Storosios žarnos vėžio genetiniai ir epigenetiniai pokyčiai, etiopatogenezė, rizikos veiksniai, gydymas: literatūros apžvalga

Background. Colorectal cancer (CRC) ranks as the third leading cause of cancerrelated mortality worldwide. Recent years have witnessed an increase in the incidence of CRC. The main reasons are ageing population, increased consumption of processed food, obesity, genetic predispositions. Aim. To review the latest scientific developments and novel factors on the epidemiology, etiology, pathoge­nesis of colon cancer, focusing on the influence of genetics and epigenetics, risk factors, and the advancement of prevention and treatment methods. Material and methods. The research method is a literature review. Publications were searched in the PubMed database using the following keywords and their combinations in English: colon cancer, colorectal cancer, management, prevalence, causes, risk factors, genetic and epigenetic changes. Selection criteria for publications: scientific articles in English relevant to the research topic and 90% of articles published in the last 10 years (2014–2024). Results. Using theoretical analysis methods, 72 publications were selected that met the inclusion criteria. Our findings emphasize the central role of genetic mutations (particularly in APC, TP53, KRAS and MMR) and epigenetic alterations, such as DNA methylation and histone modification, in the pathogenesis of colorectal cancer. These genetic and epigenetic factors drive the progression from benign polyps to malignant carcinomas, with environmental, lifestyle, and chronic disease factors also playing a critical role. In particular, diet, physical inactivity, smoking and alcohol significantly increase risk, especially in men and those over 50. Innovations such as CRISPR/Cas9 offer new avenues for targeted treatments, while advances in vaccines and liquid biopsy techniques are improving immune response activation and disease monitoring. In addition, diets rich in fiber, antioxidants and healthy fats, as well as the use of probiotics and NSAIDs, are key to reducing cancer risk through their anti-inflammatory effects and promoting gut health. Conclussions. This review highlights the significant impact of genetic and epigenetic factors on colorectal cancer (CRC) development, in addition to the role of lifestyle and environmental exposures. It highlights the potential of CRISPR/Cas9, immunotherapies, and liquid biopsies in pioneering personalized CRC treatments and early detection. Advances in prevention and technology promise a new era of personalized, effective CRC management strategies.Įvadas. Storosios žarnos vėžys yra trečia pagal dažnumą mirštamumo nuo vėžio priežastis pasaulyje. Pastaraisiais metais susirgimų storosios žarnos vėžiu dažnis išaugo. Pagrindinės priežastys – senėjanti visuomenė, padidėjęs perdirbto maisto vartojimas, nutukimas, genetinis polinkis. Tikslas – apžvelgti naujausią mokslinę literatūrą apie storosios žarnos vėžio epidemiologiją, etiologiją, patogenezę, aptarti dažniausius genetinius pokyčius, lemiančius storosios žarnos vėžio atsiradimą, epigenetikos vaidmenį storosios žarnos vėžio patogenezėje, rizikos veiksnius, prevenciją, gydymo metodus. Tyrimo medžiaga ir metodai. Tyrimo metodas – mokslinės literatūros apžvalga. Publikacijų ieškota PubMed duomenų bazėje, naudojant šiuos reikšminius žodžius ir jų derinius anglų kalba: storosios žarnos vėžys (angl. colon cancer), kolorektalinis vėžys (angl. colorectal cancer), valdymas (angl. management), paplitimas (angl. prevalence), priežastys (angl. causes), rizikos veiksniai (angl. risk factors), genetiniai ir epigenetiniai pokyčiai (angl. genetic and epigenetic changes). Publikacijų atrankos kriterijai: moksliniai straipsniai anglų kalba, atitinkantys tyrimo temą ir 90 proc. paskelbti per pastaruosius 10 metų (2014–2024). Rezultatai. Atrinktos 72 publikacijos, atitinkančios įtraukimo į tyrimą kriterijus. Taikant teorinės analizės metodus, galutinai atrinktos 65 publikacijos. Išvadose pabrėžiamas pagrindinis genetinių mutacijų (ypač APC, TP53, KRAS ir MMR) ir epigenetinių pakitimų, tokių kaip DNR metilinimas ir histono modifikavimas, vaidmuo kolorektalinio vėžio patogenezėje. Šie genetiniai ir epigenetiniai veiksniai skatina progresavimą nuo gerybinių polipų iki piktybinių karcinomų. Aplinkos, gyvenimo būdo ir lėtinių ligų veiksniai taip pat atlieka svarbų vaidmenį. Visų pirma, mityba, fizinis neveiklumas, rūkymas ir alkoholis smarkiai didina susirgimų riziką, ypač vyrams ir vyresniems negu 50 m. asmenims. Tokios naujovės kaip CRISPR/Cas9 siūlo naujas tikslinio gydymo galimybes, o pažanga vakcinų ir skystųjų biopsijos metodų srityje gerina imuninio atsako aktyvavimą ir ligos stebėjimą. Be to, dietos, gausios skaidulų, antioksidantų ir sveikųjų riebalų, taip pat probiotikų ir NVNU vartojimas dėl uždegimą slopinančio poveikio yra labai svarbūs veiksniai, siekiant sumažinti vėžio riziką ir gerinti žarnyno sveikatą. Išvados. Apžvalgoje aptariamas reikšmingas genetinių ir epigenetinių veiksnių poveikis gaubtinės ir tiesiosios žarnos vėžio (angl. CRC) vystymuisi, taip pat apžvelgiama gyvenimo būdo ir aplinkos poveikio įtaka. Pabrėžiamas CRISPR/Cas9, imunoterapijos ir skystųjų biopsijų potencialas, pirmaujantis ankstyvos stadijos ligai nustatyti ir individualizuotam kolorektaliniam vėžiui (angl. CRC) gydyti. Prevencijos ir technologijų pažanga prognozuoja naują individualizuotų, veiksmingų kolorektalinio vėžio valdymo strategijų erą

HAMLET cytotoxicity in colorectal cancer cell models with different mutation status in Vitro

HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) is a proteolipid complex of partially unfolded α-lactalbumin and several oleate residues. Its efficacy as a selective killer of tumor cells has been documented in vitro and in vivo in several animal models [1]. HAMLET interacts with multiple tumor cell compartments, affecting cell morphology, metabolism, proteasome function, chromatin structure and cell viability [2]. Colorectal cancer is one of the most frequent malignancies worldwide, being second in males and third in females for its frequency and ranking fourth and third for cancer-related deaths among males and females, respectively [3]. KRAS and BRAF are major oncogenic drivers of colorectal cancer (CRC) [4]. The aim of this study was to evaluate antitumoral activity of the HAMLET complex on three different CRC cell lines (LoVo, WiDr, Caco-2) with different mutation status (KRAS/BRAF, wild type). HAMLET complex was prepared using controlled temperature (partial protein unfold) combined with mixing/shaking with olein acid additive (acid incorporation in protein structure) [5]. Cytotoxicity of complex (metabolic activity and viability of the cells) was evaluated using 6 h exposition and different concentration in compliance with MTT and clonogenic assay protocols. The results suggest that HAMLET affects cell metabolism, this effect is severe and at the same time irreparable for cells, leading to cell death. The complex exhibits cytotoxicity in dose-response manner against all cell lines. However, BRAF mutant cells seems to be more resistant to HAMLET in comparison to KRAS mutants and wild type cells. HAMLET has anticancer potency for CRC in in vitro modelGamtos mokslų fakultetasLietuvos sveikatos mokslų universitetas. Medicinos akademijaVytauto Didžiojo universiteta

Surgical site infection after gastrointestinal surgery in children : an international, multicentre, prospective cohort study

Introduction Surgical site infection (SSI) is one of the most common healthcare-associated infections (HAIs). However, there is a lack of data available about SSI in children worldwide, especially from low-income and middle-income countries. This study aimed to estimate the incidence of SSI in children and associations between SSI and morbidity across human development settings. Methods A multicentre, international, prospective, validated cohort study of children aged under 16 years undergoing clean-contaminated, contaminated or dirty gastrointestinal surgery. Any hospital in the world providing paediatric surgery was eligible to contribute data between January and July 2016. The primary outcome was the incidence of SSI by 30 days. Relationships between explanatory variables and SSI were examined using multilevel logistic regression. Countries were stratified into high development, middle development and low development groups using the United Nations Human Development Index (HDI). Results Of 1159 children across 181 hospitals in 51 countries, 523 (45 center dot 1%) children were from high HDI, 397 (34 center dot 2%) from middle HDI and 239 (20 center dot 6%) from low HDI countries. The 30-day SSI rate was 6.3% (33/523) in high HDI, 12 center dot 8% (51/397) in middle HDI and 24 center dot 7% (59/239) in low HDI countries. SSI was associated with higher incidence of 30-day mortality, intervention, organ-space infection and other HAIs, with the highest rates seen in low HDI countries. Median length of stay in patients who had an SSI was longer (7.0 days), compared with 3.0 days in patients who did not have an SSI. Use of laparoscopy was associated with significantly lower SSI rates, even after accounting for HDI. Conclusion The odds of SSI in children is nearly four times greater in low HDI compared with high HDI countries. Policies to reduce SSI should be prioritised as part of the wider global agenda.Peer reviewe

Exploring the cost-effectiveness of high versus low perioperative fraction of inspired oxygen in the prevention of surgical site infections among abdominal surgery patients in three low- and middle-income countries

Background: This study assessed the potential cost-effectiveness of high (80–100%) vs low (21–35%) fraction of inspired oxygen (FiO2) at preventing surgical site infections (SSIs) after abdominal surgery in Nigeria, India, and South Africa. Methods: Decision-analytic models were constructed using best available evidence sourced from unbundled data of an ongoing pilot trial assessing the effectiveness of high FiO2, published literature, and a cost survey in Nigeria, India, and South Africa. Effectiveness was measured as percentage of SSIs at 30 days after surgery, a healthcare perspective was adopted, and costs were reported in US dollars ($). Results: High FiO2 may be cost-effective (cheaper and effective). In Nigeria, the average cost for high FiO2 was$216 compared with $222 for low FiO2 leading to a −$6 (95% confidence interval [CI]: −$13 to −$1) difference in costs. In India, the average cost for high FiO2 was $184 compared with$195 for low FiO2 leading to a −$11 (95$15 to −$6) difference in costs. In South Africa, the average cost for high FiO2 was$1164 compared with $1257 for low FiO2 leading to a −$93 (95% CI: −$132 to −$65) difference in costs. The high FiO2 arm had few SSIs, 7.33% compared with 8.38% for low FiO2, leading to a −1.05 (95% CI: −1.14 to −0.90) percentage point reduction in SSIs. Conclusion: High FiO2 could be cost-effective at preventing SSIs in the three countries but further data from large clinical trials are required to confirm this

Stoma-free survival after anastomotic leak following rectal cancer resection: worldwide cohort of 2470 patients

Background: The optimal treatment of anastomotic leak after rectal cancer resection is unclear. This worldwide cohort study aimed to provide an overview of four treatment strategies applied. Methods: Patients from 216 centres and 45 countries with anastomotic leak after rectal cancer resection between 2014 and 2018 were included. Treatment was categorized as salvage surgery, faecal diversion with passive or active (vacuum) drainage, and no primary/secondary faecal diversion. The primary outcome was 1-year stoma-free survival. In addition, passive and active drainage were compared using propensity score matching (2: 1). Results: Of 2470 evaluable patients, 388 (16.0 per cent) underwent salvage surgery, 1524 (62.0 per cent) passive drainage, 278 (11.0 per cent) active drainage, and 280 (11.0 per cent) had no faecal diversion. One-year stoma-free survival rates were 13.7, 48.3, 48.2, and 65.4 per cent respectively. Propensity score matching resulted in 556 patients with passive and 278 with active drainage. There was no statistically significant difference between these groups in 1-year stoma-free survival (OR 0.95, 95 per cent c.i. 0.66 to 1.33), with a risk difference of -1.1 (95 per cent c.i. -9.0 to 7.0) per cent. After active drainage, more patients required secondary salvage surgery (OR 2.32, 1.49 to 3.59), prolonged hospital admission (an additional 6 (95 per cent c.i. 2 to 10) days), and ICU admission (OR 1.41, 1.02 to 1.94). Mean duration of leak healing did not differ significantly (an additional 12 (-28 to 52) days). Conclusion: Primary salvage surgery or omission of faecal diversion likely correspond to the most severe and least severe leaks respectively. In patients with diverted leaks, stoma-free survival did not differ statistically between passive and active drainage, although the increased risk of secondary salvage surgery and ICU admission suggests residual confounding

Use of Telemedicine for Post-discharge Assessment of the Surgical Wound: International Cohort Study, and Systematic Review with Meta-analysis

Objective: This study aimed to determine whether remote wound reviews using telemedicine can be safely upscaled, and if standardised assessment tools are needed. Summary background data: Surgical site infection is the most common complication of surgery worldwide, and frequently occurs after hospital discharge. Evidence to support implementation of telemedicine during postoperative recovery will be an essential component of pandemic recovery. Methods: The primary outcome of this study was surgical site infection reported up to 30-days after surgery (SSI), comparing rates reported using telemedicine (telephone and/or video assessment) to those with in-person review. The first part of this study analysed primary data from an international cohort study of adult patients undergoing abdominal surgery who were discharged from hospital before 30-days after surgery. The second part combined this data with the results of a systematic review to perform a meta-analysis of all available data conducted in accordance with PRIMSA guidelines (PROSPERO:192596). Results: The cohort study included 15,358 patients from 66 countries (8069 high, 4448 middle, 1744 low income). Of these, 6907 (45.0%) were followed up using telemedicine. The SSI rate reported using telemedicine was slightly lower than with in-person follow-up (13.4% vs. 11.1%, P<0.001), which persisted after risk adjustment in a mixed-effects model (adjusted odds ratio: 0.73, 95% confidence interval 0.63-0.84, P<0.001). This association was consistent across sensitivity and subgroup analyses, including a propensity-score matched model. In nine eligible non-randomised studies identified, a pooled mean of 64% of patients underwent telemedicine follow-up. Upon meta-analysis, the SSI rate reported was lower with telemedicine (odds ratio: 0.67, 0.47-0.94) than in-person (reference) follow-up (I2=0.45, P=0.12), although there a high risk of bias in included studies. Conclusions: Use of telemedicine to assess the surgical wound post-discharge is feasible, but risks underreporting of SSI. Standardised tools for remote assessment of SSI must be evaluated and adopted as telemedicine is upscaled globally

Stoma-free Survival After Rectal Cancer Resection With Anastomotic Leakage: Development and Validation of a Prediction Model in a Large International Cohort.

Objective:To develop and validate a prediction model (STOMA score) for 1-year stoma-free survival in patients with rectal cancer (RC) with anastomotic leakage (AL).Background:AL after RC resection often results in a permanent stoma.Methods:This international retrospective cohort study (TENTACLE-Rectum) encompassed 216 participating centres and included patients who developed AL after RC surgery between 2014 and 2018. Clinically relevant predictors for 1-year stoma-free survival were included in uni and multivariable logistic regression models. The STOMA score was developed and internally validated in a cohort of patients operated between 2014 and 2017, with subsequent temporal validation in a 2018 cohort. The discriminative power and calibration of the models' performance were evaluated.Results:This study included 2499 patients with AL, 1954 in the development cohort and 545 in the validation cohort. Baseline characteristics were comparable. One-year stoma-free survival was 45.0% in the development cohort and 43.7% in the validation cohort. The following predictors were included in the STOMA score: sex, age, American Society of Anestesiologist classification, body mass index, clinical M-disease, neoadjuvant therapy, abdominal and transanal approach, primary defunctioning stoma, multivisceral resection, clinical setting in which AL was diagnosed, postoperative day of AL diagnosis, abdominal contamination, anastomotic defect circumference, bowel wall ischemia, anastomotic fistula, retraction, and reactivation leakage. The STOMA score showed good discrimination and calibration (c-index: 0.71, 95% CI: 0.66-0.76).Conclusions:The STOMA score consists of 18 clinically relevant factors and estimates the individual risk for 1-year stoma-free survival in patients with AL after RC surgery, which may improve patient counseling and give guidance when analyzing the efficacy of different treatment strategies in future studies