Method for prediction of haematogenic metastasis of diffuse gastric cancer

FIELD: medicine.

SUBSTANCE: what is presented is a method for prediction of haematogenic metastasis of diffuse gastric cancer by immunohistochemistry of the primary tumour preparations. For the purpose of the study, the antibodies Cyclophilin A Antibody (CypA) clone NBP 1-54388 at the working dilution of 1:1200. If there is a positive CypA cytoplasmic expression in the primary tumour cells, a low risk of haematogenic metastasis is predicted.

EFFECT: invention enables predicting the low risk of haematogenic metastasis accompanying diffuse gastric cancer and avoiding excessive adjuvant therapy.

2 dwg, 2 tbl, 2 ex

 

The invention relates to medicine, specifically to Oncology, and relates to methods for predicting low risk of hematogenous metastasis in the diffuse type of gastric cancer.

Currently one of the most important histological classification of gastric cancer is the classification proposed by Lauren P. separation of tumors in the intestinal and diffuse types [1]. Despite significant advances in diagnosis and prognosis of the disease in cancer of the stomach are still high morbidity and mortality from this disease [2].

The most significant prognostic parameters, predicting hematogenous the dissemination, which is one of the most frequent causes of death of patients with gastric cancer, consider the depth of germination the walls of the body, intravascular invasion, the severity of angiogenesis in the tumor site and lymphogenous metastasis[3, 4, 5].

Closest to the present invention is a method for determining indicators five-year survival rate and intensity of expression in the primary tumor indicator of apoptosis p53 proposed IkeguchiM., Cai J., N. Yamane et al. (1999). At high rates of expression of the five-year survival rate is 82%, with a low of 60%. The known method is not sufficiently accurate and informative in terms of forecasting emetogenic metastasis in diffuse gastric cancer the Disadvantage of this method is the fact, the study is carried out on the total group of patients with gastric cancer without specifying histotype tumor, does not specify a particular boundary values relating to "high" and "low" [6]. In addition, five-year survival is a broad concept, including cases of occurrence of deaths not only from distant metastasis.

A new technical challenge - improving the accuracy and informative way.

To solve the problem in the method for predicting hematogenous metastasis in the diffuse type of gastric cancer by immunohistochemical studies of drugs of the primary tumor for research use antibodies Cyclophilin A Antibody (CypA)clone NBP1-54388 when working dilution of 1:1200 and in the presence of positive cytoplasmic expression of Sura in the cells of the primary tumor predicts a low risk of hematogenous metastasis.

The method is as follows. In patients found in the operational material diffuse type gastric cancer performed immunohistochemistry preparations of the primary tumor. For detection of expression of cyclophilin A use antibodies Cyclophilin A Antibody (CypA) clone NBP1-54388, working dilution 1:1200, firms Novus, USA. Detect the presence of cells with positive cytoplasmic expression of CypA in primary tumors with what Olson magnification (×400). In cases with positive expression of CypA predict a low risk of hematogenous metastasis.

The essence of the proposed method is illustrated by the following examples.

Example 1. Patient S., 43, with diffuse type gastric cancer without preoperative chemotherapy, stage T2N3M0. The study of the risk of hematogenous metastasis according to the proposed method. When immunohistochemical study was determined by the positive expression of CypA in the cells of the primary tumor. Within 60 months of follow-hematogenous metastasis has not occurred.

Example 2. Patient O., 31, with diffuse type gastric cancer without preoperative chemotherapy, stage T2N3M0. When immunohistochemical study was determined by negative expression of CypA. 24 months after surgery the patient appeared hematogenous metastases in the liver.

The selection marker driven by the study of literature data, patent sources and analyzed clinical observations. Cyclophilin A (CypA) is a protein localized in the cytosol, one of the representatives of the family of immunophilins, catalyzes the reaction of CIS-TRANS isomerization of X-Pro peptide bond [3]. It is shown that this protein is involved in regulation of cell growth and differentiation [4]. In addition to the cytosolic form, there is secretiruema form, which sintesio the t activated macrophages [5]. The extracellular form of CypA acts as an agent of chemotaxis regulating the migration of monocytes, neutrophils, eosinophils and T-cells [5]. This protein possesses immunomodulatory activity, stimulating the maturation and antigen presenting function of dendritic cells [4]. In recent years there have been many studies that have revealed the overexpression of CypA in malignant tumors of various localizations [7, 8]. However, the exact role of CypA in carcinogenesis is not fully clear.

Criteria of the proposed method are selected on the basis of data analysis of clinical studies

The study included 29 patients with intestinal and 17 with diffuse type gastric cancer stage T1-3N0-3M048% men and 52% women. The average patient age of 59.5±10,1 years. Preoperative treatment of patients was not performed. The operation was carried out in volume Subtotal distal gastrectomy, gastroektomii proximal gastrectomy, Subtotal palliative gastrectomy surgery Billroth 2. The follow-up period was 5 years.

Histological type of gastric cancer was defined according to the classification proposed by Lauren P., 1965. Immunohistochemically the study was performed according to standard methods. For detection of expression of cyclophilin A (CypA) was used antibodies Cyclophilin A Antibody (clone NBP 1-543 88) (razocherovanie 1:1200) company Novus, USA. We determined the presence of cells with positive cytoplasmic expression of the studied marker at large magnification (h). Statistical processing of results was performed using the software package Statistica 6,0 for Windows.

In groups of patients with intestinal and diffuse types of gastric cancer was evaluated expression of CypA (figure 1, 2). The frequency of occurrence of cases with positive expression of CypA did not differ in patients with intestinal and diffuse types of gastric cancer (table 1).

In patients with diffuse type tumors hematogenous metastases were detected less frequently with positive expression of CypA, while in the intestinal type of gastric cancer, the incidence of distant metastases was not associated with the presence of CypA expression (table 2). The sensitivity of the method was 40%, the specificity determining the proportion of persons with a low risk of hematogenous metastasis - 100%.

Thus, the proposed method allows us to predict a low risk of hematogenous metastasis and to avoid excessive aggressive adjuvant therapy.

Sources of information used in the preparation of descriptions:

1. Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma [Text] / P. Lauren // Acta. Pathol. Environ. Scand. - 1965. No. 64. - P.31-49.

2. Tenderenda M. Expression of CD34 in gastric cancer and its correlation with histology, stage, proliferation activity, p53 expression and apoptotic index / M. Tenderenda, P. Rutkowski, D. Jesionek-Kupnika, R. Kubiak // Pathol Oncol Res. - 2001. - Vol.7(2). - P.129-34.

3. Fischer G. Determination of enzymatic catalysis for the cis-trans-isomerization of peptide binding in proline-containing peptides [Text] / G. Fischer, H. Bang, C. Mech // Biomed. Biochim. Acta. - 1984. - Vol 43. - P.1101-1111.

4. Bharadwaj, U. Effects of cyclophilin A on myeloblastic cell line KG-1 derived dendritic like cells (DLC) through p38 MAP kinase activation [Text] / U. Bharadwaj, R. Zhang, H. Yang, M. Li, L.X. Doan, C. Chen, Q. Yao // J. Surg. Res. - 2005. - Vol.127. - P.29-38.

5. Sherry C. Identification of cyclophilin A as A proinflammatory secretory product of lipopolysaccharide-activated macrophages [Text] / B. Sherry, N. Yarlett, A. Strupp, A. Cerami // Proc. Natl. Acad. Sci. - 1992; - Vol.89. - P.3511-3515.

6. IkeguchiM., Cai J., N. Yamane et al. // Cancer (Philad.). - 1999. - V.85. - P.2329-2335.

7. Lee J. Role of Cyclophilin A during Oncogenesis / J. Lee // Arch Pharm Res. - 2010. - VoL 33. P.181-187.

8. Obchoei S. Cyclophilin A enhances cell proliferation and tumor growth of liver fluke-associated cholangiocarcinoma / S. Obchoei, S. M. Weakley, S. Wongkham, Wongkham C, Sawanyawisuth K, Q. Yao, C. Chen // Mol Cancer. - 2011. - Vol.10. - P.102.

Application

Figure 1. The expression of CypA in cribrosa structures in intestinal type gastric cancer (HC. ×400).

Figure 2. The expression of CypA in discrete tumor cells with diffuse type gastric cancer (HC. ×400).

Table 1. The frequency of occurrence of cases of CypA expression in tumor cells in intestinal and diffuse type of gastric cancer.

Table 2. The relationship of CypA expression in tumor cells with the presence of hematogenous metastases in the intestinal type of gastric cancer.

Table 1
The same type of cancer is the RCU The expression of CypA (number of patients, ach, %)
negativepositive
Intestinal3/29 (10%)26/29 (90%)
Diffuse2/17 (12%)15/17 (88%)
χ2=0,02; p=0,88

Table 2
Expression of cyclophilin AHematogenous metastases (number of patients, ach, %)
not (M0)there are (M+)not (M0)there are (M+)
intestinal typediffuse type
negative3/3 (100%)0/3 (0%)0/2 (0%)2/2 (100%)
positive22/26 (85%)4/26 (15%)12/15 (80%) 3/15 (20%)
χ2=0.53; p=0,46χ2=5,4; p=0.01

A method for predicting hematogenous metastasis in the diffuse type of gastric cancer by immunohistochemical studies of drugs of the primary tumor, characterized in that for carrying out studies using antibodies Cyclophilin A Antibody (CypA) clone NBP 1-54388 when working dilution of 1:1200, and in the presence of positive cytoplasmic expression of CypA in the cells of the primary tumor predicts a low risk of hematogenous metastasis.



 

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