Vol 45, No 8 (2017)


Comparative analysis of serum and tumor vascular endothelial growth factor, insulin-like growth factor 1, matrix metalloproteinase 7 levels in patients with ovarian cancer

Plieva Y.Z., Ermilova V.D., Tereshkina I.V., Kushlinskiy D.N., Shelepova V.M., Utkin D.O., Khokhlova S.V., Dvorova E.K., Payanidi Y.G., Zhordania K.I.


Aim: To perform a comparative analysis with simultaneous measurement of vascular endothelial growth factor (VEGF), insulin-like growth factor 1 (IGF1) and matrix metalloproteinase 7 (MMP7) in serum samples taken from healthy women and ovarian cancer patients; to perform association of these markers with their expression in primary tumors depending on clinical, morphological and biochemical characteristics of the disease and its prognosis. Materials and methods: We assessed 54 treatment-naïve patients with ovarian cancer aged from 23 to 74 years (mean ± SD, 53.2 ± 1.9), being at various FIGO stages of the disease. The control group consisted of 120 healthy women of matched age and reproductive status, in whom serum biomarker levels were studied. Patient survival was assessed by the Kaplan-Meier method, with survival curves compared with log-rank test. All analyses were done with “STATISTICA” and SPSS software. Results: Serum VEGF levels in ovarian cancer patients were significantly (p < 0.0001) higher compared those in the control. The most informative cut-off values differentiating the groups studied were serum VEGF values of < 350 pg/ml (median value in the control) and > 505 pg/ml (upper quartile in the control). With 505 pg/ml taken as a threshold, the test had sensitivity of 79.6% and specificity of 75%. Another cut-off value of serum VEGF level between the patients with ovarian cancer and the control group (510 pg/ml) was derived from ROC curves and 75% sensitivity and 78.2% specificity. No acceptable cut-off value for serum IGF1 to differentiate between the patients with ovarian cancer and the controls could be obtained from the ROC curves. Serum MMP7 levels in the patients with ovarian cancer were significantly higher than those in the control group (Mann-Whitney test p < 0.0001). With ROC curves, the best sensitivity to specificity ratio for MMP7 value of 4.6 ng/ml was obtained to differentiate between the patients with ovarian cancer and the controls (sensitivity 83.3%, and specificity 81%). The variance analysis did not reveal any association between serum VEGF, IGF1 and MMP7 and age of patients with ovarian cancer, tumor histology, concomitant somatic and gynecological diseases, and CA-125 levels. Serum VEGF and IGF1 levels did not correlate with the stage of ovarian cancer, in contrast to MMP7, whose levels were significantly higher in stages IIIc–IV. The median VEGF level significantly increased as the degree of differentiation decreased from 510 to 622 pg/ml (p < 0.002), while median IGF1, on the contrary, decreased from 219 to 116 pg/ml (p < 0.0001). There was a direct correlation between serum and tumor VEGF levels in ovarian cancer patients (r = 0.65, p < 0.0001). On the contrary, there was an inverse correlation between serum and tumor IGF1 levels (r = -0.68, p < 0.0001). Serum and tumor MMP7 levels remained unrelated to each other. Tumor VEGF, IGF1 and MMP7 content was unrelated to the age of the patients, their reproductive status, presence of concomitant somatic and gynecological diseases, histology of ovarian cancer, and serum CA-125 levels. VEGF levels in the tumor were not associated with the stage of ovarian cancer, but in patients with initial stages Ia and Ib stages MMP7 values significantly lower (2.1 ng/mg protein) compared to those in stages IIIc and IV (6.1 and 4.7 ng/mg protein, respectively, p < 0.05). Similar pattern was noted for IGF1: tumor IGF1 values in the patients with stages Ia–Ib were significantly lower (0.5 ng/mg protein) than those with stages IIIc–IV (median, 1.3–1.4 ng/mg protein). A significant increase in both serum and tumor VEGF levels was detected in the patients with ovarian cancer with decreased degree of differentiation. On the contrary, tumor IGF1 levels, but not serum ones, were significantly increased from 0.6 to 1.4 ng/ml in the patients with poorly differentiated ovarian cancer. MMP7 tumor expression did not depend on the degree of its differentiation. Serum VEGF levels above 700 pg/ml and tumor levels of above 590 ng/mg protein should be considered as unfavorable prognostic factors in patients with ovarian cancer.

Almanac of Clinical Medicine. 2017;45(8):616-627
pages 616-627 views

Clinical associations of vascular endothelial growth factor in patients with systemic sclerosis

Alekperov R.T., Alexandrova E.N., Novikov A.A., Ananyeva L.P.


Aim: To assess serum levels of vascular endothelial growth factor (VEGF) and its clinical correlates in patients with systemic sclerosis (SSc). Materials and methods: Forty six (46) patients with SSc aged from 19 to 77 years (median, 50 years), with duration of the disease from 0.5 to 24 years (median, 7 years) were recruited into the study. There were equal numbers of the patients with limited (LSSc) and diffuse (DSSc) types of the disease (23 patients in each group, or 50%). All patients underwent clinical examination, including measurement of the forced vital capacity (FVC), diffusing capacity of the lung for carbon monoxide (DLCO) and pulmonary artery systolic pressure (PASP). Serum VEGF-A levels were determined by immunoenzyme assay in the patients and in 20 healthy controls. Results: VEGF levels in the healthy individuals were in the range from 0.2 to 264 pg/mL (median, 90.2). In SSc patients they varied from 0.02 to 1034.2 pg/mL (median, 147.2), with mean VEGF levels being over 2-fold higher than that in the control group (212.35 ± 253.93 and 97.74 ± 71.46 pg/mL, respectively; p = 0.032). DSSc patients had VEGF levels of 0.02 to 599.8 pg/mL (median, 93.6), whereas in LSSc they were from 0.02 to 1034.2 pg/mL (median, 162.4). Mean VEGF level in LSSc was higher than in DSSc (267.11 ± 268.74 vs 120.4 ± 141.09 pg/mL, respectively; p = 0.012). Current or past digital ulcers were found in 19 (41%) of all patients. Mean VEGF level in the patients with digital ulcers was higher than in those without ulcers; however, the difference was not statistically significant. PASP exceeded 30 mm Hg in 19 (43%) of the patients. VEGF levels in the patients with PASP of less than 30 mm Hg and ≥ 31 mm Hg were in the range of 0.02 to 363.6 pg/mL (median, 79.6) and 0.2–1034.2 pg/mL (median, 222.3), respectively. Mean VEGF level in the patients with high PASP was significantly higher than that in the patients with normal PASP (р = 0.0042). In the patients with DLCO ≥ 50% and < 50% serum VEGF levels were found to be 0.02 to 599.8 pg/mL (median, 59.75) and 0.02 to 1034.2 pg/mL (median, 195.9), respectively. Mean VEGF levels in the patients with DLCO of less than 50% was significantly higher than in the patients with DLCO of 50% and above (364.2 ± 381.95 and 128.55 ± 142.7, respectively, р = 0.034). FVC was decreased (< 80% of predicted) in 11 (26%) of 43 patients. Mean VEGF levels in the patients with low FVC was higher than in those with normal FVC, although the difference was non-significant. There was a moderate direct association between VEGF levels and PASP values (R = 0.4; p = 0.007). Also, a trend towards an inverse correlation between DLCO and VEGF levels was observed, which was however non-significant (R = -0.28; р = 0.07). Conclusion: A significant proportion of SSc patients have high serum VEGF levels. A close association with some clinical correlates indicates a pathogenetic role of VEGF in SSc. Further studies are necessary to clarify the precise contribution of VEGF into SSc pathophysiology.

Almanac of Clinical Medicine. 2017;45(8):628-634
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The potential of mitral valve quantification in cardiovascular surgery

Tolstikhina A.A., Mashina T.V., Mrikaev D.V., Dzhanketova V.S., Gromova O.I., Golukhova E.Z.


Objective: To identify specifics of mitral valve anatomy in patients with mitral insufficiency of various origin using the Mitral Valve Quantification (MVQ) technique for an optimal choice of mitral valve repair strategy. Materials and methods: The study included 30 patients (17 male and 13 female) with organic or functional mitral regurgitation of various grades (mean age, 48 ± 5 years). The patients were categorized into three groups depending on the etiology of mitral insufficiency. The first group included 15 patients with degenerative mitral valve regurgitation, the second one included 9 patients with ischemic mitral regurgitation, and the third one was a control group with 6 patients with minimal mitral regurgitation and no structural heart abnormalities. A geometrical model of the mitral valve was developed by the MVQ technique with a Philips iE33 ultrasound machine. In all patients, we assessed the geometrical parameters of the mitral annulus, the type of leaflet defects and chordal apparatus of the mitral valve, leaflet coaptation length, and the angle between the aortic and mitral valves. Results: The following patterns were found at comparison of the geometrical parameters of the fibrous mitral annulus. Compared to other groups, the patients with ischemic mitral regurgitation had higher antero-posterior diameter and commissural diameters (48.7 and 45.7 mm, respectively; р < 0.05). They also had higher values of the tenting height and tenting volume, i.e., the mitral coaptation depth (11.9 ± 2.1 mm and 5.9 ± 2.8 mL, respectively; p < 0.05). The prevalence of mitral valve prolapse was higher in the patients with degenerative mitral regurgitation (prolapse height, 6.4 ± 0.9 mm, prolapse volume, 1.3 ± 0.1 mL; р < 0.001). The leaflet coaptation length tended to be higher in the patients with organic lesions of the mitral valve (30 ± 7.5 mm), while the shortest coaptation length was typical for the control group (23 ± 1.6 mm): however, the difference was not statistically significant. The results of the mitral valve chordae tendinea measurements demonstrated that the anterolateral chord was the longest one (31.2 mm versus 21.3 mm of the postero-medial chord) in the group with degenerative mitral valve abnormalities; whereas in those with the ischemic mitral insufficiency and in the control group both chords had similar length. Conclusion: The MVQ allows for diagnosis of the mitral valve abnormalities and makes it possible to perform quantitative and qualitative assessment of the mitral valve geometry in patients with the valve abnormalities of various origins, which may significantly contribute to the choice of mitral valve repair strategy.

Almanac of Clinical Medicine. 2017;45(8):635-643
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Extracorporeal photochemotherapy and methotrexate in the treatment of atypical oral lichen planus

Molochkov A.V., Molochkova Y.V., Kil'dyushevskiy A.V., Glazkov A.A.


Background: Some authors have successfully used methotrexate in the treatment of atypical oral lichen planus (LP) and noted its good tolerability. High clinical efficacy of the extracorporeal photochemotherapy (ECP) has been also reported in the treatment of such patients. However, there is no information on the long-term results of methotrexate and ECP and their combination in the treatment of atypical LP. Aim: To study clinical efficacy and long-term results of the combination of routine therapy with the ECP course and a single injection of methotrexate at a dose of 10 mg in patients with atypical LP of the oral cavity and the skin. Materials and methods: This was a prospective study with an active control. Eighteen (18) patients with various forms of atypical LP of the oral cavity (hypertrophic, erosive/ulcerative, exudative/hyperemic forms) and the skin (hypertrophic, pigmented, atrophic, follicular forms) were administered the combination of routine therapy (chloroquine, doxycycline, vitamin B6, topical corticosteroids), an ECP course, and a single injection of methotrexate at a dose of 10 mg. Two hours before the ECP session all patients were given 8-methoxypsoralen. Peripheral mononuclear cells were isolated with a cell separator and treated with ultraviolet radiation (λ = 320–400 nm), then the monocyte cell mass was re-infused to the patient. The treatment course included 4 sessions performed every other day. A single injection of methotrexate was given in the middle of the ECP course. Clinical efficacy was assessed with the Thongprasom scale of activity of the disease and by visual analog scale (VAS) for pain assessment in patients with oral lesions. Results: The treatment was well tolerated and was not associated with methotrexate-related immune abnormalities. At one month after the 4th ECP session, the mean Thongprasom score was decreased from 5 to 2.2 ± 1.2 (p < 0.001). At Week 24 after the treatment, 15 (83.2%) of patients had no painful symptoms (VAS score of 0). The clinical effect was associated with a significant decrease in correlation of CD3+CD8+ cells with СD38+ (r = 0.47, p > 0.05). Assessment of the results in the time period from 1 to 3 years (mean, 2.25 ± 0.96 years) showed no relapse in 13 (72.2%) of patients, and at 3 years, there was no recurrence in 7 cases (38.9%). Conclusion: The results obtained enable to consider the method of combination therapy with ECP plus a single intramuscular injection of methotrexate at a dose of 10 mg as an alternative therapeutic approach to refractory lesions of atypical LP of oral cavity.

Almanac of Clinical Medicine. 2017;45(8):644-651
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Sedation with dexmedetomidine reduces the duration of delirium treatment in sufferers with severe concomitant trauma

Bershadskiy F.F., Ulitkina O.N., Skripkin Y.V., Likhvantsev V.V.


Rationale: Delirium would deteriorate the outcomes and treatment results in the patients with severe concomitant trauma. Its treatment efficacy is especially relevant for such patients. Aim: To identify an optimal sedation strategy for delirium in the sufferers with severe concomitant trauma. Materials and methods: Sixty (60) patients with delirium that developed against the background of severe concomitant trauma were included into this randomized, retrospective-prospective study. One group of patients (n=30) was sedated with dexmedetomidine, the other one (n=30), with propofol. Results: In the group with dexmedetomidine sedation, the duration of delirium was 6 [5–6] days, whereas in the propofol group, 7 [6–8] days (p=0.003). The type of sedation was not associated with the severity of delirium, whose maximum ICDSC score was 7 [4–7] points in the propofol group and 6 [4–6] points in the dexmedetomidine group (p=0.32). Conclusion: Compared to propofol, dexmedetomidine may help to reduce the duration of treatment for non-specific delirium in severe concomitant trauma by 1 day.


Almanac of Clinical Medicine. 2017;45(8):652-657
pages 652-657 views

Assessment of the risk of osteoporotic vertebral fractures of the 2nd and 3rd degree in women in reproductive age and men under 50 with type 1 diabetes mellitus

Vodyanova O.V.


Rationale: Patients with type 1 diabetes mellitus (DM1) have higher rates of any fractures than those without diabetes. Aim: To identify significant predictors of the osteoporotic vertebral fractures of the 2nd and 3rd degrees and to develop a  statistical model for the risk assessment in DM1 patients. Materials and methods: 97 DM1 patients and 77 control aged below 50 participated in this cross-sectional study. Multiple logistic regressions were used to assess the risk of osteoporotic vertebral fractures of the 2nd and 3rd degrees in DM1 patients. Results: Patients with DM1  had a  statistically significantly lower bone mineral density (BMD) (Z-criterion) in all areas of the axial skeleton, compared to that in the control group (p< 0.001). Osteoporotic vertebral fractures were significantly more frequent (p=0.0385) in DM1 patients than in the controls. The subgroup of DM1  patients with osteoporotic vertebral fractures (n=8) had higher daily insulin requirement per kg of bodyweight compared to that in the subgroup of the patients without fractures (n=89; р=0.029), as well as lower axial BMD (Z-criterion L1–L4, p=0.002; femoral neck Z-criterion, p< 0.001; proximal femoral Z-criterion, p=0.002). We developed a  statistical regression equation model including two parameters: 1) presence or absence of low femoral neck BMD based on the dual X-ray absorptiometry, 2)  daily insulin requirement per kg of bodyweight. Conclusion: The statistical model has the sensitivity of 87% and specificity of 75% to predict that the DM1 patients would have low or high risk of osteoporotic vertebral fractures of the 2nd and 3rd degree.

Almanac of Clinical Medicine. 2017;45(8):658-664
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Modern approaches to the management of recurrent urinary tract infections in women

Rebrov B.A.


In the recent years, relapses of infectious and inflammatory diseases of the urinary tract (UTI) have become more common. Doctors in many specialties face the problem of recurrent UTIs. The effectiveness of antibiotics is worsening, while antibiotic resistance is increasing. This review article deals with prevention and treatment of patients with recurrent UTIs. Risk factors for recurrent UTIs are reviewed separately for women in their pre- and post-menopausal age. Based on the literature and our own experience, we discuss therapeutic and preventive measures for these disorders. Today, preventive measures for recurrent UTIs involve not only lifestyle modification, herbal treatments and improvement of immune response, but also vaginal estrogen replacement therapy in postmenopausal women, immune prophylaxis, normalization of urinary output, water-induced diuresis, urine acidification, vaginal application of the lactobacilli, long-term low-dose and/or postcoital drug prophylaxis in various combinations. It is emphasized, that current guidelines on the prevention of recurrent UTIs are primarily focused on non-antibiotic measures. However, the necessary prerequisite or initiation of any prevention regimen is a negative urine culture after the eradication of the pathogen. A list of the most common herbal preparations is included into the review. Immunoactive prophylaxis and stimulation of an individual immune response is considered to be a  new strategy in the management of patients with recurrent UTIs. Characteristics of antibacterials are given from the evidence-based perspective. Individual and sexual hygiene are both important conditions for the successful prevention of UTI relapses and successful treatment of recurrent UTIs.

Almanac of Clinical Medicine. 2017;45(8):665-673
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The role of hypoxia-induced factor in the regulation of oxygen homeostasis during reparative regeneration in compromised microcirculation

Izmaylov S.G., Beschastnov V.V., Ryabkov M.G., Leont'ev A.E., Lukoyanychev E.E., Bagryantsev M.V., Orlinskaya N.Y.


The aim of the present review is to find an answer to the clinically important question on the mechanisms regulating the activity of reparative regeneration in hypoxic conditions and potential ways to modify this process. In the recent studies, compensated hypoxia is characterized as a trigger for the regeneration, with the central regulating factor being the member of the cytokine family, hypoxia-inducible factor-1 (HIF-1). Changes in the concentration of this protein modulates cell migration, angiogenesis and epithelialmesenchymal integration; it also stimulates the proliferation of endothelial cells and fibroblasts, playing a  major role in the stimulation of wound healing, especially with compromised microcirculation, for example, diabetes mellitus.


Almanac of Clinical Medicine. 2017;45(8):674-680
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A rare case of isolated erosive ulcerative lichen planus of the vermilion zone

Molochkova Y.V., Amkhadova M.A., Perlamutrov Y.N., Bobrov M.A.


Unlike oral lichen planus (LP), isolated LP of the vermilion zone is a rare disease. It has a higher risk of malignization compared to other LP types, especially with the long course of the disease, which is to be related to frequent injuries and insolation of the area. In its turn, erosive/ulcerative form of LP under adverse circumstances (smoking, external irritants, immunosuppression, etc.) may antedate leukoplakia or transform into cancer; this clinical type of oral LP is difficult to differentiate from invasive squamous cancer. We describe a  clinical case of isolated erosive LP of the vermilion of the lower lip, long lasting and resistant to therapy. Due to persisting erosion on the lip, we performed an assessment by immunohistochemistry and histology to exclude squamous cell carcinoma. After the malignancy had been excluded and the diagnosis has been made, the patient was administered the treatment with aromatic retinoid acitretin, which was effective and led to complete epithelialization of the lesion. In patients with a long lasting, persistent LP of the vermilion, diagnostic biopsy should be performed to exclude malignization before administration of treatment.


Almanac of Clinical Medicine. 2017;45(8):681-685
pages 681-685 views

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