Introduction

Colorectal cancer is one of the most prevalent cancers with an estimated 1.8 million newly developed cases and 0.9 million cancer-related deaths in 2020.Resection of adenomatous polyps decreases the incidence and mortality of colorectal cancer. Narrow-band imaging (NBI) and linked color imaging (LCI) are the most predominantly conducted image-enhanced endoscopy using short-wavelength light but their usefulness in screening and surveillance colonoscopy remains controversial.

Aims & Methods

Our aim in this study was to investigate the superiority of LCI over NBI for ADR.
This is an open-label, two-arm, parallel, 1:1, multicenter, randomized, controlled, right-sided colonoscopy study and included patients who underwent colonoscopy at six endoscopy centers in Japan from November 2020 through November 2023. The patients were randomly assigned to undergo a proximal-sided colonoscopy (cecum and ascending colon) with LCI or 2G-NBI followed by WLI. The primary outcome included the ADR and secondary outcomes involved polyp detection rate (PDR), polyp miss rate, and adenoma miss rate. This study was registered on November 4, 2020, in the Japan Registry of Clinical Trials (jRCT1012200007).

Results

During the study period, 1,655 patients were randomly assigned to the LCI group (828 patients, primary LCI followed by secondary WLI) and the 2G-NBI group (827 patients, primary 2G-NBI followed by secondary WLI), and 776 patients in the LCI group and 752 patients in the 2G-NBI groups were finally analyzed. The ADRs were 26.7% and 23.4% and the PDRs were 32.6% and 28.9% in primary LCI and 2G-NBI, respectively, with no statistically significant differences in ADR and PDR between groups (P = 0.14 and P = 0.12). However, multivariate regression analysis revealed primary LCI observation as an independent predictor for reducing PDR in the secondary WLI (Odds ratio [OR]: 0.72, 95% confidence interval [CI]: 0.53−0.97, P = 0.029). Moreover, polyp analysis demonstrated that miss rates of adenomas and polyps were significantly lower in the LCI group than in the NBI group (OR: 0.54, 95% CI: 0.39−0.76 in adenoma; OR: 0.59, 95% CI: 0.44−0.78 in polyp).

Conclusion

LCI is not superior to 2G-NBI in ADR and PDR in a clinical right-sided colonoscopy setting. However, LCI significantly reduced miss rates of adenomas and polyps.

Disclosure

Naohisa Yoshida has received lecture and/or consulting fees from Fujifilm and Olympus; Shoko Ono has received lecture and/or consulting fees from Fujifilm and Olympus; Momoko Tsuda has received lecture and/or consulting fees from Fujifilm; Nobuaki Yagi have received lecture and/or consulting fees from Fujifilm and Olympus; Mototsugu Kato has received lecture and/or consulting fees from Fujifilm. The remaining authors disclose no conflicts.

Introduction

Colorectal cancer (CRC) remains a leading cause of cancer-related deaths in the U.S., with persistent disparities across racial and ethnic groups. Current uniform screening guidelines overlook population differences in risk. Polygenic risk scores (PRS) offer a pathway to personalized, risk-stratified screening, but their cost-effectiveness across diverse populations is unclear.

Aims & Methods

In this study, we estimated the cost-effectiveness of PRS-based, risk-stratified screening across four major U.S. racial and ethnic groups (White, Black, Asian and Hispanic), modelling lifetime costs, quality-adjusted life-years gained (QALYGs), and colonoscopy use to assess both overall and subgroup-specific outcomes.
PRS data from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) were used to stratify individuals into risk 40 groups. The microsimulation model MISCAN-Colon was used to determine the optimal colonoscopy screening strategy for each risk group within the racial and ethnic groups. Investigated strategies varied in terms of starting age (40–60 years), stopping age (70–85 years), and screening interval (5–15 years). Within each racial and ethnic group, the cost-effectiveness of the optimal strategies of the 40 risk groups was compared with uniform colonoscopy screening (ages 45–75, every 10 years).

Results

Risk-stratified screening produced different recommendations across risk levels and populations. For low-risk groups, strategies ranged from no screening in Whites and Blacks to a one-time colonoscopy at age 55 for Asians and at age 60 for Hispanics. In contrast, for high-risk groups, all populations benefited most from intensive screening with colonoscopy every 5 years from ages 40–85. Across all racial and ethnic groups, PRS-guided screening outperformed uniform strategies, preventing more CRC cases and deaths but at the cost of higher colonoscopy use and costs. In constrained analyses, when QALYGs were fixed to the level of uniform screening, risk-stratified screening reduced costs by 6–27% and when costs were fixed to the level of uniform screening QALYGs increased by 8–29% These efficiency gains were most pronounced in Hispanics (–27% costs; +29% QALYGs) and Asians (–14% costs; +13% QALYGs), with smaller but consistent improvements in Whites (-9% costs; +12% QALYGs) and Blacks (-6% costs; +8%QALYGs).

Table 1. Lifetime Effects and Costs per 1,000 40-Year-Old Individuals for No Screening, Uniform Screening, and PRS-Guided Risk-Stratified Screening at a $100,000/QALYG Threshold, With QALYGs- and Cost-Constrained Analyses, Stratified by Racial and Ethnic Group (Results only for Hispanics and Asians)
Asians

Conclusion

PRS-guided screening may offer a pathway to more tailored CRC prevention, with modest overall gains but potentially greater cost savings and health benefits in Hispanics and Asians.

References

1. Carethers JM. Racial and ethnic disparities in colorectal cancer incidence and mortality. Adv Cancer Res. 2021;151:197-229.
2. May FP, Yang L, Corona E, Glenn BA, Bastani R. Disparities in Colorectal Cancer Screening in the United States Before and After Implementation of the Affordable Care Act. Clin Gastroenterol Hepatol. 2020;18(8):1796-804 e2.
3. Dixon P, Keeney E, Taylor JC, Wordsworth S, Martin RM. Can polygenic risk scores contribute to cost-effective cancer screening? A systematic review. Genet Med. 2022;24(8):1604-17.
4. Tamlander M, Jermy B, Seppälä TT, Färkkilä M, FinnGen, Widén E, et al. Genome-wide polygenic risk scores for colorectal cancer have implications for risk-based screening. Br J Cancer. 2024;130(4):651-9.

Disclosure

No conflicts of interest.

Introduction

There is a widespread agreement that age is a significant predictor of impaired response to nutritional support. For the same amount of protein and energy provided, the increase in weight and fat-free mass is significantly lower in older persons. This is generally attributed to anabolic resistance, and impaired absorption is usually considered non-existent/irrelevant. Nevertheless, in older rats gradual changes of the intestinal mucosa were observed, including reductions in villus height/width and density, which reduce absorption. Despite this, the aging influence on human intestinal mucosa is a matter of debate, and the lack of knowledge is partially explained by the exclusion criteria of older patients from most research protocols.

Aims & Methods

We aimed to evaluate potential histological and ultrastructural changes associated with aging that may reflect reduced absorption in older people.
The present single-center study is observational and prospective. Younger (18-45 years) and older (≥70 years) adults referred for upper endoscopy for reasons unrelated with intestinal alterations were included and underwent duodenal biopsies. Those biopsies were analyzed for histological, histomorphometric and ultrastructural changes. Histologic analysis was performed using optical microscopy with hematoxylin–eosin staining observed by two pathologists, including one expert gastrointestinal pathologist. All samples were analyzed for the presence of mucosal atrophy according to the adapted Marsh–Oberhuber classification and histomorphometric evaluation of duodenal villi length in micrometers, with at least two villi being measured through the use of an automatic scale. For transmission electron microscopy, duodenal fragments were fixed in 3% glutaraldehyde in cacodylate buffer (0.1 M, pH 7.4) overnight at 4 °C. The fixed fragments were rinsed and post-fixed in 1.0% osmium tetroxide for 1 h in the same buffer and dehydrated in graded ethanol passages. The fragments were embedded in a mixture of Epon and Araldite after two 15-min passages in propylene oxide. Thin sections, cut on a ultramicrotome with a diamond knife, were stained on the grid with uranyl acetate and lead citrate and examined with a electron microscope.

Results

A total of 84 patients were included (38 men/46 women), 33 with 18-45 years and 50 with ≥70 years. There were no duodenal endoscopic or microscopic changes apart from mucosal atrophy that was evident in one older adult. The median villi length was 0.35 mm (0.23-0.43 mm) in older persons, lower than in younger adults (0.65 mm; 0.37-0.79 mm) (p<0.01). On ultrastructural evaluation, the enterocytes of older group showed several changes suggesting compromise of the normal cell physiology. These changes were not observed in younger adults, who displayed normal cell architecture with regular microvilli structure and normal organelles.

Conclusion

Aging is associated with histological, histomorphometric and ultrastructural changes in the intestinal mucosa that can be linked with reduced absorptive capacity. Besides anabolic resistance, this could be a reason for the reduced response to nutritional support found in older citizens.

References

1. Soenen S, Rayner CK, Jones KL, et al. The ageing gastrointestinal tract. Curr Opin Clin Nutr Metab Care. 2016 Jan;19(1):12-8.
2. Patel BA, Patel N, Fidalgo S, et al. Impaired colonic motility and reduction in tachykinin signalling in the aged mouse. Exp Gerontol 2014; 53:24 – 30.
3. Saffrey MJ. Aging of the mammalian gastrointestinal tract: a complex organ system. Age 2014; 36:9603.
4. Ren WY, Wu KF, Li X, et al. Age-related changes in small intestinal mucosa epithelium architecture and epithelial tight junction in rat models. Aging Clin Exp Res 2014; 26:183 – 191.
5. Thomson AB. Small intestinal disorders in the elderly. Best Pract Res Clin Gastroenterol. 2009;23(6):861-74.
6. Nalapareddy K, Zheng Y, Geiger H. Aging of intestinal stem cells. Stem Cell Reports. 2022 Apr 12;17(4):734-740.

Introduction

Hepatocellular carcinoma (HCC) is the sixth most common malignancy and the third leading cause of cancer-related deaths globally, with increasing incidence and mortality rates. Most patients are diagnosed at advanced stages, missing the opportunity for radical treatment. Sorafenib, a tyrosine kinase inhibitor, is the first-line treatment for advanced HCC; however, drug resistance typically develops within 6 months. Therefore, elucidating the mechanisms of sorafenib resistance and identifying new therapeutic targets are of significant importance. Our study focuses on the role and mechanism of Ribonucleotide Reductase M2 (RRM2) in sorafenib resistance in HCC.

Aims & Methods

The primary objective of this study is to investigate the role of RRM2 in sorafenib resistance in HCC and explore its underlying mechanisms. We aim to clarify whether RRM2 regulates aerobic glycolysis via the HIF-1α/HK2 pathway, thereby affecting sorafenib sensitivity. Our methods include:

• Analyzing RRM2 expression in HCC tissues and its correlation with clinical outcomes, such as disease-free survival (DFS) and overall survival (OS).
• Establishing sorafenib-resistant HCC cell lines (LM3-SR and SMMC7721-SR) and manipulating RRM2 expression using lentiviral vectors for knockdown and overexpression.
• Conducting in vitro experiments to assess the effects of RRM2 on cell proliferation, apoptosis, glycolysis, and sorafenib sensitivity using assays such as CCK8, flow cytometry, and Seahorse analysis.
• Performing in vivo studies using a nude mouse xenograft model to evaluate the impact of RRM2 knockdown on tumor growth and sorafenib efficacy.
• Utilizing RNA-seq, Western blot, PCR, and other techniques to investigate the molecular mechanisms, including the potential regulation of HIF-1α and HK2 by RRM2.

Results

• Clinical Correlation: RRM2 expression was significantly higher in HCC tissues compared to adjacent normal tissues. Higher RRM2 levels were associated with shorter DFS and OS in HCC patients.
• In Vitro Findings: RRM2 knockdown in sorafenib-resistant HCC cells (LM3-SR and SMMC7721-SR) increased sensitivity to sorafenib, as evidenced by reduced cell viability and increased apoptosis. Additionally, RRM2 knockdown decreased glycolysis, as indicated by reduced lactate production and glucose uptake. Conversely, RRM2 overexpression in HCC cells promoted resistance to sorafenib and enhanced glycolysis.
• Molecular Mechanisms: RRM2 regulated the expression of glycolytic enzymes, particularly HK2, through the HIF-1α pathway. Knockdown of RRM2 reduced HIF-1α and HK2 expression, while overexpression of HIF-1α or HK2 could reverse the effects of RRM2 knockdown on glycolysis and sorafenib sensitivity.
• In Vivo Validation: In a nude mouse xenograft model, RRM2 knockdown enhanced the inhibitory effects of sorafenib on tumor growth, as demonstrated by reduced tumor volume and increased apoptosis.

Conclusion

Our study demonstrates that RRM2 plays a crucial role in sorafenib resistance in HCC by regulating aerobic glycolysis via the HIF-1α/HK2 pathway. Targeting RRM2 or its downstream pathways may represent a promising strategy to overcome sorafenib resistance and improve therapeutic outcomes in HCC patients. Future work will focus on further elucidating the molecular mechanisms and exploring the potential clinical applications of RRM2 as a therapeutic target.

Disclosure

The authors declare that they have no conflict of interest.