Research progress in immune-related liver injury caused by immune checkpoint inhibitors / 国际生物医学工程杂志

In recent years, immune checkpoint inhibitors (ICIs) have made great progress in the treatment of tumor patients, prolonging their survival. However, the expansion of immunity against tumors with ICIs may also cause an imbalance in immune tolerance, leading to immune-related adverse events (irAEs). Immune-mediated liver injury caused by ICIs (ILICI) is one of the more common types of irAEs. In this review paper, the definition, epidemiology, risk factors, pathogenesis, pathology, clinical manifestations, treatment, recurrence, and re-treatment of ILICI were summarized to provide a basis for clinical diagnosis and treatment.

Practice and analysis of clinical pharmacist participating in the treatment of a case of acanthoma caused by navulizumab / 中国药房

This paper reports the clinical pharmacist participated in the diagnosis and treatment of a patient with acanthoma caused by nivolumab. This patient developed acanthoma 2 weeks after medication， involving scalp， neck， trunk， back of hand， sole of foot and other parts， with moderate pruritus. The clinical pharmacist determined it as “yes” according to the causality evaluation method of adverse reactions. After reviewing the literature， clinical pharmacists found that acanthoma caused by immune checkpoint inhibitors was more commonly seen in male elderly patients with malignant melanoma， and mainly involved the trunk， extremities and hands. Under the general principle of considering the effectiveness， safety， economy and accessibility of therapeutic drugs， the clinical pharmacist finally decided to give the patient a comprehensive treatment scheme of Halometasone cream for external use + oral administration of Retinoic acid capsules + oral administration of Ebastine tablets after discussion with the doctor， with maximum respect for the patient’s wishes，and continued to use navulizumab for immunotherapy. At the same time， pharmaceutical care and psychological counseling were conducted by clinical pharmacist. Finally， the patient successfully completed the treatment， and the acanthoma gradually subsided after the end of navulizumab treatment. The diagnosis and treatment process of this patient indicated that the participation of clinical pharmacists is helpful to improve the continuity and safety of immunotherapy.

Correlation Analysis between Thyroid Function Abnormality and Efficacy in Patients with Advanced Non-small Cell Lung Cancer after Immunotherapy / 中国肺癌杂志

BACKGROUND@#Thyroid function abnormality (TFA) is one of the common adverse reactions in patients with advanced non-small cell lung cancer (NSCLC) treated with immunotherapy, but the risk factors of TFA and its relationship with efficacy are not completely clear. The purpose of this study was to explore the risk factors of TFA and its relationship with efficacy in patients with advanced NSCLC after immunotherapy.@*METHODS@#The general clinical data of 200 patients with advanced NSCLC in The First Affiliated Hospital of Zhengzhou University from July 1, 2019 to June 31, 2021 were collected and analyzed retrospectively. χ² test and multivariate Logistic regression were used to explore the risk factors of TFA. Kaplan-Meier curve was drawn and Log-rank test was used for comparison between groups. Univariate and multivariate Cox analysis was used to explore the efficacy factors.@*RESULTS@#A total of 86 (43.0%) patients developed TFA. Logistic regression analysis showed that Eastern Cooperative Oncology Group Performance Status (ECOG PS), pleural effusion and lactic dehydrogenase (LDH) were factors influencing TFA (P<0.05). Compared with normal thyroid function group, the median progression-free survival (PFS) of patients in the TFA group was significantly longer (19.0 months vs 6.3 months, P<0.001), and the objective response rate (ORR) (65.1% vs 28.9%, P=0.020) and disease control rate (DCR) (100.0% vs 92.1%, P=0.020) of the TFA group were better than those of the normal thyroid function group. Cox regression analysis showed that ECOG PS, LDH, cytokeratin 19 fragment (CYFRA21-1) and TFA were factors influencing prognosis (P<0.05).@*CONCLUSIONS@#ECOG PS, pleural effusion and LDH may be risk factors affecting the occurrence of TFA and TFA may be a predictor of the efficacy of immunotherapy. Patients with advanced NSCLC who have TFA after immunotherapy may obtain better efficacy.

A Real-world Study on the Incidence and Outcome of Immune-related Adverse Events in Lung Cancer Patients / 中国肺癌杂志

BACKGROUND@#Immune-related adverse events (irAEs) are commonly occurred in patients treated with immune checkpoint inhibitors. However, evidence of irAEs derived from the Chinese population is relatively lacking. The aim of this study was to investigate the incidence and outcomes of irAEs in Chinese patients with lung cancer after receiving immune checkpoint inhibitors (ICIs).@*METHODS@#Clinical and follow-up data from lung cancer patients who received at least one time of ICIs from January 2018 to September 2021 at Huadong Hospital, Fudan University were included. Statistical descriptions and Kaplan-Meier method were used to analyze the overall incidence of irAEs, as well as the incidence and outcomes of each type of irAEs.@*RESULTS@#135 patients were included in the study. 106 patients (78.5%) presented at least one type of irAEs, and the median time to first irAEs onset was 28 d. Most irAEs occurred at early time after treatment, and most irAEs were mild-moderate and reversible. 57 patients (42.2%) died at the study cutoff. The mortality rate of severe irAEs was 12.6% (n=17), and among them 7 patients (41.2%) died of pneumonitis. The median progression-free survival (PFS) and overall survival (OS) time of the total population was 505 d (95%CI: 352-658) and 625 d (95%CI: 491-759), respectively. Patients who presented any irAEs achieved a longer PFS than those who did not (median PFS: 533 d vs 179 d, P=0.037, HR=0.57), while patients who presented skin toxicities achieved a longer OS than patients who did not (median OS: 797 d vs 469 d, P=0.006, HR=0.70).@*CONCLUSIONS@#In real-world settings, irAEs in lung cancer patients were commonly observed, with pneumonitis as the most common fatal irAEs. In addition, patients who presented any irAEs may tend to achieve a longer PFS.

Case analysis of multiple endocrine adverse reactions associated with immune checkpoint inhibitors / 中华内分泌代谢杂志

Objective:To investigate the clinical features of multiple endocrine gland dysfunction in patients with tumors after using immune checkpoint inhibitors(ICIs).Methods:Cases with two or more abnormalities of endocrine gland function after immunotherapy were collected from the Department of Endocrinology, Zhongshan Hospital, Fudan University between January 2019 and January 2022. Clinical manifestations, laboratory tests, imaging, treatment and prognosis were analyzed.Results:A total of 12 patients were included, 6 males and 6 females, aged(61.2±10.0) years old. All patients received programmed cell death protein-1(PD-1) monoclonal antibody therapy, and the time to endocrine abnormality ranged from 9 to 94 weeks after administration. All patients developed primary hypothyroidism, 11 of them had isolated adrenocorticotropic hormone deficiency, and 1 had primary adrenal insufficiency.Conclusion:ICIs can involve multiple endocrine glands simultaneously or successively, mainly manifested as primary hypothyroidism and isolated adrenocorticotropic hormone deficiency. It is essential to assess the function of the pituitary and target glands in patients treated with ICIs to improve the safety of immunotherapy.

Real-world study evaluating the incidence of liver damage conditions in patients with primary liver cancer using immune checkpoint inhibitor-based combination therapy / 中华肝脏病杂志

Objective: To evaluate the incidence of immune checkpoint inhibitor-based combination therapy-induced liver damage in patients with primary liver cancer. Methods: Clinical data of 65 hospitalized cases of primary liver cancer treated with programmed cell death-1 its ligand programmed death-ligand 1 (PD-1/PD-L1) antibody in the Department of Infectious Diseases of the Second Affiliated Hospital of Chongqing Medical University from January 1, 2018 to March 31, 2021 were retrospectively analyzed. The degree of liver injury before and after treatment was assessed according to CTCAE v5.0. Patients were grouped according to gender, age, presence or absence of cirrhosis, baseline Child-Pugh score, BCLC stage, and treatment regimen to compare the incidence of liver injury under different conditions. The χ (2) test or rank-sum test was used for comparison among multiple groups. Results: 46 cases (70.77%) had liver damage of any grade according to the CTCAE V5.0 criteria during the treatment and observation period. All 6 cases who received standardized anti-hepatitis B virus (HBV) treatment developed liver damage. 10 (15.38%), 15 (23.08%), 19 (29.23%), and 2 (3.08%) cases had grade 1, 2, 3, and 4 liver damage respectively. There was no statistically significant difference in the incidence of liver damage between male and female patients (68.33% and 100%, P = 0.180). There was no statistically significant difference in the incidence of liver damage among different age groups (P = 0.245). The incidence of liver damage in cirrhotic and non-cirrhotic group was 72.22%, and 63.64% (P = 0.370), respectively. The incidence of liver damage in patients with baseline Child-Pugh class A, B, and C were 71.43%, 61.11% and 100%, respectively, and the difference was not statistically significant (P = 0.878). The incidence of liver damage was not statistically significantly different under different BCLC stages (P = 1.000). The incidence of liver damage in the PD-1/PD-L1 antibody monotherapy, PD-1/PD-L1 antibody combined with targeted drug therapy, and PD-1/PD-L1 antibody combined with TACE/radiofrequency ablation treatment group were 60.00%, 67.85%, and 86.67%, respectively. There was no statistically significant difference in the incidence of liver damage between the treatment regimen (P = 0.480). Conclusion: Immune checkpoint inhibitor therapy-induced liver damage is common in patients with primary liver cancer; however, it rarely severely endangers the patient's life. Additionally, patient's gender, age, presence or absence of cirrhosis, baseline liver function, BCLC stage and the immunotherapy regimen has no effect on the incidence of immune-related liver damage.

Clinical value of 18F-FDG PET/CT imaging for detecting immune related adverse events of the combined immunotherapy in hepatobiliary carcinoma / 中华核医学与分子影像杂志

Objective:To investigate the capability of 18F-FDG PET/CT imaging in monitoring combined immunotherapy response and detecting immune related adverse events (irAEs) in patients with advanced hepatobiliary carcinoma. Methods:From August 2018 to July 2019, 21 patients (14 males, 7 females, age (58.5±10.0) years) with advanced hepatobiliary carcinoma routinely underwent 66 18F-FDG PET/CT examinations in Peking Union Medical College Hospital. SUV max, the occurrence time and symptoms of irAEs were obtained and analyzed. Therapy response (complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), progressive metabolic disease (PMD)) was evaluated according to PET response criteria in solid tumors (PERCIST). Results:(1) Clinical results. Twenty-two irAEs occurred in 16 patients, while were not found in 5 patients. Six organs were involved, including thyroiditis(8), colitis(5), pneumonitis(4), rash(2), hepatitis(2), myositis and fasciitis(1). The appearance time of each irAEs were (103.0±58.0), (141.6±103.5), 34.0(6.0, 308.8), 9 and 117, 62 and 67, and 87 d after therapy, respectively. PET/CT detected all pneumonitis and myositis and fasciitis, but no rash and hepatitis were found. For colitis and thyroiditis, PET/CT detected 4 and 6 times respectively. (2) PET/CT signs of irAEs. Except thyroiditis, all irAEs lesions exhibited exudative changes in CT and high-avidity in PET. SUV max of the lesions were 9.0(7.9, 17.6) (colitis), 7.1±3.2 (thyroiditis), 5.3 and 8.6 (pneumonitis), 4.1 (myositis and fasciitis), respectively. (3) Therapy assessment. Among 21 patients, there were 7 for PMR, 9 for SMD, 5 for PMD, which were 7, 8, 1 in patients with irAEs and 0, 1, 4 in patients without irAEs. Conclusions:Patients with advanced hepatobiliary carcinoma can benefit from combined immunotherapy. 18F-FDG PET/CT can be used to evaluate the efficacy of immunotherapy by detecting the changes of tumor lesions and the occurrence of irAEs simultaneously. However, it is necessary to use CT to distinguish tumor progression from irAEs.

18F-FDG PET/CT in detecting immune-related adverse events / 中华核医学与分子影像杂志

Immune checkpoint inhibitors (ICIs) have shown significant efficacy in clinical trials and applications of various malignant tumors, and have been approved for clinical application in China. ICIs can cause immune-related adverse events (irAEs), which may affect any organs. Early identification and appropriate treatment can improve patient outcome. 18F-FDG PET/CT is capable of early detection of irAEs and provides effective clinical guidance. This article reviews the clinical application of 18F-FDG PET/CT in detecting irAEs, including typical imaging findings and research progress.

Meta-analysis of the correlation between immune-related adverse events and efficacy of immune checkpoint inhibitors in the treatment of non-small cell lung cancer / 中国药房

OBJECTIVE To sy stematically evaluate the relations hip between immune-related adverse events （irAEs） and efficacy of immune checkpoint inhibitors （ICIs） in the treatment of non-small cell lung cancer （NSCLC），and to provide evidence-based reference for clinical application of ICIs and safety evaluation. METHODS PubMed，Embase，Cochrane Library ， Web of Science ，CNKI，Wanfang database ，VIP and CBM were searched to collect prospective or retrospective cohort studies on the correlation between irAEs and efficacy of ICIs in the treatment of NSCLC. The retrieval time was from the inception to June 30th，2021. After literature screening and data extraction ，Newcastle-Ottawa scale was used to evaluate the quality of included literatures. Meta-analysis and publication bias analysis were performed by using RevMan 5.3 software；Stata 15.0 software was used for sensitivity analysis. RESULTS A total of 7 957 patients were included in 31 studies. Meta-analysis showed that the objective response rate （ORR）[RR＝2.34，95％CI（1.98，2.76），P＜0.000 01]，progression-free survival （PFS）[HR＝0.49，95％CI （0.44，0.55），P＜0.000 01] and overall survival （OS）[HR＝0.45，95％CI（0.39，0.53），P＜0.000 01] of irAEs group as well as ORR[RR＝1.88，95％CI（1.57，2.25），P＜0.000 01]，PFS [HR ＝0.59，95％CI（0.50，0.69），P＜0.000 01] and OS [HR ＝0.58，95％CI （0.48，0.70），P＜0.000 01] of this group at 6th week were all significantly higher or longer than non irAEs group. According to organ specificity ，severity and quantity of irAEs，subgroup analysis showed that skin ，gastrointestinal and endocrine system ，mild irAEs（grade 1-2）and one or more than 2 kinds of irAEs were significantly correlated with the improvement of PFS and OS （P＜ 0.05），while liver and lung ，severe irAEs（≥ grade 3）were not significantly correlated with the improvement of PFS and com OS （P＞0.05）. Sensitivity analysis results showed that the results of the above-mentione d meta-analysis were relatively robust. The results of publication bias showed that there was may be some possibility of publication bias in this study. CONCLUSIONS For NSCLC patients treated with ICIS ，the occurrence of irAEs may be related to their good prognosis. The irAEs may be a predictor of the efficacy of ICIs.

Research progress on the correlation between dermatological immune-related adverse events and clinical outcome of PD-1/PD-L1 inhibitors / 国际肿瘤学杂志

Immunotherapy represented by PD-1/PD-L1 inhibitors has become the main treatment of malignant tumors. However, the adverse events caused by immunotherapy can not be ignored. Among them, dermatological immune-related adverse events (irAEs) occur with the highest incidence. Most dermatological irAEs belong to grade Ⅰ-Ⅱ, which does not affect the application of PD-1/PD-L1 inhibitors. The pathogenesis of dermatological irAEs is not fully understood. The most common types of dermatological irAEs are rash, pruritus and vitiligo. The domestic PD-1 inhibitor camrelizumab has unique adverse reactions of reactive cutaneous capillary endothelia proliferation (RCCEP) . It is found that dermatological irAEs can predict the clinical efficacy of PD-1/PD-L1 inhibitors in patients with malignant melanoma and non-small cell lung cancer (NSCLC) , especially RCCEP can be used as a potential biomarker of the efficacy of camrelizumab in the treatment of NSCLC, hepatocarcinoma, and esophageal cancer.

Multi-target combinatory strategy to overcome tumor immune escape / 医学前沿

Immune therapy has become the fourth approach after surgery, chemotherapy, and radiotherapy in cancer treatment. Many immune checkpoints were identified in the last decade since ipilimumab, which is the first immune checkpoint inhibitor to cytotoxic T-lymphocyte associated protein 4, had been approved by the US Food and Drug Administration (FDA) for the treatment of unresectable or metastatic melanoma in 2011. The use of several antibody drugs that target PD1/PD-L1 for various cancer treatments has been approved by the FDA. However, fewer people are benefitting from immune checkpoint inhibitor treatment in solid cancers. Approximately 80% of patients do not respond appropriately because of primary or acquired therapeutic resistance. Along with the characterization of more immune checkpoints, the combinatory treatment of multiimmune checkpoint inhibitors becomes a new option when monotherapy could not receive a good response. In this work, the author focuses on the combination therapy of multiple immune checkpoints (does not include targeted therapy of oncogenes or chemotherapy), introduces the current progression of multiple immune checkpoints and their related inhibitors, and discusses the advantages of combination therapy, as well as the risk of immune-related adverse events.

Current research status on immune-related adverse events / 中华胃肠外科杂志

Immune checkpoint inhibitors have progressed rapidly over the past decade and have become one of the most promising oncology treatments. However, immune checkpoint inhibitors reduce T-cell tolerance and lead to a unique spectrum of immune-related adverse events (IRAE). IRAE can involve multiple systems, including endocrine, gastrointestinal, respiratory and skin systems and there is no predictive marker with high specificity and sensitivity. Mild IRAE can be alleviated by discontinuing immune checkpoint inhibitors while severe IRAEs require active intervention. The first-line treatment is glucocorticoids, and immunosuppressants can be considered in refractory cases. However the optimal choice of immunosuppressants is currently controversial. This review provides an overview of the epidemiology and possible mechanisms of immune-related adverse events, outlines some promising predictive biomarkers, and describes several immunotherapy-related organ toxicity and management.

Endocrine dysfunction induced by immune checkpoint inhibitors / Disfunción endocrina inducida por inhibidores de los puntos de control inmune

Abstract Since their approval in 2011, immune checkpoint inhibitors (ICPis) are increasingly used to treat several advanced cancers. ICPis target certain cellular molecules that regulate immune response resulting in antitumor activity. The use of these new agents needs careful monitoring since they brought a whole new spectrum of adverse events. In this review, we aim to describe different endocrine dysfunctions induced by ICPis and to underline the importance of diagnosing and managing these adverse effects. Immune-related endocrine toxicities include thyroid dysfunction, hypophysitis and, less frequently, type 1 diabetes, primary ad renal insufficiency and hypoparathyroidism. Diagnosis of endocrine adverse events related to ICPis therapy can be challenging due to nonspecific manifestations in an oncological scenario and difficulties in the biochemical evaluation. Despite the fact that these endocrine adverse events could lead to life-threatening consequences, the availability of effective replacement treatment enables continuing therapy and together with an interdisciplinary approach will impact positively on survival.

Resumen Desde su aprobación en 2011, el uso de los inhibidores de los puntos de control inmunes (ICPis) se ha ex tendido para el tratamiento de diversas neoplasias en estadios avanzados. Los ICPis tienen como blanco ciertas moléculas de las células que regulan la respuesta inmune favoreciendo una actividad antitumoral. El uso de estos nuevos agentes requiere un monitoreo específico, ya que se han vinculado con un amplio y nuevo espectro de efectos adversos. El objetivo de esta revisión es describir las diferentes disfunciones endocrinas inducidas por los ICPis y destacar la importancia del diagnóstico y manejo oportuno de estos efectos adversos. Los efectos adversos inmunes endocrinos incluyen disfunción tiroidea, hipofisitis y con menor frecuencia, diabetes tipo 1, insuficiencia suprarrenal primaria e hipoparatiroidismo. El diagnóstico de eventos adversos endocrinos relacionados con la terapia ICPis es un desafío debido a su presentación clínica inespecífica en un escenario oncológico y a las dificultades en la evaluación bioquímica. Estos eventos adversos endocrinos podrían tener consecuencias potencialmente letales, pero la disponibilidad de un tratamiento de reemplazo eficaz permite continuar la terapia y, junto con un enfoque interdisciplinario, generar un impacto positivo en la supervivencia.

Endocrine Disorders Induced by PD-1/PD-L1 Inhibitor and Related Treatment / 肿瘤防治研究

Immune checkpoint therapy is a new mode of tumor therapy. At present, many kinds of PD-1/PD-L1 inhibitors have been approved for clinical application on various tumors, such as malignant melanoma, lung cancer, bladder cancer, lymphoma, etc. However, with the gradual promotion and application in clinical practice, various immune-related adverse reactions caused by PD-1/PD-L1 inhibitors have attracted extensive attention. Especially in recent years, a number of adverse reactions related to endocrine gland injury have been reported. This paper reviews the research status and corresponding clinical treatment methods of endocrine gland related adverse reactions caused by PD-1/PD-L1 inhibitors.

Recent Advance in Biomarkers for Predicting Immune-related Adverse Events Caused by Immune Checkpoint Inhibitors / 肿瘤防治研究

In recent years, tumor immunotherapy with immune checkpoint as the target has attracted much attention because of its remarkable efficacy. However, with the application of immune-checkpoint inhibitors (ICIs), more and more immune-related adverse events (irAEs) have been reported. IrAEs impose an additional risk of death on tumor patients treated with ICIs, limiting the widespread use of ICIs. To help patients actively prevent irAEs, biomarkers with the predictive value of irAEs are of great significance. This paper reviews the biomarkers with predictive value for irAEs from the aspects of serology, genetics and microbiology.

Progress in Application of TNF-α Inhibitors in Immune Checkpoint Therapy / 肿瘤防治研究

Immune checkpoint inhibitors significantly improves the prognosis of patients with advanced malignancy, but it is also associated with off-target toxicity caused by activation of the immune system, known as immune-related adverse events (irAEs). Severe irAEs will lead to temporary or permanent termination of immunotherapy, which greatly affects its clinical application. At present, glucocorticoids are mainly used to treat irAEs clinically. On one hand, severe adverse reactions will cause serious damage to patients' health; on the other hand, the extensive application of glucocorticoids will affect the efficacy of immune checkpoint inhibitors. In recent years, TNF-α inhibitors have shown significant effect in reducing toxic and side effects. This paper reviews the progress of TNF-α in preventing and treating irAEs.

Analysis of Drug Use in a Lung Squamous Carcinoma Patient with Immune Checkpoint Inhibitors Associated Adrenocortical Insufficiency / 中国药房

OBJECTIVE：To explore the role of clinical pharmacists in the diagnosis and tre atment of immune checkpoint inhibitor related adrenocortical insufficiency ，so as to provide reference for the diagnosis and treatment of similar cases. METHODS：A lung squamous carcinoma patient with tumor immunotherapy ，who received long-term intravenous infusion of Pembrolizumab injection ，was hospitalized for more than 10 days due to fatigue and poor appetite. The clinical pharmacists consulted the literature and evaluated the correlation of ADR on the basis of patient ’s physical examination results （plasma cortisol 16.41 nmol/L at 8：00 in the morning on the second day of admission ，adrenocorticotropic hormone 8.39 pg/mL，serum electrolyte sodium 126.00 mmol/L，chlorine 88.00 mmol/L，etc.）and medication history （receiving the treatment with immune checkpoint inhibitors）. The clinical pharmacists assisted the doctor to confirm that the patient was adrenocortical insufficiency ，and the correlation with pembrolizumab was “very likely ”. On the basis of discontinuation of pembrolizumab ，it was recommended to take Hydrocortisone tablets orally （20 mg at 8：00 in the morning and 10 mg at 4：00 in the afternoon ）for glucocorticoid physiological dose substitution therapy. Before treatment ，the patient and his families should be educated on the use of drugs ，pharmaceutical care should be implemented to evaluate the glucocorticoid doseand efficacy during treatment ，and medication education was carried out at discharge. RESULTS ：The doctor adopted theli_xyan suggestions of the clinical pharmacist. On the 5th day after @126.com administration，the symptoms of adrenocortical insufficiency were significantly impro ved，and the patient was discharged with medicine. CONCLUSIONS ：During the treatment of the patient ， the clinical pharmacist gave full play to his pharmaceutical expertise ，assisted the doctor to formulate an appropriate medication plan，and carried out medication education for the patient and his family members ，so as to ensure the effectiveness and safety of the patient ’s medication. It is suggested that the baseline examination of patients should be improved before immune checkpoint inhibitor treatment ，including physical examination and plasma cortisol level at 8：00 in the morning ；the frequency of monitoring plasma cortisol level and serum electrolyte level at 8：00 in the morning. should be increased during medication ；the patients should be followed up for at least 1 year after withdrawal ，so as to early detect and treat immune checkpoint inhibitor related adrenocortical dysfunction.

Meta-analysis of Non-immune Related Adverse Event s Caused by ICIs Alone or Combined with Routine Che- motherapy in the Treatment of Non-small Cell Lung Cancer / 中国药房

OBJECTIVE：To systematically evaluate the occurren ce of non-immune related adverse events （AEs）caused by immune checkpoint inhibitors （ICIs）alone or combined with routine chemotherapy in the treatment of non-small cell lung cancer （NSCLC），and to provide evidence-based reference for clinical medication. METHODS ：Retrieved from PubMed ，Cochrane Library，Embase，CNKI，CBM，VIP and Wanfang database during the inception to Oct. 2020，randomized controlled trials （RCT） about ICIs alone or combined with routine chemotherapy （trial group ）versus routine chemotherapy or placebo combined with routine chemotherapy （control group ） were collected. After literature screening and data extraction ，the quality of included literatures were evaluated with bias risk evaluation tool recommended by Cochrane systematic evaluator manual 5.1.0. Meta-analysis was performed by using Rev Man 5.3 software and Stata 15.0 software. Sensitivity analysis was conducted with Stata 15.0 software. Inverted funnel plot and Egger ’s test were used to analyze publication bias. RESULTS ：A total of 20 RCTs were included ， involving 12 283 patients. Results of Meta-analysis showed that the incidence of all grades and s evere AEs ，anemia，neutropenia， vomiting and alopecia as well as the incidence of thrombocytopenia，nausea and peripheral neuropathy in all grades of trial group were all significantly lower than control com group（P＜0.05）. There was no statistical significance in the incidence of termination of treatment ， death， severe thrombocytopenia， severe nausea and severe peripheral neuropathy or all grades and severe diarrhea between 2 groups（P＞0.05）. Subgroup analysis showed that the incidence of all grade and total severe AEs ，the incidence of anemia ，neutropenia，thrombocytopenia，clinically relevant symptoms （except for severe diarrhea），termination of treatment and death of patients receiving ICIs alone in trial group were significantly lower than control group（P＜0.05）. The incidence of ermination of treatment and death ，the incidence of nausea ，vomiting，diarrhea and alopecia in all grade ，severe diarrhea of patients receiving ICIs and chemotherapy in trial group were all significantly higher than control group （P＜0.05）. Sensitivity analysis supported the above results. Analyze publication bias results showed that the possibility of publication bias in this study was small. CONCLUSIONS ：For NSCLC patients ，the safety of ICIs is better than that of routine chemotherapy or placebo combined with routine chemotherapy in the treatment-related AEs ，hematologic toxicity and clinically relevant symptoms ；however，the risks of treatment discontinuation ，AEs-induced deaths ，and all-grade nausea ，vomiting， diarrhea，alopecia and severe diarrhea will be increased in the ICIs combined with routine chemotherapy.

Advances on immune-related adverse events associated with immune checkpoint inhibitors / 医学前沿

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.

Endocrinopatías por inmunoterapia oncológica / Endocrinopathies by oncological immunotherapy

La relación entre inmunidad y cáncer es compleja. Las células tumorales desarrollan mecanismos de evasión a las respuestas del sistema inmunitario. Esta capacidad permite su supervivencia y crecimiento. La inmunoterapia ha transformado el tratamiento oncológico mejorando la respuesta inmunitaria contra la célula tumoral. Esta se basa en el bloqueo de los puntos de control inmunitario mediante anticuerpos monoclonales contra la molécula inhibidora CTLA-4 (antígeno 4 del linfocito T citotóxico [CTLA-4]) y la proteína 1 de muerte celular programada y su ligando (PD-1/PD-L1). Aunque los inhibidores de los puntos de control inmunitario (ICIs) son fármacos bien tolerados, tienen un perfil de efectos adversos conocido como eventos adversos inmunorrelacionados (EAI). Estos afectan varios sistemas, incluyendo las glándulas endocrinas. Los eventos adversos endocrinos más frecuentes son la disfunción tiroidea, la insuficiencia hipofisaria, la diabetes mellitus autoinmune y la insuficiencia suprarrenal primaria. El creciente conocimiento de estos efectos adversos endocrinos ha llevado a estrategias de tratamiento efectivo con el reemplazo hormonal correspondiente. El objetivo de esta revisión es reconocer la incidencia de estas nuevas endocrinopatías, la fisiopatología, su valoración clínica y el manejo terapéutico. (AU)

The relationship between immunity and cancer is complex. Tumor cells develop evasion mechanisms to the immune system responses. This ability allows their survival and progression. Immunotherapy has transformed cancer treatment by improving the immune response against tumor cells. This is achieved by blocking immune checkpoints with monoclonal antibodies against cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 and its ligand (PD-1 / PD-L1). Although the immune checkpoint inhibitors (ICIs) are well tolerated drugs, they have a profile of adverse effects known as immune-related adverse events (irAES). These involve diverse systems, including the endocrine glands. The most frequent endocrine immune-related adverse events are thyroid and pituitary dysfunction, autoimmune diabetes mellitus and primary adrenal insufficiency. The increasing knowledge of these irAES has led to effective treatment strategies with the corresponding hormonal replacement. The objective of this review is to recognize the incidence of these new endocrinopathies, the physiopathology, their clinical evaluation, and therapeutic management. (AU)