New Possibilities of Treatment of Cervical Dysplasia

State Institution "Institute of Pediatrics, Obstetrics and Gynecology named after Academician O.M. Lukyanova National Academy of Medical Sciences of Ukraine "

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Introduction

Among the factors that determine the state of reproductive health (RH) of the female population of Ukraine is of particular importance the growing number of precancerous and cancerous diseases of the reproductive organs that occur from year to year. Among the oncopathology of the reproductive system, the first place is occupied by cervical cancer (CC).

It is known that precancerous conditions lead to carcinogenic processes, so special attention should be paid to cervical dysplasia (cervical dysplasia), which occurs more often on the background of infection with human papilloma virus (HPV).

There is no doubt that HPV is of paramount importance in the genesis of neoplastic processes occurring in cervical cells (OCC). In most countries of the world and in Ukraine, the fight against the increase in the incidence of cervical cancer is carried out through preventive and curative vaccination. However, at present, vaccination against HPV types 16 and 18 is available in our country. It should also be borne in mind that in the presence of the virus in a woman's body, any vaccination is already ineffective.

In recent decades, there has been a tense epidemiological situation regarding the increase in HPV infection among women of childbearing age (WCA).

According to the WHO, up to 500,000 new cases of cervical cancer are diagnosed in the world each year, and about 240,000 women die from cervical cancer each year. World statistics show that nearly 20 million people in the United States are infected with IDPs. Half (50%) of sexually active men and women get HPV once in a lifetime. By the age of 50, at least 80% of women become infected with HPV. About 6 million people are infected with IDPs each year.

In the United States, there are 2.8 million cases of abnormal PAP testing each year, more than 10,000 cases of HPV-related cervical cancer, and about 4,000 deaths from cervical cancer.

In 93% of cases, cervical cancer is caused by HPV, of which in 70% of cases - 16 and 18 types.

In Ukraine, data on the number of women infected with HPV are not very informative.

Chronic inflammatory diseases of the genital organs (CIDGO) pose a significant threat to women's reproductive health, which, if not diagnosed and treated in time, affects the risk of other reproductive health disorders.

Dysplasia

Dysplasia is a process of disruption of the transformation of the cylindrical epithelium into squamous. This process is a normal regenerative mechanism, during which the organelles are flattened, the vacuoles and the cell volume are reduced. If during this transformation the virus enters the cell and uses it for replication, the cell either dies or stops the process of its transformation. The most common method of diagnosing the cervix is ​​a Pap test, or Pap smear. The only standard of cytological results is the protocol approved at a conference in Bethesda (USA) by a group of experts, this protocol is recognized by the World Health Organization and the American Society of Cytopathology.

An important pathogenetic mechanism for inducing cervical cell proliferative activity under HPV is activation of retinoblastoma protein phosphorylation by binding to E7 protein, activation of transcription factors (eg E2F), and initiation of cell transition to S phase phase interphase. In turn, the E6 protein is known for its ability to inhibit the activity of proapoptotic proteins (such as p53) also promotes pathological proliferation by inhibiting apoptosis. Genes encoding the production of E6 and E7 proteins belong to the group of "early" genes of circular double-stranded HPV DNA.

Recent modern research on the diagnosis of non-plastic processes of the cervix was aimed at determining the E7 protein in cervical mucus by enzyme-linked immunosorbent assay.

Studies have shown that E7 protein was detected in 81% of dysplasias and in 75% of cases of cervical cancer. Determination of this protein can be an important diagnostic criterion for these diseases.

Changes in the cells of the cervix occur not only against the background of infection with viruses or other microbial factors, but also with the participation of changes in redox processes in cells.

In Ukraine, given the high incidence of cervical cancer and cervical cancer, there is an urgent need to prevent cancer. Therefore, the definition of modern treatment options can be a prevention of oncopathology.

Goal

Identify new treatment options for cervical dysplasia in WCA.

Materials and methods of research

We comprehensively examined 50 WCA with CIDGO in which MSM was detected.

All surveyed women underwent:

• colposcopic examinations,

• cytological examinations,

• determined the state of the microbiocenosis of the vagina and the level of tumor necrosis factor alpha (TNF-α)

All studies were conducted before and after treatment, in accordance with the order of the Ministry of Health of Ukraine №236 from 02.04.2014.

Colposcopy of the cervix was performed on all examined women on the device "OlympusOCS 500" in the dynamics before and after treatment.

Colposcope OLYMPUS OCS-500

The study of the microbiocenosis of the genital organs included the determination of the species and quantitative composition of the microflora. Analysis of the bacterial spectrum of the vagina and accounting for the results was carried out in accordance with the order of the Ministry of Health of Ukraine №234 from 10.05.2007.

Detection of HPV was performed by the molecular biological method "Polymerase Chain Reaction", which refers to amplification methods. The method is that with the help of DNA polymerase and RNA ligase enzymes, a larger number of identical fragments of HPV DNA is obtained and identified by gel electrophoresis.

Serum obtained from venous blood of some of the studied women was used for immunological examination. The concentration of cytokines (tumor necrosis factor) was determined by enzyme-linked immunosorbent assay.

Cytological smears from the cervical canal were removed with a special brush "Cervex-Brush" to obtain material from the transformation zone.

"CERVEX BRUSH" sampling brush

After collection, the material was applied in a thin layer on a glass, dried in air, fixed in a mixture of Nikiforov 10-20 minutes and then painted according to Romanovsky - Gimse and Papanicolaou. Studies of the drugs were performed on a microscope "Olympus CN-2" in the mode of transmitted light.

Olympus C-2 microscope

Evaluation of dysplastic processes in WCA was performed according to the cytological classification "Bethesda system" (2001).

We used API-NORM® NEO (vaginal suppositories), which is a natural anti-inflammatory agent to prevent neoplastic processes in gynecological diseases, in the complex therapy of cerebral palsy and treatment of CKD.

The composition of the remedy API-NORM® NEO includes a balanced composition based on beekeeping products and herbal components.

The main components:

• activated propolis extract

• hypericum extract

• marigold extract

• celandine extract

• periwinkle pink extract

• sea buckthorn oil

Excipients

• polysorbate

• dimethyl sulfoxide

• polyethylene oxide

• ascorbic acid

• beeswax

This drug differs from drugs of similar orientation by its balanced combination of bee products and plant components. The combination of these components has a complex effect, which reduces the clinical manifestations of acute and chronic inflammatory diseases of the pelvis and urinary system. Herbal components and bee products that are part of this drug have a high level of effectiveness and safety in terms of evidence-based medicine.

To achieve the goal of the study, our choice was based on the drug API-NORM® NEO (vaginal suppositories) because this multi-component preparation of natural ingredients has a proven complex effect, namely:

• anti-inflammatory

• immunomodulatory

• adaptogenic

• antispasmodic

• analgesic

• antioxidant

API-NORM® NEO enhances phagocytic activity and activates the nonspecific immune response, inhibits malignancy and prevents malignant cell transformation, as well as prevents unauthorized cell division, which stops tumor growth.

In the complex therapy of cervical cancer on the background of CIDGO API-NORM® NEO (vaginal suppositories) was prescribed one candle per night after hygienic procedures for 20 days. After 30 days, a repeat course of 10 days with colposcopic and cytological control was prescribed.

In the effective treatment of WCA on the background of CIDGO for prophylactic purposes, the drug was used for 5 days a month for 3 months with colposcopic and cytological control.

API-NORM® (rectal suppositories), which is a natural anti-inflammatory agent indicated for urological and proctological diseases, was prescribed for the treatment and prevention of inflammatory diseases of the genital organs in men - sexual partners of women who underwent treatment for cervical dysplasia on the background of CIDGO.

Results and discussion

The survey involved 50 women aged 15 to 40 years.

Determination of clinical features of the state of the cervix and changes in RH, microbiocinosis, immune parameters and features of CIDGO was carried out depending on the colposcopic changes in CMM.

The results of clinical and colposcopic examination of women allowed to establish the degree of abnormal changes in the epithelium of the CMM.

Thus, the first degree of abnormal colposcopic picture was detected in 10 women (20%), and the remaining women - 40 (80%) showed the second degree of abnormal colposcopic picture.

The data in the table show that the first degree of abnormal colposcopic picture (delicate mosaic, delicate punctuation, thin acetic-white epithelium; irregular, "geographical" border) is more common in women aged 26-30 years. In addition, the second degree of abnormal colposcopic picture (dense acetic-white epithelium, rough mosaic, rough punctuation, leukoplakia (keratosis, hyperkeratosis, erosion) is more common in the same age group, but it should be noted that such changes are quite common). 0%) occur in very young women aged 20-25 years.

Different CIDGO were observed in women with CC

The data in the table show that in all women with CD dysplasia there was a state of CC, vagina more often in combination with the inflammatory state of the uterine appendages.

Various changes in reproductive health were observed in the women surveyed.

The data in the table show that all surveyed women suffered from CIDGO. The high frequency of RH changes is an unfavorable background that may worsen the clinical course of CC dysplasia.

The study of the state of microbiocinosis of urogenital organs showed a high frequency of detection of pathogenic microflora at the level of the genitals.

It should be noted that in the examined women with CKD and CMM dysplasia, the identified pathogenic microorganisms were found in associations: the most frequent combinations were representatives of pathogenic coccal microflora in combination with chlamydia and yeast-like fungi. Infection with sexually transmitted infections (STIs).

The determination of PVI showed that the surveyed women were more likely to have highly oncogenic types of HPV types 16 and 33, respectively 30 (60.0%) and 16 (32.0%). The rest of the women had strains of HPV with less oncogenicity.

In order to determine the state of the pathogenetic indicator of immunity, we determined the content of the cytokine TNF-α in the serum of venous blood using enzyme-linked immunosorbent assay. The results of the study showed a significant increase in TNF-α, which was 62.1 pg / ml.

Because TNF-α is a proinflammatory cytokine and is a factor in nonspecific immune response, it can be argued that women with CMM dysplasia on the background of COPD caused by pathogenic microflora infection with STIs and HPV infection have negative changes in cytokine status.

Colposcopic picture was adequate in all patients. The zone of type 1 transformation was determined in 84% of women, the zone of type 2 transformation was determined in 16% of women. Signs of normal colposcopic picture such as nabothian cysts were detected in 25% of women, open ducts of glands were detected in 36% of subjects. In all examined women, the squamous epithelium was mature, no signs of atrophy were observed.

More than half of women, namely 54% of the size of the altered epithelium was 2 cervical quadrants, and occupied an average of 45 ± 12% of the CMM surface.

The first degree of abnormal colposcopic picture was determined in the form of delicate mosaic in 26% of women, delicate punctuation in 18% of women, fine acetic-white epithelium in 23% of women.

The second degree of abnormal colposcopic picture in the examined women was determined in the form of rough mosaic in 19% of women, rough punctuation in 18% of women, dense aceto-white epithelium in 26% of women. Among the nonspecific signs of an abnormal colposcopic picture, the presence of CMM erosion can be noted in 67% of cases. The presence of unstained areas during the Schiller test was observed in all examined women.

There were no signs of invasive growth in the examined women.

CMM endometriosis was found in 8% of subjects, signs of CMM treatment in 20% of women, and polyps in 5% of women surveyed, respectively.

The colposcopic picture of the vaginal walls in the examined women was not changed.

Pappanicolau cytological smears were satisfactory, processed and examined in all women.

The studied samples did not contain intraepithelial lesions or oncopathology.

Inflammatory infiltration was present in 78% of the smears examined.

Among the cells of the transformation zone, svamous cells of the superficial intermediate and parabasal layers were determined.

Cells in the smear were placed separately in 23% of surveyed women, formed cell complexes in 25% of women, and placed in layers in 27% of women.

Among the glandular epithelial cells in the smear were found mainly high prismatic secretory cells (45%) and metaplastic cells (31%), in 6% of cases small cubic reserve cells were detected.

Among the degenerative features of epithelial cells, fatty or hydropic cytoplasmic dystrophy (69% of cases), formation around nuclear "halos" (31% of cases) and increase in the size of nuclei (25% of cases) were most often identified.

Signs of viral epithelial damage were identified in all women examined.

Clinical manifestations of PVI were detected in 30 (60%) women - in the clinical form; in 17 (34%) women - subclinical form; in 3 (6%) women - latent form.

The same trend was observed with regard to the age distribution of women affected by highly oncogenic and low-oncogenic types of HPV.

Comprehensive treatment of CMM dysplasia was performed on the basis of existing international protocols.

After a comprehensive treatment, signs of inflammation at the level of the genitals disappeared in all women with CMM dysplasia. Effective signs of complex treatment with API-NORM® NEO were normalization of microbiocinosis, according to colposcopy - no abnormal colposcopic picture, according to cytological examination - no changes characteristic of DSM and reduction of cytokine TNF-α, to 31.1 <0.02).

The results of these studies showed that in women with CMM dysplasia there was a normalization of microbiocinosis and colposcopic picture. Also after treatment, a positive cytological picture of Pappanicola smears was observed.

CONCLUSIONS

New approaches in the diagnosis of atypical colposcopic picture expand the possibilities of conservative treatment of benign cervical diseases.

The drug API-NORM® NEO, which has a complex action, namely: anti-inflammatory, immunomodulatory, adaptogenic, antispasmodic, analgesic and antioxidant. API-NORM® NEO enhances phagocytic activity and activates a nonspecific immune response, inhibits malignancy and prevents malignant cell transformation, as well as prevents unauthorized cell division, which stops tumor growth. has a positive effect on the processes of epithelization of true erosion and rejection of pathological cells.

The effectiveness of the inclusion of API-NORM® NEO in the complex therapy of cervical dysplasia of the drug has been confirmed.