Introduction

Radical resection in the rectum is associated with significant morbidity and poses a mortality risk, particularly in elderly or comorbid patients. Early or T1 rectal cancer is often curable and can be managed with local endoscopic resection techniques with reduced morbidity and negligible mortality. To establish a pathway for appropriate treatment of these early lesions through the multidisciplinary team (MDT), an early rectal cancer working party (ERCWP) was formed to evaluate management trends and outcomes within our hospital network. The ERCWP was multi-speciality comprising of gastroenterologists, colorectal surgeons and radiation oncologists.

Aims & Methods

A retrospective review was performed across four institutions that make up our network to identify all patients with a new diagnosis of localised (T1-T4,N0,M0) rectal or recto-sigmoid cancer between January 2015 and August 2023. Patients with confirmed adenocarcinoma staged as T1N0M0 or T2N0M0 were included in the analysis. Available electronic medical records from the time of index resection and all encounters for the following 12 months were reviewed. Patients were excluded if their treatment was completed at an outside institution. Patient outcomes were stratified by location of tumour (rectum / recto-sigmoid) and mode of resection (Endoscopic resection, Local surgical excision or Radical surgical resection). Major adverse events included any one of the following: ostomy, deep incisional site infection, abscess, wound dehiscence, pneumonia, sepsis, septic shock, acute renal failure, deep venous thrombosis, pulmonary embolus, stroke/cerebrovascular accident, myocardial infarction, ventilator >48 hours, still in hospital >30 days, cardiac arrest, reoperation, readmission and/or mortality.

Results

A total of 111 localized (T1/T2,N0) and 153 locally advanced (T3/T4,N0) lesions were newly diagnosed during the study period. 95/111 patients with localized disease were included (M=62/95, 65.3% F=33/95, 34.7%). Mean age was 67.8 years in the endoscopy group and 67.0 years in the radical surgical resection group. Mortality was 2.2% in the group of patients who had surgery (1/46). There was no mortality in patients who received endoscopic resection. Major adverse events were recorded in 16/46 (34.8%) of patients who underwent surgery. There were no major adverse events in patients who received endoscopic resection. Mean length of stay was 1.47 days in patients who had endoscopic resection and 10.2 days in patients who had radical resection. Mean length of stay was prolonged where there was a treatment related major adverse event (14.8 days, mean difference 9.8 days, p=<0.001). 78.5% (51/65) of the cohort with T1 cancer was low risk (well or moderately well differentiated and no lymphovascular invasion). Of the 16 patients with T1 rectal cancer who underwent definitive surgery, 15 (93.8%) were suitable for cure by en-bloc endoscopic excision. Following establishment of the ERCWP in 2020, there have been no cases of radical resection in the rectum for T1 cancer. For T1 cancer in the rectum, major adverse events were 5/34 (14.7%) pre ERCWP formation and 1/13 (7.7%) post ERCWP formation (p=<0.001).

Conclusion

Surgery carries a high risk of morbidity in patients with rectal cancer. Endoscopic resection carries a favourable risk profile and is currently being underutilised. Formation of a local expert group focusing on outcomes in T1 cancer can reduce unwarranted variation and similar groups should be formed at local institutions to optimise patient outcomes.

Introduction

Gastric cancer (GC) is a multifactorial disease, with a significant microbial contribution. Beyond Helicobacter pylori, the bacterium most commonly linked to GC, lactic acid-producing bacteria (LAB) have been frequently reported to be more abundant in later stages of the gastric carcinogenesis cascade. LAB are known for producing considerably large amounts of the oncometabolite lactate, which is strongly linked to the main hallmarks of cancer (i.e., inflammation, immune escape, angiogenesis, invasion, and metastasis).

Aims & Methods

We aimed to understand the potential association of LAB with gastric precancerous lesions (GPL) and GC in two high-risk populations (Colombian Mestizo and Han Chinese). DNA and RNA were simultaneously extracted from snap frozen gastric biopsies from subjects presenting with functional dyspepsia, GPL (atrophic gastritis, intestinal metaplasia, and dysplasia), and GC. 16S gene (DNA, n=257) and transcript (cDNA, n=129) amplicons (V4 region) were sequenced with Illumina MiSeq 2x250 bp. Alpha, beta, and per-taxa analyses were performed.

Results

H. pylori significantly impacted the diversity and composition of the gastric microbiota. Gastric active microbiota (cDNA) assessment showed that there were significant differences in beta diversity between FD controls and GPL and GC patients. Further, there were strong positive associations between LAB, including Otu00023.Lactobacillus (100% similarity to Lactobacillus gasseri), Otu00045.Limosilactobacillus (100% similarity to Limosilactobacillus fermentum), Otu00046.Oribacterium (100% similarity to Oribacterium sinus), Otu00120.Streptococcus (100% similarity to Streptococcus anginosus), and Otu00232.Limosilactobacillus (100% similarity to Lactobacillus timonensis) and disease status (GPL and GC). These findings were maintained even when Otu00001.Helicobacter (100% similarity to H. pylori) was removed from the analysis, evidencing a strong signature of LAB regardless of the presence of H. pylori in the active gastric microbiota. Enrichment of Otu00046.Oribacterium and Otu00023.Lactobacillus in GPL and GC patients, was validated when the gastric resident/transient microbiota was assessed (DNA).

Conclusion

The gastric active microbiota of GPL and GC patients from two high-risk populations geographically and ethnically diverse is significantly dominated by LAB (Otu00046.Oribacterium and Otu00023.Lactobacillus), demonstrating a potential role for these bacteria in the pathogenesis of GC. Assessment of the viable gastric microbiota appears to be more informative compared to resident/transient microbiota assessment.

Introduction

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome caused by mutations in the APC gene, a negative regulator of the Wnt signaling pathway. It is characterized by the development of hundreds to thousands of Wnt-driven adenomatous polyps in the colon. To prevent the inevitable progression to colorectal cancer, patients with FAP typically undergo total proctocolectomy in early adulthood. Currently, no effective medical therapy exists for FAP. Casein kinase I alpha (CKIα), another negative regulator of Wnt signaling, has emerged as a potential therapeutic target. Prior work in our lab demonstrated that, unlike APC loss, epithelial deletion of Csnk1a1 (CKIα) in the gut does not induce tumorigenesis. Instead, it activates a non-canonical DNA damage response, leading to robust p53 stabilization and suppression of tumorigenic changes. Given that TP53 mutations are typically late events in the adenoma–carcinoma sequence, early-stage lesions in FAP often retain wild-type p53. Unlike sporadic adenomas, which can be resected during colonoscopy, the high polyp burden in FAP precludes endoscopic management, underscoring the need for effective chemoprevention.

Aims & Methods

Our aim in this work was to investigated CKIα as a therapeutic target in preclinical models of FAP.
We employed Csnk1a1^fl/fl, APC^fl/fl, Villin-CreERT2, and CDX2-CreERT2 transgenic mice for in vivo studies, with tamoxifen-inducible gene ablation. Intestinal organoids derived from normal and tumor tissues were used for ex vivo experiments.

Results

In vivo, simultaneous deletion of APC and CKIα in intestinal epithelium did not further enhance Wnt target gene expression compared to APC loss alone. Instead, dual knockout (DKO) stabilized p53, promoted apoptosis, and blocked the dysplastic progression normally observed in APC-deficient gut tissue. In organoid models, treatment with the novel CKIα degrader BTX1050 selectively inhibited tumor-derived organoid proliferation, but did not fully eliminate tumor-initiating cells. We therefore tested A51, a dual CKIα and CDK7/9 inhibitor developed in our lab, which both stabilized and activated p53 and suppressed transcription of super-enhancer-driven oncogenes. A51 treatment significantly downregulated Myc and Mcl1, increased apoptosis in tumor organoids, but only partially suppressed tumor growth in vivo. Notably, A51 induced MAPK pathway activation, as indicated by increased pERK levels. This prompted combination therapy with A51 and the MEK inhibitor trametinib, which demonstrated potent synergistic anti-tumor activity in both organoid and mouse models.

Conclusion

CKIα depletion exerts anti-tumor effects in intestinal tumor models with wild-type p53. Our findings support the combination of A51 and MEK inhibition as a promising "chemical polypectomy" approach for FAP patients.

Disclosure

n/a

Introduction

Intentional foreign body ingestion (iFoBI) is seen mainly among prisoners for secondary gains and in patients with psychiatric illness. European Society of Gastrointestinal Endoscopy (ESGE) guideline suggests that endoscopic removal is preferred for objects retained in the esophagus, large (≥2.5 cm in diameter) objects retained in the stomach, or long (≥ 5-6cm) or sharp objects in the stomach and proximal duodenum. We have seen a surge in the number of admissions with iFoBI at our hospital related to a change in pain medication policy at a local prison, with ensuing protests action. This presented an opportunity to study the outcomes and certain aspects of management in this group of patients. There is limited data on the outcome of non-endoscopic management of sharp ingested foreign bodies and the impact on length of stay. The aim of this study was to describe our experience and outcomes of patients admitted with iFoBI at our centre.

Aims & Methods

We performed an observational retrospective study of all patients presenting with iFoBI at our hospital between October 2021 and December 2022 during which time we had a surge of admissions with iFoBI related to a change in pain medication policy at a local prison, with ensuing protests action. The nature, number, and location of ingested foreign body on imaging, outcomes as well as the management method including conservative, endoscopic removal and surgical treatment were analysed. We also analysed timing of endoscopy, impact of diet and laxatives and length of stay.

Results

A total of 49 episodes of iFoBI in 25 patients presented during the study period. All patients were male prisoners with a median age 33 years and 59% of UAE nationality. None of the episodes of iFoBI presented with oesophageal impaction. Ingested objects were variable in number and type, but they were mostly metallic, and 11 objects were regarded as high-risk objects such as sharp metal objects ≥ 5cm. Upper endoscopy was carried out in 11/49 based on ESGE guidelines of which 55% were after working hours which imposed a significant impact on the service. Most objects were not within endoscopic reach on presentation and patients were managed conservatively. Only one patient required surgical intervention to remove a 9 cm sharp metallic object that became impacted at the ileocecal junction and was causing significant edema and peri-terminal ileum inflammation as seen on cross sectional imaging. There was no relationship between the timing of endoscopy and complications such as perforation or obstruction (p value 0.035) or length of stay (p value 0.036). However, length of stay was prolonged while waiting for psychiatric evaluation (p value 0.056).

Conclusion

The majority of ingested foreign bodies, including sharp metallic objects, pass through the gastrointestinal tract spontaneously and without complications. Middle of the night endoscopy, which has significant impact on staff and resources, can be avoided in most cases of iFoBI except those with esophageal impaction. Most patients can be managed with watchful waiting and serial exams. Effective management strategy requires multidisciplinary approach to address the root causes for this behaviour with the aim of reducing future admissions with iFoBI.

References

1. Birk M, Bauerfeind P, Deprez PH, et al. Removal of foreign bodies in the upper gastrointestinal tract in adults: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline. Endoscopy. 2016;48(5):489-496. doi:10.1055/s-0042-100456
2. Yadollahi S, Buchannan R, Tehami N, et al. Endoscopic management of intentional foreign body ingestion: experience from a UK centre. Frontline Gastroenterol. 2021;13(2):98-103. Published 2021 Apr 8. doi:10.1136/flgastro-2021-101776