 2020 and December 2023. The population was categorized into a cardiotoxicity group and a non-cardiotoxicity group based on the presence of cardiac biomarkers and electrocardiogram abnormalities that could not be attributed to other diseases within 30 days after initiation ICI therapy. The dataset was split into training (70%) and testing (30%) sets. Logistic Regression (LR), Random Forest (RF), and XGBoost models were constructed in Python, with variables selected based on each model's characteristics. The models were compared based on predictive performance, which was measured by area under the curve (AUC) and decision curve analysis (DCA). The best model was explained using SHapley Additive exPlanation (SHAP). A total of 419 patients were included. The XGBoost model demonstrated the highest predictive performance with an AUC of 0.83, outperforming LR (AUC: 0.80) and RF (AUC: 0.74) models. DCA confirmed the XGBoost model's superior net benefit. Among the selected predictors, cardiac troponin T (cTnT) emerged as the most important variable, demonstrating the highest feature importance. The XGBoost model proposed could assist clinicians in personalized risk stratification for patients on ICI therapy, facilitating precise monitoring of cardiotoxicity and tailored treatment strategies.

To provide an update on the literature regarding diagnosis and management of immune checkpoint inhibitor myocarditis.

The diagnosis of immune checkpoint inhibitor myocarditis has evolved to include more reliance on performing endomyocardial biopsy to clarify the diagnosis in selected cases. Additionally, there is recognition of a spectrum of disease both clinically and on endomyocardial biopsy suggesting that there is a range of severity from mild to fulminant. The treatment of immune checkpoint inhibitor myocarditis is shifting towards increased use of additional immunosuppressive medications as steroid sparing agents. There are increased studies including two randomized controlled trials evaluating abatacept in the treatment of immune checkpoint inhibitor myocarditis. This review summarizes the latest literature regarding diagnosis and management of immune checkpoint inhibitor myocarditis and provides our experience and approach to this rare but potentially fatal condition.

Immunotherapy has significantly improved the survival rates of lung cancer patients. However, prevalent adverse immune reactions associated with this treatment can detrimentally affect their quality of life. Coping strategies play a crucial role throughout the cancer treatment process. Consequently, this study hypothesised that coping strategies act as a mediating factor between symptom clusters and quality of life. This study intended to provide a theoretical foundation and empirical data to support the optimisation of coping strategies for lung cancer patients, thereby enhancing their overall quality of life.

This study consisted of a cross-sectional survey. Data were collected using the Memorial Symptom Assessment Scale, the Medical Coping Modes Questionnaire, the Quality of Life Questionnaire-Lung Cancer 43, and a self-designed General Information Evaluation Form. The data were fitted, and the model was refined using the maximum likelihood estimation method. Additionally, the Bootstrap method was employed to assess mediating effects.

In total, 240 participants completed the survey. During immunotherapy, lung cancer patients predominantly adopted the acceptance-resignation coping strategy, which served as a mediating factor between symptom clusters and quality of life. In contrast, the mediating effects of confrontation and avoidance coping strategies between symptom clusters and quality of life were not significant.

Both symptom clusters and the acceptance-resignation coping strategy negatively impacted quality of life, with acceptance-resignation serving as a mediating factor between symptom clusters and quality of life. Future research should focus on developing interventions for cognitive behaviour to improve coping strategies and quality of life throughout the disease trajectory.

Since the introduction of immunotherapy and targeted therapies, patients not only have adequate tumoral response to these treatments, but their quality of life has improved due to milder toxicities. However, due to their wide mechanisms of action, the toxicity profile for these therapies is broad, can have an insidious onset, and their recognition can be challenging. Rarely, some of these toxicities can cause significant morbidity if not diagnosed early and lead to intensive care unit (ICU) admission and death. Anesthesiologists are likely to encounter not only a wide spectrum of these toxicities but also a wide range of severity. In some cases, they could be the first to make the diagnosis and therefore need to be prepared to rapidly assess, establish differentials, perform a diagnostic workup, and evaluate the impact the toxicity could have on the patients' care during the perioperative period. In this article, we set to review toxicities of novel cancer therapies such as checkpoint inhibitors and targeted therapies, that could present in the perioperative setting. This article will help as a guide for anesthesiologists to recognize their clinical presentation, the approach to their diagnosis, and their impact on patient care.

One to 2% of patients undergoing immune checkpoint inhibitor (ICI) therapy develop ICI-induced pancreatitis (ICI-IP). A small subset of these patients develop recurrent pancreatitis, even after discontinuation of ICI therapy. This case series presents 2 patients with recurrent steroid-responsive ICI-IP who were managed with immunomodulators as steroid-sparing agents. Both patients were maintained on immunomodulators for approximately 2 years before discontinuation of the agents, with no further recurrence or complications of pancreatitis. This case series highlights the use of mycophenolate mofetil and azathioprine for the management of recurrent ICI-IP.

The precise incidence of immune-related adverse events (irAEs) remains unclear. This pharmacovigilance study investigated acute pancreatitis (AP) associated with immune checkpoint inhibitors (ICIs) using real-world data from the FDA Adverse Event Reporting System (FAERS).

Disproportionality analysis employing reporting odds ratios (RORs) was conducted to detect AP signals in ICI-treated patients compared to the entire FAERS database.

A total of 152,042 individual patients were included in the dataset from which we identified a cohort of 921 acute pancreatitis adverse events (AEs). The severe outcome of acute pancreatitis was death, with a rate of 13.6% (125/921). Immune checkpoint inhibitor (ICI)-related acute pancreatitis AEs were classified into two categories (pancreatitis and immune-mediated pancreatitis) based on the type of adverse event observed. ICI treatments were significantly correlated with the risk of ICIs-induced acute pancreatitis (AP) but varied among different drugs. The median time to AP onset was 57 days, with events occurring throughout the first year post-ICI initiation.

Our findings provide an enhanced understanding of potential acute pancreatitis related adverse events and provide actionable insights for the early detection and management of ICI related pancreatic adverse events.

Immune checkpoint inhibitors (ICIs) have revolutionized hepatocellular carcinoma (HCC) treatment, while immune-related adverse events (IRAEs) pose significant challenges. We report a 60-year-old male with unresectable HCC who developed Guillain-Barré syndrome (GBS), a rare but severe neurologic complication, after three cycles of sintilimab plus bevacizumab biosimilar and conventional transarterial chemoembolization (c-TACE). The patient presented with progressive ascending weakness, reaching symmetric quadriparesis with proximal muscle strength of 2/5 in upper limbs and 1/5 in lower limbs. Following sintilimab discontinuation, treatment with intravenous immunoglobulin (2 g/kg) and oral prednisone (30 mg/day) achieved complete neurological recovery within one month. Given the patient's favorable initial tumor response and strong request, immunotherapy was cautiously reinstated using tislelizumab after thorough clinical evaluation. Following four cycles of treatment, significant tumor response enabled successful conversion surgery with major pathological response (necrosis rate >70%). With 26-month survival and no evidence of recurrence, this case demonstrates the potential feasibility of ICI rechallenge with an alternative PD-1 inhibitor following sintilimab-induced GBS. Our experience suggests that ICI-related neurological adverse events may be drug-specific rather than class-specific, potentially providing valuable treatment options for patients showing favorable tumor response despite experiencing severe IRAEs, though larger studies are needed for validation.

Immune checkpoint inhibitors (ICIs)-induced cardiac injury is a life-threatening immune-related adverse events (irAEs). However, the current understanding of its pathogenesis and therapeutic options is relatively limited. We aimed to provide a comprehensive overview of the myocardial inflammatory injury process and underlying mechanisms associated with ICIs.

We conducted a descriptive analysis of lung cancer patients with ICIs-induced myocarditis at our institution and validated our clinical findings using single-cell sequencing (scRNA-seq) data. Furthermore, we established animal and cellular models to investigate the underlying mechanisms.

Our findings revealed that lung cancer patients with ICIs-induced myocarditis exhibit an early increase in peripheral blood monocytes, which migrate to the heart and differentiate into macrophages, ultimately leading to myocardial inflammation. Mechanistically, programmed death-1 (PD-1) inhibition triggers myocardial inflammation through the activation of the signal transducer and activator of transcription 1 (STAT1)/nuclear factor kappa-B (NF-κB)/oligomerization domain (NOD)-like receptor thermal protein domain-associated protein 3 (NLRP3) signaling pathway and drives the polarization of macrophages towards the M1 phenotype. However, the ubiquitin (Ub)-autophagy pathway degrades NLRP3 inflammasomes, resulting in the gradual resolution of inflammation and the transition of M1 macrophages to the M2 phenotype. Finally, mouse experiments confirmed that NLRP3 inhibition using MCC950 effectively alleviates myocardial inflammatory injury.

We recommend monitoring fluctuations in peripheral blood monocyte counts in lung cancer patients undergoing ICIs treatment. Additionally, MCC950 holds potential as a therapeutic agent for ICIs-induced cardiac inflammation injury.

Immune checkpoint inhibitor-induced colitis (irColitis) is a common and severe adverse reaction to immune checkpoint inhibitors (ICIs), significantly impacting the treatment outcomes and quality of life of cancer patients. Epidemiological studies indicate that the incidence of irColitis is associated with factors such as the type of ICIs, the patient's gender, age, and medical history. Although the exact pathophysiology remains unclear, irColitis is thought to be related to immune system activation and dysregulation, gut microbiota imbalance, and impaired epithelial barrier function. This review summarized the epidemiology, clinical presentation, diagnostic criteria, and pathogenesis of irColitis. Additionally, the standard and novel therapeutic strategies of irColitis, including corticosteroids, biologics, and gut microbiota interventions, more importantly the potential and application of Traditional Chinese Medicine (TCM). Future researches call for deeper mechanistic investigations, the development of biomarkers, and reveal the integration of TCM therapies within individual immunotherapy frameworks.

This is a rare case of nivolumab-induced multiorgan toxicity presenting as concurrent myocarditis and interstitial pneumonia in an 81-year-old patient with metastatic renal cell carcinoma. Immune checkpoint inhibitor (ICI)-associated myocarditis, a high-mortality immune-related adverse event (irAE), often presents with nonspecific symptoms, complicating early diagnosis, particularly when coexisting with other irAEs. In this case, the diagnosis was supported by elevated cardiac biomarkers, multimodal imaging findings (echocardiography, cardiac MRI, and coronary CT angiography), and electrocardiogram (ECG) abnormalities, including new-onset atrial fibrillation and right bundle branch block, indicative of myocardial involvement. High-dose methylprednisolone (1 g/day) was initiated on the second hospital day, followed by a gradual tapering regimen based on troponin trends and clinical improvement, leading to the resolution of myocarditis. This case underscores the importance of early recognition of ECG abnormalities as a diagnostic clue and highlights the diagnostic challenges of distinguishing myocarditis from other irAEs in patients receiving ICIs.

Corticosteroid is effective in alleviating immune-related adverse events (irAEs) of immune checkpoint blockade (ICB). However, prophylactic use of corticosteroid to prevent irAEs is not recommended due to a looming concern that it may attenuate anti-tumor effect of ICB. This study aims to investigate whether corticosteroid premedication may compromise anti-tumor efficacy of dual ICB, a regimen that may cause significant irAEs.

Orthotopic BNL 1MEA.7R.1 and subcutaneous Hepa1-6 syngeneic hepatocellular carcinoma (HCC) models were used. Low-dose (LD; 10 µg) or high-dose (HD; 200 µg) dexamethasone (Dexa) was intraperitoneally administered before each dose of anti-CTLA-4 and anti-PD-1. Tumor shrinkage, T cell priming, cytokine quantitation, as well as cytotoxicity and single-cell RNA-sequencing (scRNA-seq) of tumor-infiltrating T cells were assessed.

In the orthotopic model, dual immune checkpoint blockade (dICB) plus phosphate buffered saline (PBS) significantly reduced the mean tumor weight (adjusted for SE) (0.73±0.18 g vs 2.45±0.54 g; p=0.03), while neither LD nor HD Dexa premedication affected dICB-induced tumor shrinkage. In the subcutaneous model, dICB plus PBS or LD Dexa yielded a complete tumor response (CR) rate of 100%, while dICB plus HD Dexa yielded a CR rate of 85.7% (p>0.05, comparing to dICB plus PBS). ScRNA-seq analysis demonstrates that Dexa did not affect dICB-induced reduction of major clusters of exhausted CD4+ and CD8+ T cells but halved dICB-induced expansion of effector memory CD8+ T cells. Nevertheless, Dexa premedication, regardless of dosage, did not diminish dICB-induced T cell priming, cytokine production, or cytotoxicity of tumor-infiltrating CD8+ T cells.

Corticosteroid premedication does not significantly compromise anti-tumor efficacy of dICB treatment in murine HCC models. These results suggest that clinical investigations of prophylactic corticosteroids to alleviate severe irAEs may be feasible.

Chemoimmunotherapy is the primary treatment approach for non-small cell lung cancer (NSCLC); however, it is associated with immune-related adverse events (irAEs). Corticosteroids can control irAEs through their anti-inflammatory and immunosuppressive effects. Dexamethasone (DEX) is a potent corticosteroid commonly used to prevent chemotherapy-induced nausea and vomiting (CINV). This study aimed to the association of corticosteroids used to alleviate CINV and irAE occurrence.

This retrospective study included patients with NSCLC who underwent chemoimmunotherapy across eight hospitals. Cases lacking aprepitant use were excluded. All corticosteroids for CINV were standardized to intravenous DEX doses, and cutoff values were calculated using receiver operating characteristic curve analysis. Logistic regression analysis was performed to investigate irAE risk factors.

The cutoff value for DEX was 15.9 mg (area under the curve, 0.58; 95% confidence interval, 0.45-0.70; sensitivity, 0.63; specificity, 0.61), with 99 and 76 patients in the DEX < 15.9 and ≥ 15.9 mg groups, respectively. Patients in the DEX < 15.9 mg group had a significantly higher incidence of irAE than patients in the DEX ≥ 15.9 mg group (P = 0.03). Multivariate analysis identified that DEX < 15.9 mg was a risk factor for irAEs (P = 0.04; odds ratio: 2.51; 95% confidence interval, 1.03-6.09).

Corticosteroids with DEX equivalent doses of < 15.9 mg in combination with aprepitant for CINV may elevate the risk of irAEs. Therefore, diligent monitoring for irAEs occurrence is warranted in regimens utilizing DEX-equivalent corticosteroid doses of < 15.9 mg combined with aprepitant for CINV prevention.

Tislelizumab is a monoclonal antibody with high binding affinity for programmed death-1 (PD-1) receptors. In patients with extensive-stage small-cell lung cancer (ES-SCLC), the first-line use of tislelizumab combined with chemotherapy has shown significant efficacy. However, with the widespread use of PD-1 inhibitors, there are increasing reports of immune-related adverse events (irAEs) in clinical practice, with immune-related hepatitis (IRH) being particularly common. This article reports a case of an ES-SCLC patient (cT3N3M0 cStage IIIB) who developed corticosteroid-resistant hepatitis and recovered through dual immunosuppressant therapy. The patient was a 67-year-old male, diagnosed with ES-SCLC, who received a combination therapy of etoposide, cisplatin, and tislelizumab. Three weeks after the fourth treatment cycle, the patient experienced symptoms, such as decreased appetite, itching, yellow urine, and jaundice, and was diagnosed with IRH, manifested as "Grade 3 total bilirubin increase," "Grade 3 alanine transaminase increase," and "Grade 3 aspartate transaminase increase." Despite intravenous injection of methylprednisolone (MP) 100 mg/day (2 mg/kg) and oral administration of mycophenolate mofetil (MMF) 1 g twice daily, liver function continued to be impaired. In this context, tacrolimus (TAC) (5 mg, twice daily) was added to the therapy, and the IRH level was reduced from Grade 3 to normal. Subsequently, TAC and MMF were gradually reduced and eventually discontinued. Unfortunately, after discontinuing immunosuppressants, IRH recurred. Although the patient still responded to TAC combined with MMF, liver function recovery took a longer time. Due to persistent liver dysfunction, the patient failed to receive second-line chemotherapy and ultimately passed away due to disease progression. Through this case, we hope to emphasize the importance of reasonably extending the use of immunosuppressants to avoid the recurrence of IRH and reduce the premature discontinuation of immunosuppressants. Besides, when tumor progression and IRH recurrence occur simultaneously, providing effective immunosuppressive therapy and reasonably arranging systemic anti-tumor therapy may bring clinical benefits to patients.

This study aimed to elaborate on the incidence, clinical features, and management of immune checkpoint inhibitors (ICIs) related cardiovascular adverse events (CVAEs) in real-world practice.

We performed a retrospective chart review study on patients receiving at least one dose of ICI therapy at a Chinese tertiary hospital from March 2020 to March 2021. CVAEs were identified through clinical assessment and the Naranjo algorithm. The management and outcomes of CVAEs were monitored over a median follow-up duration of 8 months.

Among the included 203 patients, 4.4% (9/203) developed CVAEs, including heart failure (n = 3), arrhythmia (n = 2), myocarditis (n = 2), and pericardial disease (n = 2), with a proportion (6/9) tending to be severe (grade 3 or grade 4). CVAEs were more common in older patients (mean age: 73.6 ± 9.2 years) and those with hypertension (p = 0.02) or heart failure (p = 0.01). Adherence to the American Society of Clinical Oncology (ASCO) guidelines for managing CVAEs was low (44%), with most cases showing partial resolution by the last follow-up.

We reported that the incidence of ICI-related CVAEs in the Chinese institution was higher than that in some prior studies. Adherence to guidelines for managing ICI-related CVAEs is found to be suboptimal in real-world practice and highlighted as a needed improvement.

Tumor metastasis is a phenomenon in which tumor cells grow in distant organs far from their primary site and is the final and most lethal manifestation of cancer. Most patients with cancer succumb to metastatic disease, not primary tumors. The occurrence of cardiac metastases is rare, but any primary tumor can potentially metastasize to the heart. The present report describes a 71-year-old male with stage IV lung squamous cell carcinoma who was diagnosed with cardiac metastases. These were identified as pedicled structures in the left atrium and left ventricle via echocardiography and positron emission tomography/computed tomography (PET/CT) prior to curative therapy. PET/CT imaging confirmed increased uptake of the tracer in these regions, indicating malignancy. Given the high expression of programmed cell death-ligand 1, the patient was treated with sintilimab immunotherapy. Despite a transient increase in liver function markers during treatment, the patient completed eight cycles of immunotherapy. Notably, both the primary lung tumor and cardiac metastases were markedly reduced in size, indicating a positive therapeutic response. The present case underscores the potential efficacy of immunotherapy in the management of cardiac metastases originating from lung cancer.

Immune checkpoint inhibitors (ICIs) have shown remarkable efficacy against various cancers in clinical practice. However, ICIs can cause immune checkpoint inhibitor-associated pancreatic injury, often leading to drug withdrawal, and then patients must go to specialized treatment. The patients, their primary tumors are sensitive to ICIs therapy, may experience treatment delays due to such adverse reactions. Therefore, there is a need for systematic clinical researches on immune-related pancreatic toxicity to provide a clinical basis for its prevention and treatment.

This study involved the collection of data from patients treated with ICIs and addressed pancreatic injury with preemptive treatment before continuing ICIs therapy. Then, we also statistically analyzed the incidence of pancreatic injury in patients with different courses and combined treatment, and the success rate of rechallenge treatment.

The study included 62 patients, with 33.9% (21/62) experiencing varying degrees of pancreatic injury. Patients with pancreatic injury, 10 cases evolved into pancreatitis, representing 47.6% (10/21) in the pancreatic injury subgroup and 16.1% (10/62) of the total patient cohort. Preemptive treatment was administered to 47.6% (10/21) of patients with pancreatitis, the effective rate was 100%. Among these patients, 70% (7/10) underwent successful rechallenge with ICIs. The occurrence of pancreatic injury was positively correlated with the treatment duration (P < 0.05) but showed no significant correlation with combination therapies (P > 0.05).

The likelihood of pancreatic injury increased with longer treatment durations with ICIs; no significant association was found between the incidence of ICIs-related pancreatic damage and combination therapies. Preemptive treatment for immune-related pancreatitis is feasible, allowing some patients to successfully undergo rechallenge with ICIs therapy.

Immune checkpoint inhibitors (ICI) represent new anticancer agents and have been used worldwide. However, ICI can potentially induce life-threatening severe cutaneous adverse reaction (SCAR), such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), hindering continuous ICI therapy. We examine 6 cohorts including 25 ICI-induced SJS/TEN patients and conduct single-cell RNA sequencing (scRNA-seq) analysis, which shows overexpression of macrophage-derived CXCL10 that recruits CXCR3+ cytotoxic T lymphocytes (CTL) in blister cells from ICI-SJS/TEN skin lesions. ScRNA expression profiles and ex vivo blocking studies further identify TNF signaling as a pathway responsible for macrophage-derived CXCL10 and CTL activation. Based on the trajectory analysis, ICI-activated T cells from whole blood are proposed to serve as the initial cells involved in inflammation, that lead to monocytes differentiating into macrophages and increasing their susceptibility to migrate to the lesion sites. Compared with systemic corticosteroids treatment, ICI-induced SJS/TEN patients treated with biologic TNF blockade showed a significantly rapid recovery and no recurrence of SCAR with continuous ICI therapy. Our findings identify that macrophage-eliciting CTL contribute to the pathogenesis of ICI-induced epidermal necrolysis and provide potential therapeutic targets for the management and prevention of SCAR induced by ICI therapy.

Immunology-based therapies are emerging as an effective cancer treatment, using the body's immune system to target tumors. Immune checkpoints, which regulate immune responses to prevent tissue damage and autoimmunity, are often exploited by cancer cells to avoid destruction. The discovery of checkpoint proteins like PD-1/PD-L1 and CTLA-4 was pivotal in developing cancer immunotherapy. Immune checkpoint inhibitors (ICIs) have shown great success, with FDA-approved drugs like PD-1 inhibitors (Nivolumab, Pembrolizumab, Cemiplimab), PD-L1 inhibitors (Atezolizumab, Durvalumab, Avelumab), and CTLA-4 inhibitors (Ipilimumab, Tremelimumab), alongside LAG-3 inhibitor Relatlimab. Research continues on new checkpoints like TIM-3, VISTA, B7-H3, BTLA, and TIGIT. Biomarkers like PDL-1 expression, tumor mutation burden, interferon-γ presence, microbiome composition, and extracellular matrix characteristics play a crucial role in predicting responses to immunotherapy with checkpoint inhibitors. Despite their effectiveness, not all patients experience the same level of benefit, and organ-specific immune-related adverse events (irAEs) such as rash or itching, colitis, diarrhea, hyperthyroidism, and hypothyroidism may occur. Given the rapid advancements in this field and the variability in patient outcomes, there is an urgent need for a comprehensive review that consolidates the latest findings on immune checkpoint inhibitors, covering their clinical status, biomarkers, resistance mechanisms, strategies to overcome resistance, and associated adverse effects. This review aims to fill this gap by providing an analysis of the current clinical status of ICIs, emerging biomarkers, mechanisms of resistance, strategies to enhance therapeutic efficacy, and assessment of adverse effects. This review is crucial to furthering our understanding of ICIs and optimizing their application in cancer therapy.

Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy, but their use is limited by the development of autoimmunity in healthy tissues as a side effect of treatment. Such immune-related adverse events (IrAE) contribute to hospitalizations, cancer treatment interruption and even premature death. ICI-induced autoimmune diabetes mellitus (ICI-T1DM) is a life-threatening IrAE that presents with rapid pancreatic beta-islet cell destruction leading to hyperglycemia and life-long insulin dependence. While prior reports have focused on CD8+ T cells, the role for CD4+ T cells in ICI-T1DM is less understood. Here, we identify expansion CD4+ T follicular helper (Tfh) cells expressing interleukin 21 (IL-21) and interferon gamma (IFNG) as a hallmark of ICI-T1DM. Furthermore, we show that both IL-21 and IFNG are critical cytokines for autoimmune attack in ICI-T1DM. Because IL-21 and IFNG both signal through JAK-STAT pathways, we reasoned that JAK inhibitors (JAKi) may protect against ICI-T1DM. Indeed, JAKi provide robust in vivo protection against ICI-T1DM in a mouse model that is associated with decreased islet-infiltrating Tfh cells. Moreover, JAKi therapy impaired Tfh cell differentiation in patients with ICI-T1DM. These studies highlight CD4+ Tfh cells as underrecognized but critical mediators of ICI-T1DM that may be targeted with JAKi to prevent this grave IrAE.

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.

In this editorial, we explore the impact of immunotherapy and its safety in patients with advanced gastric cancer (GC) and liver involvement. GC, a formidable adversary in the oncology landscape, presents its most challenging battlefront when it reaches stage IV, often characterized by liver metastases. The prognosis for patients at this advanced stage is daunting, with systemic chemotherapy traditionally offering a median overall survival slightly over a year. However, the landscape of treatment is evolving, with new strategies and therapies offering a glimmer of hope.

Immune checkpoint inhibitor-related pneumonitis (CIP) stands out as a particularly severe adverse event caused by immune checkpoint inhibitors, with a substantial real-world incidence ranging from 13 to 19%. While systemic corticosteroids represent the standard treatment for CIP, therapeutic options become limited in cases where patients do not respond to corticosteroid therapy. Such patients are classified as having steroid-resistant CIP, often associated with a poor prognosis. This case study provides insight into the symptoms, diagnostic process, and treatment approach for steroid-resistant CIP. Notably, successful management is demonstrated through the utilization of cyclosporine, highlighting its potential mechanisms of action in effectively treating steroid-resistant CIP.

We present the case of a 53-year-old male with stage IV. A non-small cell lung cancer (NSCLC), who experienced elevated fever, cough, and dyspnea subsequent to immunotherapy treatment. Based on his medical history, clinical manifestations, and radiological findings, the patient was diagnosed with CIP. Initial administration of led to improvement, but during the subsequent tapering of corticosteroid therapy, a resurgence of CIP occurred, resulting in respiratory failure. Consequently, we arrived at the diagnosis of steroid-resistant CIP, prompting the implementation of a combination therapy with cyclosporine and corticosteroids to establish stable disease control. Upon systematic reduction of corticosteroid dosage, the patient maintained a favorable response with no recurrence.

This marks the first instance of effectively managing steroid-resistant CIP through the combined use of cyclosporine and corticosteroids. Presently, cases of steroid-resistant CIP remain infrequent, necessitating vigilant and meticulous monitoring within clinical settings. Notably, there exists no distinct guideline specifying a singular agent for rescuing patients unresponsive to corticosteroid therapy. Therefore, cyclosporine emerges as a promising and efficacious treatment alternative for individuals unresponsive to corticosteroid intervention in the context of CIP.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of patients with relapsed or refractory hematologic malignancies, but it comes with unique toxicities, notably cytokine release syndrome and ICANS (immune effector cell-associated neurotoxicity syndrome). As experience with CAR T-cell therapy grows, distinct and infrequent neurologic complications are becoming increasingly evident. Recently, reports of acute myelopathy after the administration of CAR T-cell therapies have been accumulating. Despite the establishment of consensus guidelines for managing ICANS, there remains limited guidance on the appropriate investigations and treatments for this rare complication. In this manuscript, we delve into the clinical features, pathophysiology, and strategies for the optimal management of acute myelitis after CAR T-cell therapy and draw insights from reported cases in the literature.

Drug-induced liver injury (DILI) is a major concern for oncology drugs in clinical practice and under development. Monitoring cancer patients for hepatotoxicity is challenging as these patients may have abnormal liver tests pre-treatment or on-study for many reasons including liver injury due to past oncology treatments, hepatic metastases, medical co-morbidities such as heart failure, and concomitant medications. At present, there are no regulatory guidelines or position papers that systematically address best practices pertaining to DILI detection, assessment and management in oncology patients.

The goals of this review are (1) to examine and interpret the available evidence and (2) to make recommendations for detection, monitoring, adjudication, and management of suspected hepatocellular DILI during oncology clinical trials.

This manuscript was developed by the IQ Consortium (International Consortium for Innovation and Quality in pharmaceutical development) DILI Initiative that consists of members from 17 pharmaceutical companies, in collaboration with academic and regulatory DILI experts. The manuscript is based on extensive literature review, expert interpretation of the literature, and several rounds of consensus discussions.

This review highlights recommendations for patient eligibility for clinical trials with or without primary/metastatic liver involvement, as well as changes in liver tests that should trigger increased monitoring and/or discontinuation of study drug. Guidance regarding causality assessment for suspected DILI events, rechallenge and dose-modification is provided.

This review brings together evidence-based recommendations and expert opinion to provide the first dedicated consensus for best practices in detection, assessment, and management of DILI in oncology clinical trials.

Immune checkpoint inhibitors (ICIs), including anti-programmed cell death protein 1 and its ligand (PD-1/PD-L1) as well as anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4), have been widely used for treating solid tumors. Myocarditis is a potentially lethal immune-related adverse events (irAEs) caused by ICIs therapy. The treatment of steroid-refractory myocarditis is challenging. We reported two non-small-cell lung cancer patients with steroid-refractory myocarditis induced by ICI. The symptoms were not resolved after pulse corticosteroid therapy and subsequent treatment including intravenous immunoglobulin and mycophenolate mofetil. Considering the level of serum interleukin (IL)-6 decreased by > 50% and level of serum tumor necrosis factor-α (TNF-α) increased during the course of the disease, infliximab was used. Myocarditis gradually alleviated after infliximab treatment. The cases revealed that specific cytokine inhibitors have promising roles in the treatment of steroid-refractory myocarditis. Infliximab could be considered for patients with low level of IL-6 and elevated level of TNF-α.

With the successive development of chemotherapy drugs, good results have been achieved in clinical application. However, myocardial toxicity is the biggest challenge. Anthracyclines, immune checkpoint inhibitors, and platinum drugs are widely used. Targeted drug delivery, nanomaterials and dynamic imaging evaluation are all emerging research directions. This article reviews the recent literature on the use of targeted nanodrug delivery and imaging techniques to evaluate the myocardial toxicity of antineoplastic drugs, and discusses the potential mechanisms.

Chimeric antigen receptor (CAR) T-cell therapy (CART) has transformed the treatment landscape of hematologic cancer, but has negligible effects for adult solid cancers. In this trial, an autologous CAR T-cell product demonstrated antitumor activity in heavily pretreated patients with metastatic colorectal cancer (mCRC).

To evaluate the safety and efficacy of guanylate cyclase-C (GCC19) CART in participants with metastatic colorectal cancer (mCRC).

This single-arm, nonrandomized, phase 1 trial was conducted at the First Hospital of Jilin University from December 3, 2020, to April 13, 2022. Data analysis was conducted from May 2022 to April 2024. Adults with relapsed and refractory mCRC expressing GCC were treated with GCC19CART, a mixture of autologous CAR T cells transduced with lentiviral vectors expressing genes that encode either CD-19 CAR or GCC CAR.

Safety and tolerability of CAR T-cell therapy targeting GCC in patients with mCRC without therapeutic options is capable of conferring a reasonable likeliness of clinical benefit. Other outcomes included objective response rate, progression-free survival, overall survival, and immune activation.

Of 15 patients 9 (60%) were women, and the median (range) age was 44 (33-61) years. Treatment with GCC19CART was associated with the development of cytokine release syndrome and diarrhea in most patients, all of which were self-limited and manageable. The objective response rate was 40%, with a partial response in 2 of 8 and 4 of 7 patients treated with either 1 × 106 cells/kg or 2 × 106 cells/kg. Median overall survival was 22.8 months (95% CI, 13.4-26.1) at data cutoff; the median progress-free survival was 6.0 months in the high dose level group (95% CI, 3.0 to not available).

The results of this nonrandomized clinical trial suggest that GCC19CART was safe and tolerable in heavily pretreated patients with mCRC and is the first CAR T-cell therapy known to produce objective clinical activity in refractory cancer. Given the paucity of effective therapeutics developed for colorectal cancer in recent decades, the observation that CD-19 CART target engagement can robustly induce GCC19CART target engagement sufficient to produce objective activity may serve as a foundation to develop effective cellular therapy in mCRC and other solid cancers.

Chinese Clinical Trial Registry: ChiCTR2000040645.