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.

Clinical Case Summary

Crohn’s disease (CD) is a multi-factorial immune-mediated inflammatory condition of the gastrointestinal tract (GIT). While CD-related granulomas typically occur within the GIT, they can appear in other areas such as lymph nodes, mesentery, peritoneum, liver, and lungs. This case highlights a rare instance of renal granuloma secondary to CD and discusses an effective treatment approach. An 18-year-old male presented to a GP with a one-year history of abdominal pain. There was no significant medical or family history. Physical examination was unremarkable. Laboratory findings showed raised white cell count, elevated erythrocyte sediment rate, and renal dysfunction. He was referred to a nephrologist who noted additional symptoms of diarrhoea and occasional per-rectal bleeding with no significant improvement in symptoms or renal function after complete cessation of non-steroidal anti-inflammatory drugs. Renal biopsy confirmed acute interstitial nephritis and granuloma, therefore he was referred to a gastroenterologist to rule out CD or sarcoid. Colonoscopy showed pancolitis with rectal sparing and segmental biopsies revealed chronic colitis with granulomas confirming CD. Fecal calprotectin was raised. Further investigations ruled out autoimmune disease, tuberculosis and sarcoidosis as causes for renal impairment. Treatment involved steroid tapering followed by intravenous infliximab induction and maintenance therapy with subcutaneous injections fortnightly. Renal function and GIT symptoms improved with infliximab monotherapy, though dose escalation to weekly infliximab injections was required at seven months due to loss of response from subcutaneous infliximab. At one year, colonoscopy showed endoscopic remission, with ongoing improvement in renal function (creatinine 194 to 111 umol/L) and resolution of pyuria. In conclusion, we present a rare case of CD-associated interstitial nephritis, showing a positive clinical response to infliximab monotherapy.

References

1. Lamb CA, Kennedy NA, Raine T, et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut. 2019;68:s1-s106.
2. Eade MN, Cooke WT, Williams JA. Liver disease in Crohn's disease. Scand J Gastroenterol. 1971;6:199-204.
3. Whitehead R. Pathology of Crohn's disease. In: Kirsner JB, Shorter RG, eds. Inflammatory bowel disease. 2nd ed. Philadelphia: Lean and Febiger; 1980:296-310.

Disclosure

Nil

Introduction

Acute infusion-related reactions (IRRs) are common adverse events associated with infliximab, affecting up to 23% of patients. Their etiology involves cytokine release, complement activation, and mast cell degranulation. Consequently, individuals with a history of immunological hypersensitivity reactions are often perceived to be at high risk due to their exaggerated immune responses, and are frequently prescribed premedication.

Aims & Methods

We aimed to determine if patients with immunological hypersensitivity background, receiving infliximab for inflammatory bowel disease (IBD), have an increased risk of IRRs. This retrospective cohort study included all patients diagnosed with IBD who underwent intravenous (IV) infliximab at our centre over a 13-year period. All patients received standard infliximab 2-hour infusion protocol, preceded by premedication with 200mg of IV hydrocortisone. IRRs were defined as any type of mild to severe reaction occurring during infusion or within 2 hours of its completion. Patients were considered to have an allergic predisposition if they had atopic diathesis (such as allergic rhinitis, asthma or atopic dermatitis) or a documented history of allergy to other medications.

Results

Ninety-five patients, with a mean age of 35 ± 13 years at the initiation of infliximab therapy, were included in the study, with females accounting for 52.6%. The majority of patients were diagnosed with Crohn’s disease (n=76, 80%), while the remaining 19 patients (20%) had ulcerative colitis. A history of allergy was reported in 20 patients (21.1%) within the cohort.
Over the study period, a total of 258 person-years (PY) of exposure to infliximab were recorded, with a median of 12 infusions per patient (interquartile range: 5-33). In most cases, infliximab therapy was combined with immunomodulators (n=63, 66.3%).
Fourteen IRRs occurred during the follow-up period, resulting in an overall incidence rate of 49.5 per 1000 PY. Patients with and without a history of immunological hypersensitivity showed comparable incidence rates of IRRs (32.5 per 1000 PY and 57.8 per 1000 PY, respectively), as well as similar cumulative incidence (15% and 22.7%, respectively). No statistically significant difference was observed between the two groups (p=0.446).

Conclusion

Having an immunological hypersensitivity background does not appear to increase the risk of developing acute infliximab infusion-related reactions. Consequently, it does not warrant specific premedication or additional precautionary measures.

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.