CN116008568A - Early diagnosis kit for myocarditis related to immune checkpoint inhibitor - Google Patents
Early diagnosis kit for myocarditis related to immune checkpoint inhibitor Download PDFInfo
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Abstract
The invention relates to an early diagnosis kit for myocarditis related to immune checkpoint inhibitor, belonging to the technical field of biological medicine. The invention provides a diagnostic reagent and a diagnostic kit for immune checkpoint inhibitor related myocarditis, which are used for detecting the resistin level of peripheral blood of a tumor patient receiving ICIs treatment and judging whether early myocardial damage of the ICIs related myocarditis exists or not. The invention provides application of a reagent for detecting the level of resistin in preparation of an ICIS related myocarditis diagnosis kit. The method and the diagnostic reagent provided by the invention have the advantages of high sensitivity, good specificity, low cost and convenient and quick detection, and can be used for early diagnosis of myocarditis related to immune checkpoint inhibitors.
Description
Technical Field
The invention relates to an early diagnosis kit for myocarditis related to immune checkpoint inhibitor, belonging to the technical field of biological medicine.
Background
In recent years, immunotherapy of tumors has been attracting attention as an emerging therapeutic means. Immune Checkpoint Inhibitors (ICIs) are currently widely used tumor immunotherapy. ICIs include inhibitors of apoptosis protein 1 (PD-1 inhibitors), ligand PD-L1 inhibitors, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors, and the like. ICIs stimulate inhibited cytotoxic T cells by modulating the T cells, so that they target and recognize tumor cells, activate and kill tumor cells. However, the process can also cause damage to normal tissues of patients while enhancing immune function, and autoimmune adverse reactions such as myocarditis, hepatitis, pneumonia and the like can occur. The incidence of ICIs-related myocarditis, although low, can be life threatening and requires major attention.
There are various methods for diagnosing ICIs-related myocarditis: (1) endocardial myocardial biopsy is currently the gold standard for diagnosing ICIs-related myocarditis. The most common histological manifestation of ICIs-related myocarditis is lymphocyte infiltration with T cells as the main component, but due to limited lesion range, diseased regions may not be detected during endocardial myocardial biopsy, and the result is false negative. (2) In past case-control studies, cardiac Magnetic Resonance (CMR) has only 30% of the detection rate of ICIs-related myocarditis. 1 retrospective study showed that of the normal ICIs-related myocarditis patients with Left Ventricular Ejection Fraction (LVEF), 48% of patients exhibited Late Gadolinium Enhancement (LGE) when diagnosed with CMR, whereas only 26% of patients had short time reversal recovery (STIR) sequence elevation on T2-weighted imaging, so diagnosis of excluding ICI-related myocarditis by only LGE or T2-weighted imaging was not accurate. (3) About 90% of patients show elevated troponin and 70% of patients show elevated N-terminal brain natriuretic peptide precursors (NT-proBNP) or Brain Natriuretic Peptide (BNP), other enzymes such as Creatine Kinase (CK) and its isozymes (CK-MB), etc. However, since tumor-associated inflammatory reactions can also lead to long-term elevation of NT-proBNP, the diagnostic specificity of NT-proBNP is poor. Whereas elevated troponin indicates that cardiomyocytes have been subjected to irreversible injury and that high-sensitivity troponin detection costs are high, increasing the economic burden of tumor patients; (4) the electrocardiogram of 40-90% of patients with myocarditis can have abnormal manifestations, such as nonspecific changes of atrioventricular block, bundle branch block, ventricular tachycardia, QT interval prolongation, and the like. (5) There was a decrease in LVEF in echocardiography of less than 50% of patients with ICIs-related myocarditis.
Specific diagnostic criteria for ICIs-related myocarditis are not involved in the guidelines for immune adverse reactions such as american clinical oncology (ASCO), national integrated cancer network (NCCN), european oncology institute (eso), oncology immunotherapy Society (SITC), etc. Although reference may be made to diagnostic criteria for myocarditis due to conventional etiology, in clinical practice, erroneous inactivation of ICIs is common due to lack of accepted criteria for diagnosis of ICIs-related myocarditis. In 2019, bonaca proposed diagnostic criteria for ici s-related myocarditis. In 2020, diagnosis standards for ici s-related myocarditis are also proposed by the consensus of the immune checkpoint inhibitor-related myocarditis monitoring and management chinese specialists: i.e. meets any 1 of the following that can be diagnosed as ICIs-related myocarditis. (1) Histopathological diagnosis of myocarditis (endocardial myocardial biopsy or autopsy). (2) CMR manifests myocarditis with clinical syndrome and any 1 of the following: (1) elevated cardiac injury biomarkers; (2) electrocardiographic evidence of myocardial-pericarditis. (3) Echocardiography is new of abnormalities in wall motion that cannot be explained by other diagnoses (e.g., acute coronary syndrome, stress cardiomyopathy, sepsis) and satisfies all of the following conditions: (1) clinical syndrome conforms to myocarditis; (2) elevated cardiac injury markers; (3) electrocardiographic evidence of myocardial-pericarditis; (4) angiography or other examination excludes obstructive coronary artery disease.
The diagnostic criteria for ICIs-related myocarditis are also subject to objective conditions for domestic use: (1) hospitals capable of performing myocardial biopsies are extremely limited. (2) The oncology hospitals do not develop CMR examinations basically, and CMR can be completed in the comprehensive hospitals. (3) the condition of critically ill patients is not suitable for CMR examinations. Thus, there are quite limited cases in which "unequivocally diagnosed myocarditis" can be achieved, and more cases are "more likely or possible myocarditis". Therefore, in view of the above, there is a need in the art to obtain a marker that can detect ICIs-related myocarditis early, sensitively, economically and efficiently.
Adipose tissue not only has energy storage functions, but also can secrete a large number of active factors that affect energy metabolism, vasculitis response, and immunity, with recent views indicating that fat is likely to be the largest endocrine organ in the human body. Fat in the abdomen, buttocks, limbs, etc. is far from the heart and blood vessels, and secreted fat factors constitute a major source of peripheral fat factors. Peripheral fat factors act endocrinologically on the cardiovascular system. The fat factors secreted by blood vessels or pericardiac adipose tissue affect the heart or blood vessels primarily through paracrine secretion. Resistin (Resistin) is a newly discovered fat factor in recent years, and has been confirmed to be closely related to glycolipid metabolism and inflammatory diseases, and serum Resistin levels are markedly elevated in patients suffering from chronic inflammatory diseases such as obesity and ulcerative colitis. Clinical studies have demonstrated that resistin is closely related to the development of adverse cardiovascular events and that the primary mechanism may be related to inflammation. A recent clinical study has included 1913 ethnic subjects with atherosclerotic cardiovascular disease, and found that the higher the serum resistin level, the higher the incidence of cardiovascular adverse events such as heart failure, coronary heart disease, etc., after an average follow-up of 7.2 years. In addition, by measuring the serum resistin levels of 130 patients with stable coronary heart disease, the higher the serum resistin levels are found after Cox regression analysis, the higher the total patient mortality and heart failure and the risk of cardiovascular events thereof are. In summary, resistin is not only associated with the occurrence of adverse cardiovascular disease, but also with the severity of cardiovascular disease.
Disclosure of Invention
The invention aims to solve the technical problem of how to detect the ICIS related myocarditis early, sensitively, economically and efficiently.
To achieve the object of the present invention, the present invention provides a diagnostic reagent for immune checkpoint inhibitor-related myocarditis, which is used for detecting the level of resistin in peripheral blood of a tumor patient undergoing ICIs treatment.
The invention provides a diagnostic kit for immune checkpoint inhibitor-related myocarditis, which comprises a detection reagent for detecting the resistin level of peripheral blood of a tumor patient undergoing ICIs treatment.
The invention provides a detection method of early myocardial injury of myocarditis related to immune checkpoint inhibitor, which is used for judging whether the early myocardial injury of the myocarditis related to ICIs exists by detecting the resistin level of peripheral blood of a tumor patient receiving ICIs treatment.
The invention provides application of a reagent for detecting the level of resistin in preparation of an ICIS related myocarditis diagnosis kit.
The invention provides a detection system, which comprises a data processing device and a substance for detecting the level of resistin; the data processing device comprises a data input module, a data recording module, a data comparison module and a conclusion output module; the data input module is configured to input a magnitude of a resistin level of a sample to be tested; the data recording module is configured to store the magnitude of the resistance element level of the sample to be tested and a judging threshold value; the data comparison module is configured to receive the magnitude of the resistance level of the sample to be tested, which is sent by the data input module, and call the judgment threshold value from the data recording module and compare the judgment threshold value with the magnitude of the resistance level of the sample to be tested; the conclusion output module is configured to receive the comparison result sent by the data comparison module and judge the comparison result according to a preset judgment condition; determining whether the subject has early myocardial damage to ICIs-related myocarditis.
Preferably, the substance that detects the level of resistin comprises reagents and/or instrumentation that detect the magnitude of the level of resistin.
The invention provides a storage device which stores a plurality of instructions for executing the detection steps of the detection system.
Compared with the prior art, the invention has the following beneficial effects:
the invention can detect the expression quantity of resistin in peripheral blood to determine whether the detected person has ICIS related myocarditis, and the detection is more convenient and economical and has high specificity. The invention can be used for early diagnosis of ICIS-related myocarditis.
Drawings
FIG. 1 is a graph comparing the concentration of resistin in peripheral blood of a group of patients undergoing conventional chemotherapy, a group not undergoing ICI immunotherapy and a group undergoing ICI immunotherapy in combination with myocarditis.
FIG. 2 is a graph of sensitivity and specificity ROC for resistin assays to determine whether ICis-associated myocarditis is present in a subject.
FIG. 3 is a graph of an analysis of the correlation of resistin concentration with troponin T (cTnT) concentration and days of myocarditis development.
Detailed Description
In order to make the invention more comprehensible, preferred embodiments accompanied with the accompanying drawings are described in detail as follows:
the invention aims to provide a diagnostic reagent for immune checkpoint inhibitor-related myocarditis, which is used for detecting the level of resistin in peripheral blood of a tumor patient who is receiving ICIs treatment.
The invention provides a diagnostic kit for immune checkpoint inhibitor-related myocarditis, which comprises a detection reagent for detecting the resistin level of peripheral blood of a tumor patient undergoing ICIs treatment.
The invention provides a detection method of early myocardial injury of myocarditis related to immune checkpoint inhibitor, which is used for judging whether the early myocardial injury of the myocarditis related to ICIs exists by detecting the resistin level of peripheral blood of a tumor patient receiving ICIs treatment.
The invention provides application of a reagent for detecting the level of resistin in preparation of an ICIS related myocarditis diagnosis kit.
The invention provides a detection system, which comprises a data processing device and a substance for detecting the level of resistin; the data processing device comprises a data input module, a data recording module, a data comparison module and a conclusion output module; the data input module is configured to input a magnitude of a resistin level of a sample to be tested; the data recording module is configured to store the magnitude of the resistance element level of the sample to be tested and a judging threshold value; the data comparison module is configured to receive the magnitude of the resistance level of the sample to be tested, which is sent by the data input module, and call the judgment threshold value from the data recording module and compare the judgment threshold value with the magnitude of the resistance level of the sample to be tested; the conclusion output module is configured to receive the comparison result sent by the data comparison module and judge the comparison result according to a preset judgment condition; determining whether the subject has early myocardial damage to ICIs-related myocarditis. The substance for detecting the level of resistin comprises a reagent and/or an instrument for detecting the level of resistin.
The invention provides a storage device which stores a plurality of instructions for executing the detection steps of the detection system.
The invention aims to assist in determining the presence or absence of ICIs-related myocarditis by detecting the level of resistin in the peripheral blood of a tumor patient undergoing ICIs treatment.
Examples
The experimental process:
three groups of patients receiving traditional chemotherapy (Negative control), ICI immunotherapy without myocarditis (Non-Myo), ICI immunotherapy with myocarditis (Myo) were collected using 10ml blood collection tubes, baseline data of patients are shown in Table 1, 1000rpm, and supernatants were collected after centrifugation for 10 minutes. Peripheral blood resistin concentrations were then detected by enzyme-linked immunosorbent assay (ELISA), followed by a rank sum test to compare the differences in the distribution of resistin concentrations among the three groups of people.
Table 1:
experimental results:
the results of the three groups of experiments found that there was no difference in peripheral blood resistin concentration (p > 0.05) between the group receiving conventional chemotherapy and the group receiving ICI immunotherapy without myocarditis, and that the group receiving ICI immunotherapy without myocarditis had significantly increased resistin concentration (p=0.028) (see fig. 1) and AUC was 0.783 (see fig. 2). Correlation analysis showed no obvious correlation between the concentration of resistin and troponin T (cTnT) and the number of days that myocarditis occurred (Time from myocarditis onset to blood), but higher resistin concentrations at early stages of myocarditis occurrence were observed, and the resistin concentrations tended to decrease gradually with increasing days (fig. 3).
As shown in fig. 1, the comparison of the concentrations of resistin in peripheral blood of a group of patients undergoing conventional chemotherapy (Negative control), a group not undergoing ICI immunotherapy (ici+non-Myo), and a group undergoing ICI immunotherapy (ici+myo); the ordinate is the resistin concentration and the abscissa is the three sets of data histograms.
As shown in fig. 2, a graph of sensitivity and specificity ROC for determining whether an ici s-associated myocarditis exists in a subject is determined for resistin detection.
FIG. 3 is a graph showing the correlation of resistin concentration with troponin T (cTnT) concentration and days of myocarditis development. Wherein the ordinate in panel A is troponin T (cTnT) concentration and the abscissa is resistin concentration. In panel B, the ordinate indicates the number of days in which myocarditis occurred, and the abscissa indicates the concentration of resistin.
In 2001, resistin was discovered from the selection of adipocyte genes in the study of rodent insulin sensitization mechanisms. The resistin can promote insulin resistance, regulate lipid balance, regulate endothelial dysfunction, promote myocardial hypertrophy, etc. Epidemiological studies have associated an increase in circulating resistin with an increased risk of type 2 diabetes, markers of inflammation, myocardial infarction and atherosclerosis. As described above, ICIs-related myocarditis is mainly increased inflammatory cell infiltration mediated by abnormal activated T cells and myocardial damage is aggravated due to cytotoxic reaction, and patient myocarditis tissue pathological reports also prove that myocardial tissue at a lesion part presents obvious inflammatory edema, so that an inflammation index related to myocardial tissue damage probably becomes a clinical biomarker for detecting ICIs-related myocarditis.
The expression quantity of the resistin in peripheral blood is higher than that of cTnT, the detection is more convenient and economical, and the resistin can be rapidly increased in the early stage of the occurrence of ICis related myocarditis; at the same time we found that there was no difference in resistin concentration between the group receiving traditional chemotherapy and the group receiving ICI immunotherapy without myocarditis, suggesting that resistin may be more specific for immunotherapy-related myocardial damage.
The implementation of the invention comprises the following steps:
when a tumor patient receives ICIs, the patient regularly extracts peripheral blood to detect liver and kidney functions, the patient is added with resistin to detect, and when the concentration of the resistin is too high, the patient should be warned of the possibility of myocarditis, and at the moment, the myocardial zymogram, cardiac ultrasound and nuclear magnetic resonance can be rechecked to judge whether the ICIs-related myocarditis occurs.
While the invention has been described with respect to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Equivalent embodiments of the present invention will be apparent to those skilled in the art having the benefit of the teachings disclosed herein, when considered in the light of the foregoing disclosure, and without departing from the spirit and scope of the invention; meanwhile, any equivalent changes, modifications and evolution of the above embodiments according to the essential technology of the present invention still fall within the scope of the technical solution of the present invention.
Claims (7)
1. A diagnostic reagent for immune checkpoint inhibitor-related myocarditis, wherein the diagnostic reagent is used to detect resistin levels in peripheral blood of a tumor patient undergoing ICIs treatment.
2. A diagnostic kit for immune checkpoint inhibitor-related myocarditis comprising a detection reagent for detecting resistin levels in peripheral blood of a tumor patient undergoing ICIs treatment.
3. A detection method of early myocardial injury of myocarditis related to immune checkpoint inhibitor is characterized in that whether the early myocardial injury of the myocarditis related to ICIs exists is judged by detecting the resistin level of peripheral blood of a tumor patient receiving ICIs treatment.
4. An application of a reagent for detecting the level of resistin in preparing a diagnosis kit for ICIS-related myocarditis.
5. A test system comprising data processing means and a substance for detecting levels of resistin; the data processing device comprises a data input module, a data recording module, a data comparison module and a conclusion output module; the data input module is configured to input a magnitude of a resistin level of a sample to be tested; the data recording module is configured to store the magnitude of the resistance element level of the sample to be tested and a judging threshold value; the data comparison module is configured to receive the magnitude of the resistance level of the sample to be tested, which is sent by the data input module, and call the judgment threshold value from the data recording module and compare the judgment threshold value with the magnitude of the resistance level of the sample to be tested; the conclusion output module is configured to receive the comparison result sent by the data comparison module and judge the comparison result according to a preset judgment condition; determining whether the subject has early myocardial damage to ICIs-related myocarditis.
6. The system according to claim 5, wherein: the substance that detects resistin levels includes reagents and/or instrumentation that detect the magnitude of resistin levels.
7. A storage device storing a plurality of instructions for performing the detecting steps of the detecting system as claimed in claim 5.
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