CN106248945A - Patients with hepatocellular carcinoma is carried out method, system and the test kit of the packet of hepatocarcinoma radical excision prognosis situation - Google Patents
Patients with hepatocellular carcinoma is carried out method, system and the test kit of the packet of hepatocarcinoma radical excision prognosis situation Download PDFInfo
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Abstract
The method that the postoperative recurrence risk to the patients with hepatocellular carcinoma planning to implement tumor radical cure excision that the present invention provides a kind of number based on Cyfra21-1 (CK19) and the joint-detection of glypican-3 GPC3 (GPC3), the differentiation state of tumor cell and tumor to be index is estimated.According to the method, can in the preoperative patient reasonably be screened, to reduce the transfer after tumor radical cure excision, recurrence；Additionally, according to the method, it is also possible to the transfer of tumor postoperative to patients with hepatocellular carcinoma excision, risk of recurrence are estimated, and then instruct clinician to having high transfer, the case enforcement monitoring closely of risk of recurrence and processing in early days.
Description
Technical field
The invention belongs to accurate medical domain, specially relate to planning to implement or row tumor radical cure excision has met rice
The patients with hepatocellular carcinoma of blue standard carries out the method for prognosis situation analysis, system and Related product, by the method, system and phase
Patients with hepatocellular carcinoma can be taked the neoplasm metastasis after tumor radical cure excision, recurrence wind by the result that the enforcement of pass product obtains
Danger assessment and prediction provide average information or auxiliary information.
Background technology
Primary hepatocarcinoma is one of malignant tumor that sickness rate is the highest in world wide, there are about the people of more than 1,000,000 every year
Newly suffer from this sick.It is the first that China's onset of liver cancer number occupy the world all the time, and the most about 230,000 people die from hepatocarcinoma, accounts for whole world hepatocarcinoma patient
The 53% of death toll, ranks China's malignant tumor rate of dying of illness the first.Although liver transplantation at present is considered as generally acknowledged treatment hepatocarcinoma
Effective means, but due to for liver source shortage, the resection operation of liver neoplasm just become treatment hepatocarcinoma the most general
All over the therapeutic strategy carried out.
It is now recognized that the tumor radical cure excision of early hepatocyte cancer patient has preferable prognosis.But major part research
Display, in 3 years of the early hepatocarcinoma meeting Milan standard, relapse rate can reach 40%-50%.Wherein the recurrence in 3 years is the most most
Number is owing to the transfer of primary tumor cancerous cell is sent out.It is the most based on substantially histopathological indications to the assessment of patient tumors,
Such as diameter of tumor and tuberosity number.These indexs fail to carry out tumor and patient from the cell behaviors of tumor comprehensively
Assessment, especially for the hepatocarcinoma being in very in early days.
In recent years, along with the discovery of some hepatocarcinoma biological markers so that hepatocarcinoma is occurred by the mankind, the understanding of development has
Significant progress.Although Cyfra21-1 (CK19) or the table of Monophosphoinositideproteoglycans proteoglycans-3 (GPC3) in hepatocarcinoma
Reach with operation in patients after neoplasm metastasis, recurrence relation seen from report, but joint-detection CK19 or GPC3 carry out Asia to hepatocarcinoma
Classify and patient's prognosis is carried out layering and there is not yet open report.
Summary of the invention
For the problems referred to above, it is an object of the invention to provide and the plan meeting Milan standard is carried out or has carried out hepatocarcinoma
The patients with hepatocellular carcinoma of radical excision carries out the method and system of prognosis situation packet.
It is a further object to provide the test kit used with the method or system in combination.
Technical scheme is as follows.
Prognosis of the present invention includes recurrence in the liver of the postoperative tumor of hepatocarcinoma radical resection, extrahepatic metastases and trouble
Person is without recurrence existence.
On the one hand, the present invention provides a kind of plan to meeting Milan standard carry out or carried out hepatocarcinoma radical excision
The patients with hepatocellular carcinoma method that carries out prognosis situation packet, described method includes:
(1) CK19 (Cyfra21-1) and the GPC3 (phosphorus of the Tissues of Hepatocellular Carcinoma cells in sample of described patient are detected
Acyl inositol Dan Baiduotang proteoglycan PG-3) expression, and based on expression to patient's assignment: as coexpression CK19 and GPC3
CK19+/GPC3+, assignment 1 point；Do not express as expression GPC3 but do not expressed CK19-/GPC3+ or CK19 and GPC3 of CK19
CK19-/GPC3-, assignment 0 point；
(2) the differentiation situation of the Tissues of Hepatocellular Carcinoma sample of described patient is detected, and based on differentiation situation to patient's assignment:
As for the low differentiation of tumor, assignment 1 point；As in tumor differentiated or tumor break up, assignment 0 point；
(3) tumor nodule number in the liver of described patient is detected, and based on tuberosity number to patient's assignment: as 1
The single-shot of tumor nodule, assignment 0 point；Multiple as 2-3 tumor nodule, assignment 1 point；With
(4) assignment obtained in step (1), step (2) and step (3) is summed up, obtain total tax of described patient
Value, is thus defined as the patient being always entered as 0 point hepatocarcinoma radical resection postoperative good prognosis group, will always be entered as 1 point
Patient be defined as the postoperative general prognosis group of hepatocarcinoma radical resection, or the patient being always entered as 2 points or 3 points is defined as liver
The postoperative poor prognosis group of cell carcinoma radical resection.
In the present invention, described Tissues of Hepatocellular Carcinoma sample is obtained from the preoperative liver of described patient and wears biopsy or hepatocarcinoma
Radical excision.
Preferably, step (1) detects by described Tissues of Hepatocellular Carcinoma sample is carried out immunohistochemical staining
CK19 and GPC3 expression；
Preferably, described immunohistochemical staining utilizes the monoclonal antibody being respectively directed to CK19 and GPC3 to carry out；More
Preferably, described immunohistochemical staining utilizes the fluorescein-labeled monoclonal being respectively directed to CK19 and GPC3 of different colours
Antibody is carried out.CK19 and GPC3 is expressed as feminine gender or the positive and judges according to the general standard of this area.
According to the detailed description of the invention of the application, described immunohistochemical staining utilizes rabbit anti-human CK19 monoclonal antibody
(ab52625, Abcam company) and mouse anti human GPC3 monoclonal antibody (ab129381, Abcam company) are carried out；Or it is described
Immunohistochemical staining utilize for CK19 monoclonal antibody (FITC labelling, ab87014, Abcam company) and for
Monoclonal antibody (the Alexa of GPC3647 labellings, ab199813, Abcam company) carry out.
Preferably, step (2) detects point by described Tissues of Hepatocellular Carcinoma sample carries out Hematoxylin-eosin dyeing
Change situation.
Preferably, step (3) is passed through the preoperative results of imaging of hepatocarcinoma radical resection or hepatocarcinoma is effected a radical cure
The gross examination result of the Operated Specimens obtained in excision is to determine tumor nodule number in patient's liver；
The most preferably, described results of imaging is obtained from enhanced CT or strengthens nuclear magnetic scanning imaging.
On the other hand, the present invention provides a kind of plan to meeting Milan standard carry out or carried out hepatocarcinoma radical resection
The patients with hepatocellular carcinoma of art carries out the system of prognosis situation packet, and described system includes:
(1) bioassay module:
(1-A) CK19 and GPC3 expression analysis module, described module is set to Tissues of Hepatocellular Carcinoma based on described patient
CK19 and the GPC3 expression of cells in sample is to patient's assignment: such as the CK19+/GPC3+ for coexpression CK19 and GPC3, compose
It is worth 1 point；As do not expressed, for expressing GPC3, the CK19-/GPC3-that CK19-/GPC3+ or CK19 and GPC3 of CK19 do not express,
Assignment 0 point；
(1-B) histopathology fractional analysis module, described module is set to Tissues of Hepatocellular Carcinoma based on described patient
The differentiation situation of sample is to patient's assignment: as the low differentiation of tumor, assignment 1 point；As for tumor differentiated or tumor are broken up, composed
It is worth 0 point；With
(1-C) tumor number analyzes module, and described module is set to tumor nodule number in liver based on described patient
To patient's assignment: such as the single-shot for 1 tumor nodule, assignment 0 point；Multiple as 2-3 tumor nodule, assignment 1 point；
And
(2) data processing module:
Described module is set to add from the assignment of module in module in module, (1-B) in (1-A) and (1-C)
With, obtain total assignment of described patient, and it is postoperative good pre-that the patient being always entered as 0 point is defined as hepatocarcinoma radical resection
Rear group, the patient being always entered as 1 point is defined as the postoperative general prognosis group of hepatocarcinoma radical resection, or will always be entered as 2 points
Or the patient of 3 points is defined as the postoperative poor prognosis group of hepatocarcinoma radical resection.
Preferably, the Tissues of Hepatocellular Carcinoma sample in described system is obtained from the preoperative liver of described patient and wears biopsy or liver is thin
Born of the same parents' cancer radical excision.
In the system that the present invention provides, it is preferable that the module in (1-A) is also configured to detect CK19 and GPC3 and expresses feelings
Condition；
Preferably, CK19 and GPC3 is detected by described Tissues of Hepatocellular Carcinoma sample is carried out immunohistochemical staining
Expression；
It is highly preferred that described immunohistochemical staining utilizes the monoclonal antibody being respectively directed to CK19 and GPC3 to carry out；
It is highly preferred that described immunohistochemical staining utilizes the fluorescein-labeled Dan Ke being respectively directed to CK19 and GPC3 of different colours
Grand antibody is carried out.
According to the detailed description of the invention of the application, described immunohistochemical staining utilizes rabbit anti-human CK19 monoclonal antibody
(ab52625, Abcam company) and mouse anti human GPC3 monoclonal antibody (ab129381, Abcam company) are carried out；Or it is described
Immunohistochemical staining utilize for CK19 monoclonal antibody (FITC labelling, ab87014, Abcam company) and for
Monoclonal antibody (the Alexa of GPC3647 labellings, ab199813, Abcam company) carry out.
In the system that the present invention provides, it is preferable that in (1-B), module is also configured to detect described differentiation situation；
Preferably, by described Tissues of Hepatocellular Carcinoma sample is carried out Hematoxylin-eosin dyeing detect differentiation situation.
In the system that the present invention provides, it is preferable that in (1-C), module is swollen in being also configured to detect the liver of described patient
Tumor tuberosity number；
Preferably, preoperative by the preoperative results of imaging of hepatocarcinoma radical resection or hepatocarcinoma radical resection
Tumor nodule number in the gross examination result of Operated Specimens determines patient's liver in results of imaging or art；
The most preferably, described results of imaging is obtained from enhanced CT or strengthens nuclear magnetic scanning imaging.
Another aspect, the present invention also provides for method or the test kit of system in combination use, the described reagent of a kind of present invention
Box includes:
(A) for detecting the reagent of CK19 and the GPC3 expression of Tissues of Hepatocellular Carcinoma cells in sample；With
(B) for detecting the reagent of the differentiation situation of Tissues of Hepatocellular Carcinoma sample.
In the test kit that the present invention provides, it is preferable that the reagent in (A) includes for described Tissues of Hepatocellular Carcinoma
Sample carries out the reagent of immunohistochemical staining；
Preferably, described reagent includes the monoclonal antibody of CK19 and GPC3；It is highly preferred that described reagent includes different face
The fluorescein-labeled monoclonal antibody being respectively directed to CK19 and GPC3 of color.
In the test kit that the present invention provides, it is preferable that the reagent in (B) includes for described Tissues of Hepatocellular Carcinoma sample
Product carry out the reagent of Hematoxylin-eosin dyeing.
Specifically, first, the method for the present invention, system and test kit relate to the Tissues of Hepatocellular Carcinoma sample detecting patient
CK19 and the GPC3 expression of middle cell, and based on this expression patient carried out the CK19+ of coexpression CK19 and GPC3/
GPC3+, express GPC3 but do not express the CK19-/GPC3-that CK19-/GPC3+ and CK19 and GPC3 of CK19 do not express point
Group.
CK19 and GPC3 is expressed as feminine gender or the positive and judges according to the general standard of this area.The present invention's
In preferred implementation, the monoclonal antibody of available CK19 and GPC3 detects, when expressing CK19's or GPC3 in sample
The 5% of cell >=all cells, it is judged that for the positive；And when express CK19 or GPC3 cell < the 5% of all cells, it is judged that for
Negative.And when utilizing the fluorescein-labeled monoclonal antibody of different colours to detect, when observing that cells in sample shows phase
Answer color, it is judged that for the positive；When observing that cells in sample does not shows respective color, it is judged that for feminine gender.
Second, the method for the present invention, system and test kit relate to pathological diagnosis and the histological of patient tumors.As
Defined herein, according to following standard, tumor is carried out basic, normal, high differentiation and judge:
Differentiated: the tumor cell arrangement thin beam texture less than 3 layers, or false gland sample, acinus spline structure.And cell is big
Little more consistent, atypia that core is slight；
Middle differentiation: the 1. tumor cell arrangement thin beam texture less than 3 layers, or false gland sample, acinus spline structure, cell is big
Little inconsistent, core moderate atypia, without multinuclear oncocyte or tumor giant cell；Or the 2. tumor cell arrangement beam-like more than 3 layers
Structure (thick beam texture) or nido structure and entity structure, but cell size is more consistent, and core moderate atypia, without 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.
3rd, the method for the present invention, system and test kit relate to the analysis of the tumor nodule number of patient.Described patient accords with
Closing Milan standard, the most as defined herein, in patient's liver being detected, tumor nodule number is 1, it is judged that tie for tumor
The single-shot of joint, in patient's liver being detected, tumor nodule number is 2-3, it is judged that multiple for tumor nodule.Tumor nodule
The gross examination result in the preoperative results of imaging of hepatocarcinoma radical resection or hepatocarcinoma radical excision can be passed through
Judge.
Exemplarily, the present invention provides the described method of employing, system and test kit can carry out following implementation process:
Can be in hepatocarcinoma radical resection preoperative enforcement technical scheme 1:
1. select the patients with hepatocellular carcinoma meeting Milan standard to enter analysis below according to imaging data.
2. the Tissues of Hepatocellular Carcinoma utilizing preoperative liver to wear biopsy acquisition carries out the immunohistochemical staining of CK19 and GPC3, by liver
Carcinoma patients is divided into tri-kinds of molecular isoforms of CK19+/GPC3+, CK19-/GPC3+ and CK19-/GPC3-, wherein have CK19-/
The assignment of GPC3+ or CK19-/GPC3-phenotype 0 point, has the assignment 1 point of CK19+/GPC3+ phenotype.
Preferably, this immunohistochemistry technology is to utilize CK19 and GPC3 monoclonal antibody cutting continuously tumor tissues
Sheet carries out immunohistochemical staining, with observe the tumor cell of expressing CK19 or GPC3 whether >=all tumor cells
5% judges positive or negative for standard, and the expressions of both such as tumor cell is the positive, is i.e. recorded as CK19+/GPC3+；As
Tumor cell only shows that GPC3 is positive, then be recorded as CK19-/GPC3+；Such as tumor cell CK19 and the GPC3 the most no positive table of dyeing
Reach, be then recorded as CK19-/GPC3-.
Preferably, different colours fluorescein-labeled CK19 and GPC3 monoclonal antibody is utilized jointly to dye, as long as
Observe that tumor cell expresses CK19 and GPC3 simultaneously, be i.e. recorded as CK19+/GPC3+；GPC3 sun is only shown such as tumor cell
Property, then it is recorded as CK19-/GPC3+；As tumor cell CK19 and GPC3 dye the most no positive expression, then be recorded as CK19-/
GPC3-。
3. the tumor tissues utilizing preoperative liver to wear acquisition carries out HE dyeing, and tumor is divided into height, neutralizes low three kinds of differentiation shapes
State, wherein has the tumor assignment 0 point of height or middle differentiation, has PD tumor assignment 1 point.
4., according to the number of tumor nodule in the liver of preoperative enhanced CT or enhancing magnetic resonance imaging acquisition, patient is divided into
Single-shot and multiple (2-3 tumor) two kinds of situations, wherein have the assignment 0 point of single-shot tumor nodule, have multiple tumor nodule
Assignment 1 point.
5. the assignment score that patient tumors immunophenotype, differentiation state and single multi-are sent out three classification indicators is added, permissible
Obtain 0 or 1 or 2 or 3 point.
6. the patient that must be divided into 0 point is defined as Hepatectomy low-grade recurrent risk group (good prognosis group), will
The patient being divided into 1 point is defined as rank risk of recurrence group in Hepatectomy (general prognosis group), will must be divided into 2 points or 3 points
Patient is defined as Hepatectomy high-level risk of recurrence group (difference prognosis group).
Or, can be in hepatocarcinoma radical resection postoperative enforcement technical scheme 2:
1. according to strengthening NMR (Nuclear Magnetic Resonance) imaging or enhanced CT imaging examination result selected from the hepatocarcinoma trouble meeting Milan standard
Person carries out analysis below.
2. the Tissues of Hepatocellular Carcinoma utilizing total surgical resection specimen to obtain carries out the immunohistochemical staining of CK19 and GPC3,
Patients with hepatocellular carcinoma is divided into tri-kinds of molecular isoforms of CK19+/GPC3+, CK19-/GPC3+ and CK19-/GPC3-, wherein has
The assignment of CK19-/GPC3+ and CK19-/GPC3-phenotype 0 point, has the assignment 1 point of CK19+/GPC3+ phenotype.
CK19 and GPC3 is expressed as negative or positive judgement with technical scheme 1.
3. the tumor tissues utilizing total surgical resection specimen to obtain carries out HE dyeing, tumor be divided into height, neutralize low by three
Plant differentiation state, wherein there is the tumor assignment 0 point of high and middle differentiation, there is PD tumor assignment 1 point.
4. according to the gross examination of total surgical resection specimen or preoperative enhanced CT or strengthen what nuclear magnetic scanning imaging obtained
The number of tumor nodule in liver, is divided into single-shot and multiple (2-3 tumor) two kinds of situations patient, wherein has single-shot tumor
Assignment 0 point, there is the assignment 1 point of multiple tumor.
5. the assignment score that patient tumors immunophenotype, differentiation state and single multi-are sent out three classification indicators is added, permissible
Obtain 0 or 1 or 2 or 3 point.
6. the patient that must be divided into 0 point is defined as Hepatectomy low-grade recurrent risk group (good prognosis group), will
The patient being divided into 1 point is defined as rank risk of recurrence group in Hepatectomy (general prognosis group), will must be divided into 2 points or 3 points
Patient is defined as Hepatectomy high-level risk of recurrence group (difference prognosis group)
Present invention demonstrates that, in conjunction with the tuberosity of CK19 or GPC3 joint-detection, the differentiation state of hepatocarcinoma and tumor
The tumor resection prognosis of patients with hepatocellular carcinoma can be effectively grouped by number, this packet can to patient's had postoperative recurrent tumor with
Transfer is effectively layered and predicts offer intermediate object program or auxiliary information.Therefore, the present invention is for screening suitable hepatocarcinoma
The patients of excision, improves therapeutic effect, saves the aspects such as social resources significant；Meanwhile, to hepatocyte
The postoperative tumor recurrence of cancer excision, the assessment shifted risk, can enable the clinician to the height according to risk of recurrence real
Execute monitoring and take corresponding preventive measure.
After the packet of above-mentioned prognosis situation is carried out for a large amount of patients with hepatocellular carcinomas, find: the hepatocyte in good prognosis group
Cancer patient, after its tumor radical cure excision, actual relapse rate is about 32.47%, and average nothing recurrence life span is
61.2 months, have the simple preferable curative effect of tumor radical cure excision, but postoperative should carry out close tumor monitoring and
Early find neoplasm metastasis or recurrence, take further remedy measures to improve overall survival in time.Liver in general prognosis group
Carcinoma patients, after its tumor radical cure excision, actual relapse rate is 55.81%, average without recurrence life span
It it is 32.6 months.And the patients with hepatocellular carcinoma in difference prognosis group, actual relapse rate after its tumor radical cure excision
Being 91.43%, average nothing recurrence life span is only 9.6 months.Therefore, the patient in general prognosis group and difference prognosis group, as
Fruit selects tumor radical cure excision, postoperative should carry out closer lesion detection to find neoplasm metastasis or recurrence early,
Take further remedy measures to improve overall survival in time.
Accompanying drawing explanation
Hereinafter, describe embodiment of the present invention in detail in conjunction with accompanying drawing, wherein:
Fig. 1: 1 all enters to organize the survival curve of case according to embodiments of the present invention, and wherein Figure 1A is shown as the existence of four groups
Curve, Figure 1B shows the survival curve merging into three groups；
Fig. 2: 2 (technical scheme 1) according to embodiments of the present invention, tumor tissues CK19 and the GPC3 immunity worn based on liver divide
The patients with hepatocellular carcinoma tumor radical cure excision prognosis grouping flow chart of type, differentiation and tumor number；
Fig. 3: 2 (technical scheme 1) according to embodiments of the present invention, the survival curve of patient population in the different group of display；
Fig. 4: 2 (technical scheme 1) according to embodiments of the present invention, shows the ROC curve of sorting technique of the present invention, below curve
Amassing 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 scheme 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 excision prognosis grouping flow chart of immunophenotyping, differentiation and tumor number；
Fig. 6: 3 (technical scheme 2) according to embodiments of the present invention, the survival curve of patient population in the different group of display；
Fig. 7: 3 (technical scheme 2) according to embodiments of the present invention, shows the ROC curve of sorting technique of the present invention, below curve
Amassing is 0.788 (95% confidence interval is 0.649-0.927), and wherein dotted line is the reference line obtained according to Milan standard.
Detailed description of the invention
Referring to specific embodiment, the present invention is described.Only it will be appreciated by those skilled in the art that these embodiments
For the present invention is described, it limits the scope of the present invention never in any form.
Experimental technique in following embodiment, if no special instructions, is conventional method.Medicine used in following embodiment
Material raw material, reagent material etc., if no special instructions, be commercially available purchase product.
Embodiment 1By identifying that the risks and assumptions without recurrence existence in prediction HCC patient sets up the packet of the present invention
Method
1. patient and method
Patient and tissue samples
Collect Beijing YouAn Hospital, Capital Medical University and PLA 304 during in January, 2007 in November, 2010
Case 346 example of the hepatocarcinoma excision of hospital.This research meets Declaration of Helsinki and criticizes through local Ethics Committee
Standard, person under inspection all signs Informed Consent Form.All cases are preoperative without chemotherapy, radiotherapy or interventional therapy.Excision
Other enter group standard and include: (1) primary tumor stove, satellite stove and multiple stove can be by radical excisions, and (2) liver function is Child
A or B of Pugh classification, remains liver after (3) excision and enough maintains physiological function and without surgical contraindication.Wherein 198 examples meet
Above-mentioned enter group standard and Milan standard, the prognostic analysis studied for this.
The clinic of the HCC being included in prognostic analysis, histological data (n=198) sum up in Table 1: classified variable and
Checking with X 2 test or Student T more respectively between continuous variable.Refer to play the same day from operation without recurrence life span
For the first time at a distance or local recurrence or last follow up time.Patient occurred the death time to be considered several before tumor recurrence
According to deleting mistake.Kaplan-Meier method is used for drawing survival curve, and difference log-rank between curve is checked.
All tissue samples first pass around the formaldehyde of 10% and fix, and the tumor tissues then cut is by dehydration, transparent, leaching
Wax, embedding program process, 4 μm serial section, and carry out Hematoxylin-eosin (HE) dyeing.The diagnosis of all of HCC and histology
Classification is based on set histological criterion, pathology doctors more than 2 associate chief physician's ranks utilize double-blind method to carry out
Assessment.
The baseline clinical characteristics of all patients that table 1. research includes
HBV, hepatitis B；HCV, hepatitis C；CK, cytokeratin；GPC3, Monophosphoinositideproteoglycans proteoglycans-3
2. single factor analysis:
Clinic according to patient and pathological examination, will include Gender, age, whether have liver cirrhosis, naked eyes tumor bolt,
Under mirror, tumor bolt, histological grade, CK19/GPC3 expression pattern, 8 factors of tumor nodule number are used for single factor analysis, knot
Fruit finds, has hemangioma bolt (P < 0.01), low point of histology under 5 i.e. naked eyes tumor bolt (P < 0.01), mirror in above-mentioned eight factors
Change (P < 0.01), CK19+/GPC3+ immunophenotype (P < 0.01) and tumor nodule number are 2 or 3 (P < 0.01) and the swelling of patient
Tumor is closely related without recurrence life span.Result see table 2.
Table 2. is for the single factor analysis of tumor recurrence
CK, cytokeratin；GPC3, Monophosphoinositideproteoglycans proteoglycans-3
The most multifactor COX regression analysis:
Include above-mentioned 5 factors in multiplicity.Result shows, CK19+/GPC3+ immunophenotype [Hazard ratio (HR)=
1.782,95% confidence interval (CI)=1.137 2.793, P=0.012], tumor low differentiation (HR=1.969,95%CI=
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) it is that patient tumors is without recurring the independent predictor of life span.Result see table 3.
The predictive factors analysis of table 3. tumor recurrence
4. for predicting the multifactor risk integral model without recurrence existence of HCC patient:
In returning according to COX, the beta coefficient of prognosis correlation factor sets the risk score of the factor.Reference in each variable becomes
Amount is entered as 0 point, and the item with the variable of minimum beta coefficient is entered as 1 point.Based on this by other variable standardization,
Institute's value round number is as risk score.The weighted score of each risks and assumptions in each case is added and obtains
Each case overall risk score.According to mentioned above principle, in present case, a tumor must be divided into 0, two or three tumor to be divided into
1；High or middle differentiation tumor must be divided into 0, and the tumor of differencing must be divided into 1；CK19-/GPC3+ or CK19-/GPC3-HCC score
Being 0, CK19+/GPC3+HCC must be divided into 1.Result see table 4.
Table 4. Multivariate Cox Regression analysis and score based on beta coefficient
HCC, hepatocarcinoma；HR: Hazard ratio；CI: confidence interval；CK, cytokeratin；GPC3, phosphatidylinositols albumen
Polysaccharide-3
According to above-mentioned integrating system, all enter to organize case and be divided into four groups (scores: 0,1,2,3 point).Draw the life of four groups
Depositing curve, result is shown in Fig. 1, and wherein Figure 1A shows to be divided into that the survival curve of 2 and 3 is substantially overlapping (P ＞ 0.05), merges
To Figure 1B.The most all enter to organize case and be divided into three groups, good prognosis group (O divides), general prognosis group (1 point) and difference prognosis
Group (2-3 divides).Survival analysis shows, the average nothing recurrence existence in two years of good prognosis group, general prognosis group and difference prognosis group
Phase is respectively 61.2 months, 32.6 months and 9.6 months, and actual relapse rate is respectively 32.47% (25/77), 55.81% (48/
86) and 91.43% (32/35).Log-rank finds that the RFS between three groups has statistical significance (P ＜ 0.01).Result sees below
Table 5.
Table 5. survival analysis based on the excision sample HCC patient to meeting Milan standard
HCC, hepatocarcinoma；RFS: without recurrence existence；CI: confidence interval
5. the assessment of pair model prediction ability
The predictive ability of model is estimated by ROC curve areas under (AUC).When AUC < 0.5 hints model
Predictive ability cannot accept.Meanwhile, Akaike's Information Criterion (Akaike information criterion, AIC) by with
Predictive ability between relatively each factor, the model of AIC value minimum is the most optimum.In this model, AUC is 0.715 (95%
CI:0.645-0.786), P=0.000, the corresponding AIC value of this model is 1067.707, is in all risks and assumptions
Low.Point out this model compared with other single factor test risks and assumptions, there is optimal predictive ability.Result see table 6.
The multifactor scoring of table 6. and AIC and AUC of other key elements
| Rating Model and other key elements | AIC value | AUC (95%CI) | P |
| Multifactor risk score system | 1067.707 | 0.715(0.645-0.786) | 0.000 |
| CK19/GPC3 expresses (dividing three groups) | 1095.187 | 0.617(0.539-0.694) | 0.005 |
| CK19/GPC3 expresses (dividing 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 (divides two groups) | 1090.403 | 0.615(0.536-0.693) | 0.005 |
| Tuberosity number (divides three groups) | 1097.820 | 0.616(0.538-0.694) | 0.005 |
| Tuberosity number (divides two groups) | 1095.108 | 0.615(0.538-0.693) | 0.005 |
| Blood capillary 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 2In the preoperative hepatocarcinoma based on transcutaneous aspiration biopsy of liver lesions to meeting Milan standard of hepatocarcinoma radical resection
Patient carries out prognosis situation packet (technical scheme 1)
The tumor operation collecting the patients with hepatocellular carcinoma meeting Milan standard from Haidian District Beijing Grade III Class A hospital is cut
Except case 35 example, all patients all once carried out transcutaneous aspiration biopsy of liver lesions hepatocarcinoma radical resection is preoperative, and from Pathology Deparment's number
Obtain patient tumors differentiation degree and CK19, GPC3 immunohistochemical staining result according to storehouse, obtain patient image from Medical Imaging Department
Information.
The method, system and the test kit that use the present invention to provide carry out prognosis to the patients with hepatocellular carcinoma meeting Milan standard
Situation is grouped, and result see table 7.
Specific implementation process is shown in Fig. 2.
Patient's post-operative survival rates information in being obtained each group by this institute doctor's Effect of follow-up visit by telephone.Enter to organize case based on each in table 7
Classification that immunophenotype, Tumor Differentiation and single multi-are sent out and score, use method in embodiment 1 to calculate the excision of each corrective surgery
Postoperative metastasis and risk of recurrence cumulative score, and survival curve and the ROC curve of patient in each group is drawn according to result, result is divided
Do not see Fig. 3 and Fig. 4 (using the diagonal that obtains according to Milan standard as reference line).
Result shows, in three groups, total recurrence after resection rate of patient population is 45.71% (16/35), and is assigned to liver
In cell carcinoma radical resection postoperative good prognosis group, the postoperative actual relapse rate of patient population is 23.53% (4/17), is assigned to liver
In the postoperative general prognosis group of cell carcinoma radical resection, the postoperative actual relapse rate of patient population is 50% (6/12), is assigned to hepatocyte
After cancer radical excision, in difference prognosis group, the postoperative actual relapse rate of patient population is 100% (6/6).Hence it is demonstrated that the side of the present invention
Method, system and test kit can by patients with hepatocellular carcinoma being carried out prognosis situation packet, to patient's had postoperative recurrent tumor with turn
The effectively layering of shift-in row and prediction provide intermediate object program or auxiliary information, contribute to more effectively before excision to operation in patients after
Transfer and risk of recurrence be layered.
Embodiment 3Hepatocarcinoma radical resection postoperative based on the postoperative gross specimen of excision to meeting Milan standard
Patients with hepatocellular carcinoma carries out prognosis situation packet (technical scheme 2)
The tumor operation collecting the patients with hepatocellular carcinoma meeting Milan standard from Haidian District Beijing Grade III Class A hospital is cut
Except case 47 example.Patient tumors differentiation degree and CK19, GPC3 immunohistochemical staining result, patient is obtained from Pathology Deparment data base
Iconography information obtains and combines personal letter gross specimen inspection and finally determines from Medical Imaging Department.
The method, system and the test kit that use the present invention to provide carry out prognosis to the patients with hepatocellular carcinoma meeting Milan standard
Situation is grouped, and result see table 8.
Specific implementation process is shown in Fig. 5.
Patient's post-operative survival rates information in being obtained each group by this institute doctor's Effect of follow-up visit by telephone.Enter to organize case based on each in table 8
Classification that immunophenotype, Tumor Differentiation and single multi-are sent out and score, use method in embodiment 1 to calculate the excision of each corrective surgery
Postoperative metastasis and risk of recurrence cumulative score, and survival curve and the ROC curve of patient in this queue, result is drawn according to result
See Fig. 6 and Fig. 7 (using the diagonal that obtains according to Milan standard as reference line) respectively.
Result shows, in three groups, total recurrence after resection rate of patient population is 40.42% (19/47), and is assigned to liver
In cell carcinoma radical resection postoperative good prognosis group, the postoperative recurrence after resection rate of patient population is 17.39% (4/23), is divided
In the postoperative general prognosis group of hepatocarcinoma radical resection, the postoperative actual relapse rate of patient population is 46.67% (7/15), is divided
In the postoperative poor prognosis group of hepatocarcinoma radical resection, the postoperative actual relapse rate of patient population is 88.89% (8/9).Hence it is demonstrated that
The method of the present invention, system can be by carrying out prognosis situation packet with test kit to patients with hepatocellular carcinoma, to swollen after operation in patients
Tumor recurrence and transfer provide intermediate object program or auxiliary information, contribute to more effectively after excision to the transfer after operation in patients and
Risk of recurrence is layered.
Specific description of embodiments of the present invention above is not limiting as 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, all should belong to the model of claims of the present invention
Enclose.
Claims (11)
1. the patients with hepatocellular carcinoma that the plan to meeting Milan standard carries out or carry out hepatocarcinoma radical excision is carried out
The method of prognosis situation packet, described method includes:
(1) CK19 and the GPC3 expression of the Tissues of Hepatocellular Carcinoma cells in sample of described patient is detected, and based on expressing feelings
Condition is to patient's assignment: such as the CK19+/GPC3+ for coexpression CK19 and GPC3, assignment 1 point；As do not expressed for expressing GPC3
The CK19-/GPC3-that CK19-/GPC3+ or CK19 and GPC3 of CK19 does not expresses, assignment 0 point；
(2) detect the differentiation situation of the Tissues of Hepatocellular Carcinoma sample of described patient, and based on differentiation situation to patient's assignment: as
The low differentiation of tumor, assignment 1 point；As in tumor differentiated or tumor break up, assignment 0 point；
(3) tumor nodule number in the liver of described patient is detected, and based on tuberosity number to patient's assignment: as 1 tumor
The single-shot of tuberosity, assignment 0 point；Multiple as 2-3 tumor nodule, assignment 1 point；With
(4) assignment obtained in step (1), step (2) and step (3) is summed up, obtain total assignment of described patient, by
The patient being always entered as 0 point is defined as hepatocarcinoma radical resection postoperative good prognosis group by this, will always be entered as the patient of 1 point
It is defined as the postoperative general prognosis group of hepatocarcinoma radical resection, or the patient being always entered as 2 points or 3 points is defined as hepatocarcinoma
The postoperative poor prognosis group of radical resection.
Method the most according to claim 1, it is characterised in that described Tissues of Hepatocellular Carcinoma sample is obtained from described patient's
Preoperative liver wears biopsy or hepatocarcinoma radical excision.
Method the most according to claim 1 and 2, it is characterised in that by described Tissues of Hepatocellular Carcinoma sample in step (1)
Product carry out immunohistochemical staining to detect CK19 and GPC3 expression；
Preferably, described immunohistochemical staining utilizes the monoclonal antibody being respectively directed to CK19 and GPC3 to carry out；More preferably
Ground, described immunohistochemical staining utilizes the fluorescein-labeled monoclonal antibody being respectively directed to CK19 and GPC3 of different colours
Carry out.
The most according to the method in any one of claims 1 to 3, by described Tissues of Hepatocellular Carcinoma sample in step (2)
Carry out Hematoxylin-eosin dyeing and detect differentiation situation.
Method the most according to any one of claim 1 to 4, preoperative by hepatocarcinoma radical resection in step (3)
The gross examination result of the Operated Specimens obtained in imaging examination or hepatocarcinoma radical excision is to determine patient's liver
Interior tumor nodule number；
Preferably, described results of imaging is obtained from enhanced CT or strengthens nuclear magnetic scanning imaging.
6. the patients with hepatocellular carcinoma that the plan to meeting Milan standard carries out or carry out hepatocarcinoma radical excision is carried out
The system of prognosis situation packet, described system includes:
(1) bioassay module:
(1-A) CK19 and GPC3 expression analysis module, described module is set to Tissues of Hepatocellular Carcinoma sample based on described patient
CK19 and the GPC3 expression of middle cell is to patient's assignment: such as the CK19+/GPC3+ for coexpression CK19 and GPC3, assignment 1
Point；As do not expressed, for expressing GPC3, the CK19-/GPC3-that CK19-/GPC3+ or CK19 and GPC3 of CK19 do not express, compose
It is worth 0 point；
(1-B) histopathology fractional analysis module, described module is set to Tissues of Hepatocellular Carcinoma sample based on described patient
Differentiation situation to patient's assignment: as the low differentiation of tumor, assignment 1 point；As in tumor differentiated or tumor break up, assignment 0
Point；With
(1-C) tumor nodule number analyzes module, and described module is set to tumor nodule number in liver based on described patient
To patient's assignment: such as the single-shot for 1 tumor nodule, assignment 0 point；Multiple as 2-3 tumor nodule, assignment 1 point；
And
(2) data processing module:
Described module is set to sum up from the assignment of module in module in module, (1-B) in (1-A) and (1-C),
To total assignment of described patient, and the patient being always entered as 0 point is defined as hepatocarcinoma radical resection postoperative good prognosis group,
The patient being always entered as 1 point is defined as the postoperative general prognosis group of hepatocarcinoma radical resection, or will always be entered as 2 points or 3 points
Patient be defined as the postoperative poor prognosis group of hepatocarcinoma radical resection.
System the most according to claim 6, it is characterised in that described Tissues of Hepatocellular Carcinoma sample is obtained from described patient's
Preoperative liver wears biopsy or hepatocarcinoma radical excision.
8. according to the system described in claim 6 or 7, it is characterised in that in (1-A), module is also configured to detect CK19 and GPC3
Expression；
Preferably, by described Tissues of Hepatocellular Carcinoma sample is carried out immunohistochemical staining detect CK19 and GPC3 express
Situation；
It is highly preferred that described immunohistochemical staining utilizes the monoclonal antibody being respectively directed to CK19 and GPC3 to carry out；More excellent
Selection of land, described immunohistochemical staining utilizes the fluorescein-labeled monoclonal anti being respectively directed to CK19 and GPC3 of different colours
Body is carried out.
9., according to the system according to any one of claim 6 to 8, in (1-B), module is also configured to detect described differentiation situation；
Preferably, by described Tissues of Hepatocellular Carcinoma sample is carried out Hematoxylin-eosin dyeing detect differentiation situation.
10., according to the system according to any one of claim 6 to 9, in (1-C), module is also configured to detect the liver of described patient
Dirty interior tumor nodule number；
Preferably, by the excision obtained in the preoperative results of imaging of hepatocarcinoma radical resection or Resection of Hepatocellular Carcinoma
The gross examination result of specimen determines tumor nodule number in patient's liver；
It is highly preferred that described results of imaging is obtained from enhanced CT or strengthens nuclear magnetic scanning imaging.
11. 1 kinds of test kits used with the method according to any one of claim 1 to 10 or system in combination, described test kit
Including:
(A) for detecting the reagent of CK19 and the GPC3 expression of Tissues of Hepatocellular Carcinoma cells in sample；With
(B) for detecting the reagent of the differentiation situation of Tissues of Hepatocellular Carcinoma sample；
Preferably, the reagent in (A) includes the examination for described Tissues of Hepatocellular Carcinoma sample carries out immunohistochemical staining
Agent；It is highly preferred that described reagent includes the monoclonal antibody of CK19 and GPC3；It is highly preferred that described reagent includes different colours
The fluorescein-labeled monoclonal antibody being respectively directed to CK19 and GPC3；
Preferably, the reagent in (B) includes the examination for described Tissues of Hepatocellular Carcinoma sample carries out Hematoxylin-eosin dyeing
Agent.
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