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виражена вогнищева iнфiльтрацiя лiмфоцитами, мононуклеарами, вогнища розростання грануляцшно! тканини та щ№но! сполучно! тканини у виглядi окремих прошаркав.
Висновки. Знаходження конкременту в просвт сечоводу в термш до 7 днiв не викликае значних мiкроскопiчних змiн, ввдбуваеться потовщення шару епiтелiоцитiв, огранiзацiя вах шарiв сечоводу збережена, ознаки склерозування або некрозу вiдсутнi. Данi змши не мають значного ефекту на умови проведения операцп.
При розмщент конкременту в сечоводi в строк 1 мюяць визначаеться бiльш значш морфологiчнi змiни iз ознаками десквамацп поверхневих шарiв уротел1я, набряку та запальних змiн в пiдслизовий оболонцг Такi змiни вже можуть слугувати фактором, що ускладнюе проведення малошвазивних втручань при лiкуваннi уретеролiтiазу та призводить по зниження !х ефективностг
Якщо тривалiсть знаходження конкременту в сечоводi бiльша за 3 мюящ, нами вiдмiчено злущення уротелiя з оголенням базально! мембрани. У шдслизовш основi спостерiгаеться виражений набряк, дифузна дезоргашзащя сполучнотканинних волокон, вогнища розростання грануляцшно! тканини та щ№но! сполучно! тканини у виглядi окремих прошаршв. Так1 змiни мають прямий вплив на ступiнь вiзуалiзацi! конкременту при ендоскотчних втручаннях, швидк1сть фрагментацп та екстракцй' фрагментiв, як наслщок, збiльшення загально! тривалостi операцй' та ризишв iнтра- та пiсляоперацiйних ускладнень.
Лггература.
1. Türk C, Knoll T, Petrik A, et al. EAU guidelines on interventional treatment for urolithiasis. Eur. Urol. 2015;69(3):475-82.
https://doi.org/10.1016/j. eururo.2015.07.041.
2. Assimos D, Krambeck A, Miller NL et al. Surgical management of stones: American Urological Association/Endourological Society Guideline. J. Urol. 2016;196(4):1153-1160. https://doi.org10.1016/j.juro.2016.05.090.
3. McClinton S, Cameron S, Starr K, et al. TISU: Extracorporeal shockwave lithotripsy, as first treatment option, compared with direct progression to ureteroscopic treatment, for ureteric stones: study protocol for a randomised controlled trial. Trials. 2018;19:286. https://doi.org/10.1186/s13063-018-2652-1.
4. Shinde S, Al Balushi Y, Hossny M, et al. Factors Affecting the Outcome of Extracorporeal Shockwave Lithotripsy in Urinary Stone Treatment. Oman. Med. J. 2018; 33(3): 209-17. https://doi.org/10.5001/omj.2018.39.
5. Sanca K, Kafkasli A, Yazici Ö, et al. Ureteral wall thickness at the impacted ureteral stone site: a critical predictor for success rates after SWL. Urolithiasis. 2014;43(1):83-8. https://doi.org/10.1007/s00240-014-0724-6.
6. Minei S, Yamazaki T, Kaya H, et al. Characterization of ureteral lesions associated with impacted stones. Int. J. Urol. 1999;6(6):281-5. https://doi.org/ 10.1046/j.1442-2042.1999.00067.x.
7. Hamamoto S, Okada S, Inoue T, et al. Prospective evaluation and classification of endoscopic findings for ureteral calculi. Sci. Rep. 2020;10:12292. https://doi.org/10.1038/s41598-020-69158-w.
8. Лесовой В.Н., Яковцова И.И., Данилюк С.В., и др. Морфофункциональное состояние стенки мочеточника при экспериментальном моделировании уретеролитиаза // Урология. 2017. Т. 21. №1(80). С.22-27. [Lesovoy VN, Yakovtova II, Danilyuk SV, et al. Morphofunctional state of the ureter wall in the experimental modeling of uretherolithiasis. Urologiya. 2017; 21,1(80):22-7. (In Russ).].
Karasev I.A. Malikhova O.A.
Vereshak V. V. Stroganova A.M.
Affiliation: N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia, Kashirskoye shosse 24, 115478-Moscow, Russia
REVIEW IN ENDOSCOPIC DIAGNOSTICS AND MOLECULAR FEATURES OF SERRATED COLORECTAL NEOPLASIA.
Colorectal cancer (CRC) is one of the leading causes of death from cancer in many countries of the world, both in men and women, and these rates are on the rise. About 1.8 million new colorectal cancer cases were diagnosed in 2018, and they also account for 8% of all cancer deaths. The 5-year survival rates for patients with stage I and II cancer are 95% and 82%. Despite the continuous development of diagnostic and therapeutic methods (for example, colonoscopy, flexible sigmoidoscopy, and tests based on chromatographic analysis), colorectal cancer is often detected at a stage of significant spread. In order to reduce morbidity and mortality, timely detection and treatment of precancerous conditions of the colon is necessary.
Screening plays an important role in the detection of colorectal cancer, and its early diagnosis has a significant impact on survival rates. Moreover, obligate precancerous lesions can be diagnosed and removed.
Colorectal cancer in most cases develops as a result of the degeneration of adenomatous formations or along the jagged path Considering that the average time of development of adenocarcinoma from precancer takes about 10 years, changes in the intestinal microflora may be a promising marker for screening precancerous conditions of the colon. The commensal gut microbiota plays an important role in various systemic functions, which include
modulation of the immune system, neurohormonal activity, intestinal barrier, and epithelial integrity. Immune dysregulation, dysbiosis, and epithelial destruction contribute to colorectal cancer carcinogenesis. Detecting changes in DNA can also be used to screen for colorectal cancer. Fragments of circulating methylated DNA are found in the blood of patients with colorectal cancer. But now, research shows low sensitivity.
Numerous molecular genetic studies of colorectal cancer have revealed a number of genetic disorders, most of which are inherited in an autosomal dominant manner and significantly increase the risk of neoplasia.
Keywords: colorectal cancer, microbiota, molecular genetic research, serrated neoplasia, biomarkers, endoscopy, screening
The increase in the incidence of colorectal cancer in recent years has been observed in all economically developed countries of North America and Western Europe. In the Russian Federation, over the past 10 years, there has been a more than 30% increase in patients with tumors of this localization [1].
According to the World Health Organization, there are more than 800,000 new cases of colorectal cancer with a high mortality rate in the first year of life after diagnosis. According to forecasts, in 10 years this figure will be more than 1 million per year [2].
The exact understanding of the pathogenesis of toothed tumors is not reliably determined, it is obvious that the development of neoplasms is influenced by molecular genetic factors, microbial composition, chronic inflammation,chemical and biological carcinogens[3].
The frequency of serrated neoplasias in the population varies from 0.7 to 2 %, but it is not possible to establish the true figures due to significant difficulties in endoscopic, morphological and molecular genetic diagnostics. [4]
Serrated formations are found throughout the colon, more than 38% - in the right parts. Tumors located in the ascending colon have their own morphological features compared to other localizations, have more expanded crypts and pronounced denticulation in their basal segment.[5]
The colon mucosa is regularly colonized by a huge number of microbial associations (17 families, 45 genera, more than 1000 species). Most of them are obligate anaerobes (bifidobacteria, bacteroids, etc.) - up to 90%; another 8-9% are facultative aerobes (lactobacilli, Escherichia coli, enterococci)[8]. Part of the facultative and transient microflora (Clostridia, Klebsiella, proteus, staphylococci, etc.) accounts for no more than 1-2% of the microbiome[9].
Normobiocenosis of the colon performs a number of important functions for the macroorganism: colonization resistance, immunological protection, participates in metabolic processes, synthesizes vitamins and mediators. When the eubiosis of the colon is suppressed, conditionally pathogenic and pathogenic microorganisms begin to multiply, and then dominate, thus forming colonic dysbiosis of varying degrees, which plays a leading role in the theory of bacterial carcinogenesis [10].
The bulk of the microbiota of the large intestine is located parietally, forming microcolonies protected from external influences by exo-polysaccharide-mucin biofilm, which is involved in the protection of the colon mucosa. The smallest part of the microorganisms remains in the lumen of the colon. The relationship of
the macroorganism with the microbiota of the colon is based on the principles of mutualism. [11].
In recent years, evidence has been obtained for the significance of intestinal microbiome disorders in carcinogenesis. According to the results of the Backhed F study. et al. (2013), the microbiota of patients with colorectal epithelial tumors contains significantly fewer varieties of bacteria than in healthy individuals. The comparative population of the intestinal tract of Clostridium in healthy volunteers was 77.8%, and in patients with colorectal cancer - 68.6% [12]. At the same time, patients with dentate formations had significantly increased levels of Fusobacteria, Actinobacteria, and Bacteroides. In addition, when comparing the number of Firmicutes bacteria, the authors found a significant reduction in the content of Clostridium and Coprococcus in the group of people with colorectal cancer compared to the control group. This type of bacteria is directly responsible for the enzymatic conversion of carbohydrates and dietary fiber into butyrate, which has anti-inflammatory activity and inhibits carcinogenesis. The results of the study suggest that the imbalance of the microbial community is considered a risk factor for colorectal carcinogenesis [13]. However, at the moment there are no large randomized studies and convincing data supporting the theory of bacterial carcinogenesis.
The main mechanisms of neoplastic transformation of host cells are considered to be the synthesis of pathological metabolites by intestinal bacteria and the production of genotoxins (toxic reactive oxygen species and reactive nitrogen), as a result of which the mechanisms of repair and apoptosis processes are disrupted [14].
Chronic inflammation is considered a significant condition for the development of dentate formations, a number of studies have revealed that the 5-year cumulative risk of inflammatory bowel disease is 33 %-54 % [15]. Inflammatory mediators (for example, tumor necrosis factor, cytokines - IL6, IL1b) activate the transcription nuclear factor (NF-kB), which promotes the carcinogenesis of tooth formations [13].
The carcinogenesis of serrated neoplaplasmas of the colon is a complex process, the leading pathogenetic features of which are the activation of the MAPK kinase pathway (in the vast majority of cases, due to somatic BRAF mutations) and epigenetic dysregulation due to hypermethylation of the promoter regions of a number of genes and the formation of so-called CIMP-phenotype[6].These events are determined already at the early stages of the neoplastic process and are actively involved in the evolution of hyperplastic polyps (microvesicular, goblet-shaped),
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toothed polyps on a wide base to toothed adenomas (traditional, broad-based, unclassified). The culmination of this pathway is an irreversible transformation into a malignant epithelial tumor - a colon adenocarcinoma[7].
Serrated polyps
The somatic profile of microvesicular polyps (MP) is characterized by similar genetic abnormalities with sessile serrated polyps (SSP), however, whether MPs are precursors of SSP or the latter should be considered as epithelial formations de novo is still a subject of discussion, as well as the question of driver mechanisms that start the process of transformation of MP into SSP. In this connection, there are no pathognomonic molecular markers that allow differentiating these lesions from each other, and histological examination is the "gold standard" in diagnosing this pathology. In the overwhelming majority of cases, the most frequent molecular event in MP and SSP are somatic BRAF mutations, the frequency of which, according to some authors, reaches 70-80% in MP and up to 90% in PSO [16, 17]. The CIMP phenotype associated with BRAF mutations, however, is significantly more often diagnosed in SSP (up to 50% of cases) and significantly less often in MP (10%) [18, 19].
The molecular characteristics of goblet polyps (PD) are poorly understood, in which somatic mutations in the KRAS gene are one of the prevailing genetic disorders (up to 50% of cases). In later studies, it was shown that the presence of a goblet cell component in dentate polyps without signs of dysplasia is a predictor of the presence of KRAS mutations [20].
Serrated adenomas
Despite the fact that some researchers attribute typical serrated adenomas (TSA) to the group of formations without signs of dysplasia, most authors consider TSA as adenomas with a low degree of dysplastic changes and minimal proliferative activity, however, a significantly larger number of genetic events compared with MP and SSP [21]. In half of the cases, BRAF mutations are diagnosed in TSA and in a third - KRAS mutations [22, 23, 24]. The CIMP phenotype is naturally more common in BRAF-associated adenomas [25].
If BRAF-positive TSA evolve from MP and SSA, then the nature of KRAS-positive TSA is not so obvious with an equal probability of developing both de novo and from previous KRAS-positive polyps [26, 27].
In addition to activating the MAPK kinase pathway, a recent study by Sekine et al. It was shown that TSA with a mutant KRAS type are characterized by a high frequency of RSPO translocations, and BRAF-positive TSA with somatic mutations are characterized by pathogenic variants in the RNF43 gene. In this case, both RSPO transcripts and RNF43 mutations in the overwhelming majority of cases are detected at the stage of the transition from MP and SSP to SSA, i.e. are potential molecular markers of dysplastic changes in polyps [28]. In contrast to broad-based serrated adenomas, hypermethylation of the
East European Scientific Journal #2(66), 2021 29 promoter region of the MLH1 gene in TSA is casuistically rare [29].
Dysplastic SSP or sessile serrated adenomas (SSA) are the most well-studied group of dysplastic colon masses at the molecular level. The leading epigenetic event in SSA is methylation of the promoter region of the MLH1 gene, which is determined in 1573% of cases [30, 31]. The lowest value of this indicator in terms of studies is due to the attribution of serrated polyps with intestinal metaplasia or flat "early" TSA to SSA. In turn, the largest number of hypermethylated adenomas (as a result, and with an unstable system of mismatched DNA base repair (MMR)) was noted for true SSA [32]. Assessment of the MLH1 status is an important step in diagnosing the degree of dysplastic changes in adenomas. Loss of expression of this marker at the molecular level confirms clinically significant dentate dysplasia [Crockett]. Another risk factor identified as an indirect marker of a high risk of hypermethylation of the promoter region of the MLH1 gene is the presence of the -93G / A (rs1800734) polymorphism at the 5 'end of the gene, associated with increased expression of the DCLK3 gene, which in turn activates the neoplastic process [105De palma]. In general, SSA is naturally associated with a direct correlation between the BRAF mutant status, CIMP phenotype, and microsatellite instability. An increase in the severity of dysplastic changes in both TSA and SSA correlates with the sequential inactivation of p16 and TP53 in most cases [33, 34, 35].
Changes in the WNT pathway, the leading pathogenetic link in the pathogenesis of epithelial neoplasms of the colon, are diagnosed in dentate formations, as a rule, at the stage of pronounced dysplastic changes. At the same time, somatic mutations in the APC gene are determined in dentate polyps and adenomas much less frequently in comparison with tubulovillous formations with chromosomal instability (CI) at the basis of molecular abnormalities (36% in TSA vs> 90% in adenomas with CI) [36, 37 (crockett)]. An alternative way of activating the WNT pathway in SSA is hypermethylation of regulatory regions of genes that antagonize the WNT pathway, such as SFRP, AXIN2, and MCC, or mutations in the RNF43-ZRNF3 complex, which are diagnosed in 86% of tumors with hypermethylation of MLH1 [38, 39, 35 (Croc)].
Serrated polyposis
A rare disease associated with multiple lesions of the colon is serrated polyposis (SP), the overlying parts of the gastrointestinal tract are not involved in the pathological process, as well as there are no specific extraintestinal manifestations [40].
Some of the cases of SP are familial. Approximately one third of patients with SP note the presence of at least one relative of the first degree of relationship with colon cancer, and only 5% with RR [41, 42]. To date, only the RNF43 gene has been identified as a potential candidate gene for the development of a hereditary variant of SP, however,
30 East European Scientific Journal #2(66), 2021 and germline mutations in this gene are responsible for the development of only 2% of cases of SP [43-47].
The differential diagnosis of SP is carried out with such hereditary syndromes as MUTYH-associated polyposis, mixed polyposis, Cowden's syndrome and other PTEN-associated conditions. Phenotypic overlap with these pathologies is expressed in an oligopolypous lesion of the colon with the growth of dentate formations. Determination of the syndromological affiliation in such cases can be achieved by clinical and anamnestic data or by molecular verification of the diagnosis. The latter, however, in some cases remains uninformative, and the etiology of SP, with the exclusion of frequent hereditary pathology, but a burdened family history, remains unspecified and refers to the "family variant" of polyposis.
The current criteria for the diagnosis of SP include:
1. Presence of at least 5 serrated polyps / adenomas proximal to the rectum, all larger than 5 mm and at least two larger than 10 mm or
2. The presence of more than 20 serrated polyps / adenomas of any size throughout the colon, at least 5 of which are determined proximal to the rectum;
Wherein:
1. Any histological variant of serrated polyps / adenomas is taken into account;
2. Cumulative count of serrated polyps / adenomas throughout life.
According to European studies, among patients with ZP, only 25% of patients meet the first criterion, 45% - the second and 30% meet both criteria, respectively [52, 53].
Patients with SP are at increased risk of developing colon cancer, and in most cases the disease is diagnosed simultaneously with SP. Risk factors associated with the maximum risk of malignant transformation include: compliance with both clinical criteria, the presence of more than two SSP proximal to the splenic flexure, or at least one serrated polyp with dysplasia, or one tubulo-tuberous adenoma with severe dysplasia. Retrospective data indicate 30% of CRC cases among the cohort of patients with SP [54]. The "classical" CRC associated with SP, in terms of its molecular characteristics, corresponds to the genetic portrait of SSA, accumulating BRAF mutations and CIMP phenotype in half of the cases [55]. KRAS-positive forms account for less than 5% [56].
Colonoscopy is the "gold standard" and, at the same time, an essential component of the comprehensive diagnosis of precancerous conditions and early forms of colon cancer.
Creation and introduction into clinical practice of the latest high-resolution video endoscopic studies with the use of additional imaging methods, such as NBI, I-scan, optical and electronic magnification (ZOOM, double focus), etc. significantly improves the capabilities of CRC diagnosis, especially on early stages. These functions make it possible to expand the capabilities of video colonoscopy, helping to solve more and more complex diagnostic tasks, achieving results comparable to the morphological examination
of biopsy material obtained from the detected pathological foci.
Clarification during colonoscopy with a white light examination (as well as with an examination under the conditions of the use of clarifying technologies) of the concepts of endoscopic semiotics of squamous epithelial neoplasms of the colon, allows at the preoperative stage to visually recognize them among themselves and to distinguish from them: a) hyperplastic ( not carrying a malignant potential) and subject to dynamic observation, b) serrated and adenomatous, subject to removal by one or another (endoscopic / surgical) method. [57]
The technique of narrow-spectrum endoscopy (NBI, i-Scan) is based on the predominant absorption of light of a certain wavelength by hemoglobin. The use of this technique in combination with optical magnification makes it possible to evaluate the microvascular pattern of the neoplasm surface using the classification of Y. Sano et al.
The I-Scan Pentax technology is based on postprocessing of reflected light.
It consists of three image processing algorithms: surface enhancement (SE), tone enhancement (TE), and contrast enhancement (CE).
I-scan SE highlights the structure of the tissue surface, which can be used to locate lesion boundaries or show lesion spread (eg, inflammation, tissue atrophy). I-scan TE aims to enhance the imaging of vascular and tissue architecture.
I-scan SE technology allows you to better see the structure of the mucous tissue, to determine the boundaries of the affected areas. This feature is especially useful for detecting flat lesions, as it helps to better see the edges of the lesion and determine its boundaries.
These additional details help to correctly classify mucosal lesions. Neoplastic changes in the vasculature and tissue surface structure can be differentiated from non-neoplastic structures. Figure 1-3
At the moment, three types of serrated formations are described in the world literature: "sessile serrated adenoma (SSA), classical serrated adenoma) and mixed polyp (MP)." [58]
These three types of serrated neoplasia have subtle architectural differences, but equally pronounced carcinogenic potential [59].
"Sessile" serrated adenoma was described in 2003 by E. Torlakovic et al. [60]. Morphologically, SSA occupies a position between the classic serrated adenoma and the usual hyperplastic polyp. SSA resembles a sessile polyp in appearance, but has a branching extension at the base and tends to grow laterally in the submucosal layer of the colon. SSA has been recognized as a precursor of dysplasia in the development of adenocarcinoma [61] and is considered the most aggressive and most common type of all colon serrated. Since not enough time has passed since the discovery of this type of neoplasia for detailed research, the natural course of the development of this disease and the risk of cancer progression have not been reliably determined. Endoscopically "sessile" serrated
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adenoma, as a rule, "pale" formation, "resting" on the folds of the mucous membrane. SSA is more common in the proximal colon in middle-aged women and is larger than other denticles. Classic (traditional) serrated adenoma - can carry both low and high potential for the development of epithelial dysplasia. TSA is rare and accounts for less than 1% of all polyps [62]. It is characterized by dysplasia of the epithelium, a grooved type of surface and such cytological signs as elongation of nuclei, eosinophilic cytoplasm of epithelial cells. TSA has a pedicle, is located mainly in the left colon, which is easily detected during colonoscopy. In appearance, TSA may resemble an adenomatous polyp.
East European Scientific Journal #2(66), 2021 31 Conclusion
Serrated colorectal neoplasias are a heterogeneous group of epithelial tumors. Risk factors for malignant transformation include a number of genetic mutations, dysbiotic conditions, and chronic colitis. Until now, an optimal and rational algorithm for the diagnosis, treatment and monitoring of this group of patients has not been developed, which indicates that it is necessary to carry out multicentric and interdisciplinary studies based on 16S RNA sequencing of the intestinal microbiota, molecular genetic analysis and highresolution complex endoscopy.
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Fig. 1. Serrated adenoma with a typical mucosal "cap", the vascular pattern is erased
A
Fig. 2 A, B Serrated adenoma. A. White light inspection. B. Inspection in the narrow light image (NBI) mode.
Fig. 3 A, B Serrated adenoma on a wide base 0-1s according to the Paris classification. A. White light inspection. B. Inspection in the narrow light spectrum (NBI) mode. Expanded isolated branched vessels of the "starfish " type are defined.
1. Snover DC, Ahnen DJ, Burt RW. Serrated polyps of the colon and rectum and serrated polyposis. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, eds, et al., editors. WHO classification of tumours of the digestive system. Lyon: IARC Press;; 2010. pp. 160-165. [Google Scholar]
2. J0rgensen H, Mogensen AM, Svendsen LB. Hyperplastic polyposis of the large bowel. Three cases and a review of the literature. Scand J Gastroenterol. 1996;31:825-830. [PubMed] [Google Scholar]
3.Patil DT, Shadrach BL, Rybicki LA, Leach BH, Pai RK. Proximal colon cancers and the serrated pathway: a systematic analysis of precursor histology and BRAF mutation status. Mod Pathol. 2012;25:1423-1431. [PubMed] [Google Scholar]
4.Murakami T, Mitomi H, Saito T, Takahashi M, Sakamoto N, Fukui N, Yao T, Watanabe S. Distinct WNT/p-catenin signaling activation in the serrated neoplasia pathway and the adenoma-carcinoma sequence of the colorectum. Mod Pathol. 2015;28:146-158. [PubMed] [Google Scholar]
5.Miyoshi Y, Nagase H, Ando H, Horii A, Ichii S, Nakatsuru S, Aoki T, Miki Y, Mori T, Nakamura Y. Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum Mol Genet. 1992;1:229-233. [PubMed] [Google Scholar]
6.Kim YH, Kakar S, Cun L, Deng G, Kim YS. Distinct CpG island methylation profiles and BRAF mutation status in serrated and adenomatous colorectal polyps. Int J Cancer. 2008;123:2587-2593. [PubMed] [Google Scholar]
7. Bettington M, Walker N, Rosty C, Brown I, Clouston A, McKeone D, Pearson SA, Leggett B, Whitehall V. Clinicopathological and molecular features of sessile serrated adenomas with dysplasia or carcinoma. Gut. 2017 Jan;66(1):97-106. doi: 10.113 6/gutjnl-2015-310456.
8. Todd B Sheridan 1, Hubert Fenton, Marc R Lewin, Ashlie L Burkart, Christine A Iacobuzio-Donahue, Wendy L Frankel, Elizabeth Montgomery. Sessile serrated adenomas with low- and high-grade dysplasia and early carcinomas: an immunohistochemical study of serrated lesions "caught
in the act". Am J Clin Pathol. 2006 Oct;126(4):564-71. doi: 10.1309/C7JE8BVL8420V5VT.
9. Borowsky J, Dumenil T, Bettington M, Pearson SA, Bond C, Fennell L, Liu C, McKeone D, Rosty C, Brown I, Walker N, Leggett B, Whitehall V.The role of APC in WNT pathway activation in serrated neoplasia. Mod Pathol. 2018 Mar;31(3):495-504. doi: 10.103 8/modpathol.2017.150.
10. Bettington ML, Walker NI, Rosty C, Brown IS, Clouston AD, McKeone DM, Pearson SA, Klein K, Leggett BA, Whitehall VL. A clinicopathological and molecular analysis of 200 traditional serrated adenomas. Mod Pathol. 2015 Mar;28(3):414-27. doi: 10.103 8/modpathol.2014.122.
11. Wiland HO 4th, Shadrach B, Allende D, Carver P, Goldblum JR, Liu X, Patil DT, Rybicki LA, Pai RK. Morphologic and molecular characterization of traditional serrated adenomas of the distal colon and rectum. Am J Surg Pathol. 2014 Sep;38(9):1290-7. doi: 10.1097/PAS.0000000000000253.
12. Tsai JH, Liau JY, Lin YL, Lin LI, Cheng YC, Cheng ML, Jeng YM. Traditional serrated adenoma has two pathways of neoplastic progression that are distinct from the sessile serrated pathway of colorectal carcinogenesis. Mod Pathol. 2014 Oct;27(10):1375-85. doi: 10.1038/modpathol.2014.35.
13. Bettington M, Rosty C, Whitehall V, Leggett B, McKeone D, Pearson SA, Walker N. A morphological and molecular study of proposed early forms of traditional serrated adenoma. Histopathology. 2018 Dec;73(6):1023-1029. doi: 10.1111/his.13714.
14. Winnie C Fernando 1, Mariska S Miranda 2, Daniel L Worthley 3, Kazutomo Togashi 4, Dianne J Watters 5, Barbara A Leggett 6, Kevin J Spring 7 The CIMP Phenotype in BRAF Mutant Serrated Polyps from a Prospective Colonoscopy Patient Cohort Gastroenterol Res Pract 2014;2014:374926. doi: 10.1155/2014/374926.
15. Liu C, Bettington ML, Walker NI, Dwine J, Hartel GF, Leggett BA, Whitehall VL. CpG Island Methylation in Sessile Serrated Adenomas Increases With Age, Indicating Lower Risk of Malignancy in Young Patients. J.Gastroenterology. 2018 Nov;155(5):1362-1365.e2. doi: 10.1053/j.gastro.2018.07.012.
L»
BBSM
16. Cho H, Hashimoto T, Yoshida H, Taniguchi H, Ogawa R, Mori T, Hiraoka N, Saito Y, Sekine S. Reappraisal of the genetic heterogeneity of sessile serrated adenoma/polyp. Histopathology. 2018 Oct;73(4):672-680. doi: 10.1111/his.13688.
17. Hashimoto T, Tanaka Y, Ogawa R, Mori T, Yoshida H, Taniguchi H, Hiraoka N, Kojima M, Oono Y, Saito Y, Sekine S. Superficially serrated adenoma: a proposal for a novel subtype of colorectal serrated lesion. Mod Pathol. 2018 Oct;31(10):1588-1598. doi: 10.1038/s41379-018-0069-8.
18. Hashimoto T, Yamashita S, Yoshida H, Taniguchi H, Ushijima T, Yamada T, Saito Y, Ochiai A, Sekine S, Hiraoka N. WNT Pathway Gene Mutations Are Associated With the Presence of Dysplasia in Colorectal Sessile Serrated Adenoma/Polyps. Am J Surg Pathol. 2017 Sep;41(9):1188-1197. doi: 10.1097/PAS.0000000000000877.
19. Kirstine Oh 1, Mark Redston, Robert D Odze. Support for hMLH1 and MGMT silencing as a mechanism of tumorigenesis in the hyperplastic-adenoma-carcinoma (serrated) carcinogenic pathway in the colon. Hum Pathol. 2005 Jan;36(1):101-11. doi: 10.1016/j.humpath.2004.10.008.
20. Kriegl L, Neumann J, Vieth M, Greten FR, Reu S, Jung A, Kirchner T. Up and downregulation of p16(Ink4a) expression in BRAF-mutated polyps/adenomas indicates a senescence barrier in the serrated route to colon cancer. Mod Pathol. 2011 Jul;24(7):1015-22. doi: 10.1038/modpathol.2011.43.
21. Bond CE, Umapathy A, Ramsnes I, Greco SA, Zhen Zhao Z, Mallitt KA, Buttenshaw RL, Montgomery GW, Leggett BA, Whitehall VL. p53 mutation is common in microsatellite stable, BRAF mutant colorectal cancers. Int J Cancer. 2012 Apr 1;130(7):1567-76. doi: 10.1002/ijc.26175.
22. Carr NJ, Mahajan H, Tan KL, Hawkins NJ, Ward RL.Serrated and non-serrated polyps of the colorectum: their prevalence in an unselected case series and correlation of BRAF mutation analysis with the diagnosis of sessile serrated adenoma. J Clin Pathol. 2009 Jun;62(6):516-8. doi: 10.1136/jcp.2008.061960.
23. Higuchi T, Sugihara K, Jass JR.Demographic and pathological characteristics of serrated polyps of colorectum. Histopathology. 2005 Jul;47(1):32-40. doi: 10.1111/j.1365-2559.2005.02180.x.
24. IJspeert JE, Rana SA, Atkinson NS, van Herwaarden YJ, Bastiaansen BA, van Leerdam ME, Sanduleanu S, Bisseling TM, Spaander MC, Clark SK, Meijer GA, van Lelyveld N, Koornstra JJ, Nagtegaal ID, East JE, Latchford A, Dekker E; Clinical risk factors of colorectal cancer in patients with serrated polyposis syndrome: a multicentre cohort analysis. Dutch workgroup serrated polyps & polyposis (WASP).Gut. 2017 Feb;66(2):278-284. doi: 10.1136/gutjnl-2015-310630.
25. Carballal S, Rodríguez-Alcalde D, Moreira L, Hernández L, Rodríguez L, Rodríguez-Moranta F, Gonzalo V, Bujanda L, Bessa X, Poves C, Cubiella J, Castro I, González M, Moya E, Oquiñena S, Clofent J, Quintero E, Esteban P, Piñol V, Fernández FJ, Jover R,
East European Scientific Journal #2(66), 2021 33 Cid L, López-Cerón M, Cuatrecasas M, López-Vicente J, Leoz ML, Rivero-Sánchez L, Castells A, Pellisé M, Balaguer F; Colorectal cancer risk factors in patients with serrated polyposis syndrome: a large multicentre study. Gastrointestinal Oncology Group of the Spanish Gastroenterological AssociationGut. 2016 Nov;65(11):1829-1837. doi: 10.1136/gutjnl-2015-309647.
26. Daniel L Edelstein 1, Jennifer E Axilbund, Linda M Hylind, Katharine Romans, Constance A Griffin, Marcia Cruz-Correa, Francis M Giardiello. Serrated polyposis: rapid and relentless development of colorectal neoplasia. Gut. 2013 Mar;62(3):404-8. doi: 10.1136/gutjnl-2011-300514.
27. Gala MK, Mizukami Y, Le LP, Moriichi K, Austin T, Yamamoto M, Lauwers GY, Bardeesy N, Chung DC. Germline mutations in oncogene-induced senescence pathways are associated with multiple sessile serrated adenomas. Gastroenterology. 2014 Feb;146(2):520-9. doi: 10.1053/j.gastro.2013.10.045.
28. Buchanan DD, Clendenning M, Zhuoer L, Stewart JR, Joseland S, Woodall S, Arnold J, Semotiuk K, Aronson M, Holter S, Gallinger S, Jenkins MA, Sweet K, Macrae FA, Winship IM, Parry S, Rosty C;Lack of evidence for germline RNF43 mutations in patients with serrated polyposis syndrome from a large multinational study. Genetics of Colonic Polyposis Study. Gut. 2017 Jun;66(6):1170-1172. doi: 10.1136/gutjnl-2016-312773.
29. Quintana I, Mejías-Luque R, Terradas M, Navarro M, Piñol V, Mur P, Belhadj S, Grau E, Darder E, Solanes A, Brunet J, Capellá G, Gerhard M, Valle L. Evidence suggests that germline RNF43 mutations are a rare cause of serrated polyposis. Gut. 2018 Dec;67(12):2230-2232. doi: 10.1136/gutjnl-2017-315733.
30. Yan HHN, Lai JCW, Ho SL, Leung WK, Law WL, Lee JFY, Chan AKW, Tsui WY, Chan ASY, Lee BCH, Yue SSK, Man AHY, Clevers H, Yuen ST, Leung SY. RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation. Gut. 2017 Sep;66(9):1645-1656. doi: 10.1136/gutjnl-2016-311849.
31. Win AK, Walters RJ, Buchanan DD, Jenkins MA, Sweet K, Frankel WL, de la Chapelle A, McKeone DM, Walsh MD, Clendenning M, Pearson SA, Pavluk E, Nagler B, Hopper JL, Gattas MR, Goldblatt J, George J, Suthers GK, Phillips KD, Woodall S, Arnold J, Tucker K, Field M, Greening S, Gallinger S, Aronson M, Perrier R, Woods MO, Green JS, Walker N, Rosty C, Parry S, Young JP. Cancer risks for relatives of patients with serrated polyposis. Am J Gastroenterol. 2012 May;107(5):770-8. doi: 10.1038/ajg.2012.52.
32. Rosty C, Walsh MD, Walters RJ, Clendenning M, Pearson SA, Jenkins MA, Win AK, Hopper JL, Sweet K, Frankel WL, Aronson M, Gallinger S, Goldblatt J, Tucker K, Greening S, Gattas MR, Woodall S, Arnold J, Walker NI, Parry S, Young JP, Buchanan DD. Multiplicity and molecular heterogeneity of colorectal carcinomas in individuals with serrated polyposis. .Am J Surg Pathol. 2013
34 East European Scientific Journal #2(66), 2021 Mar;37(3):434-42. doi7
10.1097/PAS.0b013e318270f748.
33.Crockett SD, Nagtegaal ID. Terminology, Molecular Features, Epidemiology, and Management of Serrated Colorectal Neoplasia. Gastroenterology. 2019 Oct;157(4):949-966.e4. doi: 10.1053/j.gastro.2019.06.041.
34.Fennell LJ, Jamieson S, McKeone D, Corish T, Rohdmann M, Furner T, Bettington M, Liu C, Kawamata F, Bond C, Van De Pols J, Leggett B, Whitehall V.MLH1-93 G/a polymorphism is associated with MLH1 promoter methylation and protein loss in dysplastic sessile serrated adenomas with BRAFV600E mutation. BMC Cancer. 2018 Jan 5;18(1):35. doi: 10.1186/s12885-017-3946-5.
35. Jass JR, Whitehall VL, Young J, Leggett B. Emerging concepts in colorectal neoplasia. Gastroenterology. 2002;123:862-876. doi: 10.1053/gast.2002.35392. [PubMed]
[CrossRef] [Google Scholar]
36. Ogino S, Goel A. Molecular classification and correlates in colorectal cancer. J Mol Diagn. 2008;10:13-27. doi: 10.2353/jmoldx.2008.070082. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
37. Gonzalo DH, Lai KK, Shadrach B, et al. Gene expression profiling of serrated polyps identifies annexin A10 as a marker of a sessile serrated adenoma/polyp. J Pathol. 2013;230:420-429. doi: 10.1002/path.4200. [PubMed] [CrossRef] [Google Scholar]
38. Pai RK, Shadrach BL, Carver P, et al. Immunohistochemistry for annexin A10 can distinguish sporadic from Lynch syndrome-associated microsatellite-unstable colorectal carcinoma. Am J Surg Pathol. 2014;38:518-525. doi: 10.1097/PAS.0000000000000148. [PubMed] [CrossRef] [Google Scholar]
39. Shida Y, Ichikawa K, Fujimori T, et al. Differentiation between sessile serrated adenoma/polyp and non-sessile serrated adenoma/polyp in large hyper plastic polyp: A Japanese collaborative study. Mol Clin Oncol. 2013;1:53-58. doi: 10.3892/mco.2012.20. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
40. Hamilton SR, Bosman FT, Boffetta P, et al. Carcinoma of the Colon and Rectum. WHO Classification of Tumours of the Digestive System. Lyon: International Agency for Research on Cancer; 2010. pp. 134-146. [Google Scholar]
41. Chetty R. Traditional serrated adenoma (TSA): morphological questions, queries and quandaries. J Clin Pathol. 2016;69:6-11. doi: 10.1136/jclinpath-2015-203452. [PubMed] [CrossRef] [Google Scholar]
42. Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology. 2007; 50: 113-30. doi: 10.1111/j.1365-
2559.2006.02549.x [PubMed] [Google Scholar]
UB
BtSgSB
43. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990; 61: 759-67. [PubMed] [Google Scholar]
44. Jass JR. Serrated adenoma and colorectal cancer. J Pathol. 1999; 187: 499-502. doi: 10.1002/(SICI) 1096-
9896(199904)187:5<499::AID-PATH309>3.0.CO;2-B [PubMed] [Google Scholar]
45. Snover DC. Update on the serrated pathway to colorectal carcinoma. Hum Pathol. 2011; 42: 1-10. doi: 10.1016/j.humpath.2010.06.002 [PubMed] [Goog le Scholar]
46. Nishihara R, Wu K, Lochhead P, Morikawa T, Liao X, Qian ZR, et al. Long-term colorectal-cancer incidence and mortality after lower endoscopy. N Engl J Med. 2013; 369: 1095-105. doi: 10.1056/NEJMoa1301969 [PMC free article] [PubMed] [Google Scholar]
47. Bond JH. Colon polyps and cancer. Endoscopy. 2003; 35: 27-35. doi: 10.1055/s-2003-36410 [PubMed] [Google Scholar]
48. Imperiale TF, Ransohoff DF. Understanding differences in the guidelines for colorectal cancer screening. Gastroenterology. 2010; 138: 1642-7 e1. doi: 10.1053/j.gastro.2010.03.027 [PubMed] [Google Scholar]
49. Carethers JM. Biomarker-directed Targeted Therapy in Colorectal Cancer. J Dig Cancer Rep. 2015; 3: 5-10. [PMC free article] [PubMed] [Google Scholar]
50. Grady WM, Carethers JM. Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology. 2008; 135: 1079-99. doi: 10.1053/j.gastro.2008.07.076 [PMC free article] [PubMed] [Google Scholar]
51. Kambara T, Simms LA, Whitehall VL, Spring KJ, Wynter CV, Walsh MD, et al. BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut. 2004; 53: 1137-44. doi: 10.1136/gut.2003.037671 [PMC free article] [PubMed] [Google Scholar]
52. Yang HM, Mitchell JM, Sepulveda JL, Sepulveda AR. Molecular and histologic considerations in the assessment of serrated polyps. Arch Pathol Lab Med. 2015; 139: 730-41. doi: 10.5858/arpa.2014-0424-RA [PubMed] [Google Scholar]
53. Chen H, Lefferts JA, Schwab MC, Suriawinata AA, Tsongalis GJ. Correlation of polypoid colorectal adenocarcinoma with pre-existing adenomatous polyps and KRAS mutation. Cancer Genet. 2011; 204: 245-51. doi: 10.1016/j.cancergen.2011.04.002 [PubMed] [Goo gle Scholar]
54. Ishii T, Notohara K, Umapathy A, Mallitt KA, Chikuba H, Moritani Y, et al. Tubular adenomas with minor villous changes show molecular features characteristic of tubulovillous adenomas. Am J Surg Pathol. 2011; 35: 212-20. doi: 10.1097/PAS.0b013e318205df20 [PubMed] [Goo gle Scholar]
ив
ЦЩВ
55. Maltzman T, Knoll K, Martinez ME, Byers T, Stevens BR, Marshall JR, et al. Ki-ras proto-oncogene mutations in sporadic colorectal adenomas: relationship to histologic and clinical characteristics. Gastroenterology. 2001; 121: 302-9. [PubMed] [Google Scholar]
56. Yadamsuren EA, Nagy S, Pajor L, Lacza A, Bogner B. Characteristics of advanced- and non advanced sporadic polypoid colorectal adenomas: correlation to KRAS mutations. Pathol Oncol Res. 2012; 18: 1077-84. doi: 10.1007/s12253-012-9547-3 [PubMed] [Google Scholar]
57. Yamane LS, Scapulatempo-Neto C, Alvarenga L, Oliveira CZ, Berardinelli GN, Almodova E, et al. KRAS and BRAF mutations and MSI status in precursor lesions of colorectal cancer detected by colonoscopy. Oncol Rep. 2014; 32: 1419-26. doi: 10.3892/or.2014.3338 [PubMed] [Google Scholar]
58. Wong K., Xie G. Updates on the Molecular Genetics of Colorectal Cancer. Colorectal Cancer Open Access. 2017;3 doi: 10.21767/24719943.100032. [CrossRef] [Google Scholar]
59. Kuipers E.J., Rösch T., Bretthauer M. Colorectal cancer screening-optimizing current
strategies and new directions. Nat. Rev. Clin. Oncol. 2013;10:130-142. doi:
10.1038/nrclinonc.2013.12. [PubMed] [CrossRef] [Google Scholar]
60. Bardhan K., Liu K. Epigenetics and colorectal cancer pathogenesis. Cancers. 2013;5:676-713. doi: 10.3390/cancers5020676. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
61. Grady W.M., Carethers J.M. Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology. 2008;135:1079-1099. doi: 10.1053/j.gastro.2008.07.076. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
62. Pancione M., Remo A., Colantuoni V. Genetic and Epigenetic Events Generate Multiple Pathways in Colorectal Cancer Progression. [(accessed on 27 February 2019)]; Available online: https ://www.hindawi.com/journals/pri/2012/50 9348/ [PMC free article] [PubMed]
Funding:This study required no funding.
Conflict of interest: The authors declare that they have no conflict of interest
УДК 616.36-002.2613.71 ГРНТИ 76.29.50
Мирхайдаров Равиль Шамилевич
Кандидат медицинских наук, директор научно-исследовательского лечебно-оздоровительного центра
«Здоровье и долголетие», Россия, г. Уфа Валишин Дамир Асхатович доктор медицинских наук, профессор кафедры инфекционных болезней с курсом ИДПО Башкирский Государственный Медицинский Университет, Россия, г. Уфа
Кильдебекова Раушания Насгутдиновна доктор медицинских наук, профессор кафедры мобилизационной подготовки здравоохранения
и медицины катастроф ГБОУ ВПО Башкирский государственный медицинский университет, Россия, г. Уфа
НОВЫЕ МЕДИЦИНСКИЕ ТЕХНОЛОГИИ В РЕАБИЛИТАЦИИ БОЛЬНЫХ ХРОНИЧЕСКИМ
ВИРУСНЫМ ГЕПАТИТОМ С
Mirkhaydarov Ravil Shamilevich
Candidate of Medicine, Senior Researcher, Research Medical and Wellness Center "Health and Longevity", Russia, Ufa
Valishin Damir Askhatovich Doctor of Medicine, Professor of
the Department of Infectious Diseases with the EITI course Bashkir State Medical University, Russia, Ufa Kildibekova Raushania Nasgutdinovna
Doctor of Medicine, Professor of the Department of Mobilization Training of Health Care and Disaster Medicine Bashkir State Medical University, Russia, Ufa
NEW MEDICAL TECHNOLOGIES IN THE REHABILITATION OF PATIENTS WITH CHRONIC VIRAL HEPATITIS C
