Method for detecting efficiency of anti-tumor therapy of skin melanomas

FIELD: medicine, oncology.

SUBSTANCE: one should carry out morphological testing of therapy results, moreover, in the course of therapy it is necessary to conduct immunohistochemical study for the levels of Ki-67 antigen expression, markers to protein-negative regulator of apoptosis: p53 and Bcl-2 and the level of melanoma marker expression HMB-45 and at decreased levels against the values in untreated tumors it is possible to state upon therapy as efficient. The innovation enables to achieve high clinical efficiency of therapy due to applying neoadjuvant autohemochemotherapy in combination with radiation therapy.

EFFECT: higher accuracy of detection.

2 ex

 

The invention relates to medicine, namely to morphological studies in Oncology, and can be used in assessing the effectiveness of treatment autohemotherapy (IGHT) and IGHT with radiation therapy of patients with melanoma of the skin.

It is known that the transformation of normal cells into tumor occurs as a result of the accumulation of the aggregate number of mutations in the genetic apparatus, leading to disruption of the mechanisms controlling the reproduction and growth of cells (see Novik A.A., finalizing T.A., Roma, NR. Introduction to the molecular biology of carcinogenesis./Edited Ulescenko. - Moscow. - Publishing house "GEOTAR - MED." - 2004. - 224 S.).

Different mutations of the gene Wt p53 is the most common genetic disorder, which is found in cancerous tumors. Several studies examining the role of immunohistochemical determination of p53 in predicting the clinical course of malignant melanoma of the skin. It has been shown that increased expression of p53 in melanoma has the best survival rate compared with the negative expression of this mutated suppressor gene (the median survival in the first group of patients was 152,4 months versus 55.7 months in the second group).

In practical terms, the level of expression of mt p53 may be a prognostic sign.

It must be emphasized that these data are in contradiction with information about PROGNOST the logical value of p53 in most other tumors (breast cancer, colon, lung and other), when increased expression of this marker is evidence of adverse outcome of the disease. For melanomas shown a sharp decline in the survival rate of patients with high p53 expression (Loggini Century, Rinaldi I., Pigitore R. et al. Immunohistochemical study of 49 cutaneus melanomas: p53, PSNA, Bcl-2 expression and multidrug resistance // Tumopi. - 2001. - Vol.87. - P.179-186).

It is known that the type of growth of the tumor mass is very important information for definitions of cancer tumor entity and its aggressiveness. In such cases, the indicator of proliferative activity it is one of the decisive factors in the choice of treatment (see Sazava T.A., Mukhina MS Antigen Ki-67 in the assessment of tumor proliferation. Its structure and function. - Oncology issues. - 2004. No. 2. S-164). The transition of the cells in the quiescent state must be accompanied by destruction or such structural changes of the protein, as a result of which he loses activity and its detection becomes impossible. Optimal marker of proliferation in this case, consider the antigen Ki-67, which is present in cells in virtually all phases of the mitotic cycle, disappears when going into a dormant period, is absent during DNA repair. Antibodies to Ki-67 is used to assess the proliferative activity of many neoplasms: malignant lymphomas, tumors of the breast, the intercessor is Oh, pancreas, lung, pituitary gland, colon. The ratio of the number of tumor Ki-67-positive cells to the total number of calculated index of proliferative activity (Ki-67). Discovered the relationship between values of Ki-67 and the degree of histological differentiation of the tumor and clinical prognosis in cancer of the endometrium, ovary, lung, bladder, tumors of the nervous system. It is shown that Ki-67 is an independent indicator for the prediction of recurrence and duration of life in patients with breast cancer and prostate glands. The present results suggest that the antigen Ki-67 can be successfully used both in the evaluation of the proliferative activity of tumors, and in the study of the mechanisms of carcinogenesis.

However, regarding the participation of Ki-67 in the remodeling of the nucleus, in the organization of microtubules in mitotic spindle, the attachment of chromosomes to the inner surface of the shell of the nucleus upon completion of cell mitosis. The functional significance of many of these interactions have not been elucidated. We do not know the use of antibody Ki-67 to assess the proliferative activity of melanoma, prediction of recurrence, duration of life of patients with melanoma of the skin.

It is known that the most accurate forecasting parameters are: the thickness of the tumor is (with grades 1, 2 and 4 mm), age, tumor location, gender of the patient, the presence or absence of ulceration, the frequency of mitoses, cellular tumor type (Pozharisski K.M., Kudaibergenova A.G., Leenman E.E. Pathomorphological characteristics and features of melanoma. Prognostic factors. Practical Oncology. - Melanoma. - № 4 (8) (December). 2001. - P.23-29).

This source of information is chosen as a prototype.

As a criterion MicroStation melanoma thickness of the tumor is measured in histological preparation with the help of ocular micrometer from the granular layer of the epidermis to the deepest point of invasion. Melanoma thinner than 0.76 mm rarely metastasize and have a good prognosis. In particular, it was shown that 8-year survival rate for melanoma thinner than 0.76 mm is 98%. Among thin melanomas most is in the form of radial growth, but about 15% of them show early signs of the vertical growth phase and respectively in 10% of patients with melanoma have been observed regional metastases. Currently, strict morphological criteria of the two phases (radial and vertical growth melanoma dramatically different in outcome, but the signs of MicroStation melanomas are still incomplete and are under investigation.

The rate of tumor growth is an important indicator of person who values her clinical course and is determined by the balance proliferative activity and apoptosis, corresponding to specific receptors. None of the many potential markers have not received compelling evidence in the possibility of its practical use to assess the clinical course and outcome of the disease, especially in relation to the individual patient.

The aim of the invention is the identification of clinical efficacy and prognostic factors of treatment outcomes of neoadjuvant IGHT and IGHT in combination with radiation therapy for patients with melanoma of the skin.

This objective is achieved in that conduct immunohistochemical study of melanoma after neoadjuvant IGHT with dacarbazine, reveal on the level of light microscopy expressed signs of disease variability tumors: necrobiotic and dystrophic processes, reduction of mitotic activity, expressed fibrillogenesis, which indicates irreversible processes in melanholicheskij cells and their destruction, in the study of melanoma after neoadjuvant IGHT with dacarbazine in combination with radiation therapy on the level of light microscopy revealed similar with the above changes, but with a greater degree of expressiveness: the effects of necrosis, apoptosis, dystrophic changes in melanocytes, the increase of fibrosis between tumor cells and in the underlying TKA and, the decrease in mitotic activity. Changes detected in cells testified to the suppression of tumor growth, reduction of DNA synthesis; then carried out on the same material after a specified treatment immunohistochemistry with markers of factors of proliferation - Ki-67, apoptosis, p53, bcl-2, CEM-45, see the expression of markers in tumor cells, however, there is a decrease in the expression of markers compared with melanomas without neoadjuvant IGHT with dacarbazine in combination with radiation therapy. The above leading morphological features are predictive factor in the effectiveness of treatment.

The invention "Method of determining the effectiveness of cancer treatment of malignant melanoma of the skin" is new, because it is unknown from level morphological studies in Oncology in assessing the effectiveness of cancer treatment.

The novelty of the invention lies in the fact that the authors performed immunohistochemical study, identify some immunohistochemical indicators of melanoma under the influence of neoadjuvant IGHT and neoadjuvant IGHT with radiation therapy and evaluate the results and prognosis of cancer treatment. In both treatments there is a decrease in the expression of proliferation factors, NIV-45, apoptosis factors. On the basis of the data morphologies the x research results highly effective neoadjuvant IGHT and IGHT in combination with radiation therapy were identified morphological parameters not previously detected during anticancer therapy that ascertain not only the effectiveness of the treatment, but also have a favorable prognosis for the further fate of the sick. This is confirmed by the good quality of life and survival of patients with melanoma of the skin.

The physiological role of antigen Ki-67 in the life of the cells is not yet clear. However, its presence on all active phases of the mitotic cycle allows the use of this protein as a universal marker of proliferation in assessing the activity of the growth of malignant tumors. The growth rate of the tumor mass is very important information for definitions of cancer tumor entity and its aggressiveness. In such cases, the indicator of proliferative activity it is one of the decisive factors in the choice of tactics of treatment.

Antigen Ki-67 presumably attributed to regulatory proteins, because their appearance coincides with the entry of cells in the mitotic cycle and content changes passivism. Ki-67 is defined in the kernel since the middle of G1-phase. As you progress through the subsequent S-G2- phase quantity gradually increases and reaches a peak in mitosis. At the end of the mitotic cycle protein quickly catabolized and no longer be detected.

It is known that the expression level of Ki67 antigen is closely associated with biologically aggressive behavior of the tumor. Found a link between the indicator of the expression of the PSNA in the tumor and the time of disease progression. Marked a definite relationship between the level of expression of a marker molecule Bcl-2 in the tumor with its sensitivity to adjuvant therapy.

Bcl-2 is a marker protein is a negative regulator of apoptosis. Increasing the level of expression of the inhibitor of apoptosis bcl-2 is often a worsening of tumor growth, increase progression and metastasis, and frequent relapses, shortening of life of the patients.

Marker of melanoma cells is antigen NIV-45. In relation to melanoma cells antibodies to NIV-45 are specific. NIV-45 (protein pre - and melanosomes) is a marker of melanoma.

The invention involves an inventive step, as a physician-morphologist is not obvious from the level of medicine in the assessment of the effectiveness of anticancer treatment of patients with melanoma of the skin by immunohistochemical study.

The invention is industrially applicable as it can be used in health when predicting the effectiveness of cancer treatment in various medical institutions, especially cancer, Oncology, oncologic dispensaries.

For the proof of the obtained results morphological studies provide some materials is ryh immunohistochemical indicators of malignant melanoma of the skin after neoadjuvant IGHT and IGHT in combination with radiation therapy, and examples of a specific implementation method for the sick.

It should be noted that in the beginning was conducted histological study on the optical level.

We conducted immunohistochemical study of malignant melanoma of the skin showed a reduction factors of proliferation Ki-67 and apoptosis: p53, bcl-2 and marker of melanoma - NIV-45. Under the effect of neoadjuvant IGHT compared with untreated tumors morphological features of factors of proliferation Ki-67, p53 apoptosis, bcl-2 is reduced or absent, expression of a marker of melanoma NIV-45 also reduced.

Under the effect of neoadjuvant IGHT in combination with radiation therapy immunohistochemically revealed similar changes, but the severity was greater, i.e. under the action of both methods neoadjuvant chemotherapy by immunohistochemical analysis, we have identified signs of therapeutic pathomorphosis.

The damaging effect on melanocytes was reduced to necrobiotic and dystrophic processes. Reduction of mitotic activity. More pronounced processes was observed with neoadjuvant IGHT in combination with radiation therapy. Decreased mitotic activity (reduction factor of proliferation Ki-67), a decrease of expression of a marker of melanoma NIV-45, markers of apoptosis (p53, bcl-2).

Neoadjuvant IGHT carried out when melanoma is skin and in combination with radiation therapy in the this localization is available for this method of exposure.

Examples of specific application "method of determining the effectiveness of cancer treatment melanoma of the skin".

Example 1

Case history No. 5 901/W.

Patient O., 1952 R., enrolled in the radiology Department 02.09.03 diagnosed with Melanoma of skin of right lower leg, St I, gr. 2. Complaints about the presence of pigmented lesions on the skin of the right tibia.

From the anamnesis: Sick about 2 years, when after injury congenital pigmented lesions on the inner surface of the upper third of the right tibia noticed growth, bleeding. Asked in August 2003, was sent to RNII.

History: Pregnancies and 5 births and 2 abortions - 3. Supracervical amputation of the uterus to the cervix without appendages about leiomyoma 15.05.1990, breast Cancer st. II. T2N0M0, gr. 3. Combined treatment in 1998 Atrophic gastritis for 7 years.

Local status: on the skin of the inner surface of the right tibia has exophytic education 15 mm above the skin for 10 mm, dark brown color. Bleeds. Regional lymph nodes are not palpable.

Central Asian. No. 20712-13 - melanoma, smarandachely option.

Ultrasound from 02.09.03 - pigment formation with signs of malignancy. In the inguinal-femoral region of the right not lazerous.

FLO from 08.09.03 - lungs and heart be the pathology.

Special treatment:

1. 02.09.03 - IGHT with dacarbazine 1000,0 mg;

2. Remote gamma-therapy to the primary tumor site and inguinal-femoral lymph nodes on the right, GENUS=3 G (38 Gr);

19.09.03 performed a wide excision of the primary tumor, replacing the defect free skin flap, trained by the method of dermateaceae.

GA. No. 709158-159 - Melanoma from epitheliopathy and nevospitannih cells. In melanocytes necrobiotic and dystrophic changes. Karyopyknosis, cario and cytolysis. In the dermis, around melanocytes development of dense fibrous connective tissue. Invasion of the fourth degree on Clark. The thickness of the tumor Breslow - 5 mm

Conducted immunohistochemistry (IGHI) with the definition of the following markers: NIV-45, p53, bcl-2, Ki-67.

Identified the following changes. A pronounced pattern of weakening reaction with areas of complete loss of expression. P53 - almost negative in the nuclei of melanocytes. Bcl-2 is no expression in the tumor cells. Ki-67 is a very weak uneven proliferation of melanocytes. A sharp decline stained tumor cells, comprising from 0 to 3%.

Thus, under the action carried out neoadjuvant IGHT with dacarbazine in combination with radiation therapy, a pronounced pathomorphosis of the tumor. Morphological features identified immunohistochemically are: reduced the e factors of proliferation Ki-67; blockade of apoptosis factors (p53, bcl-2), as well as reduced expression of the marker NIV-45.

Subsequently spent 3 courses of adjuvant IGHT with dacarbazine in a total dose of 3,000 .0 mg.

Examination in June 2004, signs of recurrence and metastases no.

Example # 2

Case history No. 16738/R.

Patient B., R. 1981, he enrolled in the radiology Department 10.11.03 with clinical diagnosis of melanoma of skin on the lower third of the left tibia, St II, gr.

From the anamnesis: Considers himself sick about 1 year, when I noticed an increase in acquired pigmented lesions. 8 months ago on a background of pregnancy noted rapid growth, ulceration. After birth appeared whisk hyperemia.

Turned 38 weeks per YEAR of Kalmykia, sent to RNII. In RNII consultation cytological preparations No. 24553-54 - pigmented melanoma.

The Council: Prof. Rubtsov V.R., Brazhnikova H. Recommended to let the patient with the turnout after birth (16.10.03).

The patient was 10.11.03, birth - 23.10.03.

Local status: On the skin shinebourne surface of the lower third of the left tibia has exophytic nodular pigmented education, dark brown color, with asymmetric fuzzy contours, whisk hyperemia, ulceration, bleeding on their own, there are allocation with a unpleasant smell, sizes 4×2,7×0,9 see

That is palpable inguinal lymph node on the left is about 1.5 cm, dense, mobile, painless.

Survey:

ECG from 13.11.03 - incomplete blockade of the right leg of the beam gissa.

FLO from 12.11.03 - data for the lung damage was not detected.

Ultrasound from 14.11.03 - chronic cholecystitis, the defeat of the inguinal lymph nodes on the left (in the groin area on the left enlarged lymph nodes up to 1.5 cm in diameter).

Ultrasound tomogram from 11.11.03 (before treatment):

Pigmented lesion located on the inner surface of the left tibia presents hypoechoic skin formation sizes 21,1×7,9×21,3 mm In the DRC, the EDC hyperintense peripheral and Central arterial blood type. PSU from 7 to 11 m/s, when the ZD-angiotensiotonography infiltration inner surface of the skin with rasprostranennye to the upper layer of subcutaneous muscle tissue.

Conclusion: Melanoma of skin of left lower leg with secondary inflammatory changes.

Ultrasound tomogram from 18.11.03 (after IGHT) Neoplasm of skin of left tibia sizes 21,3×8×17 mm, echo-structure is non-homogeneous. The number of vessels in the periphery and in the center - no significant change. The velocity of the blood flow in the tumor and in the periphery is higher (compared with the data from 11.11.03). In the left inguinal region of a single lymph node 15×6 mm

Conclusion: Melanoma of the skin (slight decrease in size); parameters tumor hemodynamics - no change (the forecast is unfavorable).

Conducted neoadjuvant therapy, including:

1) 11.11.03 and 15.11.03 - neoadjuvant IGHT with dacarbazine 1000,0 mg Without side effects;

2) 18.11.03 on 02.11.03 remote gamma-therapy to the primary tumor site with 2 tangential fields on the left groin area, RACE=3 Gr, SOD was 38 Gy without radiation reaction.

Diagnosis: Melanoma of the skin of the left tibia. St. III, gr. II, metastases in the left inguinal lymph nodes. Condition after chemoradiation treatment.

02.12.03 performed a wide excision of the primary tumor melanoma of skin of left lower leg with plastic free skin flap. Inguinal-femoral lymphadenectomy on the left. Healing primary tension. Sutures were removed on the 14th day.

GA. No. 719465-466: Melanoma of epitheliopathy and nevospitannih cells with ulceration, inflammation. In melanocytes expressed necrobiotic and degenerative processes. Slight fibrosis in the dermis. In some cells, signs of apoptosis. Invasion IV-V level on Clark. The thickness of the tumor Breslow - more than 10 mm. In lymph node metastases of melanoma.

Conducted IGHI tumors with the following markers: NIV-45, p53, bcl-2, Ki-67. Detected the following changes. NIV-45 - striking the uneven response of the tumor with areas of loss of expression. P53 - bright positive in 15-20% of melanocytes. Bcl-2 - positive distinct reaction in the tumor, however, the individual plots show tselevaya negative reaction. Ki-67 - positive uneven response in 5-20% of the nuclei of melanocytes. In the center of the slice in the area with negative NIV-45 marked by the complete absence of cell proliferation.

Thus, under the action carried out neoadjuvant IGHT with dacarbazine in combination with radiation therapy is pronounced pathomorphosis of the tumor. Morphological features identified immunohistochemically are: reduction factor of proliferation Ki-67 (i.e., the suppression of mitotic activity); blockade of apoptosis factors (p53 and bcl-2), as well as reduced expression of the marker NIV-45.

Diagnosed with Melanoma of skin of left tibia, RT4N2M0st. III, gr. III. metastases in the left inguinal lymph nodes. Condition after combined treatment.

Subsequently spent 3 courses of adjuvant IGHT with dacarbazine in a total dose of 3,000 .0 mg.

Inspection in may 2004, signs of recurrence and metastasis is not defined.

Technical and economic efficiency of the invention "Method of determining the effectiveness of cancer treatment melanoma of the skin" is that on the basis of morphological studies of some immunohistochemical markers revealed high clinical efficacy of new treatments for melanoma skin neoadjuvant IGHT in combination with radiation therapy, previously undetected morphological study.

p> Based on the identified leading morphological features became possible to establish a positive prognostic outcomes.

The method of determining the effectiveness of neoadjuvant treatment of autohemotherapy in combination with radiation therapy of malignant melanoma of the skin, including morphological study of results of treatment, characterized in that is carried out in the treatment process immunohistochemical study of expression levels of the antigen Ki-67, a marker protein is a negative regulator of apoptosis: p53 and Bcl-2 and expression level of the marker of melanoma NIV-45 and at lower levels in comparison with untreated tumors define the treatment as effective.



 

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