Autoimmunity in immune checkpoint inhibitor-induced immune-related adverse events: A focus on autoimmune skin toxicity and pneumonitis.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. However, their use is frequently associated with immune-related adverse events (irAEs) potentially affecting any organ. The mechanisms mediating such irAEs remain poorly understood and biomarkers to predict the development of irAEs are lacking. Growing evidence shows the importance of self-antigens in mediating irAEs during ICI therapy, in particular the well-described melanocyte differentiation antigens in melanoma patients. This review will focus on two novel classes of self-antigens involved in mediating autoimmune skin toxicity and pneumonitis in non-small cell lung cancer patients treated with immunotherapy. T cells specific for these self-antigens are thought to not only mediate irAEs but are thought to simultaneously mediate anti-tumor responses and are therefore associated with both autoimmune toxicity and response to ICI therapy. We further discuss emerging cellular and proteomic immune signatures of irAEs that may serve as biomarkers to help predict which patients are at higher risk of developing these irAEs. The determination of new tumor antigens involved in ICI therapy and the identification of related biomarkers brings us a step forward in the mechanistic understanding of ICIs and will help to monitor patients at higher risk of developing irAEs. Lastly, we discuss the current challenges in collecting research samples for the study of ICI-related mechanisms and in distinguishing between immune signatures of response and those of irAEs.

Cold Versus Hot Snare Endoscopic Resection of Large Nonpedunculated Colorectal Polyps: Randomized Controlled German CHRONICLE Trial.

BACKGROUND & AIMS: Endoscopic mucosal resection (EMR) is standard therapy for nonpedunculated colorectal polyps ≥20 mm. It has been suggested recently that polyp resection without current (cold resection) may be superior to the standard technique using cutting/coagulation current (hot resection) by reducing adverse events (AEs), but evidence from a randomized trial is missing. METHODS: In this randomized controlled multicentric trial involving 19 centers, nonpedunculated colorectal polyps ≥20 mm were randomly assigned to cold or hot EMR. The primary outcome was major AE (eg, perforation or postendoscopic bleeding). Among secondary outcomes, major AE subcategories, postpolypectomy syndrome, and residual adenoma were most relevant. RESULTS: Between 2021 and 2023, there were 396 polyps in 363 patients (48.2% were female) enrolled for the intention-to-treat analysis. Major AEs occurred in 1.0% of the cold group and in 7.9% of the hot group (P = .001; odds ratio [OR], 0.12; 95% CI, 0.03-0.54). Rates for perforation and postendoscopic bleeding were significantly lower in the cold group, with 0% vs 3.9% (P = .007) and 1.0% vs 4.4% (P = .040). Postpolypectomy syndrome occurred with similar frequency (3.1% vs 4.4%; P = .490). After cold resection, residual adenoma was found more frequently, with 23.7% vs 13.8% (P = .020; OR, 1.94; 95% CI, 1.12-3.38). In multivariable analysis, lesion diameter of ≥4 cm was an independent predictor both for major AEs (OR, 3.37) and residual adenoma (OR, 2.47) and high-grade dysplasia/cancer for residual adenoma (OR, 2.92). CONCLUSIONS: Cold resection of large, nonpedunculated colorectal polyps appears to be considerably safer than hot EMR; however, at the cost of a higher residual adenoma rate. Further studies have to confirm to what extent polyp size and histology can determine an individualized approach. German Clinical Trials Registry (Deutsches Register Klinischer Studien), Number DRKS00025170.

Crossfeat: a transformer-based cross-feature learning model for predicting drug side effect frequency.

BACKGROUND: Safe drug treatment requires an understanding of the potential side effects. Identifying the frequency of drug side effects can reduce the risks associated with drug use. However, existing computational methods for predicting drug side effect frequencies heavily depend on known drug side effect frequency information. Consequently, these methods face challenges when predicting the side effect frequencies of new drugs. Although a few methods can predict the side effect frequencies of new drugs, they exhibit unreliable performance owing to the exclusion of drug-side effect relationships. RESULTS: This study proposed CrossFeat, a model based on convolutional neural network-transformer architecture with cross-feature learning that can predict the occurrence and frequency of drug side effects for new drugs, even in the absence of information regarding drug-side effect relationships. CrossFeat facilitates the concurrent learning of drugs and side effect information within its transformer architecture. This simultaneous exchange of information enables drugs to learn about their associated side effects, while side effects concurrently acquire information about the respective drugs. Such bidirectional learning allows for the comprehensive integration of drug and side effect knowledge. Our five-fold cross-validation experiments demonstrated that CrossFeat outperforms existing studies in predicting side effect frequencies for new drugs without prior knowledge. CONCLUSIONS: Our model offers a promising approach for predicting the drug side effect frequencies, particularly for new drugs where prior information is limited. CrossFeat's superior performance in cross-validation experiments, along with evidence from case studies and ablation experiments, highlights its effectiveness.

Association between immune checkpoint inhibitor and cytomegalovirus infection: A pharmacovigilance study based on the adverse event reporting system.

Immune checkpoint inhibitor (ICI)-induced adverse events due to excessive immune stimulation are problematic in immunotherapy. The activation of viral infection triggered by ICI-induced dysregulated immunity has been proposed; however, this association remains inconsistent. This study investigated the association between ICI administration and cytomegalovirus (CMV) infections, a pathogen linked to immune abnormalities and reactivation, using the Food and Drug Administration Adverse Event Reporting System. We used the crude data set and immunocompromise-free data set from the fourth quarter of 2012 to 2023. The disproportionality between CMV infection and ICI was analyzed using reporting odds ratio (ROR) and information component (IC) methodologies. Disproportionality between ipilimumab and nivolumab combination case and CMV infection was observed in the crude (ROR: 2.83, 95% confidence interval [CI]: 2.32-3.47; IC: 1.48, 95% CI: 1.14-1.73) and immunocompromise-free data set (ROR: 1.76, 95% CI: 1.33-2.33; IC: 0.80, 95% CI: 0.33-1.14), whereas disproportionality between other ICI and CMV infection was not observed in the immunocompromise-free data set. Multiple sensitivity analyses and time-scan analysis also revealed the consistent disproportionality between ipilimumab and nivolumab combination cases and CMV infection, regardless of the host's immune status. While further research is warranted to validate our findings, these results highlight new insights into ICI-induced viral infections and suggest the importance of considering the possibility of CMV infections during ipilimumab and nivolumab combination therapy, regardless of the host's immune status.

Diagnosis and Management of Immune Checkpoint Inhibitor-Associated Nephrotoxicity: A Position Statement from the American Society of Onco-nephrology.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer and are now the backbone of therapy for several malignancies. However, ICIs can cause a spectrum of renal immune-related adverse events including acute kidney injury (AKI), most commonly manifesting as acute interstitial nephritis (AIN), though glomerular disease and electrolyte disturbances have also been reported. In this position statement by the American Society of Onco-nephrology (ASON), we summarize the incidence and risk factors for ICI-AKI, pathophysiological mechanisms and clinicopathological features of ICI-AKI. We also discuss novel diagnostic approaches and promising biomarkers for ICI-AKI. From expert panel consensus, we provide clinical practice points for the initial assessment and diagnosis of ICI-AKI, management and immunosuppressive therapy, and consideration for re-challenge with ICI following AKI episodes. In addition, we explore ICI use in special populations such as kidney transplant recipients and propose key areas of focus for future research and clinical investigation.

Engineering the Microbiome to Prevent Adverse Events: Challenges and Opportunities.

In the past decade of microbiome research, we have learned about numerous adverse interactions between the microbiome and medical interventions such as drugs, radiation, and surgery. What if we could alter our microbiomes to prevent these events? In this review, we discuss potential routes to mitigate microbiome adverse events, including applications from the emerging field of microbiome engineering. We highlight cases where the microbiome acts directly on a treatment, such as via differential drug metabolism, and cases where a treatment directly harms the microbiome, such as in radiation therapy. Understanding and preventing microbiome adverse events is a difficult challenge that will require a data-driven approach involving causal statistics, multiomics techniques, and a personalized means of mitigating adverse events. We propose research considerations to encourage productive work in preventing microbiome adverse events, and we highlight the many challenges and opportunities that await.

Secondary analysis of late major gastrointestinal and genitourinary toxicities in unfavorable-risk prostate cancer patients receiving docetaxel: Insights from a randomized trial.

BACKGROUND: This study sought to evaluate the late toxicity associated with neoadjuvant and concurrent docetaxel and radiation therapy in patients with prostate cancer. METHODS: A secondary analysis was performed of the phase 3 multicenter randomized trial (Dana-Farber Cancer Institute 05-043) including 350 patients with nonmetastatic unfavorable-risk prostate cancer. Patients were randomized 1:1 to receive androgen deprivation therapy, radiation therapy, and docetaxel versus androgen deprivation therapy and radiation therapy. The study assessed the cumulative incidence rates of grade 2 and grade 3 or higher gastrointestinal, genitourinary, and sexual toxicity. A multivariable Fine and Gray's competing risks regression model adjusted for age at randomization and pelvic lymph node radiation therapy was used to evaluate the treatment effect of docetaxel on time to late genitourinary and gastrointestinal toxicities. RESULTS: The study included 338 patients who primarily had minimal or no comorbidity (74.9%) and median age 66 years (interquartile range: 61,71). At a median follow-up of 10.2 years, docetaxel was not associated with increased risk of any grade 3 or higher (adjusted hazard ratio [AHR], 0.98; 95% confidence interval [CI], 0.36-2.67; p = .96) or grade 2 gastrointestinal (p = .75), genitourinary (p = .44), and sexual (p = .29) toxicity. Age was associated with increased grade 3 or higher (AHR, 1.08; 95% CI, 1.01-1.16; p = .03) and grade 2 gastrointestinal toxicity (AHR, 1.11; 95% CI, 1.03-1.20; p = .005). A nonsignificant trend (p = .09) toward increased late grade 3 or higher toxicity was observed for pelvic radiation therapy use. CONCLUSIONS: Docetaxel combined with radiotherapy has an acceptable long-term toxicity profile.

Comparison of infection risk between enzalutamide and abiraterone in patients with prostate cancer.

BACKGROUND: Enzalutamide and abiraterone may differ in their immunomodulatory effects, and the prednisone coadministered with abiraterone can be immunosuppressive. This study aimed to compare the risk of different types of infection in patients with prostate cancer receiving enzalutamide or abiraterone in combination with androgen deprivation therapy. METHODS: Patients with prostate cancer receiving enzalutamide or abiraterone in addition to androgen deprivation therapy in Hong Kong between December 1999 to March 2021 were identified in this retrospective cohort study and followed up until September 2021, death, or crossover. Outcomes, including any sepsis, pneumonia, urinary tract infection, cellulitis or skin abscess, central nervous system infections, and tuberculosis, were analyzed as both time-to-event outcomes (multivariable Fine-Gray regression, with mortality considered a competing event) and recurrent-event outcomes (multivariable negative binomial regression). RESULTS: Altogether, 1582 patients were analyzed (923 abiraterone users; 659 enzalutamide users) with a median follow-up of 10.6 months (interquartile range: 5.3-19.9 months). Compared to abiraterone users, enzalutamide users had lower cumulative incidences of sepsis (adjusted subhazard ratio [SHR] 0.70 [0.53-0.93], p = .014), pneumonia (adjusted SHR 0.76 [0.59-0.99], p = .040), and cellulitis or skin abscess (adjusted SHR 0.55 [0.39-0.79], p = .001), but not urinary tract infection (adjusted SHR 0.91 [0.62-1.35], p = .643). Associations between exposure and central nervous system infections and tuberculosis were not assessed because of low event rates. Analyzing the outcomes as recurrent events gave similar results. Enzalutamide use may be associated with a lower risk of urinary tract infection in patients with diabetes mellitus. CONCLUSIONS: Compared to abiraterone users, enzalutamide users have significantly lower risks of sepsis, pneumonia, cellulitis, or skin abscess.

Multiorgan transplant for therapy-associated lung and liver failure in a patient with stage III lung cancer.

Immunotherapy can significantly improve efficacy of cancer treatments. For locally advanced stage III lung cancers, chemoimmunotherapy in the neoadjuvant setting can achieve complete pathological response in about 40% of cases. However, optimal cancer response in patients receiving immunotherapy is sometimes associated with potentially fatal bystander injury to lung and liver. We report a successful combined double lung and liver transplantation for immunotherapy-associated respiratory failure and cirrhosis in a patient with advanced lung cancer. A 68-year-old man with stage IIIA squamous cell lung cancer encountered severe interstitial pneumonitis and nodular regenerative hyperplasia of the liver following systemic anticancer therapy that included immunotherapy and platinum-based chemotherapy. These adverse events culminated into fulminant end-stage pulmonary fibrosis and cirrhosis, which were treated with simultaneous lung and liver transplantation, complete resection of lung cancer, and mediastinal lymphadenectomy. The patient demonstrated promising early outcomes without recurrence of cancer at 12 months. Given that oncologic treatments can induce irreversible solid organ failure despite cancer control, our report suggests that in carefully selected patients without systemic metastasis and in whom complete resection of residual cancer can be performed, organ transplantation can be life-saving.

Autoimmune and auto-inflammatory adverse events after COVID-19 vaccination in the United States.

We identified 3620 autoimmune-related adverse events among 223.2 million US residents using Vaccine Adverse Events Reporting System and the COVID-19 Data Tracker. This study is the first to quantify the cumulative incidence of autoimmune and auto-inflammatory adverse events after COVID-19 vaccination. We reported autoimmune and auto-inflammatory adverse events across 6 major classes of medical conditions and stratified by age, sex, and manufacturer.

Glucagon-Like Peptide-1 Receptor Agonists Do Not Increase Aspiration During Upper Endoscopy in Patients With Diabetes.

BACKGROUND & AIMS: Glucagon-like peptide-1-receptor agonists (GLP1-RAs) have been associated with greater retention of gastric contents, however, there is minimal controlled, population-based data evaluating the potential adverse effects of GLP1-RA in the periprocedural setting. We aimed to determine if there is increased risk of aspiration and aspiration-related complications after upper endoscopy in patients using GLP1-RAs. METHODS: We used a nationwide commercial administrative claims database to conduct a retrospective cohort study of patients aged 18 to 64 with type 2 diabetes who underwent outpatient upper endoscopy from 2005 to 2021. We identified 6,806,046 unique upper endoscopy procedures. We compared claims for aspiration and associated pulmonary adverse events in the 14 days after upper endoscopy between users of GLP1-RAs, dipeptidyl peptidase 4 inhibitors (DPP4is), and chronic opioids. We adjusted for age, sex, Charlson Comorbidity score, underlying respiratory disease, and gastroparesis. RESULTS: We found that pulmonary adverse events after upper endoscopy are rare, ranging from 6 to 25 events per 10,000 procedures. When comparing GLP1-RAs with DPP4i, crude relative risks of aspiration (0.67; 95% CI, 0.25-1.75), aspiration pneumonia (0.95; 95% CI, 0.40-2.29), pneumonia (1.07; 95% CI, 0.62-1.86), or respiratory failure (0.75; 95% CI, 0.38-1.48) were not higher in patients prescribed a GLP1-RA. When comparing GLP1-RAs with opioids, crude relative risks were 0.42 (95% CI, 0.15-1.16) for aspiration, 0.60 (95% CI, 0.24-1.52) for aspiration pneumonia, 0.30 (95% CI, 0.19-0.49) for pneumonia, and 0.24 (95% CI, 0.13-0.45) for respiratory failure. These results were consistent across several sensitivity analyses. CONCLUSIONS: GLP1-RA use is not associated with an increased risk of pulmonary complications after upper endoscopy compared with DPP4i use in patients with type 2 diabetes.

Effects of Glucagon-Like Peptide-1 Receptor Agonists on Upper Gastrointestinal Endoscopy: A Meta-Analysis.

BACKGROUND AND AIMS: Limited evidence exists regarding the impact of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on upper endoscopy. Therefore, a meta-analysis was conducted to comprehensively review the available evidence on this subject. METHODS: A systematic bibliographic search was carried out until May 2024. Pooled estimates were analyzed using a random-effects model, with results presented as odds ratio (OR) and 95% confidence interval (CI). The primary outcome assessed was the rate of retained gastric content (RGC), while secondary outcomes included rates of aborted and repeated procedures, adverse event rate, and rates of aspiration. RESULTS: This analysis included 13 studies involving a total of 84,065 patients. Patients receiving GLP-1RA therapy exhibited significantly higher rates of RGC (OR, 5.56; 95% CI, 3.35 to 9.23), a trend that was consistent among patients with diabetes (OR, 2.60; 95% CI, 2.23 to 3.02). Adjusted analysis, accounting for variables such as sex, age, body mass index, diabetes, and other therapies, confirmed the elevated rates of RGC in the GLP-1RA user group (adjusted OR, 4.20; 95% CI, 3.42 to 5.15). Furthermore, rates of aborted and repeated procedures were higher in the GLP-1RA user group (OR, 5.13; 95% CI, 3.01 to 8.75; and OR, 2.19; 95% CI, 1.43 to 3.35; respectively). However, no significant differences were found in AE and aspiration rates between the 2 groups (OR, 4.04; 95% CI, 0.63 to 26.03; and OR, 1.75; 95% CI, 0.64 to 4.77; respectively). CONCLUSION: Use of GLP-1RAs is associated with increased retention of gastric contents and more frequent aborted procedures during upper endoscopy. However, the adverse event and aspiration rates do not seem different; therefore, adjusting fasting time instead of routinely withholding GLP-1RAs could be reasonable in these patients.

Outcomes of High-Grade Immune Checkpoint Inhibitor Hepatitis in Hospitalized and Nonhospitalized Patients.

BACKGROUND & AIMS: Guidelines recommend hospitalization for severe immune checkpoint inhibitor (ICI) hepatitis. We compared patient outcomes in the inpatient versus outpatient settings. METHODS: We conducted a multicenter, retrospective cohort study of 294 ICI-treated patients who developed grade 3-4 ICI hepatitis. The primary outcome was time to alanine aminotransferase (ALT) normalization (≤40); secondary outcomes included time to ALT ≤100 U/L and time to death. To account for confounding by indication, inverse probability of treatment weighting was applied to perform Cox regression. A sensitivity analysis was performed excluding patients with grade 4 hepatitis. RESULTS: One hundred and sixty-six patients (56.5%) were hospitalized for a median of 6 (interquartile range, 3-11) days. On inverse probability of treatment weighting Cox regression, hospitalization was not associated with time to ALT normalization (hazard ratio [HR], 1.11; 95% confidence interval [CI], 0.86-1.43; P = .436) or time to ALT ≤100 U/L (HR, 1.11; 95% CI, 0.86-1.43; P = .420). In the sensitivity analysis limited to patients with grade 3 hepatitis, hospitalization was also not associated with time to ALT normalization (HR, 1.11; 95% CI, 0.83-1.50; P = .474) or time to ALT ≤100 U/L (HR, 1.19; 95% CI, 0.90-1.58; P = .225). In a subgroup analysis of 152 patients with melanoma, hospitalization was not associated with reduced risk of all-cause death (HR, 0.93; 95% CI, 0.53-1.64; P = .798). Notably, despite their Common Terminology Criteria for Adverse Events classification of high-grade hepatitis, 94% of patients had "mild" liver injury based on International Drug-Induced Liver Injury Criteria. CONCLUSIONS: Hospitalization of patients with high-grade ICI hepatitis was not associated with faster hepatitis resolution and did not affect mortality. Routine hospitalization may not be necessary in all patients with high-grade ICI hepatitis and Common Terminology Criteria for Adverse Events criteria may overestimate severity of liver injury.

Strategic deactivation of mRNA COVID-19 vaccines: New applications for siRNA therapy and RIBOTACs.

The rapid development and authorization of messenger ribonucleic acid (mRNA) vaccines by Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) in 2020 marked a significant milestone in human mRNA product application, overcoming previous obstacles such as mRNA instability and immunogenicity. This paper reviews the strategic modifications incorporated into these vaccines to enhance mRNA stability and translation efficiency, such as the inclusion of nucleoside modifications and optimized mRNA design elements including the 5' cap and poly(A) tail. We highlight emerging concerns regarding the wide systemic biodistribution of these mRNA vaccines leading to prolonged inflammatory responses and other safety concerns. The regulatory framework guiding the biodistribution studies is pivotal in assessing the safety profiles of new mRNA formulations in use today. The stability of mRNA vaccines, their pervasive distribution, and the longevity of the encapsulated mRNA along with unlimited production of the damaging and potentially lethal spike (S) protein call for strategies to mitigate potential adverse effects. Here, we explore the potential of small interfering RNA (siRNA) and ribonuclease targeting chimeras (RIBOTACs) as promising solutions to target, inactivate, and degrade residual and persistent vaccine mRNA, thereby potentially preventing uncontrolled S protein production and reducing toxicity. The targeted nature of siRNA and RIBOTACs allows for precise intervention, offering a path to prevent and mitigate adverse events of mRNA-based therapies. This review calls for further research into siRNA and RIBOTAC applications as antidotes and detoxication products for mRNA vaccine technology.

Bronchoalveolar lavage fluid analysis in patients with checkpoint inhibitor pneumonitis.

BACKGROUND: Checkpoint inhibitor pneumonitis (CIP) is a relatively uncommon but potentially life-threatening immune-related adverse event (irAE). Lung biopsies have not been commonly performed for CIP patients. Bronchoalveolar lavage fluid (BALF) analysis is a useful diagnostic approach for interstitial lung disease. However, BALF features were inconsistent across different studies. METHODS: We retrospectively reviewed the medical records of 154 patients with pathologically confirmed malignancies and suffering from CIPs between July 2018 and December 2022. Patients who had bronchoalveolar lavage (BAL) data available were enrolled in our study. Patient clinical, laboratory, radiological and follow-up data were reviewed and analyzed. RESULTS: The BALF differential cell count and lymphocyte subset analysis were performed for 42 CIP patients. There were 32 males (76.2%). The mean age at diagnosis of CIP was 62.0 ± 10.4 (range: 31-78) years. The median time to onset of CIP was 98.5 days after the start of immunotherapy. There were 18 patients (42.9%) with low-grade CIPs and 24 patients (57.1%) with high-grade CIPs. The mean lymphocyte percentage was 36.7 ± 22.5%. There were 34 (81%) CIP patients with a lymphocytic cellular pattern. The median ratio of CD3+CD4+/CD3+CD8+ lymphocytes was 0.5 (0.3, 1.0). The ratio was less than 1.0 for 31 CIP patients (73.8%). However, there was no significant difference in the BALF features between patients with low-grade CIPs and those with high-grade CIPs. CONCLUSIONS: The CD3+CD8+ lymphocytosis pattern was the main inflammatory profile in the BALF of CIP patients in this cohort. Targeting CD3+CD8+ lymphocytes might be a treatment option for CIPs.

Biomarker role of thyroid irAE and PD-L1 positivity in predicting PD-1 blockade efficacy in patients with non-small cell lung cancer.

Thyroid immune-related adverse events (irAEs) are associated with programmed cell death protein 1 (PD-1) blockade efficacy in non-small cell lung cancer (NSCLC). However, their independence from PD-L1 expression and quantitative impact on predicting PD-1 blockade efficacy remain unexplored. This multicenter, retrospective, longitudinal study from Korea included 71 metastatic NSCLC patients who underwent PD-L1 expression and thyroid function testing during PD-1 blockade. Disease progression by the Response Evaluation Criteria for Solid Tumors was the main outcome. Three-stage analyses were performed: (1) multivariate Cox regression models adjusted for PD-L1 expression according to thyroid irAEs; (2) subgroup analyses; (3) regrouping and comparing predictivity of current and alternative staging. Patients with thyroid irAE + exhibited a longer progression-free survival [7/20 vs. 34/51, adjusted HR 0.19 (0.07-0.47); P < 0.001] than those with thyroid irAE-, independent of PD-L1 expression; the results remained across most subgroups without interaction. The three groups showed different adjusted HR for disease progression (Group 1: PD L1 + and thyroid irAE + ; Group 2: PD-L1 + or thyroid irAE + : 5.08 [1.48-17.34]; Group 3: PD-L1- and thyroid irAE- : 30.49 [6.60-140.78]). Alternative staging (Group 1 in stage IVB → stage IVA; Group 3 in stage IVA → stage IVB) improved the prognostic value (PVE: 21.7% vs. 6.44%; C-index: 0.706 vs. 0.617) compared with the 8th Tumor-Node-Metastasis staging. Our study suggests thyroid irAEs and PD-L1 expression are independent biomarkers that improve predicting PD-1 blockade efficacy in NSCLC. Thyroid irAEs would be helpful to identify NSCLC patients who benefit from PD-1 blockade in early course of treatment.

Multi-center retrospective review of vitiligo-like lesions in breast cancer patients treated with cyclin-dependent kinase 4 and 6 inhibitors.

PURPOSE: Cutaneous adverse effects from cyclin-dependent 4 and 6 kinase inhibitors (CDK4/6i) used in metastatic breast cancer are prevalent and well described. Vitiligo-like lesions have been reported and are rare. They can negatively impact patients' quality of life and may be associated with survival benefits. We describe the clinical characteristics of vitiligo-like lesions in an international cohort of patients treated with CDK4/6i to help improve recognition and management. METHODS: Retrospective review of patients diagnosed with vitiligo-like lesions from CDK4/6i from five academic institutions in the USA and Europe was performed. Ten patients were included in the study. RESULTS: Median age of our patients was 55 (range 37-86). Median progression-free survival was 24 months in 5 patients. The median time to rash was 10 months. Sun-exposed areas such as the arms and face were the most affected areas. Multiple skin-directed therapies such as topicals, laser, and phototherapy were trialed with minor success. Mild repigmentation was seen in one patient treated with ruxolitinib cream. CDK4/6 treatment was discontinued due to the vitiligo-like lesions in one patient. CONCLUSION: Clinical characteristics are similar to previously reported findings in case reports and series. We add topical ruxolitinib as a potential treatment option for these patients and include data regarding progression-free survival that should continue to be collected. No definitive conclusions can be made regarding survival benefits from our cohort. Clinicians should refer these patients to dermatologists to aid with management.

Risk of emergency hospital admission related to adverse events after antibiotic treatment in adults with a common infection: impact of COVID-19 and derivation and validation of risk prediction models.

BACKGROUND: With the global challenge of antimicrobial resistance intensified during the COVID-19 pandemic, evaluating adverse events (AEs) post-antibiotic treatment for common infections is crucial. This study aims to examines the changes in incidence rates of AEs during the COVID-19 pandemic and predict AE risk following antibiotic prescriptions for common infections, considering their previous antibiotic exposure and other long-term clinical conditions. METHODS: With the approval of NHS England, we used OpenSAFELY platform and analysed electronic health records from patients aged 18-110, prescribed antibiotics for urinary tract infection (UTI), lower respiratory tract infections (LRTI), upper respiratory tract infections (URTI), sinusitis, otitis externa, and otitis media between January 2019 and June 2023. We evaluated the temporal trends in the incidence rate of AEs for each infection, analysing monthly changes over time. The survival probability of emergency AE hospitalisation was estimated in each COVID-19 period (period 1: 1 January 2019 to 25 March 2020, period 2: 26 March 2020 to 8 March 2021, period 3: 9 March 2021 to 30 June 2023) using the Kaplan-Meier approach. Prognostic models, using Cox proportional hazards regression, were developed and validated to predict AE risk within 30 days post-prescription using the records in Period 1. RESULTS: Out of 9.4 million patients who received antibiotics, 0.6% of UTI, 0.3% of URTI, and 0.5% of LRTI patients experienced AEs. UTI and LRTI patients demonstrated a higher risk of AEs, with a noted increase in AE incidence during the COVID-19 pandemic. Higher comorbidity and recent antibiotic use emerged as significant AE predictors. The developed models exhibited good calibration and discrimination, especially for UTIs and LRTIs, with a C-statistic above 0.70. CONCLUSIONS: The study reveals a variable incidence of AEs post-antibiotic treatment for common infections, with UTI and LRTI patients facing higher risks. AE risks varied between infections and COVID-19 periods. These findings underscore the necessity for cautious antibiotic prescribing and call for further exploration into the intricate dynamics between antibiotic use, AEs, and the pandemic.

Assessment of inverse publication bias in safety outcomes: an empirical analysis.

BACKGROUND: The aims of this study were to assess the presence of inverse publication bias (IPB) in adverse events, evaluate the performance of visual examination, and explore the impact of considering effect direction in statistical tests for such assessments. METHODS: We conducted a cross-sectional study using the SMART Safety, the largest dataset for evidence synthesis of adverse events. The visual assessment was performed using contour-enhanced funnel plots, trim-and-fill funnel plots, and sample-size-based funnel plots. Two authors conducted visual assessments of these plots independently, and their agreements were quantified by the kappa statistics. Additionally, IPB was quantitatively assessed using both the one- and two-sided Egger's and Peters' tests. RESULTS: In the SMART Safety dataset, we identified 277 main meta-analyses of safety outcomes with at least 10 individual estimates after dropping missing data. We found that about 13.7-16.2% of meta-analyses exhibited IPB according to the one-sided test results. The kappa statistics for the visual assessments roughly ranged from 0.3 to 0.5, indicating fair to moderate agreement. Using the one-sided Egger's test, 57 out of 72 (79.2%) meta-analyses that initially showed significant IPB in the two-sided test changed to non-significant, while the remaining 15 (20.8%) meta-analyses changed from non-significant to significant. CONCLUSIONS: Our findings provide supporting evidence of IPB in the SMART Safety dataset of adverse events. They also suggest the importance of researchers carefully accounting for the direction of statistical tests for IPB, as well as the challenges of assessing IPB using statistical methods, especially considering that the number of studies is typically small. Qualitative assessments may be a necessary supplement to gain a more comprehensive understanding of IPB.

Molecular fingerprints of cardiovascular toxicities of immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by unleashing the power of the immune system against malignant cells. However, their use is associated with a spectrum of adverse effects, including cardiovascular complications, which can pose significant clinical challenges. Several mechanisms contribute to cardiovascular toxicity associated with ICIs. First, the dysregulation of immune checkpoints, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1) and its ligand (PD-L1), and molecular mimicry with cardiac autoantigens, leads to immune-related adverse events, including myocarditis and vasculitis. These events result from the aberrant activation of T cells against self-antigens within the myocardium or vascular endothelium. Second, the disruption of immune homeostasis by ICIs can lead to autoimmune-mediated inflammation of cardiac tissues, manifesting as cardiac dysfunction and heart failure, arrhythmias, or pericarditis. Furthermore, the upregulation of inflammatory cytokines, particularly tumor necrosis factor-alpha, interferon-γ, interleukin-1ß, interleukin-6, and interleukin-17 contributes to cardiac and endothelial dysfunction, plaque destabilization, and thrombosis, exacerbating cardiovascular risk on the long term. Understanding the intricate mechanisms of cardiovascular side effects induced by ICIs is crucial for optimizing patient care and to ensure the safe and effective integration of immunotherapy into a broader range of cancer treatment protocols. The clinical implications of these mechanisms underscore the importance of vigilant monitoring and early detection of cardiovascular toxicity in patients receiving ICIs. Future use of these key pathological mediators as biomarkers may aid in prompt diagnosis of cardiotoxicity and will allow timely interventions.