Clinical Studies on Thyroid Dysfunction Caused by Immune Checkpoint Inhibitors in Tumor Patients / 昆明医科大学学报

Objective To investigate the clinical characteristics and risk factors of thyroid dysfunction(TD)in malignant tumor patients treated with immune checkpoint inhibitors(ICIs).Methods A total of 157 cancer patients who were hospitalized and received ICIs treatment in the First People's Hospital of Yunnan Province from January 2019 to June 2022 were collected and divided into the normal thyroid function group and abnormal thyroid function group based on whether TD had occurred.Fifty-eight patients with the normal thyroid function and 58 patients with the abnormal thyroid function were selected,and 58 healthy adults who underwent the physical examination in our hospital were randomly selected as the control group.The baseline data on the gender,age,tumor and ICIs type,history of surgery before medication,history of radiotherapy and chemotherapy,and the related indicators of liver and kidney function,blood lipids,thyroid hormone levels and so on were collected.The relevant indicators of the three groups were statistically analyzed,and the normal thyroid function group and abnormal thyroid function group were compared to evaluate the clinical characteristics and related risk factors of TD caused by ICIs.Results 1.Among 157 patients treated with ICIs,58 cases(36.9%)had thyroid dysfunction,including 39 cases of hypothyroidism(including subclinical hypothyroidism),9 cases of hyperthyroidism(including subclinical hyperthyroidism),and 10 cases of pure related antibody abnormality.2.The analysis of the data of the normal thyroid function group,the abnormal thyroid function group and the control group showed that the age,thyroid stimulating hormone(TSH),and thyroid function of the three groups were significantly different.TSH)baseline level,free triiodothyronine(FT3)baseline level and aspartate transaminase(AST)baseline level were statistically different(P<0.05).There were significant differences in TSH baseline and radiotherapy history between the normal thyroid function group and the abnormal thyroid function group(P<0.05);Multivariate analysis showed that the radiotherapy history(OR=7.291,95% CI= 1.579-33.663,P<.05),baseline TSH level(OR=3.917,95% CI= 1.697-9.038,P<0.05)were the independent risk factors for thyroid dysfunction in cancer patients after ICIs treatment.Conclusion Hypothyroidism is the most common type of TD caused by ICIs in cancer patients.The baseline TSH level and the history of radiotherapy are the independent risk factors for thyroid dysfunction.

Chemo-resistant gestational trophoblastic neoplasia and the use of immunotherapy: A case report and review of literature

@#This is the first reported case of the use of immunotherapy in chemo-resistant Gestational Trophoblastic Neoplasia (GTN) in the country. A 41-year-old, Gravida 4 Para 3 (3013) with a diagnosis of GTN, Stage III: WHO risk score of 13 (Choriocarcinoma) was initially managed with 10 cycles of multiple agent Etoposide, Methotrexate, Actinomycin D- Cyclophosphomide and Vincristine (EMACO) and 19 cycles of Etoposide, Cisplatin- Etoposide Methotrexate and Actinomycin D (EP-EMA). With continuous rise in beta human chorionic gonadotropin (ßhCG) levels, the patient was referred to a Trophoblastic Disease Center where there was note of tumor progression to the brain. She was started on third-line salvage chemotherapy of Paclitaxel and Carboplatin (PC) with concomitant whole brain irradiation completing three cycles after which chemoresistance was again diagnosed with increasing hCG titers and increase in the number and size of the pulmonary masses which were deemed unresectable. Immunotherapy was started with Pembrolizumab showing a good response with marked fall in ßhCG levels. The onset of immune-related adverse events (irAEs) caused a marked delay in subsequent cycles of immunotherapy. With management of the irAEs, two more cycles of Pembrolizumab with fifty percent dose reduction were given with corresponding drop in ßhCG levels. However, the patient subsequently developed gram-negative septicemia with possible hematologic malignancy and finally succumbed to massive pulmonary embolism. The case highlights the importance of prompt diagnosis and referral to a Trophoblastic Disease Center and the use of immunotherapy in chemo-resistant GTN.

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.

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.

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.

Research progress of tumor immunotherapy-associated optic nerve adverse events, prevention and treatment / 中华眼底病杂志

Tumor immunotherapy includes immune checkpoint inhibitor (ICI), tumor vaccines, and adoptive cell therapy. Immunotherapy, as the main systemic treatment for advanced malignant tumors, kills tumor cells by activating the immune system and prolongs the survival of patients. However, excessive immune responses can cause immune-related adverse events (irAE), causing damage to systemic tissues. ICI are the main tumor immunotherapy drugs that cause optic nerve irAE. The most common optic nerve irAE are optic neuritis, only a few patients appeared arteritic anterior ischemic optic neuropathy. Sudden painless loss of bilateral vision is the most common clinical manifestation. In severe cases, the vision decrease to no light perception. Early diagnosis and early adequate glucocorticoid treatment can improve the symptoms. Therefore, neuro-ophthalmologists and oncologists should know the clinical characteristics of optic nerve irAE, in order to diagnose and treat early and improve the prognosis.

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.

Immune Checkpoint Inhibitors Related Cystoureteritis: A Case Report and Literature Review / 中国肺癌杂志

A patient with advanced lung adenocarcinoma developed symptoms of frequent urination and urgent urination after 14 cycles of Pembrolizumab combined with chemotherapy. After making comprehensive analysis of the results of urine routine test, renal function, cystoscope and computed tomography (CT) examination, immune checkpoint inhibitors related cystoureteritis and acute kidney injury were considered. The patient's symptoms were relieved after discontinuation of Pembrolizumab combined with chemotherapy. However, the symptoms of urinary irritation worsened significantly after rechallenging Pembrolizumab combined with chemotherapy, and the symptoms was relieved after corticosteroids treatment. If patients develop urinary symptoms during immune checkpoint inhibitors treatment, immune checkpoint inhibitors related cystoureteritis should be considered for early differential diagnosis in order to implement appropriate treatment.
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Immune Thrombocytopenia Induced by Sintilimab in Lung Cancer: A Case Report and Literature Review / 中国肺癌杂志

Immune checkpoint inhibitors (ICIs) show unique advantages in the treatment of lung cancer, making the treatment of lung cancer enter the era of immunotherapy, but ICIs will also have adverse reactions, and the incidence of immune-induced hematological toxicity is not very high. Immunotherapy-induced thrombocytopenia is a rare adverse event.We report one case of thrombocytopenia induced by ICIs and review the literature on thrombocytopenia associated with ICIs and discuss the clinical features, possible mechanisms, and optimal treatment. 
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Advances in Predictive Research of Immune Checkpoint Inhibitors-related Adverse Events / 中国肺癌杂志

The era of tumor treatment has been revolutionized by the advent of immune checkpoint inhibitors. However, while immunotherapy benefits patients, it can also lead to immune-related adverse events that may affect multiple organs and systems throughout the body, potentially even posing a life-threatening risk. The diverse clinical manifestations and onset times of these adverse events further complicate their prediction and diagnosis. The purpose of this paper is to review the clinical characteristics and predicted biomarkers of adverse events related to inhibitors at immune checkpoints, in order to help clinicians evaluate drug risks and early warn adverse events.
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Development and validation of a risk-prediction model for immune-related adverse events in patients with non-small-cell lung cancer receiving PD-1/PD-L1 inhibitors / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Lung cancer remains the leading cause of cancer deaths worldwide and is the most common cancer in males. Immune-checkpoint inhibitors (ICIs) that target programmed cell death protein-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) have achieved impressive efficacy in the treatment of non-small-cell lung cancer (NSCLC) (Pardoll, 2012; Champiat et al., 2016; Gao et al., 2022). Although ICIs are usually well tolerated, they are often accompanied by immune-related adverse events (irAEs) (Doroshow et al., 2019). Non-specific activation of the immune system produces off-target immune and inflammatory responses that can affect virtually any organ or system (O'Kane et al., 2017; Puzanov et al., 2017). Compared with adverse events caused by chemotherapy, irAEs are often characterized by delayed onset and prolonged duration and can occur in any organ at any stage of treatment, including after cessation of treatment (Puzanov et al., 2017; von Itzstein et al., 2020). They range from rash, pneumonitis, hypothyroidism, enterocolitis, and autoimmune hepatitis to cardiovascular, hematological, renal, neurological, and ophthalmic irAEs (Nishino et al., 2016; Kumar et al., 2017; Song et al., 2020). Hence, we conducted a retrospective study to identify validated factors that could predict the magnitude of the risk of irAEs in patients receiving PD-1/PD-L1 inhibitors; our approach was to analyze the correlation between the clinical characteristics of patients at the start of treatment and relevant indicators such as hematological indices and the risk of developing irAEs. Then, we developed an economical, practical, rapid, and simple model to assess the risk of irAEs in patients receiving ICI treatment, as early as possible.

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.

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.

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.

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.

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.

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.

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.

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.

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.