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Immune checkpoint inhibitors (ICIs) exert a therapeutic effect on liver cancer by enhancing the body's anti-tumor immunity and have become an important treatment method in the field of liver cancer. However, while ICIs activate the anti-tumor immunity, they also bring a series of special toxic and side effects, i.e., immune-related adverse events (irAEs). With the wide application of ICIs, irAEs have become a major challenge in clinical practice. Such irAEs have a wide potential disease spectrum and include more than 70 different pathological states, and the most common types of irAEs associated with PD-1/PD-L1 inhibitors are skin toxicity, endocrine toxicity, pneumonia, and digestive tract toxicity, while rare irAEs include the toxicity of the central nervous system and the cardiovascular, renal, and blood systems. The wide disease spectrum of irAEs requires multidisciplinary collaborative management, and at present, many academic institutions or platforms in China and globally have formulated various guidelines for irAE management. However, the management of irAEs currently lacks the support of the results of high-level prospective trials, and the characteristics of irAEs are different from the original immune diseases of various systems; therefore, its management needs to be further optimized. This article elaborates on the epidemiology of irAEs in immunotherapy for liver cancer, related risk and predictive factors, clinical features of irAEs involving different systems, and precautions for treatment and management.
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The clinical application of immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of hepatocellular carcinoma (HCC) patients. With the widespread applica-tion of ICIs in HCC, the management of immune-related adverse events (irAE) gained more and more attention. However, the complicated disease characteristics and various combination therapies in HCC throw out challenges to irAE management. Therefore, the editorial board of the 'Chinese expert consensus on the management of immune-related adverse events of hepatocellular carcinoma treated with immune checkpoint inhibitors (2021 edition)' organizes multidisciplinary experts to discuss and formulate this consensus. The consensus focuses on issues related to HCC irAE manage-ment, and puts forward suggestions, in order to improve standardized and safety clinical medication, so as to maximize the benefits of immunotherapy for patients.
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Objective:Summarize and analyze the clinical features of immune checkpoint inhibitor (ICI)-related colitis.Methods:From January 2019 to September 2020, the clinical data of 8 patients with ICI-related colitis from Peking Union Medical College Hospital were retrospectively collected and including the onset of ICI-related colitis, clinical symptoms, endoscopic and pathological findings, treatment, comorbidities and resuming of ICI. Independent sample t test was used for statistical analysis. Results:Eight patients were all male, and the median age (range) was 66 years old (55 to 74 years old), 7 cases were diagnosed with stage Ⅳ lung cancer and 1 case was diagnosed with stage Ⅲc pyelo-carcinoma. Among 8 patients, 4 cases of ICI-related colitis occurred during combination of anti-programmed death-1 (PD-1) treatment and chemotherapy, 2 cases occurred during anti-PD-1 monotherapy after combination of anti-PD-1 treatment and chemotherapy, and 2 cases occurred after anti-PD-1 monotherapy. The median time (range) was 44 d (27 to 128 d) from initial anti-PD-1 treatment to the onset of ICI-related colitis and the median time (range) was 8 d (6 to 35 d) from last anti-PD-1 treatment to onset of ICI-related colitis. The ICI efficacy of 4 patients had partial response, 2 patients had stable disease, 1 patient had disease progression, and 1 patient′s condition was not assessed. All 8 patients had moderate to severe extensive colitis. The main clinical manifestation was diarrhea (5/8), 3 patients accompanied by abdominal pain. The endoscopic findings were diffuse mucosal erosion, accompanied by ulcer in 2 patients. The main pathologic findings were cryptitis or crypt abscess, accompanied by apoptosis in 2 patients. Eight patients were all treated with glucocorticoids, among them 2 patients were further treated with biologics, due to the insufficient efficacy of glucocorticoid treatment, 4 patients had opportunistic infections. The initial prednisone dose for patients with opportunistic infections and patients without opportunistic infections was (85.00±52.60) and (60.00±23.09) mg, respectively. The prednisone treatment course was (8.75±4.03) and (7.50±3.11) weeks, respectively, and the differences were not statistically significant (both P>0.05). The colitis relapsed in all 3 patients after resuming of ICI. Conclusions:ICI-related colitis had corresponding ICI treatment history and clinical, endoscopic, and histopathological features. Glucocorticoid is the main treatment, and it is prone to relapse after resuming of ICI.
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BACKGROUND@#Perioperative treatment has become an increasingly important aspect of the management of patients with non-small cell lung cancer (NSCLC). Small-scale clinical studies performed in recent years have shown improvements in the major pathological remission rate after neoadjuvant therapy, suggesting that it will soon become an important part of NSCLC treatment. Nevertheless, neoadjuvant immunotherapy may be accompanied by serious adverse reactions that lead to delay or cancelation of surgery, additional illness, and even death, and have therefore attracted much attention. The purpose of the clinical recommendations is to form a diagnosis and treatment plan suitable for the current domestic medical situation for the immune-related adverse event (irAE).@*METHODS@#This recommendation is composed of experts in thoracic surgery, oncologists, thoracic medicine and irAE related departments (gastroenterology, respirology, cardiology, infectious medicine, hematology, endocrinology, rheumatology, neurology, dermatology, emergency section) to jointly complete the formulation. Experts make full reference to the irAE guidelines, large-scale clinical research data published by thoracic surgery, and the clinical experience of domestic doctors and publicly published cases, and repeated discussions in multiple disciplines to form this recommendation for perioperative irAE.@*RESULTS@#This clinical recommendation covers the whole process of prevention, evaluation, examination, treatment and monitoring related to irAE, so as to guide the clinical work comprehensively and effectively.@*CONCLUSIONS@#Perioperative irAE management is an important part of immune perioperative treatment of lung cancer. With the continuous development of immune perioperative treatment, more research is needed in the future to optimize the diagnosis and treatment of perioperative irAE.
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Medicinal plant Paris L. has high medicinal value. There are 8 varietas of 4 kinds of Sect. Euthya which could be used as Chinese medicine. Sect. Euthya with stout rhizomes are the source of Chinese herb Paris L. and the core source of the medicinal plants in every place of origin. Shaanxi Province is one of the major areas. This paper summarizesand analizes the research progress of Paris L. grew in Shaanxi Province including its medicinal status, effective component, pharmacological, endophytic microorganisms sequencing, resource distribution and utilization, as well as the standardized production and planting and provides suggestions for the further research and rational exploitation and utilization of medicinal plant resources of Paris L. in Shaanxi Province.
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The application of immunological checkpoint inhibitors (ICIs) has modified many treatment strategies of malignant tumors, which has become a milestone in cancer therapy. The principle of action can be explained as "brake theory". After releasing the brakes by ICIs, unprecedented systemic toxicities, even some refractory and fatal immune-related adverse effects (irAEs) may develop. In this article, we summarized the recommended treatments of grade 3-4 severe irAEs in the latest European Society for Medical Oncology (ESMO), National Comprehensive Cancer Network (NCCN)/American Society of Clinical Oncology (ASCO), Society for Immunotherapy of Cancer (SITC) and Chinese Society of Clinical Oncology (CSCO) guidelines and consensus. We also performed a systemic review of case reports and reviews of irAEs up to May 20, 2019 in PubMed and Chinese journals. Successful applications of specific immunosuppressive drugs and stimulating factors beyond the above guidelines and consensus were supplemented and highlighted, including agents blocking interleukin 6 (IL-6), rituximab, anti-tumor necrosis factor-α (TNFα) monoclonal antibody (mAb), anti-integrin 4 mAb, Janus kinase inhibitors, thrombopoietin receptor agonists and antithymocyte globulin (ATG) etc. We put some concerns of using high-dose steroids for long-term, and emphasize the secondary infections, tumor progression, and unavailability of ICI re-challenge during steroid treatment. We propose the "De-escalation Therapy" principle for severe and refractory irAEs, and suggest that immunosuppressive drugs specifically targeting cytokines should be used as early as possible. Many irAEs in the era of immunotherapy are unprecedented compared with traditional chemotherapy and small-molecule targeted therapy, which is a big challenge to oncologists. Therefore, the establishment of multidisciplinary system is very important for the management of cancer patients.
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Immunocheckpoint inhibitors (ICIs) activated the patients' tumor immunity to kill the tumor cell, and brought new hope to patients with tumor. However, a series of immunocheckpoint inhibitors related adverse effects (irAEs) may also occur based on immune injury. Glucocorticoids are the basis for the treatment of such irAEs. However, the usage, dosage and course of treatment of glucocorticoid in irAEs are different from those in classic autoimmune diseases. Meanwhile, long-term use of large doses of glucocorticoids may cause serious adverse effects too. In this paper, the mechanism, dosage forms, adverse effects and management of glucocorticoids are described in detail, providing references and suggestions for oncologists to apply glucocorticoids in clinical practice.
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The increasing use of immunocheckpoint inhibitors in tumors has brought new hope of survival to patients with advanced tumors. However, the immune system activated by immunocheckpoint inhibitors, mainly activated T-cell immunity, may attack normal tissues and organs of the human body and lead to a variety of adverse effects. In the lung, they could induce checkpoint inhibitor associated pneumonitis (CIP). CIP is different from known pulmonary interstitial pneumonitis, and had a potentially fatal risk if it was not being properly treated. We will summarize the characteristics of CIP and give our advice on how to manage immunocheckpoint inhibitor associated pneumonitis.
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Immunotherapy of malignant tumors has become a hot spot in the field of cancer research and treatment, bringing new hope to patients with advanced cancer. Activation of molecular programmer death protein-1 and T lymphocyte-associated antigen 4-related signaling pathways at the immunological checkpoint can inhibit T lymphocyte activation and thereby block the inflammatory response. Tumor cells achieve immune escape by activating the molecular pathways associated with immune checkpoints. The immune checkpoint inhibitor can wake up T lymphocytes and enhance the body's clearance of tumor cells. However, the role of immune checkpoint inhibitors is not specific to tumor cells, and it can cause side effects of multiple systems including the cardiovascular system while killing tumor cells. We will summarize the relevant cardiac side effects and give advice on how to manage it.
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Immune checkpoint inhibitors (ICIs) represent a major breakthrough in cancer therapy. Immune-related adverse events (irAEs) may occur during treatment due to their unique mechanism of action. Dermatologic toxicities appear to be one of the most prevalent irAEs. The most common symptoms are maculopapular rash and pruritus. Serious dermatologic AEs, including Stevens-Johnson syndrome and toxic epidermal necrolysis, are rare. In this review, we summarized guidelines of management of immunotherapy-related toxicities and case reports, and proposed treatment recommendation.
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Immune checkpoint inhibitors (ICIs) have been used more and more Increasingly in clinical oncology treatment, which has significantly improved the prognosis of cancer patients. Over-activation of T cells and related signaling pathways may cause immune-related adverse effects. Renal immune side-effects are relatively rare, but some of them are serious and fatal. This review analyses of the Incidence, clinical and pathological manifestations of ICIs-induced renal injury, and focuses on the differential diagnosis and treatment. Because there are many secondary factors that need to be differentiated from immune mechanism, renal biopsy should be performed if necessary to determine the important decision.
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As a new type of anti-cancer drugs, immune checkpoint inhibitors (ICIs) have shown remarkable therapeutic effects in many malignant tumors. By virtue of their targets and mechanisms of action, ICIs can cause autoimmune and inflammatory effects, termed immune-related adverse events (irAEs). Unlike traditional therapies, irAEs are latent and unstable. Severe adverse reactions will force patients to discontinue treatment and even affect their survival. Therefore, with the wide application of ICIs in clinical practice, clinicians need to fully understand the possible adverse reactions of such drugs and appropriate treatment strategies, in order to improve the survival rate and treatment effect of patients receiving ICIs. In this article, we review the incidence, clinical features, diagnosis and treatment of immune-related endocrine events that may occur with administration of ICIs.
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The increasing use of target therapy and immunocheckpoint inhibitors in cancers has brought new hope of survival to patients with advanced tumors. However, more and more adverse side-effects and toxicities of these medications had been reported, affect almost all human organs including the eye. These adverse effects may affect the entire ocular tissues, like eyelid, eye lashes, conjunctiva, cornea, uvea, retina, optic nerve and so on, which are always been ignored by patients and doctors. In this paper we will summarize the characteristics of the related ocular diseases and give our advice on how to diagnose and manage these diseases.
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Immunotherapy for malignant tumors is a hot spot in current research and treatment of cancer. The activation of programmed cell death receptor-1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA)-4 relevant signaling pathway can inhibit the activation of T lymphocytes. Tumor cells can achieve immune escape by activating this signaling pathway. By inhibiting this signaling pathway, immune-checkpoint inhibitors (ICIs) activate T lymphocytes to clear the tumor cells. Therefore, the adverse effects of ICIs are mainly immune-related adverse events (irAEs). The digestive system, including gastrointestinal tract and liver are vital organs of digestion and absorption, metabolism and detoxification, as well as important immune related organs, which are the commonly affected system of irAEs. This review separately explains the incidence, clinical features, diagnosis and treatment of liver and gastrointestinal adverse events in ICIs.
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Immune checkpoint inhibitors (ICIs) have been widely used in management of malignant tumor. Programmed death ligand 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors have been introduced to treat non-small cell lung cancer (NSCLC) in recent years. Currently, PD-1/PD-L1 inhibitors are considered to have minor side effects and do not independently increase the risk of infection. However, they may cause immune-related adverse events (irAEs) that can require immunosuppressive therapy with corticosteroids and/or immunosuppressants, leading to opportunistic infections. Furthermore, there were reports about reactivation of chronic/latent infections without irAEs. Thus, immune checkpoint inhibitor related infections have drawn more and more attention in the world. In this paper, we described the potential mechanism, available clinical data and recommendation of diagnosis and management for PD-1/PD-L1 inhibitor related infections.
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Immune checkpoint inhibitors (ICIs) have made remarkable breakthroughs in cancer treatment. However, the widely use of ICIs is associated with a spectrum of immune-related adverse events (irAEs). These adverse events can affect any organ system. In this article, we have made a systemic review about the clinical characteristics of rheumatic irAEs, and also summarized irAEs in patients with pre-exsiting rheumatic disease. We also focus on the management of rheumatic irAEs.
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Immune checkpoint inhibitors are able to reactivate the immune system therefore enhance the anti-tumor effects. However, over-activated T cells may induce immune related adverse events (irAEs). Hematological irAEs are rarely reported, which mainly represent as mono-lineage cytopenia or pancytopenia, including autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), neutropenia and aplastic anemia, sometimes even lethal, such as hemophagocytic lymphohistiocytosis. The clinical manifestations of hematological irAEs will be summarized and recommendations of diagnosis and treatment are proposed.
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Objective@#Pulmonary metastatic angiosarcoma is a rare, fatal disease that often presents as diffuse alveolar hemorrhage(DAH). In this report, clinical characteristics of pulmonary metastatic angiosarcoma were retrospectively reviewed.@*Methods@#A total of 9 patients with angiosarcoma who presented as DAH were enrolled. Clinical data included age, gender, symptoms, smoking status, physical exam findings, pulmonary function tests, and radiology.@*Results@#All patients were male with median age 41 years(range, 22 to 57 years). The most common symptom was hemoptysis(9/9). Other symptoms included dyspnea (5/9), cough(3/9), chest pain(3/9), fever(2/9,) and edema of the lower extremity and oliguria(4/9).The common misdiagnoses were tuberculosis(4/9), vasculitis(3/9) and other infection(1/9). Chest computed tomography showed bilateral,random distributed different-sized nodules(9/9),as well as ground-glass areas (9/9).The hearts, mainly right atrium, were the most common primary locations(7/9).Cardiac mass was the first manifestation in five patients by echocardiography(5/8).Two atrial masses were identified by computer tomography pulmonary angiography and magnetic resonance imaging respectively. Transbronchial lung biopsy failed to find malignancy. Computer tomography guided transthoracic needle biopsy was difficult to perform in most patients. Eight patients were diagnosed by surgical biopsy, either by lung biopsy(4/8) or cardiac biopsy(4/8).The median survival period was only 3 months after surgery.@*Conclusion@#Metastatic pulmonary angiosarcoma should be considered in patients with DAH and multiple glass ground opacity and nodules on chest CT. Careful cardiologic monitoring is necessary. Surgical biopsy is reliable for diagnosis.
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Objective To evaluate the efficacy and safety of anlotinib in patients with advanced non-small cell lung cancer (NSCLC).Methods Patients with stageⅢB/ⅣNSCLC who progressed after two lines or more regimens were randomized into anlotinib group (12 mg daily from day 1 to 14 of a 21-day cycle) or placebo group with ratio of 2:1. Study drugs or placebo were given until disease progression or intolerable toxicity. The primary endpoint was overall survival (OS), and the second endpoints were progression free survival (PFS), objective response rate, and disease control rate. Results Between April 2015 and December 2015, twenty-four patients were assigned at Peking Union Medical College Hospital. The baseline characteristics of the anlotinib group (n=16) and placebo group (n=8) were fairly comparable. The median OS was 12.7 months in anlotinib group and 11.1 months in placebo group (P=0.460). The median PFS was 4.0 months in anlotinib group and 1.4 months in placebo group (P=0.065). The common adverse events were manageable such as hypertension, hand-foot syndrome, thyroiddy sfunction. No drug-related mortality occurred. Conclusions Anlotinib had a trend of improvement in OS and PFS as third-line treatment or beyond in advanced NSCLC compared with placebo with manageable toxicity.
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Objective Pulmonary benign metastasizing leiomyoma (PBML) is a rare entity that leiomyoma of uterus metastasized to the lung.The clinical characteristics of this rare disease were analyzed in this article.Methods The detailed clinical records of 7 patients diagnosed as PBML at Peking Union Medical College Hospital between January 2001 and June 2015 were reviewed.Results All patients were women with median age of 44 years (range 28-62).Symptoms included dyspnea (2/7),chest pain (1/7),cyanosis (1/7),cough (1/7) and bloody sputum (1/7),while 4/7 cases were asymptomatic.Six patients had the past-history of leiomyoma of uterus 20 months to 14 years ago among whom 5 patients received hysterectomy.Chest CT showed bilateral,random-distributed multiple round solid nodules,or diffuse-distributed miliary nodules,or single solid nodule,even some small cavities.Extra-pulmonary metastasis was found in left superclavicular lymph node (1 case) and right heart (1 case).Histological tissues were obtained by video-assisted thoracic surgery lung biopsy (4/7),mass resection on tricuspid valve (1/7),transbronchil lung biopsy (1/7),and CT-guided percutaneous lung biopsy (1/7).Pathology showed an interlacing pattern by spindle cells having elongated nuclei without cellular atypia.Ki-67 index was less than 1％.Molecules such as smooth muscle antibody,estrogen receptor (ER) and progestrone receptor (PR) were positive in immunohistochemistry staining.Neither letrozole nor zoladex was effective.Two patients responded to bilateral adnexectomy,presenting as shrunk nodules.No relapsed disease was seen in one patient with single nodule after resection.There was only one patient with disease-related mortality,whose chest CT showed milliary nodules.Conclusion Although CT findings of PBML are similar to malignancies,the clinical outcome is good.Despite the positive expression of ER and PR,the effectiveness of hormone related treatment is limited.And periodical follow up is suggested even to those uneventful patients.