CN106248945B - Method, system and the kit of the grouping of hepatocellular carcinoma radical excision prognosis situation are carried out to patients with hepatocellular carcinoma - Google Patents
Method, system and the kit of the grouping of hepatocellular carcinoma radical excision prognosis situation are carried out to patients with hepatocellular carcinoma Download PDFInfo
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Abstract
The present invention provides one kind method that joint-detection, the differentiation state of tumour cell and the number of tumour based on Cyfra21-1 (CK19) and glypican-3 (GPC3) are assessed for the postoperative recurrence risk of the patients with hepatocellular carcinoma to planning to implement tumor radical cure resection of index.According to this method, patient reasonably can be screened in the preoperative, to reduce the transfer after tumor radical cure resection, recurrence；In addition, according to this method, the transfer of tumour, risk of recurrence after patients with hepatocellular carcinoma surgical operation can also be assessed, and then clinician is instructed to handle the case implementation monitoring and early stage closely with high transfer, risk of recurrence.
Description
Technical field
The invention belongs to accurate medical domains, are specially related to planning to implement or row tumor radical cure resection has met rice
The patients with hepatocellular carcinoma of blue standard carries out method, system and the Related product of prognosis situation analysis, passes through this method, system and phase
Patients with hepatocellular carcinoma can be taken the metastases after tumor radical cure resection, recur wind by closing the obtained result of implementations of product
Danger assessment provides average information or auxiliary information with prediction.
Background technology
Primary carcinoma of liver is one of highest malignant tumour of incidence in world wide, and there are about 1,000,000 or more people every year
Newly suffer from this disease.China's onset of liver cancer number occupy first place in the world always, and about 230,000 people die of liver cancer every year, account for global hepatocarcinoma patient
The 53% of death toll, rank China's malignant tumour die of illness rate first place.Although current liver transfer operation is considered as generally acknowledged treatment liver cancer
Effective means, but due to the shortage for liver source, it is more general that the resection operation of liver neoplasm just becomes treatment hepatocellular carcinoma
All over the therapeutic strategy carried out.
It is now recognized that the tumor radical cure resection of early hepatocyte cancer patient has preferable prognosis.But most of research
It has been shown that, meets recurrence rate in 3 years of the early liver cancer of Milan standard and can reach 40%-50%.Recurrence in wherein 3 years is most absolutely
Number is since the transfer of primary tumor cancer cell is sent out.Substantially histopathological indications were based on more to the assessment of patient tumors in the past,
Such as diameter of tumor and tubercle number.These indexs fail to carry out tumour and patient from the cell behaviors of tumour comprehensive
Assessment, especially for the hepatocellular carcinoma in very early stage.
In recent years, with the discovery of some liver cancer biological markers so that liver cancer occurs for the mankind, the understanding of development has
Significant progress.Although the table of Cyfra21-1 (CK19) or Monophosphoinositideproteoglycans proteoglycans-3 (GPC3) in hepatocellular carcinoma
Up to report visible with the postoperative metastases of patient, the relationship of recurrence, but joint-detection CK19 or GPC3 carries out Asia to hepatocellular carcinoma
Classify and patient's prognosis is layered there is not yet open report.
Invention content
In view of the above-mentioned problems, the object of the present invention is to provide to meeting the quasi- progress of Milan standard or having carried out hepatocellular carcinoma
The patients with hepatocellular carcinoma of radical excision carries out the method and system of prognosis situation grouping.
It is a further object to provide the kits used with this method or system in combination.
Technical scheme is as follows.
Prognosis of the present invention includes recurrence, extrahepatic metastases and trouble in the liver of the postoperative tumour of hepatocellular carcinoma radical resection
Person's recurrence-free survival.
On the one hand, the present invention provides a kind of quasi- progress to meeting Milan standard or has carried out hepatocellular carcinoma radical excision
Patients with hepatocellular carcinoma carry out prognosis situation grouping method, the method includes：
(1) CK19 (Cyfra21-1) and GPC3 (phosphorus of the Tissues of Hepatocellular Carcinoma cells in sample of the patient are detected
Acyl inositol proteoglycans -3) expression, and give patient's assignment based on expression：As for coexpression CK19 and GPC3
CK19+/GPC3+, assignment 1 are divided；Such as it is expression GPC3 but does not express the CK19-/GPC3+ or CK19 of CK19 and GPC3 is not expressed
CK19-/GPC3-, assignment 0 divides；
(2) the differentiation situation of the Tissues of Hepatocellular Carcinoma sample of the patient is detected, and patient's assignment is given based on differentiation situation：
Such as it is the low differentiation of tumour, assignment 1 is divided；Such as it is to break up in tumour differentiated or tumour, assignment 0 is divided；
(3) tumor nodule number in the liver of the patient is detected, and patient's assignment is given based on tubercle number：Such as it is 1
The single-shot of tumor nodule, assignment 0 are divided；It is such as the multiple of 2-3 tumor nodule, assignment 1 is divided；With
(4) assignment obtained in step (1), step (2) and step (3) is summed up, obtains total tax of the patient
Value, is thus determined as the postoperative good prognosis group of hepatocellular carcinoma radical resection by the patient for being always assigned a value of 0 point, will always be assigned a value of 1 point
Patient be determined as after hepatocellular carcinoma radical excision general prognosis group, or the patient for being always assigned a value of 2 points or 3 points is determined as liver
The postoperative poor prognosis group of cell cancer radical resection.
In the present invention, the Tissues of Hepatocellular Carcinoma sample is obtained from the preoperative liver of the patient and wears biopsy or hepatocellular carcinoma
Radical excision.
Preferably, it is detected in step (1) by carrying out immunohistochemical staining to the Tissues of Hepatocellular Carcinoma sample
CK19 and GPC3 expressions；
Preferably, the immunohistochemical staining is carried out using the monoclonal antibody for being directed to CK19 and GPC3 respectively；More
Preferably, the immunohistochemical staining utilizes the fluorescein-labeled monoclonal for being directed to CK19 and GPC3 respectively of different colours
Antibody carries out.CK19 and GPC3 is expressed as the negative or positive and is judged according to the general standard of this field.
According to the specific implementation mode of the application, the immunohistochemical staining utilizes rabbit-anti people's CK19 monoclonal antibodies
(ab52625, Abcam company) and mouse anti human GPC3 monoclonal antibodies (ab129381, Abcam company) carry out；Or it is described
Immunohistochemical staining utilizes the monoclonal antibody (FITC is marked, ab87014, Abcam companies) for CK19 and is directed to
Monoclonal antibody (the Alexa of GPC3647 labels, ab199813, Abcam companies) it carries out.
Preferably, it is detected point in step (2) by carrying out Hematoxylin-eosin dyeing to the Tissues of Hepatocellular Carcinoma sample
Change situation.
Preferably, it is effected a radical cure by the preoperative results of imaging of hepatocellular carcinoma radical resection or hepatocellular carcinoma in step (3)
The gross examination result of the Operated Specimens obtained in resection determines tumor nodule number in patient's liver；
Wherein preferably, the results of imaging is obtained from enhanced CT or enhancing nuclear magnetic scanning imaging.
On the other hand, the present invention provides a kind of quasi- progress to meeting Milan standard or has carried out hepatocellular carcinoma radical resection
The system that the patients with hepatocellular carcinoma of art carries out prognosis situation grouping, the system comprises：
(1) bioassay module：
(1-A) CK19 and GPC3 expression analysis modules, the module are set as the Tissues of Hepatocellular Carcinoma based on the patient
CK19 the and GPC3 expressions of cells in sample give patient's assignment：Such as it is the CK19+/GPC3+ of coexpression CK19 and GPC3, assigns
1 point of value；Such as it is expression GPC3 but does not express the CK19-/GPC3+ or CK19 of CK19 and CK19-/GPC3- that GPC3 is not expressed,
Assignment 0 is divided；
(1-B) histopathology fractional analysis module, the module are set as the Tissues of Hepatocellular Carcinoma based on the patient
The differentiation situation of sample gives patient's assignment：Such as it is the low differentiation of tumour, assignment 1 is divided；Such as it is to break up in tumour differentiated or tumour, assigns
0 point of value；With
(1-C) tumour number analysis module, the module are set as tumor nodule number in the liver based on the patient
Give patient's assignment：Such as it is the single-shot of 1 tumor nodule, assignment 0 is divided；It is such as the multiple of 2-3 tumor nodule, assignment 1 is divided；
And
(2) data processing module：
The module is set as adding the assignment for coming from module and module in (1-C) in module in (1-A), (1-B)
With obtain total assignment of the patient, and it is postoperative good pre- that the patient for being always assigned a value of 0 point is determined as hepatocellular carcinoma radical resection
The patient for being always assigned a value of 1 point is determined as after hepatocellular carcinoma radical excision generally prognosis group, or will always be assigned a value of 2 points by group afterwards
Or 3 points of patient is determined as the postoperative poor prognosis group of hepatocellular carcinoma radical resection.
Preferably, the Tissues of Hepatocellular Carcinoma sample in the system is obtained from the preoperative liver of the patient and wears biopsy or liver is thin
Born of the same parents' cancer radical excision.
In system provided by the invention, it is preferable that the module in (1-A) is also configured to detection CK19 and GPC3 expression feelings
Condition；
Preferably, CK19 and GPC3 are detected by carrying out immunohistochemical staining to the Tissues of Hepatocellular Carcinoma sample
Expression；
It is highly preferred that the immunohistochemical staining is carried out using the monoclonal antibody for being directed to CK19 and GPC3 respectively；
It is highly preferred that the immunohistochemical staining utilizes the fluorescein-labeled Dan Ke for being directed to CK19 and GPC3 respectively of different colours
Grand antibody carries out.
According to the specific implementation mode of the application, the immunohistochemical staining utilizes rabbit-anti people's CK19 monoclonal antibodies
(ab52625, Abcam company) and mouse anti human GPC3 monoclonal antibodies (ab129381, Abcam company) carry out；Or it is described
Immunohistochemical staining utilizes the monoclonal antibody (FITC is marked, ab87014, Abcam companies) for CK19 and is directed to
Monoclonal antibody (the Alexa of GPC3647 labels, ab199813, Abcam companies) it carries out.
In system provided by the invention, it is preferable that module is also configured to detect the differentiation situation in (1-B)；
Preferably, differentiation situation is detected by carrying out Hematoxylin-eosin dyeing to the Tissues of Hepatocellular Carcinoma sample.
In system provided by the invention, it is preferable that module is also configured to swell in the liver for detecting the patient in (1-C)
Tumor tubercle number；
Preferably, preoperative by the preoperative results of imaging of hepatocellular carcinoma radical resection or hepatocellular carcinoma radical resection
The gross examination result of Operated Specimens determines tumor nodule number in patient's liver in results of imaging or art；
Wherein preferably, the results of imaging is obtained from enhanced CT or enhancing nuclear magnetic scanning imaging.
Another aspect, the present invention also provides the kit that the method for present invention a kind of or system in combination use, the reagents
Box includes：
(A) it is used to detect the reagent of the CK19 and GPC3 expressions of Tissues of Hepatocellular Carcinoma cells in sample；With
(B) it is used to detect the reagent of the differentiation situation of Tissues of Hepatocellular Carcinoma sample.
In kit provided by the invention, it is preferable that the reagent in (A) includes for the Tissues of Hepatocellular Carcinoma
Sample carries out the reagent of immunohistochemical staining；
Preferably, the reagent includes the monoclonal antibody of CK19 and GPC3；It is highly preferred that the reagent includes different face
The fluorescein-labeled monoclonal antibody for being directed to CK19 and GPC3 respectively of color.
In kit provided by the invention, it is preferable that the reagent in (B) includes for the Tissues of Hepatocellular Carcinoma sample
Product carry out the reagent of Hematoxylin-eosin dyeing.
Specifically, first, method of the invention, system and kit are related to detecting the Tissues of Hepatocellular Carcinoma sample of patient
CK19 the and GPC3 expressions of middle cell, and based on the expression to patient carry out coexpression CK19 and GPC3 CK19+/
GPC3+, expression GPC3 but do not express the CK19-/GPC3+ and CK19 of CK19 and point of CK19-/GPC3- that GPC3 is not expressed
Group.
CK19 and GPC3 is expressed as the negative or positive and is judged according to the general standard of this field.The present invention's
It in preferred embodiment, is detected using the monoclonal antibody of CK19 and GPC3, as expression CK19 or GPC3 in sample
The 5% of cell >=all cells, is judged as the positive；And when the cell of expression CK19 or GPC3<The 5% of all cells, is judged as
It is negative.And when being detected using the fluorescein-labeled monoclonal antibody of different colours, when observe cells in sample show phase
Color is answered, is judged as the positive；When observing that cells in sample do not show corresponding color, it is judged as feminine gender.
Second, method of the invention, system and kit are related to the pathological diagnosis and histological of patient tumors.Such as
It is defined herein, basic, normal, high differentiation is carried out to tumour according to following standards and is judged：
Differentiated：Thin beam texture of the tumour cell arrangement no more than 3 layers, or false adenoid, acinus spline structure.And cell is big
It is small more consistent, core is slight atypia；
Middle differentiation：1. thin beam texture of the tumour cell arrangement no more than 3 layers, or false adenoid, acinus spline structure, cell are big
It is small inconsistent, core moderate atypia, no multinuclear oncocyte or tumor giant cell；Or 2. tumour cell arrange beam-like more than 3 layers
Structure (thick beam texture) or nido structure and entity structure, but cell size is more consistent, core moderate atypia, no multinuclear tumor
Cell or tumor giant cell；
Low differentiation：Any Histological Study, cell size is inconsistent, the pleomorphism of cell and core occurs, may occur in which multinuclear
Oncocyte or tumor giant cell.
Above-mentioned criterion can be found in：Bosman FT,Carneiro F,Hruban RH,Theise ND.WHO
Classification of Tumours of the Digestive System.forth ed.Lyon:International
Agency for Research on Cancer,2010:205-227；International Working
Party.Terminology of nodular hepatocellular lesions.Hepatology.1995；22(3):
983-93；With International Consensus Group for Hepatocellular
Neoplasia.Pathologic diagnosis of early hepatocellular carcinoma:a report of
the international consensus group for hepatocellular
neoplasia.Hepatology.2009；49(2):658-64.
Third, method of the invention, system and kit are related to the analysis of the tumor nodule number of patient.Patient's symbol
Milan standard is closed, therefore as defined herein, when detecting that tumor nodule number is 1 in patient's liver, is judged as tumour knot
The single-shot of section is judged as the multiple of tumor nodule when detecting in patient's liver that tumor nodule number is 2-3.Tumor nodule
The gross examination result in the preoperative results of imaging of hepatocellular carcinoma radical resection or hepatocellular carcinoma radical excision can be passed through
Judged.
Illustratively, the present invention is provided can carry out following implementation process using the method, system and kit：
It can be in the preoperative implementation technical solution of hepatocellular carcinoma radical resection 1：
1. the patients with hepatocellular carcinoma for meeting Milan standard according to imaging data selection enters following analysis.
2. the Tissues of Hepatocellular Carcinoma for wearing biopsy acquisition using preoperative liver carries out the immunohistochemical staining of CK19 and GPC3, by liver
Carcinoma patients are divided into tri- kinds of molecular isoforms of CK19+/GPC3+, CK19-/GPC3+ and CK19-/GPC3-, wherein with CK19-/
The assignment 0 of GPC3+ or CK19-/GPC3- phenotypes is divided, and the assignment 1 with CK19+/GPC3+ phenotypes is divided.
Preferably, which is to be cut to the continuous of tumor tissues using CK19 and GPC3 monoclonal antibodies
Piece carries out immunohistochemical staining, with observe expression CK19 or GPC3 tumour cell whether >=all tumour cells
5% judges positive or negative for standard, if the expressions of both of tumour cell is the positive, that is, is recorded as CK19+/GPC3+；Such as
Tumour cell only shows the GPC3 positives, then is recorded as CK19-/GPC3+；As tumour cell CK19 and GPC3 dye no positive table
It reaches, is then recorded as CK19-/GPC3-.
Preferably, it is dyed jointly using the fluorescein-labeled CK19 and GPC3 monoclonal antibodies of different colours, as long as
It observes tumour cell while expressing CK19 and GPC3, that is, be recorded as CK19+/GPC3+；As tumour cell only shows GPC3 sun
Property, then it is recorded as CK19-/GPC3+；If tumour cell CK19 and GPC3 dyes no positive expression, then be recorded as CK19-/
GPC3-。
3. the tumor tissues for wearing acquisition using preoperative liver carry out HE dyeing, tumour is divided into high, the low three kinds of differentiation shape of neutralization
State wherein the tumour assignment 0 with high or middle differentiation is divided there is poorly differentiated tumour assignment 1 to divide.
4. the number of tumor nodule, is divided into patient in the liver obtained according to preoperative enhanced CT or enhancing magnetic resonance imaging
Single-shot and multiple (2-3 tumour) two kinds of situations have multiple tumor nodule wherein the assignment 0 with single-shot tumor nodule is divided
Assignment 1 divide.
5. the assignment score that patient tumors immunophenotype, differentiation state and mono-/multi- are sent out to three classification indicators is added, can be with
Obtain 0 or 1 or 2 or 3 point.
6. the patient for being scored at 0 point is determined as Hepatectomy low-grade recurrent risk group (good prognosis group), will
It is divided into 1 point of patient and is determined as rank risk of recurrence group in Hepatectomy (general prognosis group), 2 points or 3 points will be scored at
Patient is determined as the high-level risk of recurrence group of Hepatectomy (poor prognosis group).
Alternatively, can be in the postoperative implementation technical solution of hepatocellular carcinoma radical resection 2：
1. being selected from the hepatocellular carcinoma trouble for meeting Milan standard according to enhancing NMR imaging or enhanced CT imageological examination result
Person carries out following analysis.
2. the immunohistochemical staining of CK19 and GPC3 is carried out using the Tissues of Hepatocellular Carcinoma that total surgical resection sample obtains,
Patients with hepatocellular carcinoma is divided into tri- kinds of molecular isoforms of CK19+/GPC3+, CK19-/GPC3+ and CK19-/GPC3-, wherein having
The assignment 0 of CK19-/GPC3+ and CK19-/GPC3- phenotypes is divided, and the assignment 1 with CK19+/GPC3+ phenotypes is divided.
CK19 and GPC3 is expressed as negative or positive judgement with technical solution 1.
3. carrying out HE dyeing using the tumor tissues that total surgical resection sample obtains, tumour is divided into high, neutralization low three
Kind differentiation state wherein dividing with high and middle differentiation tumour assignment 0 there is poorly differentiated tumour assignment 1 to divide.
4. being obtained according to the gross examination of total surgical resection sample or preoperative enhanced CT or enhancing nuclear magnetic scanning imaging
Patient is divided into single-shot and multiple (2-3 tumour) two kinds of situations by the number of tumor nodule in liver, wherein having single-shot tumour
Assignment 0 divide, divide with the assignment 1 of multiple tumour.
5. the assignment score that patient tumors immunophenotype, differentiation state and mono-/multi- are sent out to three classification indicators is added, can be with
Obtain 0 or 1 or 2 or 3 point.
6. the patient for being scored at 0 point is determined as Hepatectomy low-grade recurrent risk group (good prognosis group), will
It is divided into 1 point of patient and is determined as rank risk of recurrence group in Hepatectomy (general prognosis group), 2 points or 3 points will be scored at
Patient is determined as the high-level risk of recurrence group of Hepatectomy (poor prognosis group)
Present invention demonstrates that in conjunction with the tubercle of CK19 or GPC3 joint-detections, the differentiation state of hepatocellular carcinoma and tumour
Number can effectively be grouped the tumor resection prognosis of patients with hepatocellular carcinoma, the grouping can to patient's had postoperative recurrent tumor with
Transfer carries out effectively being layered and predict to provide intermediate result or auxiliary information.Therefore, the present invention is for screening suitable for hepatocellular carcinoma
Perform the operation the patients cut off, improves therapeutic effect, saves social resources etc. and is of great significance；Meanwhile to liver cell
Tumor recurrence, the assessment to shift risk after cancer surgical operation can enable the clinician to real according to the height of risk of recurrence
It applies monitoring and takes corresponding precautionary measures.
After carrying out above-mentioned prognosis situation grouping for a large amount of patients with hepatocellular carcinoma, find：Liver cell in good prognosis group
Cancer patient, practical recurrence rate is about 32.47% in two years after its tumor radical cure resection, and the average recurrence-free survival time is
61.2 months, have the curative effect preferable to simple tumor radical cure resection, but it is postoperative should carry out close tumor monitoring and
It is early to find metastases or recurrence, take further treatment measure to improve overall survival in time.Liver in general prognosis group
Carcinoma patients, practical recurrence rate is 55.81% in two years after its tumor radical cure resection, the average recurrence-free survival time
It is 32.6 months.And the patients with hepatocellular carcinoma in poor prognosis group, the practical recurrence rate in two years after its tumor radical cure resection
It is 91.43%, the average recurrence-free survival time is only 9.6 months.Therefore, the patient in general prognosis group and poor prognosis group, such as
Fruit selects tumor radical cure resection, postoperative to carry out closer lesion detection to find metastases or recurrence early,
Take further treatment measure to improve overall survival in time.
Description of the drawings
Hereinafter, carry out the embodiment that the present invention will be described in detail in conjunction with attached drawing, wherein：
Fig. 1：According to embodiments of the present invention 1 it is all enter group case survivorship curve, wherein Figure 1A is shown as four groups of existence
Curve, Figure 1B, which is shown, merges into three groups of survivorship curve；
Fig. 2：2 (technical solutions 1) according to embodiments of the present invention, immune point of the tumor tissues CK19 and GPC3 worn based on liver
The patients with hepatocellular carcinoma tumor radical cure resection prognosis grouping flow chart of type, differentiation and tumor number；
Fig. 3：2 (technical solutions 1) according to embodiments of the present invention, show the survivorship curve of patient population in different groups；
Fig. 4：2 (technical solutions 1) according to embodiments of the present invention, show the ROC curve of sorting technique of the present invention, below curve
Product is 0.776 (95% confidence interval is 0.616-0.937), and wherein dotted line is the reference line obtained according to Milan standard；
Fig. 5：3 (technical solutions 2) according to embodiments of the present invention, tumor tissues CK19 and GPC3 based on operation gross specimen
The patients with hepatocellular carcinoma tumor radical cure resection prognosis grouping flow chart of immunophenotyping, differentiation and tumor number；
Fig. 6：3 (technical solutions 2) according to embodiments of the present invention, show the survivorship curve of patient population in different groups；
Fig. 7：3 (technical solutions 2) according to embodiments of the present invention, show the ROC curve of sorting technique of the present invention, below curve
Product is 0.788 (95% confidence interval is 0.649-0.927), and wherein dotted line is the reference line obtained according to Milan standard.
Specific implementation mode
The present invention is described below with reference to specific embodiments.It will be appreciated by those skilled in the art that these embodiments are only
For illustrating the present invention, do not limit the scope of the invention in any way.
Experimental method in following embodiments is unless otherwise specified conventional method.Medicine as used in the following examples
Material raw material, reagent material etc. are commercially available products unless otherwise specified.
Embodiment 1The risks and assumptions of the recurrence-free survival in HCC patient are predicted by identification by establish grouping of the invention
Method
1. patient and method
Patient and tissue samples
In January, 2007 is collected to Beijing YouAn Hospital, Capital Medical University and liberation army 304 during in November, 2010
The case 346 of the hepatocellular carcinoma operation excision of hospital.This research meets Declaration of Helsinki and through local Ethics Committee batch
Standard, subject sign informed consent form.All cases are preoperative without chemotherapy, radiotherapy or interventional treatment.Operation excision
Other inclusion criterias include：(1) primary tumor stove, satellite stove and multiple stove can be by radical excisions, and (2) liver function is Child-
The A or B of Pugh classifications, remaining liver maintains physiological function and without surgical contraindication enough after (3) excision.Wherein 198 meet
Above-mentioned inclusion criteria and Milan standard are used for the prognostic analysis of this research.
It is included in the clinic of the HCC in prognostic analysis, histological data (n=198) is summarised in table 1：Classified variable and
Chi-square Test or Student T is used to examine more respectively between continuous variable.The recurrence-free survival time refers to played from the operation same day
Distant place or local recurrence or last time follow up time for the first time.Death time occurs before tumor recurrence for patient is considered several
It is lost according to deleting.Kaplan-Meier methods for drawing survivorship curve, with log-rank examined by the difference between curve.
The formaldehyde that all tissue samples first pass around 10% is fixed, and the tumor tissues then cut are by dehydration, transparent, leaching
Wax, embedding program processing, 4 μm of serial section, and carry out Hematoxylin-eosin (HE) dyeing.The diagnosis of all HCC and histology
Classification is carried out using double-blind study by pathology doctors more than 2 associate chief physician's ranks based on set histological criterion
Assessment.
The baseline clinical characteristics for all patients that the research of table 1. includes
HBV, hepatitis B；HCV, hepatitis C；CK, cytokeratin；GPC3, Monophosphoinositideproteoglycans proteoglycans-3
2. single factor analysis：
According to the clinic and pathological examination of patient, will include Gender, age, whether have hepatic sclerosis, naked eyes tumor bolt,
Tumor bolt under mirror, histological grade, CK19/GPC3 expression patterns, tumor nodule number 8 factors be used for single factor analysis, knot
Fruit finds there is 5 i.e. naked eyes tumor bolt (P in above-mentioned eight factors<0.01), hemangioma bolt (P under mirror<0.01), low point of histology
Change (P<0.01), CK19+/GPC3+ immunophenotypes (P<0.01) and tumor nodule number is 2 or 3 (P<0.01) swollen with patient
The tumor recurrence-free survival time is closely related.As a result 2 be see the table below.
Table 2. is directed to the single factor analysis of tumor recurrence
CK, cytokeratin；GPC3, Monophosphoinositideproteoglycans proteoglycans-3
3. multifactor COX regression analyses：
Above-mentioned 5 factors are included in multiplicity.The results show that CK19+/GPC3+ immunophenotypes [Hazard ratio (HR)=
1.782,95% confidence interval (CI)=1.137-2.793, P=0.012], the low differentiation (HR=1.969,95%CI=of tumour
1.292-3.001, P=0.002) and tumor nodule number be 2 or 3 (HR=2.173,95%CI=1.328-3.557, P=
0.002) be the patient tumors recurrence-free survival time independent predictor.As a result 3 be see the table below.
The predictive factors of 3. tumor recurrence of table are analyzed
4. the multifactor risk integral model of the recurrence-free survival for predicting HCC patient：
The risk score of the beta coefficient setting factor of prognosis correlation factor in being returned according to COX.Reference in each variable becomes
Amount is assigned a value of 0 point, and the item of the variable with minimum beta coefficient is assigned a value of 1 point.Based on this by other variable standardizations,
Institute's value round number is as risk score.The weighted score of each risks and assumptions in each case is added to obtain
Each case overall risk score.According to mentioned above principle, in present case, a tumour is scored at 0, two or three tumour and is scored at
1；The tumour of high or middle differentiation is scored at 0, and the tumour of differencing is scored at 1；CK19-/GPC3+ or CK19-/GPC3-HCC scores
It is scored at 1 for 0, CK19+/GPC3+HCC.As a result 4 be see the table below.
4. Multivariate Cox Regression of table is analyzed and the score based on beta coefficient
HCC, hepatocellular carcinoma；HR：Hazard ratio；CI：Confidence interval；CK, cytokeratin；GPC3, phosphatidylinositols albumen
Glycan -3
According to above-mentioned integrating system, it is all enter a group case be divided into four groups of (scores：0,1,2,3 point).Draw four groups of life
Deposit curve, the result is shown in Figure 1, wherein Figure 1A show be scored at 2 and 3 survivorship curve obvious overlapping (P ＞ 0.05), merge
To Figure 1B.Therefore it is final it is all enter a group case be divided into three groups, good prognosis group (O points), general prognosis group (1 point) and difference prognosis
Group (2-3 points).Survival analysis shows, good prognosis group, the average recurrence-free survival of general prognosis group and poor prognosis group in two years
Phase is respectively 61.2 months, 32.6 months and 9.6 months, and practical recurrence rate is respectively 32.47% (25/77), 55.81% (48/
And 91.43% (32/35) 86).Log-rank has found that the RFS between three groups has statistical significance (P ＜ 0.01).As a result it sees below
Table 5.
Table 5. is based on the survival analysis for cutting off sample to meeting the HCC patient of Milan standard of performing the operation
HCC, hepatocellular carcinoma；RFS：Recurrence-free survival；CI：Confidence interval
5. the assessment pair model prediction ability
The predictive ability of model is assessed by the area (AUC) below ROC curve.Work as AUC<0.5 hints model
Predictive ability cannot receive.Meanwhile Akaike's Information Criterion (Akaike information criterion, AIC) by with
The model of predictive ability between more each factor, AIC value minimums is relatively optimal.In this model, AUC value is 0.715 (95%
CI：0.645-0.786), P=0.000, the corresponding AIC values of the model are 1067.707, for most in all risks and assumptions
It is low.It prompts the model compared with other single factor test risks and assumptions, there is best predictive ability.As a result 6 be see the table below.
The AIC and AUC of table 6. multifactor scoring and other element
| Rating Model and other element | AIC values | AUC value (95%CI) | P |
| Multifactor risk score system | 1067.707 | 0.715(0.645-0.786) | 0.000 |
| CK19/GPC3 expression (divides three groups) | 1095.187 | 0.617(0.539-0.694) | 0.005 |
| CK19/GPC3 expresses (being divided to two groups) | 1094.638 | 0.600(0.521-0.678) | 0.015 |
| Histological grade (divides three groups) | 1086.532 | 0.629(0.551-0.706) | 0.002 |
| Histological grade (is divided to two groups) | 1090.403 | 0.615(0.536-0.693) | 0.005 |
| Tubercle number (divides three groups) | 1097.820 | 0.616(0.538-0.694) | 0.005 |
| Tubercle number (is divided to two groups) | 1095.108 | 0.615(0.538-0.693) | 0.005 |
| Capilary shifts | 1093.547 | 0.616(0.538-0.694) | 0.005 |
| Tumor bolt under mirror | 1100.316 | 0.518(0.438-0.599) | 0.655 |
CI：Confidence interval；CK, cytokeratin；GPC3, Monophosphoinositideproteoglycans proteoglycans-3
Embodiment 2Hepatocellular carcinoma radical resection it is preoperative based on transcutaneous aspiration biopsy of liver lesions to meeting the hepatocellular carcinoma of Milan standard
Patient carries out prognosis situation grouping (technical solution 1)
The tumor operation that the patients with hepatocellular carcinoma for meeting Milan standard is collected from Haidian District Beijing Grade III Class A hospital is cut
Except case 35, all patients once carry out transcutaneous aspiration biopsy of liver lesions hepatocellular carcinoma radical resection is preoperative, and from pathology department's number
Patient tumors differentiation degree and CK19, GPC3 immunohistochemical staining are obtained as a result, obtaining patient image from Medical Imaging Department according to library
Learn information.
Prognosis is carried out to the patients with hepatocellular carcinoma for meeting Milan standard using method provided by the invention, system and kit
Situation is grouped, and as a result see the table below 7.
Specific implementation process is shown in Fig. 2.
Patient's post-operative survival rates information in each group is obtained by institute doctor's Effect of follow-up visit by telephone.Based in table 7 it is each enter group case
Immunophenotype, the classification of Tumor Differentiation and mono-/multi- hair and score calculate each corrective surgery using method in embodiment 1 and cut off
Postoperative metastasis and risk of recurrence cumulative score, and according to the survivorship curve and ROC curve of patient in result drafting each group, as a result divide
Do not see Fig. 3 and Fig. 4 (using the diagonal line obtained according to Milan standard as with reference to line).
The results show that total recurrence after resection rate of patient population is 45.71% (16/35) in three groups, and it is assigned to liver
The postoperative practical recurrence rate of patient population is 23.53% (4/17) in the postoperative good prognosis group of cell cancer radical resection, is assigned to liver
The postoperative practical recurrence rate of patient population is 50% (6/12) in general prognosis group after cell cancer radical excision, is assigned to liver cell
The postoperative practical recurrence rate of patient population is 100% (6/6) in poor prognosis group after cancer radical excision.Hence it is demonstrated that the side of the present invention
Method, system and kit to patient's had postoperative recurrent tumor and can be turned by carrying out prognosis situation grouping to patients with hepatocellular carcinoma
The effectively layering and prediction of shift-in row provides intermediate result or auxiliary information, contributes to more effectively postoperative to patient before resection
Transfer and risk of recurrence be layered.
Embodiment 3Gross specimen is to meeting Milan standard after hepatocellular carcinoma radical resection is postoperative based on surgical operation
Patients with hepatocellular carcinoma carries out prognosis situation grouping (technical solution 2)
The tumor operation that the patients with hepatocellular carcinoma for meeting Milan standard is collected from Haidian District Beijing Grade III Class A hospital is cut
Except case 47.Patient tumors differentiation degree and CK19, GPC3 immunohistochemical staining are obtained as a result, patient from pathology department's database
Iconography information obtains from Medical Imaging Department and personal letter gross specimen is combined to check final determine.
Prognosis is carried out to the patients with hepatocellular carcinoma for meeting Milan standard using method provided by the invention, system and kit
Situation is grouped, and as a result see the table below 8.
Specific implementation process is shown in Fig. 5.
Patient's post-operative survival rates information in each group is obtained by institute doctor's Effect of follow-up visit by telephone.Based in table 8 it is each enter group case
Immunophenotype, the classification of Tumor Differentiation and mono-/multi- hair and score calculate each corrective surgery using method in embodiment 1 and cut off
Postoperative metastasis and risk of recurrence cumulative score, and the survivorship curve and ROC curve of patient in the queue are drawn according to result, as a result
See Fig. 6 and Fig. 7 respectively (using the diagonal line obtained according to Milan standard as with reference to line).
The results show that total recurrence after resection rate of patient population is 40.42% (19/47) in three groups, and it is assigned to liver
The postoperative recurrence after resection rate of patient population is 17.39% (4/23) in the postoperative good prognosis group of cell cancer radical resection, is divided
The postoperative practical recurrence rate of patient population is 46.67% (7/15) in general prognosis group after to hepatocellular carcinoma radical excision, is divided
Postoperative practical recurrence rate to patient population in the postoperative poor prognosis group of hepatocellular carcinoma radical resection is 88.89% (8/9).Hence it is demonstrated that
Method, system and the kit of the present invention can be postoperative to patient swollen by carrying out prognosis situation grouping to patients with hepatocellular carcinoma
Tumor is recurred provides intermediate result or auxiliary information with transfer, contribute to transfer more effectively postoperative to patient after resection and
Risk of recurrence is layered.
Specific description of embodiments of the present invention above is not intended to limit the present invention, and those skilled in the art can be according to this
Invention is variously modified or deforms, and without departing from the spirit of the present invention, should all belong to the model of appended claims of the present invention
It encloses.
Claims (17)
1. a kind of quasi- progress to meeting Milan standard or the patients with hepatocellular carcinoma for having carried out hepatocellular carcinoma radical excision carry out
The method of prognosis situation grouping, the method includes：
(1) CK19 the and GPC3 expressions of the Tissues of Hepatocellular Carcinoma cells in sample of the patient are detected, and based on expression feelings
Condition gives patient's assignment：Such as it is the CK19+/GPC3+ of coexpression CK19 and GPC3, assignment 1 is divided；Such as it is expression GPC3 but does not express
The CK19-/GPC3- that the CK19-/GPC3+ or CK19 and GPC3 of CK19 is not expressed, assignment 0 are divided；
(2) the differentiation situation of the Tissues of Hepatocellular Carcinoma sample of the patient is detected, and patient's assignment is given based on differentiation situation：Such as it is
The low differentiation of tumour, assignment 1 are divided；Such as it is to break up in tumour differentiated or tumour, assignment 0 is divided；
(3) tumor nodule number in the liver of the patient is detected, and patient's assignment is given based on tubercle number：Such as it is 1 tumour
The single-shot of tubercle, assignment 0 are divided；It is such as the multiple of 2-3 tumor nodule, assignment 1 is divided；With
(4) assignment obtained in step (1), step (2) and step (3) is summed up, obtains total assignment of the patient, by
The patient for being always assigned a value of 0 point is determined as the postoperative good prognosis group of hepatocellular carcinoma radical resection by this, will always be assigned a value of 1 point of patient
It is determined as after hepatocellular carcinoma radical excision generally prognosis group, or the patient for being always assigned a value of 2 points or 3 points is determined as hepatocellular carcinoma
The postoperative poor prognosis group of radical resection；
Wherein, the patient meets Milan standard, and the preoperative liver that the Tissues of Hepatocellular Carcinoma sample is obtained from the patient wears work
Inspection or hepatocellular carcinoma radical excision, and the method is not used in and diagnoses the illness.
2. according to the method described in claim 1, it is characterized in that, by the Tissues of Hepatocellular Carcinoma sample in step (1)
Immunohistochemical staining is carried out to detect CK19 and GPC3 expressions.
3. according to the method described in claim 2, it is characterized in that, the immunohistochemical staining is using respectively for CK19
It is carried out with the monoclonal antibody of GPC3.
4. according to the method in claim 2 or 3, which is characterized in that the immunohistochemical staining utilizes different colours
The fluorescein-labeled monoclonal antibody for being directed to CK19 and GPC3 respectively carries out.
5. according to the method described in claim 1, by carrying out haematoxylin-to the Tissues of Hepatocellular Carcinoma sample in step (2)
Eosin stains detect differentiation situation.
6. according to the method described in claim 1, in step (3) by the preoperative imageological examination of hepatocellular carcinoma radical resection or
Tumor nodule is a in patient's liver to determine for the gross examination result of the Operated Specimens obtained in person's hepatocellular carcinoma radical excision
Number.
7. according to the method described in claim 6, it is characterized in that, the results of imaging is obtained from enhanced CT or enhancing nuclear-magnetism
Scanning imagery.
8. a kind of quasi- progress to meeting Milan standard or the patients with hepatocellular carcinoma for having carried out hepatocellular carcinoma radical excision carry out
The system of prognosis situation grouping, the system comprises：
(1) bioassay module：
(1-A) CK19 and GPC3 expression analysis modules, the module are set as the Tissues of Hepatocellular Carcinoma sample based on the patient
CK19 the and GPC3 expressions of middle cell give patient's assignment：Such as it is the CK19+/GPC3+ of coexpression CK19 and GPC3, assignment 1
Point；Such as it is expression GPC3 but does not express the CK19-/GPC3+ or CK19 of CK19 and CK19-/GPC3- that GPC3 is not expressed, assigns
0 point of value；
(1-B) histopathology fractional analysis module, the module are set as the Tissues of Hepatocellular Carcinoma sample based on the patient
Differentiation situation give patient's assignment：Such as it is the low differentiation of tumour, assignment 1 is divided；Such as it is to break up in tumour differentiated or tumour, assignment 0
Point；With
(1-C) tumor nodule number analysis module, the module are set as tumor nodule number in the liver based on the patient
Give patient's assignment：Such as it is the single-shot of 1 tumor nodule, assignment 0 is divided；It is such as the multiple of 2-3 tumor nodule, assignment 1 is divided；
And
(2) data processing module：
The module is set as summing up the assignment for coming from module and module in (1-C) in module in (1-A), (1-B), obtains
It is determined as the postoperative good prognosis group of hepatocellular carcinoma radical resection to total assignment of the patient, and by the patient for being always assigned a value of 0 point,
The patient for being always assigned a value of 1 point is determined as after hepatocellular carcinoma radical excision generally prognosis group, or will always be assigned a value of 2 points or 3 points
Patient be determined as the postoperative poor prognosis group of hepatocellular carcinoma radical resection；
Wherein, the patient meets Milan standard, and the preoperative liver that the Tissues of Hepatocellular Carcinoma sample is obtained from the patient wears work
Inspection or hepatocellular carcinoma radical excision.
9. system according to claim 8, which is characterized in that module is also configured to detection CK19 and GPC3 tables in (1-A)
Up to situation.
10. system according to claim 9, which is characterized in that by the way that the Tissues of Hepatocellular Carcinoma sample is immunized
Histochemical stain detects CK19 and GPC3 expressions.
11. system according to claim 10, which is characterized in that the immunohistochemical staining is utilized and is directed to respectively
The monoclonal antibody of CK19 and GPC3 carries out.
12. the system according to claim 10 or 11, which is characterized in that the immunohistochemical staining utilizes different face
The fluorescein-labeled monoclonal antibody for being directed to CK19 and GPC3 respectively of color carries out.
13. system according to claim 8, module is also configured to detect the differentiation situation in (1-B).
14. system according to claim 13, which is characterized in that by carrying out bush to the Tissues of Hepatocellular Carcinoma sample
Element-eosin stains detect differentiation situation.
15. system according to claim 8, module is also configured to tumour knot in the liver for detecting the patient in (1-C)
Save number.
16. system according to claim 15, which is characterized in that pass through the preoperative iconography knot of hepatocellular carcinoma radical resection
Tumor nodule is a in patient's liver to determine for the gross examination result of the Operated Specimens obtained in fruit or Resection of Hepatocellular Carcinoma
Number.
17. system according to claim 16, which is characterized in that the results of imaging is obtained from enhanced CT or enhancing core
Magnetic scanning is imaged.
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| CN110189824B (en) * | 2019-06-04 | 2021-12-21 | 冯骥良 | Prognosis grouping method, device and system for primary liver cancer radical resection |
| CN110930401B (en) * | 2019-12-11 | 2023-11-10 | 大连医科大学附属第一医院 | Energy spectrum CT enhanced iodigram imaging preacademic prediction kidney transparent cell carcinoma WHO/ISUP grading method |
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| CN110930402B (en) * | 2019-12-11 | 2023-11-07 | 大连医科大学附属第一医院 | Image histology feature processing method based on DKI sequence MK (restriction enzyme) map of endometrial cancer |
| CN111948392B (en) * | 2020-07-03 | 2022-03-08 | 浙江大学 | Hepatocellular carcinoma PDX model construction method |
| CN111983231B (en) * | 2020-07-13 | 2023-05-16 | 复旦大学附属中山医院 | Application of RPS3A molecules in prediction of immune cell infiltration in tumor, immune checkpoint molecule expression level and prediction model |
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| CN112233112B (en) * | 2020-12-07 | 2021-06-01 | 深圳大学 | Prediction method of CK19 of hepatocellular carcinoma based on deep learning analysis |
| CN116930498B (en) * | 2023-08-29 | 2023-12-12 | 中国人民解放军军事科学院军事医学研究院 | Kit for predicting recurrence risk after primary hepatocellular carcinoma removal operation and application thereof |
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