Vol 50, No 1 (2022)

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Molecular genetic testing in colon cancer: clinical aspects

Martianov A.S., Kuligina E.S., Romanko A.A., Imyanitov E.N.


Molecular genetic diagnostics is an essential element to plan for management of colorectal cancer (CRC) patients. The choice of systemic treatment for CRC is impossible without molecular testing of the tumor. For instance, the assessment of the KRAS and NRAS genes is mandatory for consideration of anti-EGFR agents. Tumors with BRAF V600E mutation are characterized by aggressive behavior, the necessity of intensive cytostatic regimens, as well as by sensitivity to combination therapy with BRAF and EGFR inhibitors. Inactivation of the DNA mismatch repair, the MUTYH gene or DNA polymerase epsilon (POLE) leads to an excessive tumor mutational burden; these CRC types are highly immunogenic and therefore respond to immune checkpoint inhibitors. Some colorectal carcinomas are characterized by overexpression of the HER2 oncogene, which make them sensitive to corresponding target therapies. There are CRCs with clinical signs of hereditary predisposition, which require germline genetic testing. Nowadays the molecular diagnosis of CRC is being seriously modified due to worldwide implementation of the next-generation sequencing (NGS) and hypersensitive variants of polymerase chain reaction, for example, droplet digital polymerase chain reaction (ddPCR). Non-invasive liquid biopsy is an example of another highly useful innovation that has growing importance for CRC screening, control of surgical intervention efficacy and monitoring of the disease course.

Almanac of Clinical Medicine. 2022;50(1):1-12
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Macrophage cytotoxic activity and its role in the tumor pathogenesis

Kovaleva O.V., Podlesnaya P.A., Gratchev A.N.


Macrophages, natural killers and T cells play the central role in tumor cells destruction. The purpose of this review is to summarize the state-of-the-art perspectives of the interplay between tumor cells and tumor stroma leading both to the formation of a macrophage population incapable of effective antitumor activity and to the selection of tumor cells resistant to macrophage cytotoxicity.

Macrophages are highly versatile cells that can both stimulate the inflammatory response (type 1 macrophages, M1) and suppress it (type 2 macrophages, M2). Tumor-associated macrophages (TAMs) are considered the main regulator of the antitumor immune response and usually have anti-inflammatory properties, that is, they belong to M2 type. Tumor cells are able to affect macrophages, "reprogramming" them to perform an immunosuppressive function. In addition, TAMs stimulate angiogenesis and remodelling of the extracellular matrix necessary for metastasis.

Recently, more and more studies have been published describing a mixed TAMs phenotype with characteristics of both M2 and M1. M1 is characterized by production of pro-inflammatory cytokines, reactive oxygen species, bactericidal and cytotoxic activity. M1 can destroy tumor cells both directly and indirectly by attracting other cells. Despite the mechanisms of direct cytotoxic activity are quite variable, their effectiveness is largely dependent on the properties of a particular tumor. The cytotoxic activity of macrophages is a powerful factor that inhibits tumor initiation and progression. However, in some cases, it is not sufficient to control the tumor process. Activation of the cytotoxic activity of TAMs is one of the strategies to use macrophages for cancer treatment.

Understanding the mechanisms of macrophage cytotoxic activity and specific patterns of its manifestation in a tumor environment is of critical importance for better effectiveness of existing cancer treatments and development of promising methods for tumor immunotherapy.

Almanac of Clinical Medicine. 2022;50(1):13-20
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Clinical features of the microRNA genes methylation in borderline ovarian tumors and depending on the histological structure in ovarian malignancies

Lukina S.S., Burdennyy A.M., Filippova E.A., Pronina I.V., Kazubskaya T.P., Kushlinsky D.N., Utkin D.O., Braga E.A., Loginov V.I., Kushlinskii N.E.


Background: Borderline ovarian tumors (BOT) belong to the intermediate type between benign and malignant ovarian neoplasms. Serous borderline tumors share common molecular and genetic characteristics with serous carcinomas. An increase in the methylation level of microRNA (miRNA) genes group has been previously shown during the development and progression of ovarian cancer. However, the study results are contradictory, and their number is not sufficient for a consensus. Current study is the first to search for aberrant methylated genes of the BOT-specific microRNA and for some histological subtypes of ovarian cancer.

Materials and methods: The study was based on a set of 99 paired (tumor/healthy) ovarian tumor samples. Methylation analysis was carried out with quantitative methyl-specific polymerase chain reaction (PCR). Screening for BOT biomarkers was performed in 21 genes of miRNA.

Results: We have found that some miRNA genes (MIR124-1, MIR125B-1, MIR129-2, MIR132, MIR148A, MIR193A, MIR203A, MIR107, MIR1258, MIR339) were characterized by a high methylation level in the patients with BOT, compared to that in the tissues of healthy women. At the same time, the methylation level in the patients with malignant ovarian tumors (MOT) either differed slightly or was even lower. For the MIR129-2, MIR132, MIR148A, MIR203, MIR107 and MIR1258 genes, a higher level of methylation was detected in the BOT patients, compared to the MOT patients. The methylation level of the MIR148A gene in the BOT patients was 4-fold higher than that in the MOT (31.3% vs 7.9%, p = 0.047, multiple two-sided Kruskal-Wallis test). The methylation levels of the miRNA genes MIR148A and MIR191 were significantly reduced in serous cystadenocarcinoma and increased in serous and endometrioid adenocarcinomas.

Conclusion: Methylation of the miRNA MIR148A and MIR191 genes is significantly associated with various histological variants of ovarian cancer. We have shown an increased methylation level of a number of miRNA genes in BOT, compared to MOT. In general, epigenetic factors play a role in the clinical differences between histological forms of ovarian cancer and borderline tumors.

Almanac of Clinical Medicine. 2022;50(1):21-30
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The prognostic value of actin-binding proteins fascin and ezrin in patients with squamous cell carcinoma of the head and neck

Kondakova I.V., Kakurina G.V., Kolegova E.S., Cheremisina O.V., Korshunov D.A., Bakhronov I.A., Choinzonov E.L.


Rationale: During neoplastic transformation, epithelial cells become mobile, which is one of the main mechanisms of metastatic disease and recurrence. Cell motility is regulated by actin-binding proteins, which ensure the association/dissociation of actin filaments and their interaction with the cell membrane. Previously, we have shown the presence of actin-binding proteins in the serum from patients with squamous cell carcinoma of the head and neck (HNSCC); however, their association with the development of metastases and relapses in cancer patients has not been sufficiently studied.

Aim: To evaluate the serum levels of actin-binding proteins fascin-1 and ezrin in patients with HNSCC depending on the disease recurrence and lymphatic metastasis.

Materials and methods: Serum fascin-1 and ezrin levels before combination therapy were measured with ELISA assay in 30 HNSCC (T1-4N0-2M0) patients (mean age 56 ± 7 years).

Results: The median fascin-1 level was significantly higher in the patients with lymphatic metastases, compared to those without metastases: 0.64 (0.40; 5.89) vs 6.35 (1.72; 8.35) ng/mL, respectively (p < 0.001). At 12 to 36 months after combination therapy, the disease relapsed in 12 (40%) patients. Ezrin levels were significantly higher in the relapsed patients, compared to those without a relapse within 3 years after combination therapy: 2.55 (2.35; 2.75) vs 1.93 (1.87; 2.5) ng/mL (p = 0.02). The ROC analysis showed an association between fascin-1 serum levels with metastatic disease (AUC = 0.71, 95% confidence interval 0.57–0.85) and an association between ezrin levels and the disease relapse (AUC = 0.76, 95% confidence interval 0.57–0.94).

Conclusion: These indicators can be used for the development of minimally invasive early detection of metastases in lymphatic nodes and for the prognosis of HNSCC recurrence.

Almanac of Clinical Medicine. 2022;50(1):31-37
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Specific characteristics of metabolomics as assessed by gas chromatography-mass spectrometry in patients with adrenocortical cancer and with adrenal incidentalomas in congenital adrenal hyperplasia

Shafigullina Z.R., Velikanova L.I., Vorokhobina N.V., Malevanaya E.V., Strelnikova E.G., Bokhian V.Y., Britvin T.A., Stilidi I.S.


Background: Prolonged episodes of uncontrolled congenital adrenal hyperplasia (CAH) have been shown to result in the occurrence of secondary adrenal neoplasms. Prevalence of adrenal incidentalomas in the patients with 21-hydroxylase deficiency ranges from 11% to 82%. As assessed by gas chromatography-mass spectrometry (GC-MS), patients with adrenocortical cancer (ACC) have increased level of steroid hormone precursors due to decreased activity of adrenal steroidogenesis enzymes, mainly that of 21-hydroxylase and 11β-hydroxylase. It seems relevant to compare the specific characteristics of steroid metabolism by GC-MS in ACC patients and in patients with adrenal incidentalomas and CAH associated with 21-hydroxylase deficiency (21-OHD).

Aim: To identify (by GC-MS) common abnormalities in steroid metabolism and differential diagnostic biomarkers in ACC patients and CAH patients with 21-OHD and adrenal masses.

Materials and methods: The study included 41 patients with adrenal cortex neoplasms aged 18 to 65 years without clinical and laboratory signs of endogenous hypercortisolism. Twenty three (23) patients had non-metastatic ACC and 18 patients had CAH due to 21-OHD. The control group included 26 healthy blood donors aged 20 to 59 years. Urine steroid profiles were measured by GC-MS with a gas chromatograph-mass spectrometer (Shimadzu GCMS-QP2020).

Results: In the ACC patients, there was an increase in urinary excretion of tetrahydro-11-deoxycortisol, dehydroepiandrosterone, androstenediol-17β, etiocholanolone, pregnenediol, and 3β,16,20-pregnenetriol (3β,16,20-dP3), as well as a decrease in the 3α,16,20-dP3/3β,16,20-dP3 ratio, compared to the values in the patients with CAH due to 21-OHD. Compared to the healthy control, 21-hydroxylase, 11β-hydroxylase, 5α-reductase and 11β-hydroxysteroid-dehydrogenase (11β-HSDH) type 2 activities were lower. Compared to the ACC patients, those with CAH due to 21-OHD had higher urinary excretion of 11-oxo-pregnanetriol (11-oxo-P3) and 21-deoxy-tetrahydrocortisol and lower 5β-THF+5α-THF+THE)/11-oxo-P3 ratio of < 9.0, determination of 11-oxo-dP3, signs higher 5α-reductase activity and lower 11β-HSDH type 1 activity. The ACC patients and the patients with CAH due to 21-OHD had common abnormalities of steroid metabolism, such as lower activities of 21-hydroxylase, 3β-hydroxysteroid-dehydrogenase and 11β-hydroxylase, and no differences in urinary excretion of a number of ACC biomarkers (androgens, pregnanediol, and 5-ene-pregnenes).

Conclusion: The assessment of urinary excretion of androgens, progestagens, and glucocorticoids by GC-MS made it possible to identify common abnormalities in steroid metabolism in the patients with ACC and CAH due to 21-OHD, which confirms the role of disordered steroidogenesis in the formation of adrenocortical tumors.

Almanac of Clinical Medicine. 2022;50(1):38-46
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Comparison of the treatment results in patients with inoperable non-small cell lung cancer in clinical trials and in standard clinical practice using the pseudorandomization method

Moiseenko F.V., Fedyanin M.Y., Volkov N.M., Abduloeva N.K., Levchenko N.V., Chubenko V.A., Zhabina A.S., Stepanova M.L., Kramchaninov M.M., Artemeva E.V., Moiseyenko V.M.


Rationale: Non-small cell lung cancer (NSCLC) is an aggressive disease with median survival of 12–14 months in inoperable patients in the pre-immunotherapy era. Nowadays, under treatment with checkpoint inhibitors median survival is 19–22 months. However, only a proportion of patients are sensitive to immune therapy. In this regard, inclusion into clinical trials remains a priority option for patients from medical perspective.

Aim: To compare the results in NSCLC patients treated in accordance with the current clinical guidelines and in international clinical trials using the propensity score matching.

Materials and methods: The study included data from 344 patients with histologically verified unresectable advanced NSCLC without activating mutations, who received the 1st line systemic medical therapy at various combinations (single agent chemotherapy, platinum doublet-based therapy, chemoimmunotherapy, single agent immunotherapy) within the compulsory health insurance (CHI), and from 90 patients, who received therapy in clinical trials. A direct comparison of long-term treatment results was carried out with the log-rank method. To exclude any influence of individual factors on survival rates, an univariate regression analysis and pseudorandomization accounting for these factors were carried out.

Results: The direct comparison of the treatment results showed a higher progression-free survival rate in the patients treated according to clinical trial protocols, than in those treated under CHI (13.3 [95% confidence interval (CI) 8.1–18.5] months vs 6.4 [95% CI 5.9–6.9] months). Pseudorandomization of patients based on a combination of statistically significant parameters from the CHI and clinical trial groups showed a significantly longer time to progression in the trial group (13.3 [95% CI 8.3–18.3] vs 6.3 [95% CI 4.8–7.7] months).

Conclusion: Participation in clinical trials is per se a factor that can significantly impact the longer duration of the treatment effect. This indicates the necessity of the most active use of this tool in clinical practice.

Almanac of Clinical Medicine. 2022;50(1):47-55
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Survival analysis of patients with non-small cell lung cancer in Novosibirsk region from 2015 to 2019

Chernova G.E., Kozlov V.V., Gulyaeva L.F.


Rationale: Lung cancer is the leader in high mortality rates among other malignancies. This is largely due to the asymptomatic course of the disease and, as a consequence, to its late diagnosis. To optimize the oncology service of the Novosibirsk region in terms of diagnosis, treatment, follow-up and management of this patient category, it seems prudent to study the epidemiological characteristics of non-small cell lung cancer (NSCLC) with consideration of its histologic types.

Aim: To perform the survival analysis in patients with squamous cell lung cancer (SCLC) and adenocarcinoma of the lung (ACL) depending on their age, sex and disease stage.

Materials and methods: We analyzed medical files of patients diagnosed with SCLC (n = 3007) and ACL (n = 3049) who were treated in the Novosibirsk Regional Oncologic Dispensary from 2015 to 2019. The study included 4758 men and 1298 women (mean age, 68 years; men 66.8 years, women 69.1 years).

Results: The majority (96%) of the NSCLC patients were above 50 years of age. The 5-year survival rate of the patients with SCLC and ACL was below 20%. Median survival of the SCLC patients was 443 days (interquartile range [IQR] 138; 1241), of those with ACL, 552 (IQR 107; 1511) days. At the diagnosis of NSCLC, 67% of the patients had stage III/IV of the disease. Maximal survival (10 to 15 years) was found in the NSCLC patients aged ≥ 61 years who had been diagnosed at stage I–II of the disease. Testing of the hypothesis on the impact of histological type of NSCLC on survival at a particular disease stage (Wilcoxon-Gehan test for unpaired samples) showed an association between the survival and histological type only for stage IV (p = 0.000001); median survival in ACL IV was 80 days and in SCLC IV, 104 days.

Men comprised 87% of the SCLC group and 73% of the ACL one. In SCLC, there was no gender difference in the median survival rates (log rank test, p = 0.48). The median survival of the female patients with ACL was longer than that of the male ones (329 vs 169 days, log rank test, p = 0.000001).

The major proportion of the SCLC and ACL patients was in the age range of 61 to 75 years (59% and 50%, respectively). The least favorable outcomes were seen in the patients below 50 years of age, and the most favorable, in those above 75 years. In SCLC, the median survival was 156 days in the patients below 50 years of age, 238.5 days in those aged from 51 to 60 years, 300 days in the age of 61 to 75 years, and 487 days in the patients above 75 years of age (chi-square test 98.77097; df = 3; p = 0.000001). In ACL, the respective values were 143, 201, 210.5, and 230 days (chi-square test 23.93492; df = 3; p = 0.00003).

Conclusion: The analysis of survival of the patients with SCLC and ACL in the Novosibirsk region has shown that the disease stage and age significantly impact the median survival. These are the characteristic features of the general morbidity and mortality from NSCLC.

Almanac of Clinical Medicine. 2022;50(1):56-64
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Prevalence of iron deficiency anemia in patients with metastatic colorectal cancer

Zhabina A.S., Moiseenko F.V., Volkov N.M., Abduloeva N.K., Egorenkov V.V., Levchenko N.V., Artemeva E.V., Stepanova E.O., Nesterova E.O., Moiseyenko V.M.


Background: Iron has dual properties: it may promote both tumor growth and cell apoptosis. Compared to healthy cells, cancer cells are more dependent on the iron levels. Ferroptosis can be triggered directly in cancer cells, which would result in their self-destruction. Identification of iron balance abnormalities and their correction could impact the effects of specific treatments in cancer patients.

Aim: To assess the prevalence of iron deficiency in patients with metastatic colorectal cancer (mCRC) and to identify an association of low serum iron levels with clinical and morphological characteristics of the disease.

Materials and methods: The study included 69 treatment-naïve patients with mCRC. Iron deficiency was defined as low serum iron levels before the initiation of any specific therapy: serum iron concentration < 10.7 mcmol/L in men and < 9.0 mcmol/L in women.

Results: The mean age of the mCRC patients was 61.1 years (range, 28 to 83 years), 35/69 (50.7%) were men. The bigger proportion of the tumors was left-sided (62.3%). In 48.3% of the patients, the disease was diagnosed at the metastatic stage. The most frequent locations of metastasis were liver (41.3%) and lungs (32.1%). 55.1% (38/69) of the patients had undergone a non-radical resection or primary curative surgery. KRAS mutations were found in 37.7% of the patients. Low serum iron levels were found in 53.6% (37/69) of the total sample of the mCRC patients and in 72.4% (19/38) of the patients with a non-resected primary tumor (p = 0.05).

Conclusion: Irrespective on the clinical and morphological characteristics, the majority of patients with metastatic colorectal cancer have iron deficiency anemia before the initiation of specific anti-tumor therapy.

Almanac of Clinical Medicine. 2022;50(1):65-70
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A clinical case of a big urethral recurrence after cystectomy in a patient with invasive bladder cancer

Balkanov A.S., Vinogradov A.V., Bazaev V.V., Stepanova E.A., Garmash S.V.


The urethral recurrence (UR) of invasive bladder cancer (iBC) after cystectomy is observed in 6% of patients at highest. In this clinical observation of a 38-year old man, a mass (103 × 38 mm) was found in the proximal urethra by magnetic resonance imaging at 15 months after radical (R0) cystectomy for iBC pT4aN0M0. The clinical picture of UR was characterized by urethrorrhagia and priapism with associated advanced pain syndrome. At 3 months after surgical resection of the UR and subsequent chemotherapy, distant lung, liver and bone metastases were found, which led to the patient's death at 5 months after penectomy. This clinical case indicates that after radical cystectomy, the occurrence of a big-sized urethral recurrence of iBC can cause rapid development of distant metastatic disease.

Almanac of Clinical Medicine. 2022;50(1):71-75
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Almanac of Clinical Medicine. 2022;50(1):76-76
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