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13 pages, 4712 KiB  
Article
Adsorptive Removal Behavior of Two Activated Carbons for Bis(2-ethylhexyl) Phosphate Dissolved in Water
by Lifeng Chen, Jing Tang, Zhuo Wang, Hongling Wang, Wannian Feng, Junjie Chen, Qingqing Yan, Shunyan Ning, Wenlong Li, Yuezhou Wei and Di Wu
Toxics 2025, 13(8), 624; https://doi.org/10.3390/toxics13080624 - 25 Jul 2025
Viewed by 278
Abstract
Bis(2-ethylhexyl) phosphate (P204) is widely used in extraction processes in the nuclear and rare earth industries. However, its high solubility in water results in high levels of total organic carbon and phosphorus in aqueous environments, and may also lead to radioactive contamination when [...] Read more.
Bis(2-ethylhexyl) phosphate (P204) is widely used in extraction processes in the nuclear and rare earth industries. However, its high solubility in water results in high levels of total organic carbon and phosphorus in aqueous environments, and may also lead to radioactive contamination when it is used to combine with radionuclides. In this paper, we characterized a coconut shell activated carbon (CSAC) and a coal-based activated carbon (CBAC) for the adsorption of P204 and then evaluated their adsorption performance through batch and column experiments. The results found that, except for the main carbon matrix, CSAC and CBAC carried rich oxygen-containing functional groups and a small amount of inorganic substances. Both adsorbents had porous structures with pore diameters less than 4 nm. CSAC and CBAC showed good removal performance for P204 under low pH conditions, with removal efficiencies significantly higher than those of commonly used adsorption resins (XAD-4 and IRA900). The adsorption kinetics of P204 conformed to the pseudo-second-order kinetic model, and the adsorption isotherms conformed to the Langmuir model, indicating a monolayer chemical reaction mechanism. Both adsorbents exhibited strong anti-interference capabilities; their adsorption performance for P204 did not change greatly with the ambient temperature or the concentrations of common interfering ions. Column experiments demonstrated that CSAC could effectively fix dissolved P204 with a removal efficiency exceeding 90%. The fixed P204 could be desorbed with acetone. The findings provide an effective method for the recovery of P204 and the regeneration of spent activated carbon, which shows promise for practical applications in the future. Full article
(This article belongs to the Section Toxicity Reduction and Environmental Remediation)
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22 pages, 1241 KiB  
Systematic Review
Safety and Efficacy of Immune Checkpoint Inhibitors in Human Immunodeficiency Virus-Associated Cancer: A Systematic Scoping Review
by Ahmed D. Alatawi, Amirah B. Alaqyl, Reema J. Alalawi, Rahaf S. Alqarni, Razan A. Sufyani, Ghadi S. Alqarni, Raghad S. Alqarni, Jumana H. Albalawi, Raghad A. Alsharif, Ghada I. Alatawi, Elaf N. Albalawi, Danah A. Alanazi, Sultanah A. Naitah, Reem Sayad and Helal F. Hetta
Diseases 2025, 13(8), 230; https://doi.org/10.3390/diseases13080230 - 22 Jul 2025
Viewed by 339
Abstract
Background/Objective: People living with human immunodeficiency virus (PHIV) are at increased risk for malignancies, yet their access to immunotherapy remains limited due to concerns about safety and efficacy. This systematic scoping review evaluates the use of immune checkpoint inhibitors (ICIs) in HIV-associated cancers, [...] Read more.
Background/Objective: People living with human immunodeficiency virus (PHIV) are at increased risk for malignancies, yet their access to immunotherapy remains limited due to concerns about safety and efficacy. This systematic scoping review evaluates the use of immune checkpoint inhibitors (ICIs) in HIV-associated cancers, analyzing patient outcomes, safety profiles, and the impact on HIV status. Methods: A comprehensive literature search was conducted in databases including PubMed, Scopus, Web of Science (WoS), and Medline, up to January 2025. Studies included assessing the efficacy of ICIs in cancer patients with HIV. The primary outcomes were (a) the efficacy of immune ICIs on prognosis, progression-free survival (PFS), and overall survival (OS). Secondary outcomes were the immune-related adverse events (irAEs) and the survival rate of cancer patients receiving ICIs. Results: A total of 107 cases from 19 studies published between 2011 and 2024 were reviewed. Responses to programmed death 1 (PD-1) inhibitors varied, with 27.1% achieving partial response, 23.36% experiencing stable disease, and 6.54% achieving complete response, while 34.57% had disease progression. Adverse events, including hematologic and endocrine toxicities, were common but mostly manageable. HIV viral loads remained stable in most cases. Conclusions: PD-1 inhibitors demonstrated potential efficacy in HIV-associated malignancies with a safety profile comparable to the general population. However, disease progression remained a concern, highlighting the need for optimized patient selection. Further well-controlled trials are essential to establish treatment guidelines and ensure equitable access to immunotherapy for PHIV. Full article
(This article belongs to the Special Issue Cancer Inhibitory Receptors and Related Cancer Immunotherapy)
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20 pages, 552 KiB  
Review
Sarcopenia in Urothelial Bladder Carcinoma: A Narrative Review
by Constantin Radu Vrabie, Andreea Ioana Parosanu and Cornelia Nitipir
Medicina 2025, 61(7), 1307; https://doi.org/10.3390/medicina61071307 - 20 Jul 2025
Viewed by 274
Abstract
Background and Objectives: Urothelial bladder carcinoma includes a spectrum of malignant lesions with heterogeneous molecular, biological, and clinical features and a variable risk of progression from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive disease (MIBC) and ultimately to metastatic urothelial carcinoma (mUC). Sarcopenia, [...] Read more.
Background and Objectives: Urothelial bladder carcinoma includes a spectrum of malignant lesions with heterogeneous molecular, biological, and clinical features and a variable risk of progression from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive disease (MIBC) and ultimately to metastatic urothelial carcinoma (mUC). Sarcopenia, a condition secondary to a catabolic state, is characterized by progressive loss of skeletal muscle mass and function and is highly prevalent across all stages of bladder cancer. This review aims to synthesize current evidence regarding the clinical impact of sarcopenia and its dynamic changes throughout the disease course. Materials and Methods: A narrative literature review was conducted using PubMed, Scopus, and Cochrane databases, incorporating the most relevant published sources. Search terms included “bladder carcinoma”, “sarcopenia”, “body composition”, “NMIBC”, and “MIBC”. Case reports and congress abstracts were excluded. Results: In NMIBC treated with intravesical Bacillus Calmette–Guérin (BCG), sarcopenia has been shown to have a negative predictive value in some studies. Among patients receiving neoadjuvant chemotherapy (NAC) for MIBC, sarcopenia has been associated with increased toxicity, dose reductions, and treatment delays. In the context of radical surgery, sarcopenia correlates with increased postoperative mortality and a higher rate of severe complications. In mUC, low muscle mass is a negative prognostic factor regardless of treatment type and is associated with chemotherapy-related hematologic toxicity, although it does not appear to predict immune-related adverse events (irAEs). Conclusions: Sarcopenia is a highly prevalent and clinically relevant phenotype of urothelial bladder cancer patients, impacting prognosis, treatment response, and chemotherapy toxicity. Incorporating sarcopenia with other relevant components of body composition (BC) and systemic inflammatory markers may facilitate the development of more robust risk scores. Current evidence is primarily limited by the retrospective design of most studies. Future prospective research is needed to clarify the prognostic role of sarcopenia and support its integration into routine clinical decision-making. Full article
(This article belongs to the Section Oncology)
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25 pages, 697 KiB  
Systematic Review
Comparative Meta-Analysis of Survival, Risk, and Treatment Efficacy in Immunotherapy for Metastatic Melanoma Using Random-, Fixed-, and Mixed-Effects Models
by Jelena Ivetić, Jovana Dedeić, Srđan Milićević, Katarina Vidojević and Marija Delić
J. Clin. Med. 2025, 14(14), 5017; https://doi.org/10.3390/jcm14145017 - 15 Jul 2025
Viewed by 296
Abstract
Background: Immune checkpoint inhibitors (ICIs) have reshaped the treatment landscape of metastatic melanoma. While combination regimens often demonstrate improved response and survival compared to monotherapy, they are also associated with a higher incidence of immune-related adverse events (irAEs). Understanding the balance between benefit [...] Read more.
Background: Immune checkpoint inhibitors (ICIs) have reshaped the treatment landscape of metastatic melanoma. While combination regimens often demonstrate improved response and survival compared to monotherapy, they are also associated with a higher incidence of immune-related adverse events (irAEs). Understanding the balance between benefit and risk is essential for making informed treatment decisions, especially given the variability in reported outcomes across clinical trials. Methods: We conducted a systematic review and meta-analysis of 14 clinical trials (comprising 22 treatment arms and >5000 patients) comparing ICI monotherapy (nivolumab, ipilimumab, or pembrolizumab) and combination therapy (nivolumab + ipilimumab) in advanced melanoma. Treatment-related outcomes were synthesized using fixed-effects, random-effects, or generalized linear mixed models (GLMMs), depending on study variability. Survival data were extracted from published Kaplan–Meier curves and analyzed using longitudinal GLMMs to capture trends over time. Results: Compared to monotherapy, combination immunotherapy achieved higher clinical benefit, with an overall response of 52.2% (vs. 31.6%), a five-year overall survival of 55.7% (vs. 34.3%), and a five-year progression-free survival of 39.0% (vs. 17.2%). However, this benefit came with a higher risk of toxicity: immune-related adverse events occurred in 93.2% of patients receiving combination therapy versus in 81.9% receiving monotherapy. Differences were consistent across all individual severe toxicities. Conclusions: Combination immunotherapy offers greater long-term clinical benefit than monotherapy in metastatic melanoma but at the cost of increased toxicity. By applying models adapted to study variability, we provide more reliable estimates of treatment efficacy and risk. GLMMs provide the most robust estimates and enable the modeling of survival dynamics over time. These findings support evidence-based decision-making and highlight the value of model-informed meta-analysis in oncology. Full article
(This article belongs to the Special Issue Advances in the Diagnosis and Treatment of Skin Cancer)
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15 pages, 1947 KiB  
Article
Sonographic Signatures of Immune Checkpoint Inhibitor-Associated Musculoskeletal Adverse Events
by Hans Vitzthum von Eckstaedt, Kevin Weng, Ingeborg Sacksen, Rachael Stovall, Petros Grivas, Shailender Bhatia, Evan Hall, Scott Pollock and Namrata Singh
Cancers 2025, 17(14), 2344; https://doi.org/10.3390/cancers17142344 - 15 Jul 2025
Viewed by 367
Abstract
Background: Immune checkpoint inhibitors (ICIs) transformed cancer treatment, producing significant survival benefits. However, ICIs can trigger toxicities called immune-related adverse events (irAEs), including inflammatory arthritis (IA) and polymyalgia rheumatica (PMR)-like syndromes. Our study aimed to systematically further characterize musculoskeletal ultrasound (MSKUS) findings [...] Read more.
Background: Immune checkpoint inhibitors (ICIs) transformed cancer treatment, producing significant survival benefits. However, ICIs can trigger toxicities called immune-related adverse events (irAEs), including inflammatory arthritis (IA) and polymyalgia rheumatica (PMR)-like syndromes. Our study aimed to systematically further characterize musculoskeletal ultrasound (MSKUS) findings in patients with ICI-IA and ICI-PMR, collectively referred to as “MSK-irAEs”, and explore the role of US in guiding treatment. Methods: The authors conducted a comprehensive chart review for patients receiving ICIs undergoing MSKUS at our center’s rheumatology clinics. US examinations were performed and reviewed by two MSKUS-certified rheumatologists. Descriptive statistics were performed to summarize demographic, clinical, and treatment-related variables. US findings were categorized with a novel scoring system: 0—no signs of inflammatory arthropathy or tendinopathy, 1—potential signs of inflammation (grayscale ≥ 2, effusion without power Doppler, synovial hypertrophy in the joint), and 2—active inflammation in joints and/or tendons (characterized by power Doppler) and signs of inflammation. Results: Twenty-three patients were included. The median age was 63 years, 52% were male, and 87% were White. Melanoma was the most common cancer (48%). MSK-irAEs were diagnosed in nineteen (83%), with MSKUS showing inflammation in seventeen (74%). Sixteen (70%) received escalation in MSK-irAE treatment after MSKUS. Four (17%) had erosive disease due to MSK-irAEs, while one had erosive osteoarthritis. Individuals with inflammatory erosive changes experienced prolonged intervals between symptom onset and MSKUS, ranging from 17 to 82 months, suggesting that erosions may reflect chronic, under-recognized inflammation. On MSK-irAE therapy, nine (47%) experienced symptomatic improvement, five (26%) achieved resolution, and in four (21%) cases, it was too early to assess the response. MSKUS detected other causes of MSK symptoms besides MSK-irAEs in several patients, allowing ICI resumption in one. Conclusions: Our study highlights the clinical utility of MSKUS not only as a diagnostic tool but also to guide therapeutic decision-making. Full article
(This article belongs to the Special Issue Cancer-Therapy-Related Adverse Events)
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21 pages, 2845 KiB  
Article
Circulating Plasma Proteins as Biomarkers for Immunotherapy Toxicity: Insights from Proteome-Wide Mendelian Randomization and Bioinformatics Analysis
by Liansha Tang, Wenbo He, Handan Hu, Jiyan Liu and Zhike Li
Biomedicines 2025, 13(7), 1717; https://doi.org/10.3390/biomedicines13071717 - 14 Jul 2025
Viewed by 447
Abstract
Background: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, yet severe immune-related adverse events (irAEs) often necessitate immunotherapy discontinuation and cause life-threatening complications. Circulating plasma proteins, dynamically accessible and functionally linked to immunity, may predict and offer novel targets for irAEs. Methods: Leveraging [...] Read more.
Background: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, yet severe immune-related adverse events (irAEs) often necessitate immunotherapy discontinuation and cause life-threatening complications. Circulating plasma proteins, dynamically accessible and functionally linked to immunity, may predict and offer novel targets for irAEs. Methods: Leveraging multi-omics integration, we conducted bidirectional two-sample Mendelian randomization (MR) using protein quantitative trait loci (pQTLs) from 4998 plasma proteins and genome-wide association data of irAE phenotypes. A causal inference framework combining colocalization analysis, multivariable MR (MVMR) adjusting for body mass index (BMI) confounding, and mediation MR elucidated BMI-independent pathways. Systems biology approaches including tissue-specific expression profiling, pathway enrichment, and protein interaction network analysis revealed spatial and functional drivers of irAE pathogenesis. Results: Proteome-wide MR mapping identified eight plasma proteins (CCL20, CSF1, CXCL9, CD40, TGFβ1, CLSTN2, TNFSF12, TGFα) causally associated with all-grade irAEs, and five (CCL20, CCL25, CXCL10, ADA, TGFα) with high-grade irAEs. Colocalization prioritized CD40/TNFSF12 (all-grade) and ADA/CCL25 (high-grade) as therapeutic targets (PPH4 > 0.7). CXCL9/TNFSF12 (all-grade) and CCL25 (high-grade) exerted BMI-independent effects, suggesting intrinsic immune dysregulation mechanisms. Tissue-specific gene expression patterns, CSF1, TGFβ1 in lung, TNFSF12 in the ileum may explain organ-specific irAE vulnerabilities. High-grade irAEs correlated with compartmentalized immune dysregulation and IL-17/immunodeficiency pathway activation. Conclusions: This study establishes the causal atlas of plasma proteins in irAE pathogenesis, bridging biomarker discovery with actionable therapeutic targets. These advances align with next-generation immunotherapy goals: maximizing efficacy while taming the immune storm. Full article
(This article belongs to the Section Cell Biology and Pathology)
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17 pages, 1548 KiB  
Article
CD19-ReTARGTPR: A Novel Fusion Protein for Physiological Engagement of Anti-CMV Cytotoxic T Cells Against CD19-Expressing Malignancies
by Anne Paulien van Wijngaarden, Isabel Britsch, Matthias Peipp, Douwe Freerk Samplonius and Wijnand Helfrich
Cancers 2025, 17(14), 2300; https://doi.org/10.3390/cancers17142300 - 10 Jul 2025
Viewed by 391
Abstract
Background/Objectives: The physiological activation of cytotoxic CD8pos T cells (CTLs) relies on the engagement of the TCR/CD3 complex with cognate peptide-HLA class I (pHLA-I) on target cells, triggering cell lysis with appropriate cytokine release and minimized off-target toxicity. In contrast, current [...] Read more.
Background/Objectives: The physiological activation of cytotoxic CD8pos T cells (CTLs) relies on the engagement of the TCR/CD3 complex with cognate peptide-HLA class I (pHLA-I) on target cells, triggering cell lysis with appropriate cytokine release and minimized off-target toxicity. In contrast, current immunotherapies for CD19-expressing hematological malignancies, such as chimeric antigen receptor (CAR) T cells and bispecific T cell engagers (BiTEs), bypass TCR/pHLA interactions, resulting in CTL hyperactivation and excessive cytokine release, which frequently cause severe immune-related adverse events (irAEs). Thus, there is a pressing need for T cell-based therapies that preserve physiological activation while maintaining antitumor efficacy. Methods: To address this, we developed CD19-ReTARGTPR, a novel fusion protein consisting of the immunodominant cytomegalovirus (CMV) pp65-derived peptide TPRVTGGAM (TPR) covalently presented by a soluble HLA-B*07:02/β2-microglobulin complex fused to a high-affinity CD19-targeting Fab antibody fragment. The treatment of CD19-expressing cancer cells with CD19-ReTARGTPR makes them recognizable for pre-existing anti-CMVpp65 CTLs via physiological TCR-pHLA engagement. Results: Our preclinical data demonstrate that CD19-ReTARGTPR efficiently redirects anti-CMV CTLs to eliminate CD19-expressing cancer cells, including both established cell lines and primary chronic lymphocytic leukemia (CLL) cells. Unlike CD19-directed CAR T cells or the CD19/CD3 BiTE blinatumomab, CD19-ReTARGTPR mediated robust cytotoxic activity without triggering supraphysiological cytokine release. Importantly, this approach retained efficacy even against cancer cells with low CD19 expression. Conclusions: In summary, we provide a robust proof-of-concept study and show that CD19-ReTARGTPR offers a promising alternative strategy for T cell redirection, enabling the selective and effective killing of CD19-expressing malignancies while minimizing cytokine-driven toxicities through physiological CTL activation pathways. Full article
(This article belongs to the Special Issue New Insights of Hematology in Cancer)
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16 pages, 876 KiB  
Article
The Real-World Efficacy and Side Effects of Different Nivolumab Regimens in Japanese Patients with Advanced Melanoma: A Single-Center Retrospective Study
by Ken Horisaki, Shusuke Yoshikawa, Wataru Omata, Arata Tsutsumida and Yoshio Kiyohara
Cancers 2025, 17(14), 2299; https://doi.org/10.3390/cancers17142299 - 10 Jul 2025
Viewed by 382
Abstract
Background/Objectives: Nivolumab is a key therapy for advanced-stage melanoma; however, limited data are available from Asian populations comparing the efficacy and side effects of four dosing regimens: 3 mg/kg every 2 weeks (3mg/kgQ2W), 2 mg/kg every 3 weeks (2mg/kgQ3W), 240 mg every [...] Read more.
Background/Objectives: Nivolumab is a key therapy for advanced-stage melanoma; however, limited data are available from Asian populations comparing the efficacy and side effects of four dosing regimens: 3 mg/kg every 2 weeks (3mg/kgQ2W), 2 mg/kg every 3 weeks (2mg/kgQ3W), 240 mg every 2 weeks (240mgQ2W), and 480 mg every 4 weeks (480mgQ4W). This retrospective study evaluated Japanese patients with advanced melanoma treated with various nivolumab regimens to assess the impact of dosing interval and dosage on treatment efficacy and immune-related adverse events (irAEs). Methods: We reviewed the records of 153 participants with stage IV melanoma who received nivolumab monotherapy between February 2012 and December 2024 at Shizuoka Cancer Center. Patients were categorized by nivolumab regimen, dosing interval, and dose per body weight. We then compared treatment efficacy and incidence of irAEs across groups. Results: No significant differences were observed in objective response rate (ORR), progression-free survival (PFS), overall survival (OS), or irAE incidence between the 240mgQ2W and 480mgQ4W groups. Similar results were observed in the 3mg/kgQ2W and 2mg/kgQ3W groups. However, participants who received nivolumab within 3 weeks exhibited a significantly higher ORR than those who received nivolumab more than 3 weeks. No significant differences were found in PFS or OS. Conclusions: The administration of nivolumab at shorter intervals may provide short-term benefits in Japanese patients with advanced melanoma. However, long-term efficacy and side effects did not differ significantly across the studied nivolumab regimens. Full article
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13 pages, 1778 KiB  
Article
Rhinosinusitis as an Immune-Related Adverse Event: Clinical Characteristics, Management, and Prognostic Implications in Metastatic Melanoma Patients
by Amalia Anastasopoulou, Aikaterini Gkoufa, Panagiotis Kouzis, Georgios Kyriakakis, Michail Belivanis, Georgia Sypsa, Spyridon Bouros, Helen Gogas and Panagiotis T. Diamantopoulos
Cancers 2025, 17(14), 2297; https://doi.org/10.3390/cancers17142297 - 10 Jul 2025
Viewed by 194
Abstract
Background: Melanoma management has been revolutionized by the use of immune checkpoint inhibitors (ICIs). However, ICIs are associated with immune-related adverse events (irAEs), including rhinosinusitis, which remains underexplored. This study evaluated the incidence, characteristics, management, and prognostic implications of rhinosinusitis in patients [...] Read more.
Background: Melanoma management has been revolutionized by the use of immune checkpoint inhibitors (ICIs). However, ICIs are associated with immune-related adverse events (irAEs), including rhinosinusitis, which remains underexplored. This study evaluated the incidence, characteristics, management, and prognostic implications of rhinosinusitis in patients with melanoma under ICIs. Methods: A retrospective analysis was conducted on adult patients with melanoma treated with ICIs. Demographic, clinical, laboratory, treatment, and survival data were collected. Rhinosinusitis was defined radiographically and graded using the Harvard scoring system. Associations between rhinosinusitis and survival outcomes were analyzed. Results: Among 304 patients, 64 (21.1%) developed imaging-confirmed rhinosinusitis during ICI treatment, with 9.4% symptomatic cases. Rhinosinusitis was the sole irAE in 11.8% of patients, and 9.2% experienced it alongside other irAEs. A significant correlation with eosinophilia was observed: 39.6% of eosinophilic patients developed rhinosinusitis versus 17.1% without eosinophilia (p < 0.001). Most cases occurred during the first ICI line (86.4%), particularly with nivolumab monotherapy (32.8%). Importantly, in metastatic melanoma, rhinosinusitis was associated with significantly longer overall survival since ICI initiation (OSICI) compared to patients without rhinosinusitis (33.3 vs. 15.4 months, p = 0.025). No survival benefit was observed in the adjuvant setting. The condition was predominantly aseptic, and corticosteroids were used in 7.8%. Conclusions: This study highlights rhinosinusitis as an irAE associated with improved OS in metastatic melanoma. Further research is required to elucidate the underlying mechanisms and assess the resolution of rhinosinusitis after ICI discontinuation. Additionally, rhinosinusitis may serve as a marker of favorable prognosis in metastatic melanoma patients receiving ICIs. Full article
(This article belongs to the Section Cancer Metastasis)
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15 pages, 1323 KiB  
Article
Real-World Data on Immune-Checkpoint Inhibitors in Elderly Patients with Advanced Non-Small Cell Lung Cancer: A Retrospective Study
by José del Corral-Morales, Carlos Ayala-de Miguel, Laura Quintana-Cortés, Adrián Sánchez-Vegas, Fuensanta Aranda-Bellido, Santiago González-Santiago, José Fuentes-Pradera and Pablo Ayala-de Miguel
Cancers 2025, 17(13), 2194; https://doi.org/10.3390/cancers17132194 - 29 Jun 2025
Viewed by 472
Abstract
Background/Objectives: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases, with an increasing incidence in patients over 65 years. Although immune-checkpoint inhibitors (ICIs) have transformed the treatment landscape, elderly patients remain underrepresented in pivotal clinical trials, highlighting the [...] Read more.
Background/Objectives: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases, with an increasing incidence in patients over 65 years. Although immune-checkpoint inhibitors (ICIs) have transformed the treatment landscape, elderly patients remain underrepresented in pivotal clinical trials, highlighting the need for real-world evidence on their efficacy and tolerability in this population. Methods: We conducted a multicenter, retrospective study of advanced NSCLC patients treated with ICI alone or in combination with chemotherapy between April 2017 and December 2023. Patients were categorized into three age groups: ≤65 (younger group, YG), 66–79 (older group, OG), and ≥80 years (advanced older group, AOG). Efficacy and safety outcomes were compared across groups. Results: Among 452 patients, 221 (48.9%) were in the OG and 36 (8%) in the AOG. Median progression-free survival (PFS) was similar across groups: 8.3 months (YG), 8.4 months (OG; p = 0.872 vs. YG), and 10.5 months (AOG; p = 0.628 vs. YG). Median overall survival (OS) showed a non-significant trend favoring younger patients: 15.1 months (YG), 10.3 months (OG; p = 0.076 vs. YG), and 12.5 months (AOG; p = 0.070 vs. YG). Grade ≥ 3 immune-related adverse events (irAEs) occurred in 9.7% (YG), 5.9% (OG), and 8.3% (AOG). In patients ≥ 66 years, irAEs were associated with longer PFS (18.1 vs. 6 months; p < 0.001). Conclusions: ICIs demonstrated comparable PFS and OS across age groups, including patients aged ≥ 80 years. Chronological age did not increase irAE incidence. The development of irAEs may serve as a favorable prognostic factor in elderly patients. Full article
(This article belongs to the Special Issue Pathology, Diagnosis and Treatment in Non-small Cell Lung Cancer)
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12 pages, 1739 KiB  
Article
Local T-Cell Dysregulation and Immune Checkpoint Expression in Human Papillomavirus-Mediated Recurrent Respiratory Papillomatosis
by Hans N. C. Eckel, Su Ir Lyu, Frederik Faste, Shachi J. Sharma, Anne Nobis, Nora Wuerdemann, Maria Ziogas, Marcel Mayer, Malte C. Suchan, Kerstin Wennhold, Maria A. Garcia-Marquez, Martin Thelen, Elena Hagen, Julia Eßer, Charlotte Klasen, Oliver Siefer, Martin Otte, Hans A. Schloesser, Jens P. Klussmann, Alexander Quaas and Kevin K. Hansenadd Show full author list remove Hide full author list
Cells 2025, 14(13), 985; https://doi.org/10.3390/cells14130985 - 27 Jun 2025
Viewed by 484
Abstract
Human papillomavirus-mediated recurrent respiratory papillomatosis (RRP) is a premalignant neoplasia of the upper airway characterized by significant dysphonia and respiratory obstruction. Immune checkpoint blockade has emerged as a potential alternative to repeated surgical interventions in RRP. Here, we investigated the intralesional T-cell composition [...] Read more.
Human papillomavirus-mediated recurrent respiratory papillomatosis (RRP) is a premalignant neoplasia of the upper airway characterized by significant dysphonia and respiratory obstruction. Immune checkpoint blockade has emerged as a potential alternative to repeated surgical interventions in RRP. Here, we investigated the intralesional T-cell composition and expression of the immune checkpoints programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) in RRP. We analyzed tissue samples from 30 patients treated at a tertiary care center between 2009 and 2021, including paired samples from individual patients collected at different time points. Immunohistochemical staining was performed for CD4, CD8, CTLA-4, FoxP3, and PD-L1 and correlated with disease severity and previous adjuvant therapies. Overall disease burden and intervention-free survival were not associated with the abundance of CD4+, CD8+, or FoxP3+ T cells, nor with immune checkpoint expression. However, patients with aggressive disease exhibited a higher intralesional FoxP3/CD4 T-cell ratio. Prior intralesional cidofovir treatment was associated with reduced CD4+ T-cell infiltration. These findings suggest that a locally immunosuppressive microenvironment, reflected by an elevated FoxP3/CD4 ratio, contributes to disease severity in RRP. Consistent CTLA-4 expression across all evaluated samples supports further investigation of anti-CTLA-4 therapy, either alone or in combination with other checkpoint inhibitors. Full article
(This article belongs to the Section Cellular Immunology)
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7 pages, 898 KiB  
Case Report
Osimertinib-Induced Hepatitis Following Immunotherapy in a Patient with Lung Adenocarcinoma Harboring De Novo EGFR Exon 19 Deletion and T790M Mutations: A Case Report
by Bradley Steiner, Amanda Edmond, Monica Camou, Taylor Praska and Jiaxin Niu
Reports 2025, 8(3), 101; https://doi.org/10.3390/reports8030101 - 26 Jun 2025
Viewed by 456
Abstract
Background and Clinical Significance: Non-small-cell lung cancer (NSCLC) with EGFR mutations, particularly de novo compound mutations such as exon 19 deletions (Ex19del) with T790M substitutions, present a significant clinical challenge due to resistance to many treatments. While treating these patients, the administration of [...] Read more.
Background and Clinical Significance: Non-small-cell lung cancer (NSCLC) with EGFR mutations, particularly de novo compound mutations such as exon 19 deletions (Ex19del) with T790M substitutions, present a significant clinical challenge due to resistance to many treatments. While treating these patients, the administration of osimertinib, a third-generation EGFR inhibitor, after immunotherapy can lead to unique immune-related adverse events (irAEs), such as pneumonitis and, rarely, hepatitis. Case Presentation: A 36-year-old Filipino woman presented with metastatic NSCLC harboring de novo Ex19del and T790M mutations. Despite initial therapy with carboplatin and paclitaxel, followed by chemoimmunotherapy, the patient’s disease progressed. She subsequently developed severe hepatitis from osimertinib after her prior immunotherapy with pembrolizumab. After the hepatitis resolved with high-dose steroids, osimertinib was switched to afatinib, but her disease rapidly progressed with new metastases. A second attempt at osimertinib rechallenge, with concomitant prednisone, resulted in substantial disease control, including improved leptomeningeal disease (LMD) and no recurrence of hepatitis. Conclusions: This case underscores the feasibility of rechallenging with osimertinib in patients who experience adverse events such as hepatotoxicity, provided that appropriate management strategies, such as steroid therapy, are employed. The successful rechallenge in this case highlights the potential of osimertinib as a viable option in advanced EGFR-mutant NSCLC, even after prior treatment-related complications. Full article
(This article belongs to the Section Oncology)
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13 pages, 532 KiB  
Article
The Impact of AI-Driven Chatbot Assistance on Protocol Development and Clinical Research Engagement: An Implementation Report
by Kusal Weerasinghe, David B. Olawade, Jennifer Teke, Maines Msiska and Stergios Boussios
J. Pers. Med. 2025, 15(7), 269; https://doi.org/10.3390/jpm15070269 - 24 Jun 2025
Cited by 1 | Viewed by 483
Abstract
Background: The integration of artificial intelligence (AI) into healthcare research has the potential to enhance research capacity, streamline protocol development, and reduce barriers to engagement. Medway NHS Foundation Trust identified a plateau in homegrown research participation, particularly among clinicians with limited research experience. [...] Read more.
Background: The integration of artificial intelligence (AI) into healthcare research has the potential to enhance research capacity, streamline protocol development, and reduce barriers to engagement. Medway NHS Foundation Trust identified a plateau in homegrown research participation, particularly among clinicians with limited research experience. A generative AI-driven chatbot was introduced to assist researchers in protocol development by providing step-by-step guidance, prompting ethical and scientific considerations, and offering immediate feedback. Methods: The chatbot was developed using OpenAI’s GPT-3.5 architecture, customised with domain-specific training based on Trust guidelines, Health Research Authority (HRA) requirements, and Integrated Research Application System (IRAS) submission protocols. It was deployed to guide researchers through protocol planning, ensuring compliance with ethical and scientific standards. A mixed-methods evaluation was conducted using a qualitative-dominant sequential explanatory design. Seven early adopters completed a 10-item questionnaire (5-point Likert scales), followed by eight free-flowing interviews to achieve thematic saturation. Results: Since its launch, the chatbot has received an overall performance rating of 8.86/10 from the seven survey respondents. Users reported increased confidence in protocol development, reduced waiting times for expert review, and improved inclusivity in research participation across professional groups. However, limitations in usage due to free-tier platform constraints were identified as a key challenge. Conclusions: AI-driven chatbot tools show promise in supporting research engagement in busy clinical environments. Future improvements should focus on expanding access, optimising integration, and fostering collaboration among NHS institutions to enhance research efficiency and inclusivity. Full article
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15 pages, 1444 KiB  
Systematic Review
Management of Triple M Syndrome: A Narrative Review of Immune Checkpoint Inhibitor-Induced Myasthenia Gravis, Myositis and Myocarditis
by Martin Furlepa, Isabella Watts and Aisling S. Carr
Cancers 2025, 17(13), 2063; https://doi.org/10.3390/cancers17132063 - 20 Jun 2025
Viewed by 925
Abstract
Background: The advent of immunotherapy has revolutionised cancer treatment by harnessing the immune system to target tumour cells. However, there is increasing awareness of immunotherapy-related adverse events, which can be severe and even fatal. While system-specific immune-related adverse events (ir-AEs) are well documented, [...] Read more.
Background: The advent of immunotherapy has revolutionised cancer treatment by harnessing the immune system to target tumour cells. However, there is increasing awareness of immunotherapy-related adverse events, which can be severe and even fatal. While system-specific immune-related adverse events (ir-AEs) are well documented, growing evidence suggests the existence of overlap syndromes—distinct clusters of immune-mediated complications. One such syndrome is the overlap of myasthenia gravis, myositis and myocarditis, collectively known as Triple M (3M) syndrome. This syndrome is complex, varying in presentation and severity, with in-hospital mortality rates approaching 40%. Whilst there is consensus on the management of system-specific complications, there is no consensus guidance for the management of these overlap syndromes. Methods: In this paper, we conduct a review of the literature, analysing reported cases of 3M syndrome, focusing on treatment approaches and patient outcomes at an individual level. Conclusions: This review highlights the complexity of diagnosing and managing 3M syndrome due to inconsistent reporting, lack of standardised criteria for diagnosis, and treatment variability. While evidence remains limited, we offer broad clinical recommendations and underscore the urgent need for consensus definitions, prospective data collection, and structured treatment guidance. Full article
(This article belongs to the Special Issue Immune-Related Adverse Events in Cancer Immunotherapy)
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13 pages, 503 KiB  
Article
Neutrophil to Lymphocyte Ratio as a Biomarker for the Prediction of Cancer Outcomes and Immune-Related Adverse Events in a CTLA-4-Treated Population
by Michael M. Cunningham, Rachel Romero, Carolina Alvarez, Shruti Saxena Beem, Todd A. Schwartz and Rumey C. Ishizawar
Cancers 2025, 17(12), 2011; https://doi.org/10.3390/cancers17122011 - 17 Jun 2025
Viewed by 478
Abstract
Background/Objectives: Immune-related adverse events (irAEs) triggered by immune checkpoint inhibitor therapy (ICI) have been paradoxically associated with both significant morbidity and improved cancer outcomes. While predictive markers for irAEs have been studied in the PD-1 blockade, less is known for their role in [...] Read more.
Background/Objectives: Immune-related adverse events (irAEs) triggered by immune checkpoint inhibitor therapy (ICI) have been paradoxically associated with both significant morbidity and improved cancer outcomes. While predictive markers for irAEs have been studied in the PD-1 blockade, less is known for their role in CTLA-4 inhibition. This study aims to fill this gap by evaluating NLR and irAE incidence in a CTLA-4-treated population. Methods: This study is a single-center retrospective cohort study investigating 111 patients treated with CTLA-4 inhibition (ipilimumab) to assess associations for baseline low NLR values with cancer outcomes and irAE type and incidence. Patient charts were manually reviewed by a single physician, and unclear clinical events were assessed by a second physician reviewer. Results: In this cohort, the occurrence of more than one irAE presentation was associated with an improved cancer outcome, OR 1.48 (1.02, 2.15). When stratified by organ-specific manifestation, only endocrinologic irAEs were associated with improved cancer outcome, OR 2.82 (1.19, 6.67). A low baseline NLR was statistically significantly associated with an increased incidence of irAEs of any type, OR 4.34 (1.73, 10.9). Conclusions: These data show that irAE occurrence in cancer patients treated with CTLA-4 inhibition is associated with improved cancer outcomes, similar to that previously seen with PD-1 inhibition. It also suggests that the NLR may serve as a practical peripheral biomarker to predict both cancer response and odds of irAEs in patients treated with CTLA-4 inhibition. This low-cost and widely available tool could provide additional information for modeling cancer outcomes. Full article
(This article belongs to the Special Issue Immune-Related Adverse Events in Cancer Immunotherapy)
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