Loss of Y in regulatory T lymphocytes in the tumor micro-environment of primary colorectal cancers and liver metastases.

Male sex is a risk factor for colorectal cancer (CRC) with higher illness burden and earlier onset. Thus, we hypothesized that loss of chromosome Y (LOY) in the tumor micro-environment (TME) might be involved in oncogenesis. Previous studies show that LOY in circulating leukocytes of aging men was associated with shorter survival and non-hematological cancer, as well as higher LOY in CD4 + T-lymphocytes in men with prostate cancer vs. controls. However, nothing is known about LOY in leukocytes infiltrating TME and we address this aspect here. We studied frequency and functional effects of LOY in blood, TME and non-tumorous tissue. Regulatory T-lymphocytes (Tregs) in TME had the highest frequency of LOY (22%) in comparison to CD4 + T-lymphocytes and cytotoxic CD8 + T-lymphocytes. LOY score using scRNA-seq was also linked to higher expression of PDCD1, TIGIT and IKZF2 in Tregs. PDCD1 and TIGIT encode immune checkpoint receptors involved in the regulation of Tregs function. Our study sets the direction for further functional research regarding a probable role of LOY in intensifying features related to the suppressive phenotype of Tregs in TME and consequently a possible influence on immunotherapy response in CRC patients.

Triiodothyronine lowers the potential of colorectal cancer stem cells in vitro.

Cancer stem cells (CSCs) play a key role in the development and progression of colorectal cancer (CRC), but the influence of triiodothyronine (T3) on the biological regulation of CSCs remains unclear. In the present study, it was reported that T3 exerts significant impact on CSCs of two CRC cell lines cultured in the form of colonospheres. It was observed that the incubation of colonospheres with T3 decreased the viability, proliferative and spherogenic potential of cancer cells (P<0.05). In addition, increased apoptotic rate of CRC cells treated with T3 was revealed. Furthermore, T3­treated colonospheres were more likely to move into silenced pool in G0/G1 phase of the cell cycle. The smaller sizes of colonospheres observed after the treatment with T3 confirmed this conclusion. T3 could lower the proportion of primitive cells which supply the pool of proliferating cells within spheres. Thyroid receptors THRα1 and THRß1 and two deiodinases (DIO2 and DIO3) were affected by T3 in manner depended on clinical stage of cancer and CRC cell line used for analysis. In summary, the present study uncovered a novel function of thyroid hormones signaling in the regulation of the CSCs of CRC, and these findings may be useful for developing novel therapies by targeting thyroid hormone functions in CRC cells.

Pretransplant BMI Significantly Affects Perioperative Course and Graft Survival after Kidney Transplantation: A Retrospective Analysis.

Background. The number of kidney transplant recipients (KTRs) with overweight and obesity is increasing. It was shown that obesity is related to inferior patient and graft survival. We aimed to analyze intraoperative parameters and postoperative short and long-term course of kidney transplantation (KT) in body mass index (BMI)-stratified cohorts of KTRs. Methods. A retrospective analysis of a prospectively built database of 433 KTRs from 2014 to 2017 from a single transplant center was performed. The objective of the study was to analyze the association between BMI at the time of transplantation with intraoperative parameters, adverse events in early postoperative course, and the overall mortality and graft loss in BMI-stratified cohorts: normal (18.5 and 24.9 kg/m2), overweight (25−29.9 kg/m2) and obese (≥30 kg/m2). Results. Obesity was related to longer total procedure time (p = 0.0025) and longer warm ischemia time (p = 0.0003). The postoperative course in obese patients was complicated by higher incidence of DGF (delayed graft function), early surgical complications (defined as surgical complications <30 days from KT), reoperation rate, vascular complications, incidence of lymphocele and wound dehiscence. There was no difference between the normal weight and overweight KTRs. The one-month kidney function (p = 0.0001) and allograft survival (p = 0.029) were significantly inferior in obese patients with no difference between normal weight and overweight patients. One-year death-censored graft survival was better in patients with BMI < 30 (88.6 vs. 94.8% p = 0.05). BMI was a significant predictor of graft loss in univariate (p = 0.04) but not in multivariate analysis (p = 0.09). Conclusion. Pretransplant obesity significantly affects the intraoperative and postoperative course of kidney transplantation and graft function and survival. The course of transplantation of overweight is comparable to normal BMI KTRs, and presumably pretransplant weight reduction to the BMI < 30 kg/m2 may improve the short-term postoperative course of transplantation as well as may improve graft survival. Thus, pretransplant weight reduction in obese KTRs may significantly improve the results of kidney transplantation. Metabolic surgery may play a role in improving results of KT.

Proton pump inhibitors and colorectal cancer: A systematic review.

BACKGROUND: The use of proton pump inhibitors (PPI) is common worldwide, with reports suggesting that they may be overused. Several studies have found that PPI may affect colorectal cancer (CRC) risk. AIM: To summarize current knowledge on the relationship between PPI and CRC from basic research, epidemiological and clinical studies. METHODS: This systematic review was based on the patients, interventions, comparisons, outcome models and performed according to PRISMA guidelines. MEDLINE, EMBASE, Scopus, and Web of Science databases were searched from inception until May 17, 2021. The initial search returned 2591 articles, of which, 28 studies met the inclusion criteria for this review. The studies were categorized as basic research studies (n = 12), epidemiological studies (n = 11), and CRC treatment studies (n = 5). The quality of the included studies was assessed using the Newcastle-Ottawa Scale or Cochrane Risk of Bias 2.0 tool depending on the study design. RESULTS: Data from basic research indicates that PPI do not stimulate CRC development via the trophic effect of gastrin but instead may paradoxically inhibit it. These studies also suggest that PPI may have properties beneficial for CRC treatment. PPI appear to have anti-tumor properties (omeprazole, pantoprazole), and are potential T lymphokine-activated killer cell-originated protein kinase inhibitors (pantoprazole, ilaprazole), and chemosensitizing agents (pantoprazole). However, these mechanisms have not been confirmed in human trials. Current epidemiological studies suggest that there is no causal association between PPI use and increased CRC risk. Treatment studies show that concomitant PPI and capecitabine use may reduce the efficacy of chemotherapy resulting in poorer oncological outcomes, while also suggesting that pantoprazole may have a chemosensitizing effect with the fluorouracil, leucovorin, oxaliplatin (FOLFOX) regimen. CONCLUSION: An unexpected inhibitory effect of PPI on CRC carcinogenesis by way of several potential mechanisms is noted. This review identifies that different PPI agents may have differential effects on CRC treatment, with practical implications. Prospective studies are warranted to delineate this relationship and assess the role of individual PPI agents.

Transcutaneous Laryngeal Ultrasound for Vocal Cord Paralysis Assessment in Patients Undergoing Thyroid and Parathyroid Surgery-A Systematic Review and Meta-Analysis.

Recurrent laryngeal nerve injury is an important complication following thyroid and parathyroid surgery. Recently, Transcutaneous laryngeal ultrasound (TLUSG) has emerged as a non-invasive alternative to laryngoscopic examination for vocal cord (VC) assessment. The aim of the systematic review and meta-analysis was to determine its diagnostic accuracy in reference to laryngoscopy. It was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. MEDLINE, Scopus, Cochrane library and Web of Science databases were searched to identify relevant articles. Sixteen studies were included in the review. Pooled diagnostic accuracy was calculated based on weighted arithmetic mean and plotting forest plot. The pooled visualization rate was 86.28% and 94.13% preoperatively and postoperatively, respectively. The respective pooled sensitivity and specificity was 78.48% and 98.28%, and 83.96% (CI 95%: 77.24-88.50%) and 96.15% (CI 95%: 95.24-96.88%). The diagnostic accuracy improved if transverse and lateral approaches, and valsalva maneuver were utilized. Male gender and older age were the most crucial risk factors for VC non-visualization. TLUSG is an efficacious screening tool for vocal cord palsy due to its high sensitivity. It is likely to prevent unnecessary laryngoscopic examination in around 80% of patients, with the potential for becoming a gold standard for specific (female/young) patient cohort through assimilative modifications use, increasing expertise and development of objective measurements in the future.

Alterations in complex lipids in tumor tissue of patients with colorectal cancer.

BACKGROUND: Accumulating evidence indicates alterations in lipid metabolism and lipid composition in neoplastic tissue. Earlier nuclear magnetic resonance studies showed that the contents of major lipid groups, such as triacylglycerols, phospholipids and cholesterol, are changed in colon cancer tissue. METHODS: In this study, a more detailed analysis of lipids in cancer and tumor adjacent tissues from colorectal cancer patients, using liquid chromatography-mass spectrometry, allowed for comparison of 199 different lipids between cancer tissue and tumor adjacent tissue using principal component analysis. RESULTS: Significant differences were found in 67 lipid compounds between the two types of tissue; many of these lipid compounds are bioactive lipids such as ceramides, lysophospholipids or sterols and can influence the development of cancer. Additionally, increased levels of phospholipids and sphingolipids were present, which are major components of the cell membrane, and increases in these lipids can lead to changes in cell membrane properties. CONCLUSIONS: This study showed that many complex lipids are significantly increased or decreased in colon cancer tissue, reflecting significant alterations in lipid metabolism. This knowledge can be used for the selection of potential molecular targets of novel anticancer strategies based on the modulation of lipid metabolism and the composition of the cell membrane in colorectal cancer cells.

Neoadjuvant short-course radiotherapy with consolidation chemotherapy for locally advanced rectal cancer: a systematic review and meta-analysis.

BACKGROUND: Short-course radiotherapy with consolidation chemotherapy (SCRT-CCT) has emerged as a promising alternative to the long course chemoradiotherapy (LCRT) regimen in locally advanced rectal cancer management. The systematic review and meta-analysis is aimed at summarizing current evidence on SCRT-CCT and comparing it to LCRT. MATERIAL AND METHODS: Electronic databases of MEDLINE, Web of Science, and Cochrane library were searched using a predefined search strategy returning 3314 articles. This review included 11 studies (6 randomized trials and 5 non-randomized studies) on SCRT-CCT regimen based on seven different cohorts. Weighted arithmetic means and forest plots were generated to determine summary estimates. RESULTS: The probability of achieving pathological complete response (pCR) was higher with SCRT-CCT compared to LCRT (risk ratio [RR] = 1.75, 95% confidence interval [CI]: 1.41-2.19). No statistically significant difference in 3-year overall survival (OS) was observed between the two groups (RR= 1.06, 95% CI: 0.98-1.14). The weighted arithmetic mean of 3-year OS and pCR was 83.6% versus 80.9%, and 24.5% versus 13.6% for SCRT-CCT and LCRT, respectively. R0 resection and T-downstaging rates ranged from 69.2-100% to 47-75% for SCRT-CCT, and 71-92.3% and 41-75% for LCRT, respectively. The regimens had similar compliance, postoperative, and late toxicity, however, acute toxicity rates varied primarily due to differences in treatment protocols. CONCLUSIONS: This review highlights the ability of SCRT-CCT to produce improved tumor response with comparable OS, R0 resection, and T-downstaging at the cost of increased acute toxicity. However, heterogeneity in treatment protocols across studies makes it difficult to provide definitive conclusions regarding the regimen. Several ongoing trials are expected to provide further evidence confirming the findings of RAPIDO trial and detail appropriate SCRT-CCT protocols to improve oncological outcomes, minimize toxicity, and determine its effectiveness as the standard-of-care for locally advanced rectal cancer patients.

Adenoma to Colorectal Cancer Estimated Transition Rates Stratified by BMI Categories-A Cross-Sectional Analysis of Asymptomatic Individuals from Screening Colonoscopy Program.

Most colorectal cancers (CRC) assumedly develop from precursor lesions, i.e., colorectal adenomas (adenoma-carcinoma sequence). Epidemiological and clinical data supporting this hypothesis are limited. Therefore, the aim of the present study is to estimate relative dynamics of colorectal adenoma-carcinoma sequence for groups of screenees stratified by BMI (body mass index) based on prevalence data from Polish Colonoscopy Screening Program (PCSP). We performed a cross-sectional analysis of database records of individuals who entered the national opportunistic colonoscopy screening program for CRC in Poland. We calculated prevalence of adenomas and CRCs adjusted for sex, 5-year age group, family history of CRC, smoking, diabetes and use of aspirin, hormonal therapy and proton-pump inhibitors use. Thereafter we calculated estimated transition rate (eTR) with confidence intervals (CIs) defined as adjusted prevalence of more advanced lesion divided by adjusted prevalence of less advanced lesion. All analyzes were stratified according to the BMI categories: normal (BMI 18.0 to <25.0), overweight (BMI 25.0 to <30.0) and obese (BMI ≥ 30.0). Results are reported in the same respective order. After exclusions we performed analyses on 147,385 individuals. We found that prevalence of non-advanced adenomas is increasing with BMI category (12.19%, 13.81%, 14.70%, respectively; p < 0.001). Prevalence of advanced adenomas was increasing with BMI category (5.20%, 5.77%, 6.61%, respectively; p < 0.001). Early CRCs prevalence was the highest for obese individuals (0.55%) and the lowest for overweight individuals (0.44%) with borderline significance (p = 0.055). For advanced CRC we found that prevalence seems to be inversely related to BMI category, however no statistically significant differences were observed (0.35%, 0.31%, 0.28%; p = 0.274). eTR for non-advanced adenoma to advanced adenoma is higher for obese individuals than for overweight individuals with bordering CIs (42.65% vs. 41.81% vs. 44.95%) eTR for advanced adenoma to early CRC is highest for normal individuals, however CIs are overlapping with remaining BMI categories (9.02% vs. 7.67% vs. 8.39%). eTR for early CRC to advanced CRC is lower for obese individuals in comparison to both normal and overweight individuals with marginally overlapping CIs (73.73% vs. 69.90% vs. 50.54%). Obese individuals are more likely to develop adenomas, advanced adenomas and early CRC but less likely to progress to advanced CRC. Therefore, this study provides new evidence that obesity paradox exists for colorectal cancer.

Circulating Tumor DNA in KRAS positive colorectal cancer patients as a prognostic factor - a systematic review and meta-analysis.

BACKGROUND: Liquid biopsy is a novel tool in oncology. It provides minimally invasive detection of tumor specific DNA. This review summarizes data on presence of circulating tumor DNA in serum or plasma of CRC patients as a potential negative prognostic factor. MATERIALS AND METHODS: The systematic review was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). The search was performed using PubMed, Web of Science and Scopus. RESULTS: In total 18 articles with a total of 1779 patients met the inclusion criteria. Six out of 8 studies found that presence of ctDNA in plasma/serum was associated with inferior overall survival. All 6 studies found that high concentrations of ctDNA in plasma/serum was associated with inferior overall survival. CONCLUSIONS: Presence or high concentrations of KRAS mutation in plasma or serum were associated with inferior prognosis. Establishing cut-off concentrations is warranted for further clinical implementation of liquid biopsy.

Clinical presentation and outcomes of cholecystectomy for acute cholecystitis in patients with diabetes - A matched pair analysis. A pilot study.

PURPOSE: The primary aim of this study is to compare the clinical course and laboratory parameters of acute cholecystitis in patients with diabetes vs. patients without diabetes. MATERIALS AND METHODS: The study involved patients who underwent emergency cholecystectomy in the Department of General, Endocrine and Transplant Surgery of University Clinical Center in Gdansk (Poland) between 2007 and 2017. There were 267 patients included in the study. The control group of 197 patients was age and sex matched at a 3:1 ratio. The following was compared between the groups: symptoms at admission, course of surgery, postoperative course, length of hospitalization, total costs of hospitalization and antibiotic therapy, other than routine perioperative prophylaxis. RESULTS: There was no significant difference between the patients with and without diabetes regarding symptoms at admission. Operative and postoperative complication rates were significantly higher in the patients with diabetes. The operative time and length of hospitalization were significantly longer in the study group. The conversion rate was not higher in the study group, but classic surgery was performed significantly more often. The patients without diabetes had less pronounced symptoms with more locally advanced disease. CONCLUSIONS: Our study demonstrates that patients with diabetes have a significantly more eventful course of acute cholecystitis than patients without diabetes. Patients with diabetes should therefore be qualified for cholecystectomy early in the course of acute cholecystitis.

Patients seeking information about colonoscopy - lessons learned from Google.

INTRODUCTION: Every year in the USA over 14 million colonoscopies are performed. It requires high-quality examinations as well as a relevant information strategy. Colonoscopy compliance is not satisfactory, which to some extent might be related to patients' attitudes towards colonoscopy, which are based on information and emotions. AIM: In the current study we addressed the questions of what kind of information people seek and get when they search the Internet for "colonoscopy". MATERIAL AND METHODS: Using the Google Trends web facility we analysed search results of "colonoscopy", related searches, and annual and weekly search trends. Fields of interest analysis was performed based on the related searches. RESULTS: Patients are generally offered quality data on the first result page of a Google search biased only by Wikipedia scoring first on the result list. The number of "colonoscopy" searches is stable over the week with a significant decrease on weekends, and stable over the year with significant decrease around Thanksgiving day and in the Christmas/New Year's Eve Period. The most common field of search is colonoscopy preparation, thus underlining the importance of this part of colonoscopy. CONCLUSIONS: Internet search provides abundant information on colonoscopy. In general, this information is accessible, preferred by patients, and of good quality. This should be kept in mind by healthcare providers while educating patients about colonoscopy.

Expression of HTRA Genes and Its Association with Microsatellite Instability and Survival of Patients with Colorectal Cancer.

HtrA proteases regulate cellular homeostasis and cell death. Their dysfunctions have been correlated with oncogenesis and response to therapeutic treatment. We investigated the relation between HtrA1-3 expression and clinicopathological, and survival data, as well as the microsatellite status of tumors. Sixty-five colorectal cancer patients were included in the study. The expression of HTRA1-3 was estimated at the mRNA and protein levels by quantitative PCR and immunoblotting. Microsatellite status was determined by high-resolution-melting PCR. We found that the HTRA1 mRNA level was higher in colorectal cancer tissue as compared to the unchanged mucosa, specifically in primary lesions of metastasizing cancer. The levels of HtrA1 and HtrA2 proteins were reduced in tumor tissue when compared to unchanged mucosa, specifically in primary lesions of metastasizing disease. Moreover, a decrease in HTRA1 and HTRA2 transcripts' levels in cancers with a high level of microsatellite instability compared to microsatellite stable ones has been observed. A low level of HtrA1 or/and HtrA2 in cancer tissue correlated with poorer patient survival. The expression of HTRA1 and HTRA2 changes during colorectal carcinogenesis and microsatellite instability may be, at least partially, associated with these changes. The alterations in the HTRA1/2 genes' expression are connected with metastatic potential of colorectal cancer and may affect patient survival.

Decreased Triacylglycerol Content and Elevated Contents of Cell Membrane Lipids in Colorectal Cancer Tissue: A Lipidomic Study.

Recent evidence suggests that lipid composition in cancer tissues may undergo multiple alterations. However, no comprehensive analysis of various lipid groups in colorectal cancer (CRC) tissue has been conducted thus far. To address the problem in question, we determined the contents of triacylglycerols (TG), an energetic substrate, various lipids necessary for cell membrane formation, among them phospholipids (phosphatidylcholine, phosphatidylethanolamine), sphingolipids (sphingomyelin) and cholesterol (free, esterified and total), and fatty acids included in complex lipids. 1H-nuclear magnetic resonance (1H-NMR) and gas chromatography-mass spectrometry (GC-MS) were used to analyze the lipid composition of colon cancer tissue and normal large intestinal mucosa from 25 patients. Compared with normal tissue, cancer tissues had significantly lower TG content, along with elevated levels of phospholipids, sphingomyelin, and cholesterol. Moreover, the content of oleic acid, the main component of TG, was decreased in cancer tissues, whereas the levels of saturated fatty acids and polyunsaturated fatty acids (PUFAs), which are principal components of polar lipids, were elevated. These lipidome rearrangements were associated with the overexpression of genes associated with fatty acid oxidation, and the synthesis of phospholipids and cholesterol. These findings suggest that reprogramming of lipid metabolism might occur in CRC tissue, with a shift towards increased utilization of TG for energy production and enhanced synthesis of membrane lipids, necessary for the rapid proliferation of cancer cells.