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

Tofacitinib is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC). The recommended induction scheme is 10 mg twice daily (BID) for at least 8 weeks followed by a maintenance dose of 5 mg BID. However, some patients require 10mg bid, for 16 weeks at the induction phase. Our study aimed to assess the demographics and disease characteristics of such patients and their outcome at 24 weeks.

Aims & Methods

This was a multicenter, retrospective, observational study which included patients with moderate to severe UC, who received induction therapy with Tofacitinib 10mg bid for a 16-week period. Data were collected between July 2018 and November 2022. The primary objective was disease outcome, defined as clinical remission and/or the need of steroids. Secondary outcomes were treatment withdrawal, treatment de-escalation and adverse events.

Results

In total 31 patients, are currently enrolled in our study, from 10 IBD centres [males: 51.6%, mean age at study entry: 40.0 years, median disease duration: 7 years]. Patient demographic and clinical characteristics at baseline are shown in table 1. Four patients (12.9%) discontinued treatment before week 24, due to inadequate response. De-escalation of dosing to 5mg bid tofacitinib was attempted in 13 of 27 patients (48.1%) and was successful in 7 patients (53.8%) who maintained clinical response until week 24 of the study. Of the other 6 out of 13 patients, 6 patients received again the higher dose (10 mg bid) and regained response and only one patient discontinued treatment. Overall, 85.7% (6/7) of the patients who received tofacitinib 5mg bid and 66.7% (14/21) who received 10mg bid at 24 weeks, had received more than one biologic prior to tofacitinib (P=0.34). At week 24, the partial Mayo score was available in 26 patients; 13 patients were in steroid-free clinical remission (pMayo <2). Twelve patients had mild active disease (pMayo 2-4) and 9 of them had stopped steroids. No major adverse events were observed during the entire observation period.

Conclusion

In a real-world setting, a 24-week treatment with tofacitinib 10mg BID is safe and the majority of patients achieve clinical remission and manage to stop steroids. De-escalation at 5mg bid is successful in more than half of them. We prospectively follow up our cohort to investigate whether these preliminary results will be confirmed for a longer period.

Introduction

Subcutaneous (SC) Infliximab (IFX) is non-inferior to intravenous (IV) IFX, for maintenance of remission in inflammatory bowel disease (IBD) (1). There are limited data on factors affecting the decisions of patients who choose SC administration of biologics (2, 3). Our centre offered suitable patients SC IFX from November 2022.

Aims & Methods

(1) Determine disease-related, economic, social and personal factors that affect the decision of a patient with IBD to transition from IV to SC administration of IFX.
(2) Assess effects of SC administration on pharmacokinetics and disease control. Participants completed a questionnaire on their IBD history, personal and financial circumstances, and reasons for electing or declining to transition. Clinical and biochemical data were retrieved from the electronic patient record (EPR). A bivariable logistic regression model was used to determine factors associated with electing to transition.

Results

144 patients were offered the opportunity to transition during the study period. 80 (55.5%) agreed to transition, 64 (44.5%) declined. 101 patients (70.1%) agreed to participate in the study. 59.4% were male, 67.3% had Crohn’s disease. Age ranged was 18-82 (median 41) years. Infusion frequency was every 4 (9.8%), 6 (22.8%), 7 (2.0%), or 8 weeks (65.4%). 76% were employed/self-employed, 41.6% had a medical card and 44.6% had private health insurance. Median (IQR) travel time was 90 mins (40, 130). 48 patients (47.5%) reported that they missed school/work for their infusions. At baseline, median (IQR) laboratory results were CRP 1.2mg/L (0.6, 2.7), IFX trough 7.4mg/mL (4.9, 11.8), faecal calprotectin 39 mg/g (10, 98), IBD-Control 14 (13, 16). 8 weeks after first SC dose, median (IQR) results (n=36) were CRP 1.1mg/L (0.8, 2.0) IFX trough 17.8mg/mL (12.5, 21.4), IBD-Control 16 (14, 16). The strongest reasons to transition (% agree/ strongly agree on five-point Likert) were, “I want to transition because it will…”
(1) reduce my travel time (94.5%),
(2) fit my work/life balance better (87.3%) and
(3) reduce my time away from work/school (74.5%). The strongest reasons against transition were,
(1)I would miss having my bloods checked regularly (84.8%),
(2) I feel safer attending the infusion unit (80.4%),
(3) I would not be able to voice concerns about my treatment as easily (80.4%) and
(4) I would miss regular contact with a healthcare professional (69.6%). Table 1 shows results of binary logistic regression used to determine factors associated with the likelihood of electing to transition.

Conclusion

SC IFX is safe, effective and well-tolerated by those who choose to transition. It is attractive to many patients, because attending for IV infusions can interrupt their employment, education and family life, but cost is a significant barrier for some patients. IBD teams must be adequately resourced to assure patients who transition that they will continue to have ready access to high-quality medical care and disease monitoring. Discrepancies in healthcare markets may provide a perverse incentive to continue receiving IV biologic, for those who would prefer SC.

References

1. Schreiber S, Ben-Horin S, Leszczyszyn J, Dudkowiak R, Lahat A, Gawdis-Wojnarska B, et al. Randomized Controlled Trial: Subcutaneous vs Intravenous Infliximab CT-P13 Maintenance in Inflammatory Bowel Disease. Gastroenterology. 2021;160(7):2340-53.
2. Remy C, Caron B, Gouynou C, Haghnejad V, Jeanbert E, Netter P, et al. Inflammatory Bowel Disease Patients’ Acceptance for Switching from Intravenous Infliximab or Vedolizumab to Subcutaneous Formulation: The Nancy Experience. Journal of Clinical Medicine. 2022;11(24):7296.
3. Ventress E, Young D, Rahmany S, Harris C, Bettey M, Smith T, et al. Transitioning from Intravenous to Subcutaneous Vedolizumab in Patients with Inflammatory Bowel Disease [TRAVELESS]. Journal of Crohn's and Colitis. 2022;16(6):911-21.