CN113436721B - Establishment method and application of primary central nervous system lymphoma prognosis model - Google Patents
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Abstract
The invention discloses a prognostic model of primary central nervous system lymphoma, which comprises related prognostic indicators, risk groups corresponding to different scores of the prognostic indicators and prognostic states corresponding to the risk groups; wherein the prognostic indicators include at least two of lactate dehydrogenase and lymphocyte ratio, age, and KPS score. The invention firstly integrates the ratio of lactate dehydrogenase to lymphocyte, age and KPS score as the prognostic evaluation index of primary central nervous system lymphoma, and establishes a novel prognostic evaluation model for primary central nervous system lymphoma patients.
Description
Technical Field
The invention belongs to the technical field of biomedical detection, and particularly relates to a method for establishing a primary central nervous system lymphoma prognosis model and application thereof.
Background
Primary Central Nervous System Lymphoma (PCNSL) is a rare non-hodgkin lymphoma that occurs in the brain, spinal cord, meninges and eyes, is highly invasive, and is not accompanied by involvement of other organ systems. Clinical diagnosis and treatment of PCNSL has been a difficult problem in the field of hematological neoplasms, and the incidence of PCNSL has increased in recent years, particularly in elderly patients over 60 years of age.
In the prior art, with the use of a large dose of methotrexate, the survival of patients is improved, but the treatment effect and the disease prognosis are still not satisfactory. International Extranodal Lymphoma Study Group (IELSG) score and Memorial Sloan Keying Cancer Center (MSKCC) score are scoring systems currently used to predict prognosis in patients with PCNSL. The subjects of the IELSG scoring system were 378 PCNSL patients admitted by 23 cancer centers in 5 countries, between 1980 and 1999; however, only 105 patients had complete clinical data and were included in the model, with an average follow-up time of only 24 months.
The applicant studies found that although MSKCC and IELSG prognostic models are more widely used clinically, in view of the medical treatment progress of PCNSL, such as the use of targeted therapeutic drugs, MSKCC and IELSG prognostic models are not necessarily applicable to the current new clinical treatment modalities. More importantly, a considerable part of PCNSL patients have increased intracranial pressure, cannot carry out lumbar puncture cerebrospinal fluid examination, and cannot obtain cerebrospinal fluid protein concentration data forming an IELSG (IELSG-assisted laser desorption/ionization plasma) prognosis model, while the MSKCC prognosis model can be calculated in all PCNSL patients, but research objects of the MSKCC prognosis model come from the same institution and have the problem of selection deviation.
Disclosure of Invention
The invention aims to solve the technical problem that the existing prognosis model is not necessarily suitable for the existing new clinical treatment mode of PCNSL, and provides a method for establishing a primary central nervous system lymphoma prognosis model and application thereof.
In order to solve the problems, the invention is realized according to the following technical scheme:
in a first aspect, the present invention provides a prognostic model for primary cns lymphoma, the prognostic model comprising associated prognostic indicators, risk groups corresponding to different scores of the prognostic indicators, and prognostic statuses corresponding to the risk groups;
wherein the prognostic indicators include at least two of lactate dehydrogenase and lymphocyte ratio, age, and KPS score.
In combination with the first aspect, the present invention also provides the 1 st preferred embodiment of the first aspect, wherein the model comprises a low risk group, a medium risk group and a high risk group, and the critical ratio of lactate dehydrogenase to lymphocytes between the low risk group and the medium risk group is 166.8;
the prognosis indexes corresponding to the low risk group are that the age is less than 50 years and the ratio of the lactate dehydrogenase to the lymphocytes is less than or equal to 166.8, or the KPS is more than or equal to 70 and the ratio of the lactate dehydrogenase to the lymphocytes is less than or equal to 166.8;
the corresponding prognostic indicators of the middle risk group are that the age is less than 50 years, the ratio of lactate dehydrogenase to lymphocytes is more than 166.8, or KPS is more than or equal to 70, and LLR is more than 166.8;
the prognosis indexes corresponding to the high risk group are that the age is more than or equal to 50 years and the KPS is less than 70.
In combination with the first aspect, the present invention also provides a 2 nd preferred embodiment of the first aspect, the prognosis status of the low risk group is: the prognosis is better; prognostic status of the risk group: the prognosis is general; prognostic status of the high risk group: the prognosis is poor.
In a second aspect, the present invention also provides a prognostic model for primary central nervous system lymphoma, as shown in the following table:
in a third aspect, the present invention also provides the use of a prognostic model for primary cns lymphoma according to the first or second aspect, for assessing the prognosis of primary cns lymphoma.
In a fourth aspect, the present invention also provides a method for establishing a prognosis model of primary central nervous system lymphoma, comprising the following steps:
collecting clinical data of a patient with primary central nervous system lymphoma;
taking the overall survival time (OS) of the patient as a result, carrying out K-M survival analysis on the clinical data, and screening risk factors which obviously influence the time from initial diagnosis to death or last follow-up of the patient;
taking the overall survival time (OS) of the patient as a result, uniformly bringing the risk factors into a Cox risk proportion model for multi-factor survival analysis, and constructing a prognosis model according to the result of the multi-factor analysis;
the prognosis model comprises related prognosis indexes, risk groups corresponding to different scores of the prognosis indexes and prognosis states corresponding to the risk groups; the prognostic indicators include at least two of lactate dehydrogenase and lymphocyte ratios, age, and KPS score.
In combination with the fourth aspect, the present invention also provides the 1 st preferred embodiment of the fourth aspect, wherein the model comprises a low risk group, a medium risk group and a high risk group, and the critical ratio of lactate dehydrogenase to lymphocytes between the low risk group and the medium risk group is 166.8;
the prognosis indexes corresponding to the low risk group are that the age is less than 50 years and the ratio of the lactate dehydrogenase to the lymphocytes is less than or equal to 166.8, or the KPS is more than or equal to 70 and the ratio of the lactate dehydrogenase to the lymphocytes is less than or equal to 166.8;
the corresponding prognostic indicators of the middle risk group are that the age is less than 50 years, the ratio of lactate dehydrogenase to lymphocytes is more than 166.8, or KPS is more than or equal to 70, and LLR is more than 166.8;
the high risk group corresponds to prognostic indicators of age greater than or equal to 50 years and KPS less than 70.
In combination with the fourth aspect, the present invention also provides a 2 nd preferred embodiment of the fourth aspect, wherein the risk factor with the K-M survival analysis result P < 0.05 is selected for inclusion in the multi-factor survival analysis.
Compared with the prior art, the invention has the beneficial effects that:
the invention firstly integrates the ratio of lactate dehydrogenase to lymphocyte, age and KPS score as the prognostic evaluation index of primary central nervous system lymphoma, and establishes a novel prognostic evaluation model for primary central nervous system lymphoma patients. Clinical verification proves that the prognosis model can effectively predict the prognosis of the primary central nervous system lymphoma patient, and compared with the existing scoring standard, the prognosis model disclosed by the invention determines the risk group of the patient according to the age, KPS and the ratio of lactate dehydrogenase to lymphocytes so as to assist a clinician in judging the clinical development and disease outcome of the patient, so that accurate layered treatment is realized, and a reasonable treatment scheme and timely and effective doctor-patient communication can be more favorably formulated by the clinician.
Drawings
Embodiments of the invention are described in further detail below with reference to the attached drawing figures, wherein:
FIG. 1 is a schematic representation of the OS of low and high LLR banks;
FIG. 2 is an OS diagram of the MSKCC score for 3 risk groups;
FIG. 3 is a schematic representation of the OS of the low LLR and high LLR groups in low and medium MSKCC risk patients;
FIG. 4 is a schematic representation of OS for the low, medium and high risk groups of the prognostic model of the present invention.
Detailed Description
The preferred embodiments of the present invention will be described in conjunction with the accompanying drawings, and it will be understood that they are described herein for the purpose of illustration and explanation and not limitation.
The present invention relates to the term interpretation:
PCNSL (primary central nervous system lymphoma): primary central nervous system lymphoma;
OS (overall survival): overall lifetime;
ALC (absolute lymphocyte count): absolute lymphocyte counts;
LDH (lactate dehydrogenase): a lactate dehydrogenase;
LLR (lactate dehydrogenase-to-lymphocyte ratio): the ratio of lactate dehydrogenase to lymphocyte;
KPS scoring: karnofsky (Karnofsky, KPS, percentile) functional status score.
The prediction model according to the present invention predicts the patient OS, which is defined as the time from the time of the disease diagnosis to the time of death or the last follow-up due to any cause, and is calculated in months.
The embodiment of the invention provides a method for establishing a primary central nervous system lymphoma prognosis model, which comprises the following steps:
(1) Clinical data were collected from patients with primary cns lymphoma.
In the present invention, clinical data of PCNSL patients includes clinical data and experimental results. Wherein, the clinical data includes: gender, age, cell of origin class (GCB and ABC subtypes according to Hans algorithm), B symptoms, ECOG PS, LDH and treatment modality. The laboratory results include: peripheral blood neutrophils, lymphocyte counts, NLR (i.e., absolute numbers of neutrophils/absolute numbers of lymphocytes), dNLR (i.e., absolute numbers of neutrophils/[ total number of leukocytes-absolute numbers of neutrophils ]), and LLR (i.e., lactate dehydrogenase/absolute numbers of lymphocytes).
In a preferred implementation, the optimal critical point is searched for continuous data (such as LLR) in laboratory data by adopting the optimal approximate value of an ROC curve, and two classification groups are carried out; the classified data in the clinical data are all processed as grouped data. The johnson index in the present invention is johnson index = sensitivity + specificity-1, and the corresponding threshold at the maximum johnson index is far from the chance line (y = x), and both sensitivity and specificity are high.
(2) And (3) taking the overall survival time (OS) of the patient as a result, carrying out K-M survival analysis on the clinical data, and screening risk factors which obviously influence the time from initial diagnosis to death or last follow-up of the patient.
Specifically, the invention takes the total survival time (OS) of the patient as the end, adopts a Kaplan-Meier method to draw a survival curve, adopts log-rank to check the difference among groups, has statistical significance by taking P less than 0.05 as the difference, screens the clinical data and relevant indexes of inflammation for risk factors, and screens the risk factors which obviously influence the time from initial diagnosis to death or last follow-up of the patient.
(3) Taking the overall survival time (OS) of the patient as a result, uniformly incorporating the risk factors into the Cox risk ratio model for multi-factor survival analysis, and constructing a prognosis model according to the result of the multi-factor analysis.
Specifically, the risk factors with statistical differences are uniformly brought into a Cox risk ratio model for multi-factor survival analysis by taking the overall survival time (OS) as a result, and a prognosis model is constructed according to the result of the multi-factor analysis.
The prognosis model comprises relevant prognosis indexes, risk groups corresponding to different grades of the prognosis indexes and prognosis states corresponding to the risk groups; the prognostic indicators include at least two of lactate dehydrogenase and lymphocyte ratios, age, and KPS score.
The ratio, age and KPS score of lactate dehydrogenase and lymphocytes are firstly integrated to be used as the prognostic evaluation index of the primary central nervous system lymphoma, and a novel prognostic evaluation model for the primary central nervous system lymphoma patient is established. In the research and test process of the invention, the rise of serum LDH is an index with poorer prognosis of malignant tumor and solid tumor in a blood system and is proved to be one of prognostic indexes forming IELSG score; the decrease in Absolute Lymphocyte (ALC) is considered to be an independent factor in poor prognosis of PCNSL. Therefore, the applicant finds that the ratio LLR of the tumor load related marker (LDH) and the inflammation marker (ALC) can be used as a simple and feasible prognostic index through research.
Further, the impact of LLRs and other clinical features on OS was evaluated by analyzing prognostic indicators for PCNSL using one-way analysis and Cox regression models. Single factor analysis found the following potentially poor prognostic factors: age > 60 years, ECOG-PS > 1, plain radiotherapy, MSKCC score high risk group, NLR > 4.74 (i.e., absolute number of neutrophils/absolute number of lymphocytes), dNLR > 3.29 (i.e., absolute number of neutrophils/[ total number of leukocytes-absolute number of neutrophils ]) and LLR > 166.8; uniformly incorporating the indexes into a Cox risk ratio model to perform multi-factor survival analysis with OS; statistics show that only LLR and MSKCC scores are independent prognostic indicators of OS.
Specifically, the prognosis model comprises a low risk group, a medium risk group and a high risk group, and the critical ratio of lactate dehydrogenase to lymphocytes between the low risk group and the medium risk group is 166.8;
the prognosis indexes corresponding to the low risk group are that the age is less than 50 years and the ratio of the lactate dehydrogenase to the lymphocytes is less than or equal to 166.8, or the KPS is more than or equal to 70 and the ratio of the lactate dehydrogenase to the lymphocytes is less than or equal to 166.8;
the prognosis indexes corresponding to the stroke risk group are that the age is less than 50 years and the ratio of lactate dehydrogenase to lymphocytes is more than 166.8, or KPS is more than or equal to 70 and LLR is more than 166.8;
the high risk group corresponds to prognostic indicators of age greater than or equal to 50 years and KPS less than 70.
Prognostic status of the low risk group: the prognosis is better; prognostic status of the risk group: the prognosis is general; prognostic status of the high risk group: the prognosis is poor.
The prognosis model of primary central nervous system lymphoma is shown in the following table:
in yet another embodiment of the present invention, a receiver operating characteristic curve (ROC) is used to determine the discrimination of the prognostic models; the area under the model curve is 0.696, which indicates that the prediction model has good discrimination.
It should be noted that the critical value of LLR between the low risk group and the middle risk group is found to be 166.8 by the inventive discovery of the present invention.
In one implementation, the threshold value of the LLR is obtained by:
optimal cut-off values for LLRs were obtained using Receiver-operating-characteristics (ROC) curves by data analysis using SPSS16.0 system software (IBM, armonk, new York, US). The single factor adopts Kaplan-Meier method to carry out survival analysis, and the variable with significance (P is less than 0.05) in the single factor analysis is subjected to multi-factor analysis by using a forward conditional Cox regression model, and the difference with PP less than 0.05 has statistical significance.
Results from the patient's pretreatment blood routine and blood biochemistry are collected and LLR is calculated for each patient. In the present invention, OS was used as the end point of the study and the optimal LLR cut-off was calculated by ROC curve. The area under the ROC curve of the LLR is 0.616, and the optimal critical values corresponding to the maximum joint sensitivity and the maximum specificity are 166.8 respectively.
Further, performing survival analysis on the prognosis model, and obtaining the 5-year survival rate according to the current cumulative survival analysis ratio of the survival analysis exterior and interior; the median survival time for this fraction of patients was obtained from the median survival analysis time table, as shown below:
| risk group | Median survival | Survival rate of 5 years |
| Low risk group | 74 months old | 56.1％ |
| Middle risk group | 33 months old | 26.6％ |
| High risk group | 17 months old | 14.1％ |
Prognostic model verification
Serum LDH in biochemical examination before treatment of a patient with PCNSL for initial diagnosis and lymphocyte count (ALC) in a blood routine are collected, and LLR is calculated. Prognostic indicators according to the prognostic models of the present invention: age, KPS and LLR determine the risk group of the patient.
The follow-up visit is carried out by telephone during the treatment period of the patient, and the follow-up visit deadline is 3/2020. Until the follow-up deadline no death occurred, the last follow-up date was taken as the cutoff value for analysis. The death date was obtained from clinical history, from death registration or by phone call to patient relatives follow-up. OS is calculated in months and is defined as the time from the time of the disease diagnosis to the time of death or last follow-up due to any cause.
(1) Male patient, 65 years old, KPS score =90, ldh =143, alc =1.65, calculated to LLR =86.67.
Patients can be classified into low risk groups in the prognostic model according to LLR =86.67 and KPS = 90. The results show that: by the last follow-up date of 2020, 3 months and 3 days, the patients survive, the total survival time is 47 months, which is higher than the median survival time of PCNSL patients, and the prognosis is better.
(2) Male patient, 76 years old, KPS =60, ldh =213, alc =0.88, calculated LLR =242.05.
Patients can be classified as high risk groups in the prognostic model according to LLR =242.05, KPS =60, and age =76 years. The results show that: by 3 months 3 days after 2020 of the last follow-up date, the patient dies, the overall survival is 1 month, which is much lower than the median survival of the PCNSL patient, and the prognosis is worse.
(3) Female patient, 38 years old, KPS =90, ldh =499, alc =1.62, calculated to LLR =307.80.
Patients can be classified into a group of risks in the prognostic model according to LLR =307.80, KPS =90 and age = 38. The results show that: by the last follow-up date of 2020, 3 months and 3 days, the patient dies, and the overall survival period is 35 months, with a general prognosis.
(4) Male patient, 53 years old, KPS =90, ldh =195, alc =1.20, calculated to LLR =162.5.
Patients can be classified as low risk groups in the prognostic model according to LLR =162.5, KPS =90, and age = 53. The results show that: by the last follow-up date of 2020, 3 months and 3 days, the patient survives, the total survival period is 51 months, and the prognosis is better.
Clinical verification proves that the prognosis model can effectively predict the prognosis of the primary central nervous system lymphoma patient, compared with the existing scoring standard, the risk group of the patient is determined according to the age, KPS and the ratio of lactate dehydrogenase to lymphocyte, so that a clinician is assisted to judge the clinical development and disease outcome of the patient, accurate layered treatment is realized, and the method is more beneficial to the formulation of a reasonable treatment scheme by the clinician and timely and effective doctor-patient communication.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any way, so that any modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention will still fall within the scope of the technical solution of the present invention.
Claims (5)
1. A method for establishing a prognosis model of primary central nervous system lymphoma is characterized in that the prognosis model comprises related prognosis indexes, risk groups corresponding to different grades of the prognosis indexes and prognosis states corresponding to the risk groups;
wherein the prognostic indicators include at least two of lactate dehydrogenase and lymphocyte ratios, age, and KPS score;
the model comprises a low risk group, a middle risk group and a high risk group, and the critical ratio of lactate dehydrogenase to lymphocytes between the low risk group and the middle risk group is 166.8;
the prognosis indexes corresponding to the low risk group are that the age is less than 50 years and the ratio of the lactate dehydrogenase to the lymphocytes is less than or equal to 166.8, or the KPS is more than or equal to 70 and the ratio of the lactate dehydrogenase to the lymphocytes is less than or equal to 166.8;
the prognosis indexes corresponding to the stroke risk group are that the age is less than 50 years and the ratio of lactate dehydrogenase to lymphocytes is more than 166.8, or KPS is more than or equal to 70 and LLR is more than 166.8;
the high risk group corresponds to prognostic indicators of age greater than or equal to 50 years and KPS less than 70.
2. The method for establishing a prognostic model for primary central nervous system lymphoma according to claim 1, wherein:
prognostic status of the low risk group: the prognosis is better; prognostic status of the risk group: the prognosis is general; prognostic status of the high risk group: the prognosis is poor.
3. Use of a method of establishing a prognostic model for primary cns lymphoma according to claim 1 or claim 2, wherein said prognostic model for primary cns lymphoma is used to evaluate the prognosis of primary cns lymphoma.
4. A method for establishing a prognosis model of primary central nervous system lymphoma is characterized by comprising the following steps:
collecting clinical data of a patient with primary central nervous system lymphoma;
taking the overall survival time (OS) of the patient as a result, carrying out K-M survival analysis on the clinical data, and screening risk factors which obviously influence the time from initial diagnosis to death or last follow-up of the patient;
taking the overall survival time (OS) of the patient as a result, uniformly incorporating the risk factors into the Cox risk ratio model for multi-factor survival analysis, and constructing a prognosis model according to the result of the multi-factor analysis;
the prognosis model comprises related prognosis indexes, risk groups corresponding to different scores of the prognosis indexes and prognosis states corresponding to the risk groups; the prognostic indicators include at least two of lactate dehydrogenase and lymphocyte ratio, age, and KPS score;
the model comprises a low risk group, a medium risk group and a high risk group, and the critical ratio of lactate dehydrogenase to lymphocytes between the low risk group and the medium risk group is 166.8;
the prognosis indexes corresponding to the low risk group are that the age is less than 50 years and the ratio of the lactate dehydrogenase to the lymphocytes is less than or equal to 166.8, or the KPS is more than or equal to 70 and the ratio of the lactate dehydrogenase to the lymphocytes is less than or equal to 166.8;
the prognosis indexes corresponding to the stroke risk group are that the age is less than 50 years and the ratio of lactate dehydrogenase to lymphocytes is more than 166.8, or KPS is more than or equal to 70 and LLR is more than 166.8;
the high risk group corresponds to prognostic indicators of age greater than or equal to 50 years and KPS less than 70.
5. The method of establishing a prognostic model for primary central nervous system lymphoma according to claim 4, wherein:
and selecting the risk factors with the K-M survival analysis result P less than 0.05 to be included in the multi-factor survival analysis.
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