Vol 45, No 4 (2017)


Classification, regulation of activity, and genetic polymorphism of matrix metalloproteinases in health and disease

Shadrina A.S., Plieva Y.Z., Kushlinskiy D.N., Morozov A.A., Filipenko M.L., Chang V.L., Kushlinskii N.E.


Matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that catalyze the degradation reactions of the extracellular matrix components. In humans, 23 enzymes of this family are known, which are subdivided into 6 groups based on their structure and substrate types: collagenases, gelatinases, stromelysins, matrilizines, MMP membrane type and other MMPs. MMP functions are diverse, and an imbalance of their activity may be one of the etiological factors of various diseases. The review considers classification, regulation of activity and genetic polymorphism of matrix metalloproteinases in health and in various pathological processes in the human body. A list of the most studied polymorphic variants of MMP genes is given, their functional effects are described and the results of associative studies are presented.

Almanac of Clinical Medicine. 2017;45(4):266-279
pages 266-279 views


Clinical prospects of matrix metalloproteinases and their tissue inhibitors study in blood serum of patients with endometrial cancer and benign endometrial lesions

Gershtein E.S., Mushtenko S.V., Kuznetsov R.E., Ermilova V.D., Levchenko N.Y., Kushlinskii N.E.


Background: Despite comparatively favorable clinical course and satisfactory prognosis of endometrial cancer, the increase of its incidence observed in the last years both in this country and abroad requires the development of new approaches to early diagnostics, prognostic assessment and the choice of personalized postoperative management. Therefore, exploration of biological markers for fundamental tumor characteristics, such as invasion, metastasizing, proliferative activity, sensitivity to endogenous and exogenous regulators, are still on the agenda. The family of matrix metalloproteinases (MMPs) degrading the majority of extracellular matrix components and involved in all stages of tumor progression comprise a rich source of such markers.

Aim: Comparative evaluation of MMP-2, 7, 9 and their type 1 and 2 tissue inhibitors (TIMP) levels in the serum of patients with endometrial cancer and benign endometrial disease and in healthy women, and the analysis of its associations with the main clinical and pathologic characteristics of cancer for evaluation of their potential diagnostic and prognostic value.

Materials and methods: Ninety four patients with endometrial cancer and 53 women with benign endometrial lesions (28 with polyps, 25 with various degree of hyperplasia) were enrolled into the study. The age of cancer patients was 36 to 78 (median 60) years, of those with benign lesions, 20 to 79 (median 54) years. The control group involved 77 practically healthy women aged 19 to 75 (median 46) years. The concentrations of the markers studied were measured by direct enzyme immunoassay (ELISA) kits (Quantikine, R&D Systems, USA).

Results: A significant increase of MMP-7 and TIMP-2 levels was demonstrated both in cancer patients (median values 5.5 and 96.9 ng/ml, respectively) and in those with benign endometrial lesions (median values 5.7 and 73.2 ng/ml, respectively) as compared to the control (median values 2.1 and 60.7 ng/ml, respectively). The ROC curve allowed to establish a cutoff level for MMP-7 (3.5 ng/ml) with good sensitivity/specificity ratio for endometrial cancer (88% and 87% respectively); however, it did not allow for differentiating between benign and malignant endometrial lesions. On the contrary, MMP-2, MMP-9 and TIMP-1 levels were 1.2-1.3-fold decreased in patients with cancer and benign endometrial diseases as compared to the control; MMP-9 and TIMP-1 levels in cancer patients were also lower than in those with endometrial polyps and hyperplasia. There were no significant associations between the levels of the markers studied and the indices of progression, histological type and grade of endometrial cancer. Also, no differences between the marker levels in serum of patients with polyps or various endometrial hyperplasias were identified.

Conclusion: MMPs and TIMPs assessed in this study cannot be considered as potential diagnostic markers of endometrial cancer; however, they might be useful for disease monitoring, prognosis assessment and evaluation of sensitivity to targeted therapy.

Almanac of Clinical Medicine. 2017;45(4):280-288
pages 280-288 views

Clinical and morphological characteristic of ACTH producing tumors of various localization and the ectopic Cushing’s syndrome

Gurevich L.E., Voronkova I.A., Marova E.I., Rozhinskaya L.Y., Lapshina A.M., Britvin T.A., Komerdus I.V.


Background: Ectopic adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome is a type hypercorticism caused by ectopic production of ACTH and/or its precursors by neuroendocrine tumors (NET) of various localization, such as lung and thymus carcinoids, less frequently those of pancreas and gastrointestinal tract, medullary thyroid cancer, pheochromocytoma, small cell lung cancer, as well as some other tumor types. The wide spectrum of tumors associated with the ectopic ACTH syndrome (EAS) makes their diagnosis and treatment a complicated issue.

Materials and methods: The study was done with surgical and diagnostic biopsy samples from 60 patients who had tumors with EAS, 36 (60%) of them being bronchopulmonary carcinoids, 10 (16.7%) thymus carcinoids, 5 (8.3%) pancreatic NETs, 3 (5%) medullary thyroid cancers, 3 (5%) NETs of unknown primary localization, and NET of appendix, cecum and pheochromocytoma (one case of each, i.e. 1.7%, 1.7%, 1.7%). There were 38 female and 22 male patients (1.72:1), with their mean age of 39 ± 14 years (range, 16 to 77 years). We analyzed their clinical data, as well as the results of morphological and immunohistochemical examination of the tumors.

Results: According to the World Health Organization classification (2015), typical carcinoids (TC) of the lung were found in 77.8% (28/36) of the bronchopulmonary tumors. 22.2% (8/36) of the bronchopulmonary tumors and all thymus tumors (100%, n = 10) were classified as atypical carcinoids (ATC). Four pancreatic NETs were classified as Grade 2 (G2), 1 as G3, and NETs of the cecum and appendix as G1 and G2, respectively. At present, 29 (48%) patients are living with no relapse (mean age 39 ± 13.5 years), whereas 22 (37%) of patients developed a relapse (mean age 35 ± 13 years), and 15 (25%) of them died, regardless of the age of the patients The history of the disease was not traced in 4 cases. 5-year relapse-free survival of patients with TC of the lung was 85.7% (24/28), of those with ATC 25% (2/8), with ATC of the thymus and medullary thyroid cancer 0%. Mortality from to TC of the lung for the entire follow-up period was 3.6% (1/28), to ATC 12.5% (1/8), to ATC of the thymus and for medullary thyroid cancer 62.5% and 100%, respectively. The patients with NET of the cecum, appendix and pheochromocytoma are alive without progression for 4, 5 and 6 years, respectively. Therefore, the lowest 5-year survival of patients with EAS was observed in medullary thyroid cancer, pancreatic NET and thymus carcinoids: in 100% (3/3), 75% (3/4), and 57.1% (4/7), respectively.

Conclusion: The most unfavorable prognostic factors in the EAS are the localization of tumors in the thymus, pancreas and thyroid gland. This indicates the necessity of a differentiated treatment approaches to patients with this syndrome.

Almanac of Clinical Medicine. 2017;45(4):289-301
pages 289-301 views

Results of immunohistochemistry diagnostics of breast cancer in the region of Grodno with consideration of the BRCA1 gene mutation in triple negative cancer

Krylov A.Y., Zubritsky M.G., Kurstak I.A., Lialikau S.A., Basinski V.A.


Background: The results of immunohistochemical (IHC) assessment in breast cancer may determine not only the outcome, but also the main directions of antitumor treatment.

Aim: To study the results of IHC diagnosis of breast cancer in the Grodno region in 2010 to 2015, to determine the frequency of the BRCA1 gene mutations in triple-negative breast cancer.

Materials and methods: 2008 cases of estrogen receptor and/or progesterone receptor positive and 2445 cases of HER2/neu expressing breast cancer were extracted from the database and IHC laboratory journals of the Grodno Regional Clinical Bureau for Pathological Anatomy. Standard DAKO kits (Denmark) were used for IHC. Molecular genetic studies of DNA samples for the presence of the BRCA genes mutations were done by polymerase chain reaction in 449 women with breast cancer. BRCA1 mutation was assessed in 39 cases of triple-negative breast cancer.

Results: HER2/neu overexpression (3+) was found in 25.5% (622/2445) of all breast cancer cases, whereas of estrogen receptor and progesterone receptor positive tumors in 50.05% (1105/2008) of cases. Triple negative breast cancer was diagnosed in 19.8% (398/2008) of cases, and the mean age of the patients at the diagnosis was 56.2 years. The BRCA1 gene mutations were identified in 5 of 39 (12.8%) cases of triple negative breast cancer, which is significantly more often than in women with breast cancer without consideration of their hereditary predisposition (17/449, or 3.8%; χ2 = 4.87, p = 0.0274). Histological examination showed that among the tumors with the BRCA1 mutations, there were 3 cases with invasive ductal cancer (one G2 and two G3), one with medullary and one with undifferentiated G3 cancer. One patient had a metachronous bilateral lesion.

Conclusion: In the region of Grodno, 50% of breast cancer patients would need hormonal therapy, 25% would need treatment with trastuzumab, and 20% with cytostatic agents. The prevalence of the BRCA1 mutation in triple negative breast cancer is higher compared to that in breast cancer patients without consideration of their hereditary predisposition.

Almanac of Clinical Medicine. 2017;45(4):302-308
pages 302-308 views

Combination treatment of parotid salivary gland cancer

Balkanov A.S., Bychenkov O.A., Sipkin A.M., Gaganov L.E.


Background: Cancer of the parotid salivary gland (PSG) accounts for more than a half of all cases of salivary gland malignancies. Its treatment strategy remains a matter of debate.

Aim: To identify factors significantly associated with the 3-year survival of patients with PSG cancer after combination treatment.

Materials and methods: Thirty nine patients with morphologically confirmed PSG cancer (T1-4N0) were recruited into the study. Surgery (partial or total parotidectomy without the cervical lymphatic node dissection) was performed in 32 patients. The most frequent diagnosis (n = 10; 25.6% of all cases) was adenocarcinoma. Radiation to PSG and the regional lymphatic nodes was used in 15 patients as neoadjuvant and in 24 as adjuvant regimen. Three-year survival rates were analyzed in 36 patients by the Kaplan-Meier method, with consideration of their sex, age and the sequence of surgical and radiation treatment.

Results: The 3-year survival after combination treatment of PSG cancer patients was 82.7%. Women, patients above 60 years of age and those who received adjuvant radiation therapy demonstrated a trend towards better 3-year survival, although it was non-significant (p > 0.05).

Conclusion: Combination strategy remains an effective approach to PSG cancer irrespective of age and sex of patients. The use of radiation therapy as a single modality is possible only in exceptional cases.

Almanac of Clinical Medicine. 2017;45(4):309-313
pages 309-313 views

Enhancement of interferon treatment for large basaliomas

Molochkov A.V., Rumyantsev S.A., Khlebnikova A.N.


Background: Treatment of large basaliomas may be problematic, because relapses after the use of various treatment modalities are frequent.

Aim: To assess the efficacy of interferon therapy for primary solitary T2N0M0 basalioma.

Materials and methods: We retrospectively analyzed the results of treatment of 72 patients with primary solitary basalioma T2N0M0. The patients from the main group (n = 35) were treated with injections of recombinant interferon alfa 2b into the lesion at a dose of 2 to 3 Mio IU (total dose for the treatment course from 18 to 27 Mio IU). The reference group included 37 patients treated by cryodestruction. The results were assessed at 8 weeks after the end of interferon therapy and at 3 months after cryotherapy. The cure was confirmed cytologically at 3 months after clinical reconvalescence (formation of the scarring atrophy area or re-epithelization).

Results: The treatment was effective in 100% (35/35) of the patients from the main group. Twenty nine (82.9%) cases of basalioma required two courses of interferon therapy, 5 (14.3%) cases 3 courses, and one case (2.8%) 4 courses. In the reference group, 94.6% (35/37) of patients were cured. The difference between the proportions of the cured patients between the two groups was 5.4% (confidence interval (CI) -5.2–17.7%). Within the next 3 years of the follow-up there were no relapses in the main group, whereas the relapses were diagnosed in 9 (24.3%) of the patients from the reference group. The difference of the proportions between the two groups was 24.3% (CI 9.6–40%).

Conclusion: Based on the short- and long-term results, the efficacy of intralesional interferon administration in basalioma T2N0M0 was 100%. For tumors of more than 2 cm², an increase of the single and the total cumulative dose of recombinant interferon alfa 2b is necessary, as well as several courses of interferon treatment. Interferon therapy is more effective than cryodestruction based on the 3-year relapse-free survival.

Almanac of Clinical Medicine. 2017;45(4):314-320
pages 314-320 views

Epidemiology of uveal melanomas in Moscow

Grishina E.E., Lerner M.Y., Gemdzhian E.G.


Rationale: Melanoma of the uveal tract of the eye is among the most prevalent malignant intraocular tumors.

Aim: To identify epidemiological characteristics of uveal melanoma in Moscow.

Materials and methods: We performed a retrospective analysis of out-patient files and follow-up charts of patients with uveal melanoma in the Ophthalmological Clinical Hospital of the Department of Healthcare, Moscow, from 1977 to 2012.

Results: Within 36 years, 2547 patients with uveal melanoma have been registered, at the age of 16 to 92 years. The male to female ratio was 1:1.5. The rate of patient referrals with subsequent diagnosis of uveal melanoma has not changed from 1977 to 2000 and was on average 1.07 persons per 100,000 of the adult population. From 2001 to 2012, there was some decline in the number of referrals with uveal melanoma to the average of 0.9 persons per 100,000 of the adult population. We analyzed survival among 359 patients with uveal melanoma after enucleation surgery of the eye; 37% of them were men (63.2 ± 1.8 years) and 63% women (69.5 ± 2.7 years). Their 5-year metastasis-free survival was 65 ± 3%, whereas the 7-year survival was 60 ± 4%. The mean time to death was 5.5 years. There were no association between the life longevity and patients gender, but their survival was associated with the age of patients. The risk of death from metastatic uveal melanoma among patients above 60 years of age was on average 10% higher. After the enucleation surgery, patients with Т4 melanoma lived significantly less than those with Т1-3 tumor (5 and 6.5 years, respectively; р = 0.05).

Conclusion: The rates of diagnosis of uveal melanoma at referrals within 36 years did not increased. Epidemiology of uveal melanoma in Moscow is characterized by a high proportion of elderly women. Shorter overall and metastasis-free survival of patients with uveal melanoma after the enucleation surgery depends from a higher proportion of elderly people in the regional population and late diagnosis of the disease.

Almanac of Clinical Medicine. 2017;45(4):321-325
pages 321-325 views

Prevalence of neoplasms in acromegaly in the Moscow Region

Dreval' A.V., Chikh I.D., Trigolosova I.V., Nechaeva O.A.


Rationale: Prevalence of neoplasms in patients with acromegaly and the effects of various risk factors on their development have been insufficiently studied.

Aim: To assess the prevalence of thyroid, gastric and colon neoplasms in patients with newly diagnosed acromegaly, depending on their age, gender, duration and activity of the underlying disease.

Materials and methods: We retrospectively analyzed data extracted from out- and in-patient medical files of 108 patients with acromegaly (25 male, 93 female). Their median age was 50.5 [range 39.3 to 59] years, median duration of acromegaly 5 [range 2 to 10] years (starting from the first appearance of the first physique abnormalities). Thyroid ultrasound was performed in 96 patients, gastroscopy in 92, and colonoscopy in 89.

Results: Benign thyroid nodules were found in 50% (48/96) of patients, malignant thyroid nodules in 6.2% (6/96). Insulinlike growth factor 1 (IGF-1) levels (calculated as a percentage above upper limit of the normal range) in patients with thyroid cancer was 2.3-fold higher than in patients without nodular thyroid disease and 2-fold higher than in patients with benign thyroid nodules (р < 0.012 and p < 0.03, respectively). Malignant neoplasms were more often seen in the elderly (above 60 years of age), compared to younger adults (45 to 60 years) (30.8% and 4.3% of patients, respectively, p = 0.01). Male patients had higher prevalence of thyroid cancer than female (11.1% and 5.1%, respectively). Benign gastrointestinal neoplasms were observed in 51.7% of patients (18% had gastric polyps and 37% colon polyps). Age and duration of acromegaly in patients with gastric neoplasms were higher, than in those without them (р = 0.015 and p = 0.036, respectively). Colon neoplasms consisted of hyperplastic polyps (33.7%) and colon cancer (3% of patients). Patients with colon neoplasms were 11 years older than those without it (p = 0.015).

Conclusion: Gastrointestinal tract and thyroid gland should be diagnostically assessed in all patients at diagnosis of acromegaly, because of the higher risk of the neoplasms in these patients. The association of higher IGF-1 levels with thyroid cancer indicates that this factor may contribute to carcinogenesis and requires further studies.

Almanac of Clinical Medicine. 2017;45(4):326-332
pages 326-332 views

Effect of photodynamic therapy with the bacteriochlorophyll a derivative on growth and functional morphology of rat sarcoma M-1

Yuzhakov V.V., Romanko Y.S., Kaplan M.A., Galkin V.N., Majouga A.G., Grin M.A., Burmistrova N.V., Fomina N.K., Bandurko L.N., Sevankaeva L.E., Yakovleva N.D., Ingel I.E., Mozerov S.A., Starovoytova A.V.


Background: In recent years, the method of photodynamic therapy (PDT) has been increasingly used in clinical oncology. Three non-toxic components play a key role in realization of the anti- tumor effect of PDT: a photosensitizer (PS), local irradiation of the tumor with light/laser of a certain wavelength corresponding to the sensitizer absorption peak, and oxygen. The highly reactive biological oxidants formed during photochemical reactions exert a destructive effect on cells and tumor vasculature with subsequent activation of the immune response. Efficiency of PDT is determined by the level of PS accumulation in tumors, as well as by its photophysical parameters and photochemical activity. To create a new PS, natural chlorophylls and their derivatives with intense absorption in the long-wave region of the spectrum are of particular interest.

Aim: To study the efficacy and mechanism of PDT action (using a conjugate containing two molecules of dipropoxy-bacteriopurpurinimide with a cystamine residue as a PS) on the growth and functional morphology of transplanted solid connective tissue tumor.

Materials and methods: The study was carried out in female white outbred rats with subcutaneously implanted sarcoma M-1. PS was injected to rats of the experimental group intraperitoneally. PDT was performed during the maximal index of tumor/ healthy tissue contrast after the administration of the PS. The criterion of PDT efficacy was a change in the tumor growth/regression coefficient. The research methods included immunohistochemistry for PCNA and CD31, evaluation of mitotic activity and apoptosis of tumor cells, as well as computer analysis of microscopic images.

Results: After PDT with the new PS, a 16-fold decrease of growth coefficient of tumor nodes was registered. The photo-induced antitumor effect was shown to be due to destruction of sarcoma M-1 vascular bed, rapid inhibition of proliferative activity and devitalization of tumor cells. At early stages after PDT, destruction of the microvasculature and photo-cytostatic shock of tumor cells with subsequent development of necrosis appears to be caused by direct influence of the light flux on sensitized cellular elements in tumor parenchyma and stroma. 

Conclusion: The final result of PDT is determined by the sequence of destructive and inflammatory changes in the tumor parenchyma and surrounding tissues, as well as by a proliferative potential of malignant cells surviving after treatment. The surviving tumor cells, which determine the recurrent growth of neoplasms after PDT, are still present, maybe due to an insufficient concentration of the sensitizer in certain weakly vascularized areas of sarcoma M-1.

Almanac of Clinical Medicine. 2017;45(4):333-347
pages 333-347 views


Polyneoplasias in uveal melanoma patients detected by positron emission tomography combined with computed tomography (two clinical cases)

Avakyan K.V., Saakyan S.V., Amiryan A.G., Aslanidi I.P., Mukhortova O.V.


In addition to abdominal ultrasound and chest X-ray, positron emission tomography combined with computed tomography (PET/CT) has been increasingly used to diagnose metastatic disease in patients with uveal melanoma. We present two clinical cases of the second malignancy (synchronous polyneoplasia, colon cancer) that was eventually found during PET/CT in uveal melanoma patients performed to exclude dissemination of the neoplasm. It was shown that hybrid PET/CT is the most informative method in the diagnosis and monitoring of uveal melanoma patients. During one diagnostic procedure it enables to diagnose early stages of secondary malignancies, in addition to the assessment of metastatic dissemination.

Almanac of Clinical Medicine. 2017;45(4):348-351
pages 348-351 views

Adenoma of the non-pigmented ciliary epithelium in a 13-year old child

Saakyan S.V., Amiryan A.G., Khoroshilova-Maslova I.P., Lugovkina K.V.


Adenoma of the non-pigmented ciliary epithelium (NPCE) is a rare intraocular tumor which is often misinterpreted as a melanoma of the ciliary body or a non-tumorous process. We present a complex clinical, instrumental and morphological analysis of a case of adenoma of the NPCE growing into the base of the iris and the anterior chamber angle in a 13-year old child. Surgical treatment (iridocyclectomy) was performed. An adenoma of the NPCE was confirmed both histologically and by immunohistochemistry. At 6 months after surgery the patient's visual acuity was 1.0, with no signs of the tumor recurrence. The case can help to better understand clinical manifestation, results of the instrumental diagnostic assessments and the morphological picture of adenoma of NPCE that will be useful in the complex diagnosis of various intraocular tumors.

Almanac of Clinical Medicine. 2017;45(4):352-356
pages 352-356 views

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies