Correlation between immune-related adverse events and long-term outcomes in pembrolizumab-treated patients with unresectable hepatocellular carcinoma:A retrospective study

BACKGROUND Although immune checkpoint inhibitor(ICI)therapy has improved the prognosis of unresectable hepatocellular carcinoma(HCC),it has also resulted in unique immune-related adverse events(irAEs).The relationship between irAE and treatment outcomes in ICI-treated unresectable HCC patients remains unknown.AIM To elucidate the correlation between immune-related toxic effects and prognosis in patients with unresectable HCC treated with pembrolizumab.METHODS From March 2019 to February 2021,a total of 190 unresectable HCC(Barcelona Clinic Liver Cancer C)patients receiving pembrolizumab treatment were retrospectively reviewed.Overall survival(OS)was the primary endpoint,while objective response rate(ORR),disease control rate(DCR),and time to progression(TTP)were secondary evaluation indexes.We assessed demographics,irAEs,and outcomes by retrospective review.RESULTS One hundred and forty-three males and 47 females were included in the study.The ORR and DCR were 12.1%(23/190)and 52.1%(99/190),respectively.The median OS was 376 d[95%confidence interval(CI):340-411 d]and the median TTP was 98 d(95%CI:75-124 d).The overall incidence of treatment-related adverse events was 72.6%(138/190)and 10.0%of them were severe irAEs(grade≥3).Child-Pugh B class,portal vein tumor thrombus,extrahepatic metastasis,and hypothyroidism were the independent risk factors for survival.Patients with hypothyroidism showed a longer OS[517 d(95%CI:423-562)vs 431 d(95%CI:412-485),P=0.011]and TTP[125 d(95%CI:89-154)vs 87 d(95%CI:61-98),P=0.004]than those without irAEs.CONCLUSION Pembrolizumab-treated patients with unresectable HCC who experienced hypothyroidism have promising ORR and durable response.Hypothyroidism,an irAE,may be used as a clinical evaluation parameter of response to ICIs in unresectable HCC.

Immune-related adverse events induced by programmed death protein-1 inhibitors from the perspective of lymphoma immunotherapy

Lymphoma,which is highly malignant,stems from lymph nodes and lymphoid tissue.Lymphoma cells express programmed death-ligand 1/2(PD-L1/PD-L2),which binds with programmed cell death 1 protein(PD-1)to establish inhibitory signaling that impedes the normal function of T cells and allows tumor cells to escape immune system surveillance.Recently,immune checkpoint inhibitor immunotherapies such as PD-1 inhibitors(nivolumab and pembrolizumab)have been introduced into the lymphoma treatment algorithm and have shown remarkable clinical efficacy and greatly improve prognosis in lymphoma patients.Accordingly,the number of lymphoma patients who are seeking treatment with PD-1 inhibitors is growing annually,which results in an increasing number of patients developing immune-related adverse events(irAEs).The occurrence of irAEs inevitably affects the benefits provided by immunotherapy,particularly when PD-1 inhibitors are applied.However,the mechanisms and characteristics of irAEs induced by PD-1 inhibitors in lymphoma need further investigation.This review article summarizes the latest research advances in irAEs during treatment of lymphoma with PD-1 inhibitors.A comprehensive understanding of irAEs incurred in immunotherapy can help to achieve better efficacy with PD-1 inhibitors in lymphoma.

Analysis of characteristics and predictive factors of immune checkpoint inhibitor-related adverse events

Objective:We aimed to retrospectively analyze the toxicity profiles and predictors of immune-related adverse events(irAEs)as well as the correlation between irAEs and the clinical efficacy of multi-type immune checkpoint inhibitors(ICIs)in patients with advanced pan-cancer in a real-world setting.Methods:We retrospectively analyzed data from 105 patients with advanced pan-cancer treated with multi-type ICIs at the First Hospital of Jilin University between January 1,2016 and August 1,2020.We used logistic regression analyses to investigate the associations of irAEs with clinical baseline characteristics,blood count parameters,and biochemical indicators during treatment.Receiver operating characteristic curves were used to determine cutoff values for parameters and area under the curve values.Kaplan–Meier and Cox multivariate regression analyses were performed to estimate the relationships of baseline characteristics and irAEs with progression-free survival(PFS)and overall survival(OS).Results:A lower relative lymphocyte count(cutoff=28.5%),higher albumin level(cutoff=39.05 g/L),and higher absolute eosinophil count(AEC)(cutoff=0.175×10^(9)/L)were significantly associated with the occurrence of irAEs,among which a higher AEC(cutoff=0.205×10^(9)/L)was strongly associated with skin-related irAEs[odds ratios(ORs)=0.163,P=0.004].Moreover,a higher lactate dehydrogenase level(cutoff=237.5 U/L)was an independent predictor of irAEs of grade≥3(OR=0.083,P=0.023).In immune cell subgroup analysis,a lower absolute count of CD8+CD28−suppressor T cells(OR=0.806;95%confidence interval:0.643–1.011;P=0.062),which are regulatory T lymphocytes,was associated with the occurrence of irAEs,although the difference was not statistically significant.Furthermore,a higher percentage of CD19+B cells was associated with the occurrence of irAEs of grade≥3(P=0.02)and grade≥2(P=0.051).In addition,patients with any grade of irAE had a significantly high PFS(8.37 vs.3.77 months,hazard ratios(HR)=2.02,P=0.0038)and OS(24.77 vs.13.83 months,HR=1.84;P=0.024).Conclusions:This retrospective study reports clinical profile data for irAEs in unselected patients in a real-world setting and explored some parameters that may be potential predictive markers of the occurrence,type,or grade of irAEs in clinical practice.Evidence of a correlation between safety and efficacy may facilitate a complete assessment of the risk-benefit ratio for patients treated with ICIs.

Use of traditional Chinese medicine in the treatment of immune-related adverse events of cancer immunotherapy

Immune checkpoint inhibitors(ICPI)have shown considerable promise in the treatment of tumors.However,immune-related adverse events(irAEs)caused by ICPI have been reported in nearly every organ system.Whilst this represents a new challenge in the field of cancer treatment,traditional Chinese medicine(TCM)provides benefits in the treatment of irAEs.This article reviews the studies of the treatment of immune-related gastrointestinal diseases and dermatosis with TCM and introduces the collaborative efforts between China and France in the implementation of TCM for the treatment of irAEs.

Adverse Events following AstraZeneca COVID-19 Vaccination: A Case Study in Abidjan, Côte d’Ivoire

Introduction: Pharmaceutical companies have boosted vaccine production following the global COVID-19 pandemic. In Côte d’Ivoire, the first vaccination campaign with the AstraZeneca vaccine began on March 1, 2021, as part of the Covax program. Despite the positive benefit/risk balance, the adverse effects of vaccination should not be minimized. Objective: To identify adverse events of AstraZeneca’s COVID-19 vaccination for better management. Materials and Methods: This is a case of a 57-year-old obese (BMI = 39 kg/m2) female health care worker who experienced adverse events in March 2021 after the second dose of AstraZeneca vaccine administered 4 weeks apart. These were subject to mandatory case reporting. Results: Major post-vaccination events occurred in a noisy systemic picture with parameters showing significant disturbances. Biological surveillance remains costly and makes the accountability of the vaccine complex. Conclusion: Vaccination remains the ultimate weapon in the fight against endemic diseases but should not overshadow the reporting of adverse events.

Treatment-related adverse events of combined anti-angiogenic and immune checkpoint inhibitors:systematic review and meta-analysis

Objective Immune checkpoint inhibitor(ICI)plus angiogenesis inhibitor(AI)combination therapy is a novel treatment model for multiple cancers that normalizes vascular-immune crosstalk to potentiate cancer immunity.In this review,we summarize the characteristics of adverse effects(AEs)and all fatal cases reported in clinical studies involing ICI+AI therapy.Methods Four databases were systematically searched for eligible studies,and 28 relevant studies were selected for inclusion.Results Of the patients included,58.1%developed grade≥3 AEs.The most common fatal AEs were cardiovascular events,severe infections,and hemorrhage.Compared with AI alone,ICI+AI therapy resulted in more cases of grade≥3 proteinuria,liver injury,and fatal AEs(2.49%vs.1.28%,P=0.0041),especially respiratory toxicities and severe infections;however,ICI+AI therapy reduced hematological toxicity.Conclusion We shared comprehensive and practical safety data to review the adverse events associated with ICI+AI treatment.

Knowledge,perceptions,and practice towards adverse events following immunization surveillance among vaccination workers in Zhejiang province,China

Objective:To access the level of knowledge,perceptions,and practice towards adverse events following immunization(AEFI)surveillance among vaccination workers in Zhejiang province,China.Methods:This was a cross-sectional survey involving 768 vaccination workers.Data were collected using self-administered questionnaires and analyzed by using SAS 9.3 software.Knowledge,perceptions,and practice on AEFI surveillance were summarized using frequency tables.The mean±SD value was used as the cut-off for defining good(values≥mean)and poor(values<mean)knowledge,perceptions or practice.Binary logistic regression analysis was used to determine sociodemographic variables associated with knowledge,perceptions,and practice towards AEFI.Results:The proportions of good knowledge,perceptions and practice on AEFI surveillance were 78.13%,57.81%and 66.15%,respectively.Having a higher education background,longer years of experience,previous training on AEFI and≥30 years of age were factors associated with good knowledge,perceptions and practice on AEFI surveillance among vaccination workers.Conclusions:Over half of the respondents had good knowledge,perceptions and practice on AEFI surveillance work.Interventions on improving the vaccination workers’knowledge,perceptions and practice on AEFI surveillance should be considered in order to develop a more effective surveillance system.

Pericardial Effusion with Tamponade, an Immune-Related Adverse Event Associated with Nivolumab Therapy: A Case Report and Review of the Literature

Immune checkpoint inhibitors have shown to be very effective when treating lung cancer. Nivolumab, a programmed death-1 (PD-1) inhibitor has been approved for the treatment of metastatic non-squamous and squamous NSCLC. Immunotherapy with checkpoint inhibitors are associated with toxicities defined as immune-related adverse events (irAEs). The most common irAEs are rash, colitis, hepatitis, pneumonitis, and endocrinopathies. Although any organ system can be affected, other rare irAEs can occur and affect the bone marrow, pancreas, and the neurologic and cardiac systems. Pericardial effusion induced by immunotherapy is uncommon and has been described only in a few case reports. Immune-related adverse events usually develop within the first weeks to months after treatment initiation. This is a case report of a 52-year-old male patient with metastatic squamous-cell lung cancer who had a massive pericardial effusion secondary to treatment with nivolumab as second line treatment. During his hospital stay, the patient underwent pericardiocentesis and treatment with corticosteroids. A CT scan after these treatments revealed complete tumor response and minimal pericardial effusion. Nivolumab was definitively ceased. The patient continues to show complete response for 16 months. In general, Nivolumab is well-tolerated and has an excellent safety profile. However, it is important to be aware of life-threatening immune-related adverse events, particularly cardiac toxicity. Consensus guidelines regarding the treatment of the most common irAEs have been established. The optimal management of irAEs is based on clinical experience. It’s crucial to report new or rare irAEs to conduct prospective trials to evaluate the best treatment strategy.

Immune checkpoint inhibitor-associated ophthalmic adverse events: current understanding of its mechanisms,diagnosis, and management

Immune checkpoint inhibitors(ICIs) targeting cytotoxic T-lymphocyte antigen 4 and programmed cell death protein 1 receptor/ligand have revolutionized cancer treatment, achieving unprecedented efficacy in numerous malignancies. Despite the excellent therapeutic effects of ICIs, medications, such as pembrolizumab, ipilimumab, nivolumab, atezolizumab, avelumab, and durvalumab, typically cause a broad spectrum of toxicity events termed as immune-related adverse events(ir AEs). Out of all ir AEs, ophthalmic adverse events occur infrequently and are not comprehensively recognized. The current understanding of ophthalmic ir AEs is mainly derived from case reports and case series. In this review, based on relevant articles in the literature and current evidence, we summarize the incidences, manifestations, diagnoses, underlying mechanisms, treatments, and outcomes of ophthalmic ir AEs and discuss possible management strategies. A better understanding of these features is critical for managing patients with ICI-associated ophthalmic adverse events.

Immune Checkpoint Inhibitor Related Neuropathic Adverse Effects on Cancer Patients

With the recent development and clinical application, immune checkpoint inhibitors (ICIs) intervention is being increasingly common for multiple malignancies. With these, prospect on focus creates an increasing necessity for an early recognition with proper documentation of upcoming treatment-related toxicities. These treatment-related toxicities are generally termed as immune-related adverse effects (irAEs) [1]. It is a known fact that the upregulation of T-cell initiates autoimmunity resulting in these irAEs. The review focuses on increasing events of neuropathy associated with immunecheckpoint inhibitors, which is one of the rare neurological irAEs, therefore, the least reviewed. The severity and distribution of neurologic toxicities are important deciding factors for its management (CNS vs. PNS), although there is no strong evidence for patients treated with ICIs are specifically affected by the use of immune-modulating interventions. Furthermore, the review discusses on pathophysiology, incidence, clinical presentation, diagnosis, and management of neuropathies as a result of ICIs. Early administration of high-dose corticosteroids is the main management of neuropathies especially for grade 3 or 4 irAEs initial cessation of ICI therapy with continued steroids which are necessary. However, the optimal duration of ICI therapy to minimize the risk of toxicity should be kept under consideration.

Cardiac adverse events of immune checkpoint inhibitors in oncology patients:A systematic review and meta-analysis

BACKGROUND Immune checkpoint inhibitors(ICIs)are novel therapeutic agents used for various types of cancer.ICIs have revolutionized cancer treatment and improved clinical outcomes among cancer patients.However,immune-related adverse effects of ICI therapy are common.Cardiovascular immune-related adverse events(irAEs)are rare but potentially life-threatening complications.AIM To estimate the incidence of cardiovascular irAEs among patients undergoing ICI therapy for various malignancies.METHODS We conducted this systematic review and meta-analysis by searching PubMed,Cochrane CENTRAL,Web of Science,and SCOPUS databases for relevant interventional trials reporting cardiovascular irAEs.We performed a single-arm meta-analysis using OpenMeta[Analyst]software of the following outcomes:Myocarditis,pericardial effusion,heart failure,cardiomyopathy,atrial fibrillation,myocardial infarction,and cardiac arrest.We assessed the heterogeneity using the I2 test and managed to solve it with Cochrane’s leave-one-out method.The risk of bias was performed with the Cochrane’s risk of bias tool.RESULTS A total of 26 studies were included.The incidence of irAEs follows:Myocarditis:0.5%[95%confidence interval(CI):0.1%-0.9%];Pericardial effusion:0.5%(95%CI:0.1%-1.0%);Heart failure:0.3%(95%CI:0.0%-0.5%);Cardiomyopathy:0.3%(95%CI:-0.1%-0.6%);atrial fibrillation:4.6%(95%CI:1.0%-14.1%);Myocardial infarction:0.4%(95%CI:0.0%-0.7%);and Cardiac arrest:0.4%(95%CI:0.1%-0.8%).CONCLUSION The most common cardiovascular irAEs were atrial fibrillation,myocarditis,and pericardial effusion.Although rare,data from post market surveillance will provide estimates of the long-term prevalence and prognosis in patients with ICIassociated cardiovascular complications.

Blood and Histopathological Biomarkers of Immune-related Adverse Effects of Treatment with Immune Checkpoint Inhibitors

Immune checkpoint inhibitors have been a recent major breakthrough in the management of tumors.They have broadened the scope of management in medical oncology,which has been heavily dependent on chemotherapy.Immune checkpoint inhibitors have renewed the hope of many patients for a more effective treatment.However,Immune checkpoint inhibitors are also associated with a variety of adverse effects,most commonly immunerelated adverse events,and these are often different from the known chemotherapy-induced toxicities.Hence,there is a need to identify specific biomarkers which are able to predict or diagnose these immune-related adverse events.

Managing immune checkpoint inhibitor-associated gastritis: Insights and strategies

Immune checkpoint inhibitors(ICIs)are widely used due to their effectiveness in treating various tumors.Immune-related adverse events(irAEs)are defined as adverse effects resulting from ICI treatment.Gastrointestinal irAEs are a common type of irAEs characterized by intestinal side effects,such as diarrhea and colitis,which may lead to the discontinuation of ICIs.

Immune checkpoint inhibitor-associated gastritis:Patterns and management

Immune checkpoint inhibitors(ICIs)are widely used due to their effectiveness in treating various tumors.Immune-related adverse events(irAEs)are defined as adverse effects resulting from ICI treatment.Gastrointestinal irAEs are a common type of irAEs characterized by intestinal side effects,such as diarrhea and colitis,which may lead to the cessation of ICIs.Although irAE gastritis is rarely reported,it may lead to serious complications such as gastrorrhagia.Furthermore,irAE gastritis is often difficult to identify early due to its diverse symptoms.Although steroid hormones and immunosuppressants are commonly used to reverse irAEs,the best regimen and dosage for irAE gastritis remains uncertain.In addition,the risk of recurrence of irAE gastritis after the reuse of ICIs should be considered.In this editorial,strategies such as early identification,pathological diagnosis,mana-gement interventions,and immunotherapy rechallenge are discussed to enable clinicians to better manage irAE gastritis and improve the prognosis of these patients.

Application of immune checkpoint inhibitors and microsatellite instability in gastric cancer

In this editorial we comment on the article by Li published in the recent issue of the World Journal of Gastroenterology.We focus specifically on the application of immune checkpoint inhibitors(ICIs)and microsatellite instability(MSI)in gastric cancer(GC).The four pillars of GC management have long been considered,including surgery,chemotherapy,radiotherapy and targeted therapy.However,immunotherapy has recently emerged as a“fifth pillar”,and its use is rapidly expanding.There are four principal strategies for tumor immunotherapy:ICIs,tumor vaccines,adoptive immunotherapy and nonspecific immunomodulators.Of them,ICIs are the most advanced and widespread type of cancer immunotherapy for GC.Recent breakthrough results for ICIs have paved the way to a new era of cancer immunotherapy.In particular,inhibition of the PD-1/PD-L1 axis with ICIs,including nivolumab and pembrolizumab,has emerged as a novel treatment strategy for advanced GC.Unfortunately,these therapies are sometimes associated with often subtle,potentially fatal immune-related adverse events(irAEs),including dermatitis,diarrhea,colitis,endocrinopathy,hepatotoxicity,neuropathy and pneumonitis.We must be aware of these irAEs and improve the detection of these processes to prevent inappropriate discharges,emergency department revisits,and downstream complications.Recent studies have revealed that MSI-high or mismatch-repair-deficient tumors,regardless of their primary site,have a promising response to ICIs.So,it is important to detect MSI before applying ICIs for treatment of GC.

Gastric microbiota transplantation as a potential treatment for immune checkpoint inhibitor-associated gastritis

Immune-related adverse events(irAEs)are complications of the use of immune checkpoint inhibitors(ICIs).ICI-associated gastritis is one of the main irAEs.The gastric microbiota is often related to the occurrence and development of many gastric diseases.Gastric microbiota adjustment may be used to treat gastric disorders in the future.Faecal microbiota transplantation can alter the gut microbiota of patients and has been used for treating ICI-associated colitis.Therefore,we propose gastric microbiota transplantation as a supplementary treatment for patients with ICI-associated gastritis who do not respond well to conventional therapy.

A Case of Investigation and Diagnosis of Immune Thrombocytopenic Purpura After Vaccination of COVID-19 Inactivated Vaccine

Objective:Analyze the relationship between inoculating one case of the COVID-19 inactivated vaccine(Vero cell)and immune thrombocytopenic purpura to provide a reference for the standardized handling of adverse events following immunization.Methods:According to the"National Monitoring Program for Suspected Adverse Reactions to Vaccinations,"an on-site investigation,data collection and analysis,expert group diagnosis,and medical association assessment were conducted on a case of immune thrombocytopenic purpura in District A of Chongqing after vaccination with the inactivated COVID-19 vaccine.The assessment report was delivered to the three relevant parties,the case was reviewed,and the experience was summarized.Results:The investigation and diagnosis by the district-level vaccination abnormal reaction expert group concluded that the disease that occurred after vaccination with the COVID-19 inactivated vaccine was secondary immune thrombocytopenic purpura,an abnormal reaction to the vaccination.The medical damage was classified as Level II Grade B.The vaccine production enterprise raised objections to this conclusion.After re-assessment by the municipal-level medical association,the conclusion was consistent with that of the district-level medical association.The vaccine production enterprise did not raise any further objections.Conclusion:Through active collaboration among district and municipal-level medical associations,disease control institutions,and vaccination units,the recipients have been promptly and effectively treated,providing financial support for their subsequent treatment and safeguarding their rights.The investigation and disposal procedures for adverse events following immunization in Chongqing are clear,and the mechanism is sound.It is necessary to continue strengthening the monitoring of adverse events following immunization according to the existing plan and to ensure timely and standardized handling.Simultaneously,it is crucial to strengthen vaccine management and vaccination management.

Immune checkpoint inhibitor-related hepatotoxicity:A review

The application of immune checkpoint inhibitors(ICI)in advanced cancer has been a major development in the last decade.The indications for ICIs are constantly expanding into new territory across different cancers,disease stages and lines of therapy.With this increased use,adverse events including immune checkpoint inhibitor-related hepatotoxicity(ICH)have emerged as an important clinical problem.This along with the introduction of ICI as first-and second-line treatments for advanced hepatocellular carcinoma makes ICH very relevant to gastroenterologists and hepatologists.The incidence of ICH varies between 1%-20%depending on the number,type and dose of ICI received.Investigation and management generally involve excluding differential diagnoses and following a stepwise escalation of withholding or ceasing ICI,corticosteroid treatment and adding other immunosuppressive agents depending on the severity of toxicity.The majority of patients with ICH recover and some may even safely recommence ICI therapy.Guideline recommendations are largely based on evidence derived from retrospective case series which highlights a priority for future research.

Clinical decision support for drug related events: Moving towards better prevention

Clinical decision support(CDS) systems with automated alerts integrated into electronic medical records demonstrate efficacy for detecting medication errors(ME) and adverse drug events(ADEs). Critically ill patients are at increased risk for ME, ADEs and serious negative outcomes related to these events. Capitalizing on CDS to detect ME and prevent adverse drug related events has the potential to improve patient outcomes. The key to an effective medication safety surveillance system incorporating CDS is advancing the signals for alerts by using trajectory analyses to predict clinical events, instead of waiting for these events to occur. Additionally, incorporating cutting-edge biomarkers into alert knowledge in an effort to identify the need to adjust medication therapy portending harm will advance the current state of CDS. CDS can be taken a step further to identify drug related physiological events, which are less commonly included in surveillance systems. Predictive models for adverse events that combine patient factors with laboratory values and biomarkers are being established and these models can be the foundation for individualized CDS alerts to prevent impending ADEs.

Advances on immune-related adverse events associated with immune checkpoint inhibitors

Immunotherapy has recently led to a paradigm shift in cancer therapy,in which immune checkpoint inhibitors(ICIs)are the most successful agents approved for multiple advanced malignancies.However,given the nature of the non-specific activation of effector T cells,ICIs are remarkably associated with a substantial risk of immune-related adverse events(irAEs)in almost all organs or systems.Up to 90%of patients who received ICIs combination therapy experienced irAEs,of which majority were low-grade toxicity.Cytotoxic lymphocyte antigen-4 and programmed cell death protein-1/programmed cell death ligand 1 inhibitors usually display distinct features of irAEs.In this review,the mechanisms of action of ICIs and how they may cause irAEs are described.Some unsolved challenges,however really engrossing issues,such as the association between irAEs and cancer treatment response,tumor response to irAEs therapy,and ICIs in challenging populations,are comprehensively summarized.