OBJECTIVE: Immune checkpoint inhibitors (ICIs) have improved lung cancer prognosis; however, ICI-related interstitial lung disease (ILD) is fatal and difficult to predict. Herein, we hypothesized that pre-existing lung inflammation on radiological imaging can be a potential risk factor for ILD onset. Therefore, we investigated the association between high uptake in noncancerous lung (NCL) on 18F- FDG-PET/CT and ICI-ILD in lung cancer.
METHODS: Patients with primary lung cancer who underwent FDG-PET/CT within three months prior to ICI therapy were retrospectively included. Artificial intelligence was utilized for extracting the NCL regions (background lung) from the lung contralateral to the primary tumor. FDG uptake by the NCL was assessed via the SUVmax (NCL-SUVmax), SUVmean (NCL-SUVmean), and total glycolytic activity (NCL-TGA)defined as NCL-SUVmean×NCL volume [mL]. NCL-SUVmean and NCL-TGA were calculated using the following four SUV thresholds: 0.5, 1.0, 1.5, and 2.0.
RESULTS: Of the 165 patients, 28 (17.0%) developed ILD. Univariate analysis showed that high values of NCL-SUVmax, NCL-SUVmean2.0 (SUV threshold=2.0), and NCL-TGA1.0 (SUV threshold=1.0) were significantly associated with ILD onset (all p = 0.003). Multivariate analysis adjusted for age, tumor FDG uptake, and pre-existing interstitial lung abnormalities revealed that a high NCL-TGA1.0 (≥149.45) was independently associated with ILD onset (odds ratio, 6.588; p = 0.002). Two-year cumulative incidence of ILD was significantly higher in the high NCL-TGA1.0 group than in the low group (58.4% vs. 14.4%; p < 0.001).
CONCLUSIONS: High uptake of NCL on FDG-PET/CT is correlated with ICI-ILD development, which could serve as a risk stratification tool before ICI therapy in primary lung cancer.

BACKGROUND: Cytokine release syndrome (CRS) is an acute systemic inflammatory syndrome characterized by fever and multiple organ failure, which is triggered by immunotherapy or certain infections. Immune checkpoint inhibitors rarely cause immune-related adverse event- cytokine release syndrome (irAE-CRS). This article presents a case report of irAE-CRS triggered by coronavirus disease 2019 (COVID-19).
METHODS: A 60-year-old man with type 2 diabetes received nivolumab treatment for esophagogastric junction carcinoma and experienced two immune-related adverse events: hypothyroidism and skin disorder. Eleven days before his visit to our hospital, he had a fever and was diagnosed with COVID-19. Five days before his visit, he developed a fever again, along with general malaise, water soluble diarrhea, and myalgia of the extremities. On admission, the patient was in a state of multiple organ failure, and although the source of infection was unknown, a tentative diagnosis of septic shock was made. The patient\'s condition was unstable despite systemic management with antimicrobial agents, high-dose vasopressors, and intravenous fluids. We suspected CRS due to irAE (irAE-CRS) based on his history of nivolumab use. Steroid pulse therapy (methylprednisolone 1 g/day) was started, and the patient temporarily recovered. However, his respiratory condition worsened; consequently, he was placed on a ventilator and tocilizumab was added to the treatment. His muscle strength recovered to the point where he could live at home, and was subsequently discharged.
CONCLUSIONS: In patients previously treated with immune checkpoint inhibitors, irAE-CRS should be considered as a differential diagnosis when multiple organ damage is observed in addition to inflammatory findings. It is recommended to start treatment with steroids; if the disease is refractory, other immunosuppressive therapies such as tocilizumab should be introduced as early as possible.

BACKGROUND: In metastatic clear cell renal cell carcinoma (ccRCC), recent studies have shown promising efficacy of immune checkpoint inhibitor (ICI) combination therapy. However, there are insufficient evidences about clinical efficacy and safety of ICI combination therapy in metastatic non-ccRCC (nccRCC).
METHODS: We retrospectively investigated 44 patients treated with nivolumab plus ipilimumab (ICI + ICI group) or anti-PD-1/PD-L1 inhibitor plus tyrosine kinase inhibitors (TKI) (ICI + TKI group), and assessed clinical efficacy in both groups.
RESULTS: Of all patients, overall response rate and disease control rate for ICI combination treatments were 36.3% and 75%, respectively. The median progression-free survival (PFS) and overall survival (OS) was 8.8 and 23.9 months, respectively. Multivariate analysis revealed that the presence of liver metastasis significantly affected worse PFS and OS (p = 0.035 and p = 0.049). Importantly, PFS and OS seemed similar in ICI + ICI group and ICI + TKI group (p = 0.778 and p = 0.559). Although the discontinuation rate of the combination therapy due to adverse effects in patients aged ≥ 75 years was significantly higher compared to that in patients aged < 75 years (45% versus 12%, p = 0.017), there were no significant differences in PFS and OS between two groups (p = 0.290 and p = 0.257, respectively).
CONCLUSIONS: This study confirms clinical benefit of ICI combination therapy for metastatic nccRCC patients in real-world settings. Furthermore, the effectiveness of combination therapy was comparable between patients aged < 75 and those ≥75 years with respect to clinical prognosis.

Immune checkpoint inhibitors (ICIs), such as pembrolizumab, have transformed immuno-oncology by demonstrating efficacy against various cancers, including small-cell lung carcinoma and HER2-positive gastric cancer. Despite their benefits, ICIs can provoke immune-related adverse events, with endocrinopathies being rare but carrying significant complications. We report a case of pembrolizumab-induced diabetic ketoacidosis (DKA) in an 87-year-old woman with advanced gastric carcinoma and no prior diabetes history. The patient presented with acute hyperglycemia and metabolic acidosis and was found to have low C-peptide levels without other autoimmune markers typically associated with type 1 diabetes. This case highlights the need for awareness of pembrolizumab as a potential trigger for DKA, especially in patients without a prior diabetes diagnosis. While the management of DKA remains the same, identifying the precipitating factor allows for a comprehensive diagnostic workup and effective long-term management, maintaining the patient\'s quality of life. This case highlights the complexities of managing DKA in ICI therapy and illustrates the importance of distinguishing between classical DKA presentations and those related to ICIs.

A 73-year-old man with lung squamous cell carcinoma was administered carboplatin + nab-paclitaxel + pembrolizumab for four cycles. Subsequently, he presented with multiple purpuras on his extremities, joint swelling on his fingers, abdominal pain, and diarrhea, accompanied by acute kidney injury (AKI), increased proteinuria, hematuria, and elevated C-reactive protein levels. Skin biopsy showed leukocytoclastic vasculitis as well as IgA and C3 deposition in the vessel walls. Based on these findings, the patient was diagnosed with IgA vasculitis as an immune-related adverse event (irAE) induced by carboplatin + nab-paclitaxel + pembrolizumab. After discontinuation of pembrolizumab and glucocorticoids, the symptoms immediately resolved. Regular monitoring of skin, blood tests, and urinalysis are necessary, and the possibility of irAE IgA vasculitis should be considered in cases of purpura and AKI during treatment with immune checkpoint inhibitors.

Primary clinicians foster long-term relationships with patients and play key roles in the treatment journey for patients with cancer. Primary clinicians are important members of the multidisciplinary team, and are central in coordinating and providing supportive care. The use of immune checkpoint inhibitors in adjuvant/neoadjuvant treatments and metastatic disease requires an awareness of their long-term survival benefits and immune-related adverse events (irAEs). Primary clinicians collaborate with the oncology care team to increase irAE awareness and identify institutional and individualized approaches to manage irAEs. IrAEs can develop at any time and present with a spectrum of symptoms, making them difficult to differentiate from other conditions. IrAE management relies on early recognition, close monitoring, and intervention with corticosteroids and/or dose interruption. Delayed irAEs underscore the importance of continued clinical vigilance following treatment, as primary clinicians are patients\' most enduring point of contact. Primary clinicians have a critical role in supporting the care of patients with cancer and ensuring appropriate irAE recognition, monitoring, and intervention. Long-term continuity of care is critical for the immuno-oncology patient journey.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, lifethreatening hyperinflammatory disorder characterized by dysfunction of NK cells and cytotoxic lymphocytes. We present a rare case of a patient diagnosed with HLH who presented with persistent fever during treatment for refractory T-cell/histiocyte-rich large B-cell lymphoma (TCHRLBCL), highlighting the challenges of managing HLH in the context of refractory lymphoma. According to our review of the literature, this is the first case of HLH that developed several months into treatment for refractory TCHRLBCL and not in close temporal relation to lymphoma diagnosis.
Hemofagocitna limfohistiocitoza (HLH) je redak, životno ugrožavajući poremećaj koji se karakteriše disfunkcijom NK ćelija i citotoksičnih limfocita. Prikazujemo redak slučaj pacijenta sa dijagnozom HLH sa tegobama u vidu perzistentne temperature u toku lečenja refraktarnog \"T-cell/histiocyte-rich\" difuznog B-ćelijskog limfoma (TCHRBCL), izdvajajući izazove u lečenju ovakvog profila pacijenta. Uz osvrt na naš pregled literature, ovo je prvi opisan slučaj HLH koji se javio nekoliko meseci nakon početka lečenja TCHRBCL, a ne u uskoj vremenskoj korelaciji sa dijagnozom limfoma.

Background: There is an unmet medical need for the early detection of immune checkpoint inhibitor (ICI)-induced cardiovascular (CV) adverse events due to a lack of adequate biomarkers. This study aimed to provide insights on the incidence of troponin elevations and echocardiographic dynamics during ICI treatment in cancer patients and their role as potential biomarkers for submyocardial damage. In addition, it is the first study to compare hs-TnT and hs-TnI in ICI-treated patients and to evaluate their interchangeability in the context of screening. Results: Among 59 patients, the mean patient age was 68 years, and 76% were men. Overall, 25% of patients received combination therapy. Although 10.6% [95% CI: 5.0-22.5] of the patients developed troponin elevations, none experienced a CV event. No significant changes were found in 3D left ventricular (LV) ejection fraction nor in global longitudinal strain f (56 ± 6% vs. 56 ± 6%, p = 0.903 and -17.8% [-18.5; -14.2] vs. -17.0% [-18.8; -15.1], p = 0.663) at 3 months. There were also no significant changes in diastolic function and right ventricular function. In addition, there was poor agreement between hs-TnT and hs-TnI. Methods: Here, we present a preliminary analysis of the first 59 patients included in our ongoing prospective clinical trial (NCT05699915) during the first three months of treatment. All patients underwent electrocardiography and echocardiography along with blood sampling at standardized time intervals. This study aimed to investigate the incidence of elevated hs-TnT levels within the first three months of ICI treatment. Elevations were defined as hs-TnT above the upper limit of normal (ULN) if the baseline value was normal, or 1.5 ≥ times baseline if the baseline value was above the ULN. Conclusions: Hs-TnT elevations occurred in 10.6% of the patients. However, no significant changes were found on 3D echocardiography, nor did any of the patients develop a CV event. There were also no changes found in NT-proBNP. The study is still ongoing, but these preliminary findings do not show a promising role for cardiac troponins nor for echocardiographic dynamics in the prediction of CV events during the early stages of ICI treatment.

Immunotherapy has revolutionized oncology care, improving patient outcomes in several cancers. However, these therapies are also associated with typical immune-related adverse events due to the enhanced inflammatory and immune response. These toxicities can arise at any time during treatment but are more frequent within the first few months. Any organ and tissue can be affected, ranging from mild to life-threatening. While some manifestations are common and more often mild, such as dermatitis and colitis, others are rarer and more severe, such as myocarditis. Management depends on the severity, with treatment being held for >grade 2 toxicities. Steroids are used in more severe cases, and immunosuppressive treatment may be considered for non-responsive toxicities, along with specific organ support. A multidisciplinary approach is mandatory for prompt identification and management. The diagnosis is primarily of exclusion. It often relies on imaging features, and, when possible, cytologic and/or pathological analyses are performed for confirmation. In case of clinical suspicion, imaging is required to assess the presence, extent, and features of abnormalities and to evoke and rule out differential diagnoses. This imaging-based review illustrates the diverse system-specific toxicities associated with immune checkpoint inhibitors and chimeric antigen receptor T-cells with a multidisciplinary perspective. Clinical characteristics, imaging features, cytological and histological patterns, as well as the management approach, are presented with insights into radiological tips to distinguish these toxicities from the most important differential diagnoses and mimickers-including tumor progression, pseudoprogression, inflammation, and infection-to guide imaging and clinical specialists in the pathway of diagnosing immune-related adverse events.

Isolated adrenocorticotropic hormone (ACTH) deficiency is a rare condition characterized by the sole impairment of ACTH secretion among the various hormones produced by the pituitary gland. This leads to secondary hypoadrenocorticism, manifesting symptoms such as fatigue, anorexia, weight loss, and altered consciousness. Recently isolated ACTH deficiency has emerged as an immune-related adverse event (irAE) associated with immune checkpoint inhibitors (ICIs). In this report, we detail a case of isolated ACTH deficiency as a result of irAE. A 65-year-old man received nivolumab and ipilimumab combination therapy for esophageal cancer and approximately six weeks later, presented fatigue and anorexia, and was shown hyponatremia and hyperkalemia on blood test, and was diagnosed as isolated ACTH deficiency. Retrospective examination indicated an increase in eosinophils and a slight decrease in sodium levels shortly before thyrotoxicosis was diagnosed. These findings suggest the possibility of mild hypoadrenocorticism, potentially due to decreased ACTH secretion, existing prior to the recognition of adrenal insufficiency symptoms. Healthcare providers should maintain a heightened vigilance for eosinophilia and electrolyte imbalances during the administration of ICIs. The detection of even subtle abnormalities in these parameters should prompt immediate consultation with an endocrinologist.