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Method for prediction of recurrent non-small-cell lung cancer

Method for prediction of recurrent non-small-cell lung cancer
IPC classes for russian patent Method for prediction of recurrent non-small-cell lung cancer (RU 2498305):
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FIELD: medicine.

SUBSTANCE: what is involves is the histological examination of tissue fragments taken from the extracted lung with primary, intermediate and segmental bronchi at 4-5 cm from the tumour, and disregeneration change cases are determined in the respiratory bronchial epithelium, including: basal cell hyperplasia (BCH), squamous metaplasia (SM) and if observing a combination of basal cell hyperplasia and squamous metaplasia (BCH+SM+) in the respiratory bronchial epithelium adjacent to the tumour, a risk of developing the recurrent non-small-cell lung cancer is predicted.

EFFECT: using the declared method enables higher accuracy and information value of the prediction of the recurrent non-small-cell lung cancer.

1 tbl, 4 ex

 

The invention relates to medicine, specifically to Oncology, and relates to methods for predicting the occurrence of relapse in non-small cell lung cancer.

Lung cancer remains one of the major cause of death among cancer patients worldwide. Even after radical treatment in 60-75% of patients with small cell lung cancer (NSCLC) is the progression of cancer, which can be in the form of local recurrence, lymphogenous metastasis in the thoracic cavity or the development of distant metastases [1, 6]. From timely detection of recurrence depend on the treatment efficiency and the life expectancy of patients. Therefore, an urgent task is not only the search for methods of early detection of recurrence, but also the prediction of their development.

There are various factors influencing the occurrence of relapse in NSCLC. The dependence of the frequency of recurrence of the tumor, the stage of the disease [7, 17]. One of the adverse factors associated with high risk of locoregionally of relapse in NSCLC is the presence in patients with diabetes [17]. Great influence on the frequency of recurrence have vascular invasion and spread of tumor cells in the visceral pleura [10].

Great attention is paid to study the prognostic value of molecular-g the kinetic markers, defined in the tumor. For this purpose, methods are used CIS, PCR and immunohistochemical tissues diagnostics. Using PCR method shows the relationship between the violation of miRNA-mediated regulation of genes and progression of NSCLC[3, 4, 5, 8, 11, 14, 15, 16, 18]. It should be noted that the prognostic markers that can predict the recurrence of NSCLC, still not defined [13].

With a higher frequency of recurrence in NSCLC is associated with a high degree of malignancy [2].

Closest to the proposed method is described by T. Nakagawa (2008), according to which to adverse factors contributing to the occurrence of relapse in NSCLC include less surgical intervention than lobectomy, no Lipovskii, tumour size more T2 [12]. Nevertheless, Jung-Jyh Hung and Yu-Chung Wu (2012) analyzed the publications related to the prognostic factors of recurrence in NSCLC noted that they are inadequate for effective forecasting [7].

Thus, currently known clinical and morphological criteria for the prediction of recurrent NSCLC belong exclusively to the parameters of the primary tumor. Virtually no methods for predicting the probability of relapse in NSCLC, based on the definition of the characteristics of disregenerative respiratory epithelium adjacent to tumor lung tissue

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

To solve the problem in the method for predicting the likelihood of relapse in non-small cell lung cancer, which consists in taking into account the clinical characteristics, conduct histological examination of tissue fragments remote light with the main, intermediate or segmental bronchi, located at a distance of 4-5 cm from the tumor, in the respiratory epithelium of the bronchi determine options dysregulatory changes: basal cell hyperplasia (BCG), squamous metaplasia (PM) and in the presence adjacent to the tumor epithelium of the bronchi combination of basal cell hyperplasia with squamous metaplasia (BCG+PM+) predict the risk of recurrence of non-small cell lung cancer

The method is as follows.

...Take into account the clinical features, which include: less surgical intervention than lobectomy, no Lipovskii, tumour size more than T2. Material for morphological tumor is located from it at a distance of 4-5 cm pieces of fabric remote light with the main, intermediate or segmental bronchi. Tissue fixed in neutral formalin, carried out by a standard method and salivarium in paraffin. Sections of the bronchi thickness of 5-6 mcmorial with hematoxylin and eosin. Morphological study carried out with the help of light microscope Axiostar plus" company "K. Zeiss - Germany and performed histological examination of tissue fragments remote light with the main, intermediate or segmental bronchi, located at a distance of 4-5 cm from the tumor, in the respiratory epithelium of the bronchi, identify options dysregulatory changes: hyperplasia of goblet cells (GBq), basal cell hyperplasia (BCG), squamous metaplasia (PM) and in the presence adjacent to the tumor epithelium of the bronchi combination of basal cell hyperplasia with squamous metaplasia (BCG+PM+) predict the risk of recurrence of NSCLC.

The method is illustrated by the following examples.

Example 1. Patient M., 58 years. Central cancer of the right lung Operated in the amount of pneumonectomy right, without preoperative chemotherapy. When Example 1. Patient M., 58 years. Central cancer of the right lung Operated in the amount of pneumonectomy right, without preoperative chemotherapy. Histological examination of the tissue of the primary tumor diagnosed squamous cell carcinoma moderately differentiated non-squamous cell lung cancer, stage T2N1M0. Study according to the proposed method. According to the results of microscopic examination of histological material in respiratory is petelia bronchi, the border of the tumor identified areas of epithelium with evidence of BCG and PM (BCG+PM+). Dynamic observation of patients after 32 months after surgery had developed a relapse.

Example 2. Patient W., 52 years old. Central cancer of the left lung. Operated in the amount of pneumonectomy left. In the preoperative period held neoadjuvant chemotherapy according to the scheme: paclitaxel 175 mg/m2in/in 1 day + carboplatin AUC 6 in/in 1 day, 2 courses with an interval of 3 weeks. Histological examination of the tissue of the primary tumor diagnosed squamous cell carcinoma moderately differentiated non-squamous cell lung cancer, stage T3N0M0. Study according to the proposed method. Microscopic examination of histological material in the respiratory epithelium of the bronchi adjacent to the tumor were detected combination dysregulatory processes BCG and PM (BCG+PM+). Dynamic observation of patients after 27 months after surgery had developed a relapse.

Example 3. Patient T., 62. Peripheral cancer of the lower lobe of the right lung. Operated in the volume of the lower lobectomy right, without preoperative chemotherapy. Histological examination of the tissue of the primary tumor diagnosed adenocarcinoma moderate degree of differentiation, stage T1N0M0. Not metastatic nature adenocarcinoma l is Gogo confirmed tissues study. Study according to the proposed method. Microscopic examination of sections of the respiratory epithelium of the bronchus, the border of the tumor was identified combination dysregulatory processes: BCG and PM (BCG+PM+). Dynamic observation of patients after 25 months after surgery had developed a relapse.

Example 4. Patient P., aged 54. Central cancer proximal bronchus on the right. Operated in the amount of pneumonectomy right, without preoperative chemotherapy. Histological examination of the tissue of the primary tumor diagnosed squamous non-squamous cancer moderate degree of differentiation, stage T3N1M0. Study according to the proposed method. Microscopic examination of sections of the respiratory epithelium of the bronchus, the border of the tumor was revealed hyperplasia of goblet cells (BCG-PM-). Dynamic observation of patients within 36 months of the signs of the progression of the disease is not checked.

Criteria were chosen as a result of data analysis of clinical observations.

Studied surgical material from 112 patients with non-small cell lung cancer stage T1-4N0-xM0at the age from 41 to 73 years. In the studied sample was dominated by men - 96 (88.1 per cent), women respectively was 13 (11.9 percent).

In preparati nom period of 48 patients (42.8 per cent) received NACHT scheme: paclitaxel 175 mg/m 2in/in 1 day + carboplatin AUC 6 in/in 1 day, 2-3 courses with an interval of 3 weeks. During radical surgery 30 patients (27.5 per cent) once received IORT dose of 10-15 Gy, 18 patients (60%) before irradiation was introduced radiosensibility cisplatin/Gemzar.

Morphological diagnosis of lung cancer was defined according to "Histological classification of tumors of the lung" (who, Geneva, 2003). Preneoplastic (D I) power and neoplastic processes (D II-III degree) was evaluated according to the criteria outlined S. Lantue' joul et. al. [9]. 72 people (64,3%) were diagnosed with squamous cell carcinoma, 40 (35,7%) lung adenocarcinoma different degrees of differentiation. Squamous cell carcinoma was more common in males 69 people (61,6%). All women included in the study were found to have adenocarcinoma of various degrees of differentiation.

Material for morphological studies were swelling and held her at a distance of 4-5 cm pieces of fabric remote light with the main, intermediate or segmental bronchi. Tissue was fixed in neutral formalin, was conducted by a standard method and filled in paraffin. Sections of the bronchi thickness of 5-6 μm were stained with hematoxylin and eosin. Morphological study was carried out with the help of light microscope Axiostar plus" company "K. Zeiss - Germany.

For whom adoption is not metastatic nature of adenocarcinoma of the lung was performed immunohistochemical study. Used a panel of antibodies, including TTf-1 (Dako clone), SK (clone OV-TL 12/30, Novocastra), CK20 (clone Ks20.08, Novocastra), CEA (clone AMT28, Novocastra), CDX2 (clone AMT28, Novocastra).

Immunohistochemistry was performed according to the standard technique. Demeterova antigens was carried out by incubation of the sections in a microwave oven for 20 min in citrate buffer or EDTA-8. As Chromogen was used, diaminobenzidin (DUB). Visualization of the reaction antigen - antibody was performed using the system "Super Sensitive Polymer - HRP Detection System)) (Bio Genex, USA).

Statistical processing of results was performed using the software package Statistica 6.0 for Windows. To assess differences between groups in the frequency of occurrence of the symptom criteria were used χ2.

Defined range dysregulatory changes occurring in the areas of respiratory epithelium adjacent to the tumor. According to the results of microscopic examination of histological material in the respiratory epithelium of the bronchi, the border of the tumor was observed various options dysregulatory changes - GBq, BCG, PM and dysplasia of varying severity. Data dysregulatory changes met as independent processes, and in various combinations within the investigated fragment of tissue.

All patients were divided into groups of basal cell hyperpl the Oia in respiratory epithelium in combination with squamous metaplasia and without it. Of the 112 patients with NSCLC, 81 (72.3 per cent) adjacent to the tumor bronchial epithelium was observed BCG. While in 29 patients (35.8 per cent) of BCG combined with squamous metaplasia (BCG+PM+).

Assessed the relationship of nature disregeneration changes observed in adjacent to the tumor sites of the mucosa of the bronchus, with the incidence of recurrence. It has been found that squamous cell lung cancer relapses in 26.1% of cases occurred when adjacent to the tumor sites bronchial epithelium met type of disregenerative BCG+PM+ and only 3.3% for isolated BCG ((BCG+y); χ2=4,39; p=0.03). In cases of lung adenocarcinoma, if in the border of the tumor areas of the bronchial epithelium was observed in the combination of BCG+PM+, relapses occurred in 50% of cases.

When analyzing the frequency of occurrence of relapse in NSCLC depending on the nature of disregenerative, noted that it is in indirect communication with the combination of BCG+PM+(χ2=23,5; p=0,0000; table 1). Dynamic observation of patients during 36-42 months showed that in those cases, when in the border of the tumor epithelium of the bronchi were determined other types dysregulatory changes, the risk of recurrence is much lower. Sensitivity 90%; specificity 80%.

Thus, the proposed method can more accurately predict Vozniknovenie the relapse in NSCLC, that will allow you to optimize the management of patients.

Sources of information

Table 1
The incidence of recurrence depending on the nature of disregenerative at NSCL
The recurrence of NSCLC
Type of disregenerative no total
BCG+PM+ 9 20 29
Other types of disregenerative 1 82 83
total 10 82 112
χ2=23,5 p=0,0000

A method for predicting the likelihood of relapse in non-small cell lung cancer, which consists in taking into account the clinical characteristics, characterized in that conduct gistologicheskikh fragments of tissue remote light with the chief, intermediate or segmental bronchi, located at a distance of 4-5 cm from the tumor, in the respiratory epithelium of the bronchi determine options dysregulatory changes: basal cell hyperplasia (BCG), squamous metaplasia (PM) and in the presence adjacent to the tumor epithelium of the bronchi combination of basal cell hyperplasia with squamous metaplasia (BCG+PM+) predict the risk of recurrence of non-small cell lung cancer.

 

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