Introduction

It is known that there are sex differences in the characteristics of colorectal cancer (CRC), such as incidence and prognosis. However, there is still a lack of understanding on the underlying mechanisms of its sex difference.

Aims & Methods

The aim of this study was to investigate the correlation between the clinicopathological features and the molecular characteristics of CRC depending on sex. 1,068 patients diagnosed with CRC and treated (surgery, chemotherapy or supportive care) at Seoul National University Bundang Hospital were prospectively enrolled. Basic characteristics such as sex, age, and social history, clinical characteristics such as tumor location, stage, and survival were analyzed. In addition, molecular expressions of microsatellite instability (MSI), oncogenes including K-ras, N-ras and H-ras, and DNA mismatch repair genes including MLH-1, MSH-2, MSH-6 and PMS-2 were also investigated.

Results

There were 630 males and 438 females, with a sex ratio of 1.5:1. Risk behaviors for cancer occurrence, such as drinking and smoking, were much more common in males (p < 0.001, respectively). In females, right colon cancer was more frequent than in males (p = 0.022), which seems to be associated with the loss of MLH-1 (p < 0.001) and PMS-2 expression (p = 0.003) (Table). In multivariate regression analyses, older age (p = 0.001), lower BMI (p < 0.001), presence of symptoms (p = 0.048), advanced cancer stage (p < 0.001) and mutation of BRAF (p = 0.030) were significant risk factors for disease-related death. Females showed better overall survival (p = 0.031) as well as disease-specific survival than males (p = 0.088), and this difference was most pronounced in age 40-69 group (overall survival p = 0.024; disease-specific survival p = 0.104, respectively), while not evident in the younger and older age groups (Figure).

Conclusion

Colorectal cancer shows sex differences in various characteristics including incidence, tumor location and prognosis, which might be originated from sex hormone and molecular characteristics.

Introduction

Recently, the increase of young-onset colorectal cancer (yCRC) has been reported, and the age at which colorectal cancer screening is started has been lowered in some countries. Although the characteristics of advanced-stage yCRC or high-grade dysplasias(HGDs) have been reported, there have been few reports of early-stage yCRC or HGDs so far.

Aims & Methods

The aim of this study is to investigate the clinical and pathological characteristics of early-stage yCRC and colorectal HGDs. We retrospectively reviewed the electrical health record data of pathologically diagnosed pT1 colorectal cancers and colorectal HGDs that were resected endoscopically or surgically in our institution from January 2019 to December 2021. The pathological diagnosis was done according to the Japanese Classification of Colorectal Carcinoma. The cases were categorized into two groups: the young group (Y group) or the elderly group (E group). The definition of Group Y and Group E were patients aged 50 years or younger, and those aged 51 years or older respectively. The following factors were evaluated by univariate analysis; age, sex, and the number of experienced endoscopies of the patients; location, size, macroscopic type, histology of the lesion; and depth of invasion. Regarding the morphology or the lesions, 0-Ip, and 0-Is were categorized as protruded lesions, whereas 0-IIa and 0-IIc were categorized as superficial lesions. Statistical analysis was done by the Mann-Whitney U test for continuous variables and Fisher’s exact test for categorical variables. All tests were two-sided, and P<0.05 was considered to be statistically significant.

Results

There were 34 cases in group Y and 314 cases in group E, with a median age (range) of 45 years old (32-50) and 72 years old (51-93), respectively. Sex was male:female=20:14 and male:female=204:110. First-time examination cases were significantly higher in the Y group than in the E group (91.2%:50.6% ;P<0.0001). Regarding the location, the sigmoid colon was the most common in both Y and E groups (55.9%:30.3%). The number of CRC in the left side colon is significantly larger in the Y group than in the E group (79.4%: 62.7%; p=0.0375). In terms of macroscopic type, 0-Ip was most common in group Y(16(41.7%)), whereas 0-lla was most common in group E(137(43.6%)). The number of protruded type early-stage CRC is larger in the Y group than in the E group (82.3%: 58.9%; p=0.005). The median tumor diameter (range) was 16 mm (8-60) and 12 mm (5-155) in Y and E groups respectively. Regarding the histology, well-differentiated tubular adenocarcinoma (Tub1) was the most common histological type in both groups, they were 32(94.1%) in group Y and 282(89.8%) in group E respectively(p=0.4756). pTis (HGDs) were also the most common depth of invasion in both group, they were 25(73.5%) in group Y and 241(77.0%) in group E respectively(p=0.7903).

Conclusion

Compared with early CRC in elderly patients, early-stage yCRC and HGDs were more common in the left side colon and showed a protruded type.

Introduction

Colorectal cancer (CRC) is the 3rd most common cancer worldwide. Approximately 85% of CRC develop on a background of Wnt/β-catenin signalling impairment. Familial adenomatous polyposis (FAP), caused by inherited APC gene mutations (part of the β-catenin destruction complex), is characterized by the development of hundreds to thousands adenomatous polyps. FAP patients have up to 100% risk of developing CRC during their lifetime. The Wnt/β-catenin together with the PI3K/mTOR signalling control the self-renewal and homeostasis of intestinal stem cells and are frequently deregulated in CRC therefore representing attractive targets for chemoprevention and treatment [1], [2]. It has been shown that each pathway may be deregulated by an altered composition of the gut microbiota [3], [4], which plays an important role in the onset, development and progression of CRC thus representing potential target for prevention and potentially biomarkers for the early detection of deranged Wnt/β-catenin-driven lesions [5].

Aims & Methods

The aim of the study was to identify potential targets for the prevention and early detection of CRC in the setting of Wnt/β-catenin disruption.
Transcriptional and translational levels of Wnt/β-catenin and PI3K/mTOR pathways were evaluated by RT-qPCR and immunohistochemical analysis, respectively, in FAP adenomas (n=17 patients) and in sporadic CRC tissues (tumor stages I-III; n=15 patients). In FAP adenomas germline and somatic APC mutations were confirmed by Sanger and Targeted Next Generation Sequencing. The composition of oral, fecal and mucosal-associated microbiota was sequenced by the bacterial 16S rRNA gene. Non-diseased Faecal Immunochemical Testing positive subjects (FIT+; n=17) were included as control group.

Results

We found increased expressions of AXIN2 and cMYC, downstream targets of Wnt/β-catenin, in FAP adenomas. The activation status of PI3K/mTOR was confirmed by an increase of RPS6 gene and pS6R protein expression, indicating that germline and somatic APC mutations of FAP adenomas induce an activation of both pathways. On the other hand, compared to FAP adenomas, a higher expression of AXIN2, cMYC and cytosolic and nuclear β-catenin was found in CRC, while no changes were detected in pS6R, suggesting that the hyperactivation of Wnt/β-catenin in sporadic CRC contributes to the impairment of mTOR signalling. Importantly, we analyzed the microbiome composition in FAP and CRC settings. The oral microbiota of FAP was significantly enriched of Proteobacteria (p<0.01), which decreased in FAP adenomatous mucosal samples compared to FIT+ and CRC. In contrast, Firmicutes showed an opposite trend in FAP patients, with a decrease in the oral composition (p<0.01) and an increase in the adenomatous mucosa (p<0.05). Interestingly, a significant decrease of the CRC-protective phylum Actinobacteria was found in oral and adenomas microbiota of FAP patients compared to FIT+. In contrast, CRC fecal microbiota was enriched of Proteobacteria and a higher abundance of the well-known cancer associated families Fusobacteriaceae, Clostridiaceae and Gemellaceae was found in CRC mucosal samples compared to FIT+.

Conclusion

These findings reveal new insights into the role of Wnt/β-catenin and PI3K/mTOR pathways in influencing the homeostasis of precancerous CRC lesions. Moreover, by defining different microbial signatures in FAP patients, these results will contribute to the enhancement of non-invasive screening tools for the early detection of WNT signalling-driven colorectal cancers.

References

[1] X. Cheng, X. Xu, D. Chen, F. Zhao, and W. Wang, “Therapeutic potential of targeting the Wnt/β-catenin signaling pathway in colorectal cancer,” Biomed. Pharmacother., vol. 110, pp. 473–481, 2019, doi: https://doi.org/10.1016/j.biopha.2018.11.082.
[2] J. Zhang, T. M. Roberts, and R. A. Shivdasani, “Targeting PI3K Signaling as a Therapeutic Approach for Colorectal Cancer,” Gastroenterology, vol. 141, no. 1, pp. 50–61, 2011, doi: https://doi.org/10.1053/j.gastro.2011.05.010.
[3] M. H. Noureldein and A. A. Eid, “Gut microbiota and mTOR signaling: Insight on a new pathophysiological interaction,” Microb. Pathog., vol. 118, no. March 2018, pp. 98–104, 2018, doi: 10.1016/j.micpath.2018.03.021.
[4] O. Silva-García, J. J. Valdez-Alarcón, and V. M. Baizabal-Aguirre, “Wnt/β-catenin signaling as a molecular target by pathogenic bacteria,” Front. Immunol., vol. 10, no. SEP, pp. 1–14, 2019, doi: 10.3389/fimmu.2019.02135.
[5] J. H. Kim, Y. J. Kim, G. M. Oh, W. Jung, and S. J. Park, “How is gut microbiome of patients with familial adenomatous polyposis different from healthy people?,” Medicine (Baltimore)., vol. 101, no. 49, p. e32194, Dec. 2022, doi: 10.1097/MD.0000000000032194.

Introduction

The role of capsule endoscopy (CE) for the surveillance of small-bowel (SB) cancer in asymptomatic Lynch syndrome (LS) patients has been questioned in recent years, with contradicting results. The overall lifetime risk of SB cancer in this population is around 4-5%, with an age-dependent pattern [1]. Besides, recent data highlight that, depending on the affected path_MMR gene, the frequencies of tumors other than colorectal cancer vary and that affected patients develop subsequent cancers later in life. The aim of this meta-analysis is to evaluate the diagnostic yield (DY) of CE as a screening tool in asymptomatic LS patients.

Aims & Methods

A systematic literature search was conducted in Pubmed, Embase and Web of Science to identify all studies evaluating SB cancer surveillance with CE in asymptomatic LS patients. The primary outcome was the evaluation of the DY of CE in consecutive screening rounds, for both CE-identified pathology and histologically-confirmed pathology (i.e., adenoma or adenocarcinoma). Pooled estimates of DY were calculated from random effects models.

Results

Five studies including 583 patients were identified for data extraction and statistical analysis [2-6] [Table]. The estimated pooled DY for CE-identified pathology was 8% in the first screening round (95% confidence interval [CI] 4-12%) and 6% in the second (95% CI 2-10%). Limiting the analysis to histologically-confirmed pathology, the pooled DY of the second-round screening dropped to 0% (95% CI 0-6%). The time interval between screening rounds was approximately 2 years.
Adenomas were detected in 8 patients (4 males) with a median age of 47.5 years (interquartile range [IQR] 19), while adenocarcinomas were diagnosed in 8 patients (5 males) with a median age of 62.5 years (IQR 17.25). MLH1 was the most involved path_MMR pathogenic variant (9 out of 16 patients), followed by MSH2 and MSH6 (5 and 2 patients, respectively). No adenocarcinomas were detected in MSH6 carriers, as only adenomas were found in 2 patients, with a considerably higher median age than MSH2 and MLH1 adenoma carriers (70.5 years versus 43.5 and 45). No predominance was observed according to the anatomical location (duodenum, n=6; jejunum, n=6; ileum, n=4).

Conclusion

The detection of adenocarcinoma appeared to have a 15-year delay compared to adenomas, supporting a rather slow adenoma to carcinoma transition.
A surveillance strategy starting from the age of 50, with a time interval between procedures lengthened to at least 5 years (instead of 2) could likely be more effective in reducing the burden of advanced disease, both in terms of cost-effectiveness and efficacy. Prospective data may reveal whether a potential SB surveillance might benefit from gene-associated differences in cancer risk, similar to the recent de-escalation of CRC screening recommendations in MSH6 and PMS2 carriers [7].
In conclusion, although the DY of CE is high in detecting SB lesions in LS, the low number of positive examinations eventually resulted in an even lower number of true-positive patients, with a pooled yield proximate to 0%.
The results of this study confirm that SB cancer surveillance with CE with a 2-year interval in asymptomatic LS individuals is not an effective screening strategy.

References

[1] Dominguez-Valentin M, Sampson JR, Seppälä TT, et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med 2020;22:15–25.
[2] Saurin J-C, Pilleul F, Soussan EB, et al. Small-bowel capsule endoscopy diagnoses early and advanced neoplasms in asymptomatic patients with Lynch syndrome. Endoscopy 2010;42:1057–62.
[3] Haanstra JF, Al-Toma A, Dekker E, et al. Prevalence of small-bowel neoplasia in Lynch syndrome assessed by video capsule endoscopy. Gut 2015;64:1578–83.
[4] Haanstra JF, Al-Toma A, Dekker E, et al. Incidence of small bowel neoplasia in Lynch syndrome assessed by video capsule endoscopy. Endosc Int Open 2017;5:E622–E626.
[5] Perrod G, Samaha E, Perez-Cuadrado-Robles E, et al. Effectiveness of a dedicated small bowel neoplasia screening program by capsule endoscopy in Lynch syndrome: 5 years results from a tertiary care center. Ther Adv Gastroenterol 2020;13:1756284820934314.
[6] DeJesse J, Vajravelu RK, Dudzik C, et al. Uptake and outcomes of small intestinal and urinary tract cancer surveillance in Lynch syndrome. World J Clin Oncol 2021;12:1023–36.
[7] Peltomäki P, Nyström M, Mecklin J-P, et al. Lynch syndrome genetics and clinical implications. Gastroenterology 2023 Jan 24;S0016-5085(23)00050-1. doi:10.1053/j.gastro.2022.08.058 [Online ahead of print]

Introduction

Hepatocellular carcinoma (HCC) is the second-most deadly cancer. Pathological examination is the gold standard for subtype differentiation. Patients with macrotrabecular HCC (MTHCC) have more aggressive lesions, higher recurrence rates and poorer survival. Radiomics can be seen as a digital biopsy that allows a characterization of tumor heterogeneity and phenotypes.

Aims & Methods

This study aims to evaluate the diagnostic accuracy of radiomics in predicting MTHCC subtype, considering that this could change the approach of the patient. We performed a systematic review in PubMed, Embase and Cochrane databases, searching for studies evaluating the diagnostic accuracy of radiomics in predicting the MTHCC subtype. Statistical analysis included data pooling and heterogeneity testing.

Results

The meta-analysis included 6 studies and 529 patients. Data of the training cohort were not considered. When internal and external validation cohorts were available, both were considered. The pooled sensitivity and specificity and AUC of radiomics for predicting MTHCC were 75.3% (95% CI 66.4% to 82.5%), 71.8% (95% CI 60.6% to 80.8%) and 0.792 (95% CI 0.697 to 0.833).

Conclusion

Our study shows that radiomics does not have enough diagnostic accuracy to predict MTHCC with a high degree of certainty. However, this could be an additional resource to improve radiological diagnosis. Improvements in this field are necessary once the diagnosis of this HCC subtype can change the management of the patient.