Introduction

Post colonoscopy colorectal cancer (PCCRC) is colorectal cancer diagnosed after a normal colonoscopy with no cancer found. In England, the rate of PCCRCs has been decreasing but remains around 6.5% for colonoscopies performed from 2011-2013¹. English study suggested that 80% of PCCRCs are avoidable². We aim to analyse PCCRC cases using the local data and determine the demographics, nature of cancer and the cause of PCCRC.

Aims & Methods

The PCCRCS are identified following the linkage of Hospital Episode Statistics, Bowel cancer screening programme (BCSP) and cancer registry datasets. As new colorectal cancers are registered with the National Cancer Registration and Analysis Service (NCRAS), PCCRC cases will be identified. Each colorectal cancer (ICD-10 code C18-20) provisionally registered within the Hospital Episode Statistics dataset will be identified and determined whether a colonoscopy was performed within 6- 48 months before the diagnosis which failed to identify the cancer.
This audit includes patients diagnosed with PCCRC 6-48 months after a colonoscopy was performed in a single medical centre in England.
Once the cases had been confirmed, we reviewed the clinical, pathology and radiological findings of each case. We also looked at interval cancer which the World Endoscopy Organisation (WEO) defines as one diagnosed before the next recommended interval. Important to note that all interval cancers are PCCRCs but not all PCCRCs are interval cancer.

Results

39 cases were included and 29 were confirmed to be true PCCRC which fulfilled the above criteria. 7 did not meet the criteria. (2 index colonoscopies performed at other trusts, 3 missing data, 2 other types of cancers such as Neuroendocrine tumour and appendiceal tumour, 1 has <6 months to cancer diagnosis from index colonoscopy, 2 flexible sigmoidoscopy was performed as index colonoscopy to investigate per rectal bleeding but subsequent cancer was found in ascending colons).
52% (n=15) of patients were male with a median age of cancer diagnosis at 74 years old (range 22-84). In terms of PCCRC, 24% (n=7) presented via the National Bowel Screening Programme (BCSP), 14%(n=4) presented with per rectal bleeding, 7% (n=2) presented with abnormal imaging and the same proportion of patients presented due to anaemia, non-specific change in bowel habit, weight loss, diarrhoea, abdominal pain and surveillance for family history of gene mutation. 3% (n=1) were diagnosed after presenting for polypectomy and 3% (n=1) presented with intestinal obstruction.
In terms of investigations that led to PCCRC, 45% (n=13) were via 2-weeks-wait colonoscopy, 24% (n=7) were via National Bowel Screening Programme, 17% (n=5) were diagnosed by Computed Tomography (CT) imaging, 7% (n=2) via flexible sigmoidoscopy and 7% (n=2) was via surgically resected sample. Upon diagnosis of PCCRC, 7% (n=2) tested positive for Lynch syndrome, 24% (n=7) was tested but no marker was found and 69% (n=20) was not tested. In terms of size of PCCRC, 66% (n=19) had tumour size >2cm. 66% (n=17) of tumour size was determined by histopathological sample, 21 (n=6) via endoscopy, 3% (n=1) via CT imaging and 17% (n=6) was not known.
In terms of PCCRC staging, 48% (n=14) was Dukes’ A staging, 21% (n=6) was Dukes’ B, 7% (n=2) was Dukes’ C and 24% (n=7) was Dukes’ D. 83% (n=24) was planned for curative treatment and 17% (n=5) was planned for palliative treatment. 52% (n=16) had surgical resection only, 17% (n=29) had surgical resection and chemotherapy, 3% (n=11) had surgical resection and radiotherapy, 3% (n=1) had surgical resection, chemotherapy and radiotherapy, 7% (n=2) had chemotherapy and radiotherapy, 3% (n=1) had chemotherapy only, 3% (n=1) had endoscopic resection only and 7% (n=2) had no treatment.
In terms of the type of interval cancer, 14% (n=4) was non-interval A, 7% (n=2) was non-interval B, 66% (n=19) was non-interval C and 21% (n=4) was interval cancer. Important to note was 66% (n=19) had no further follow-up or test arranged due to adequate examination on the index endoscopy. 90% of index endoscopies report no difficulties. 75% (n=22) was due to clinician factors, 10% (n=3) was due to administrative errors such as booking delay and 10% (n=3) was due to patient factors such as patient’s decision and intercurrent illness.

Conclusion

The majority of the PCCRC had treatment with curative intent. Most PCCRC cases are due to clinician factors and measures needed to improve this. The high percentage of non-interval type C PCCRC would be explained by either a fast-growing cancer or a missed lesion since up to 90% of the index procedures reported no difficulty.

References

1. Burr NE, Derbyshire E, Taylor J, et al. Variation in post-colonoscopy colorectal cancer across colonoscopy providers in English National Health Service: population-based cohort study. BMJ 2019;367:l6090. doi:10.1136/bmj.l6090
2. Anderson R, Burr NE, Valori R. Causes of Post-colonoscopy Colorectal Cancers Based on World Endoscopy Organization System of Analysis. Gastroenterology Published Online First: January 2020. doi:10.1053/j.gastro.2019.12.03

Introduction

Inflammatory Bowel Diseases (IBD) are chronic inflammatory disorders characterized by alterations of acute relapses and remission. The past decades have brought substantial advances in the pharmacological management of IBD by a wide range of medicines. However, the sustained efficacy of the currently available anti-inflammatory therapies is still far from optimal. Therefore, the development of novel therapies represents a major unmet clinical need in this field. Recently, the enrichment of the coagulation pathway genes and among these, Plasminogen activator inhibitor 1 (PAI-1) was described in IBD, whereas PAI-1 emerged as a link between the epithelium and inflammation. Moreover, the genetic deletion of PAI-1 prevented the severity of experimental colitis in mice.

Aims & Methods

Based on these, we aimed to develop and test novel PAI-1 inhibitors for the treatment of IBD.
The novel, amino acid-based PAI-1 inhibitor, LDN-071 was synthesized by the A³SMO^® platform. The inhibitory potential and cytotoxicity effects of the peptide were determined by in vitro assays. Acute and chronic colitis was induced in mice with DSS and 10 mg/bwkg LDN-071 was administered per os. The changes of body weight, spleen weight, and colon length were measured. Haematoxylin eosin (HE) and Periodic acid-Schiff (PAS) staining were performed for histology. ELISA and qRT-PCR measurements were applied to analyze the cytokine expressions. Hydroxyproline assay was used to quantify the mucosal collagen deposition. In vivo, the toxicity of LDN-071 was determined in mice. Human colon organoid and fibroblast (FB) cell cultures were generated from IBD patients and the effects of LDN-071 were observed.

Results

LDN-071 significantly inhibited PAI-1 in vitro without decreasing the cell viability in a concentration range of 1µM-1mM. In the acute mice model, the administration of 10 mg/bwkg LDN-071 in the DSS-treated mice prevented the body weight loss, the development of bloody diarrhea, the decrease of colon length, and the increase of the spleen weight, which were displayed by the DSS+vehicle-treated animals. The histological analysis of the colon revealed that DSS treatment induced severe transmural inflammation, ulceration, loss of crypt structures, and goblet cell depletion. Importantly, all these parameters were significantly ameliorated by the administration of 10 mg/bwkg LDN-071 in the acute and chronic models as well. Additionally, mucosal gene and protein expressions of TNF-α, IL-1β, and IL-6 were significantly decreased by PAI-1 inhibition in the acute phase. Besides, the LDN-071 treatment significantly reduced the inflammation, epithelial erosion, and fibrosis caused by chronic administration of DSS. However, the collagen deposition was significantly lower in the PAI-1-inhibited DSS mice. Importantly, no signs of toxicity were observed in mice exposed to 100 mg/bwkg LDN-071 for 7 days. In our in vitro models, the PAI-1 inhibition reduced the protein level and gene expression of pro-inflammatory cytokines in human colon organoid of IBD patient. Moreover, the gene expression of fibrosis-related genes significantly decreased after the LDN-071 treatment in IBD patients-derived human FB cell culture.

Conclusion

Our results showed that LDN-071, a novel amino acid-based inhibitor of PAI-1, significantly ameliorated the severity of acute and chronic colitis in mice. However, the LDN-071 reduced the expression of inflammation- and fibrosis-related genes and proteins in vitro human models. We propose that the inhibition of PAI-1 could be a potential novel therapeutic strategy in IBD.

Disclosure

LDN-071 PAI-1 inhibitor is owned by Ladon Therapeutics Ltd.

Clinical Case Summary

Introduction: Ulcerative colitis (UC) is a chronic inflammatory disease characterized by remitting and relapsing patterns, necessitating multifaceted therapeutic interventions, among which mesalazine, or 5-aminosalicylic acid (5-ASA), is prominently utilized. Despite its typically favorable tolerability profile, mesalazine may occasionally precipitate severe adverse events, such as myocarditis.
Case presentation: A 46-year-old male recently diagnosed with UC presented with a moderate UC flare-up and was initiated on 5-ASA therapy upon admission.
Within a span of two days following initiation of oral therapy, he developed acute chest pain, palpitations, dyspnea, and desaturation, necessitating intensive care due to cardiogenic shock.
Paraclinical assessments revealed elevated troponin levels, along with electrocardiographic and echocardiographic abnormalities, including left ventricular dysfunction and reduced ejection fraction.
Discontinuation of mesalazine resulted in symptom improvement and reduction of cardiac markers. Subsequent evaluations demonstrated a recovery in cardiac function, establishing a causal relationship between myocarditis and the administration of 5-ASA. Consequently, a therapeutic switch to mercaptopurine was instituted.
Conclusion: This case underscores the infrequent yet significant hazard of mesalazine-triggered myocarditis, emphasizing the critical necessity for vigilant patient monitoring during this therapy and prompt consideration of alternative therapeutic options in the presence of severe cardiac complications.

Introduction

G-protein coupled receptor-119 (GPR119) agonism is known to modulate non-alcoholic fatty liver disease physiology. However, due to off-target effects, challenges remain for successful GPR119 agonist pharmacotherapy.
Designing a non-systemic drug candidate that locally targets gut-located receptors for incretin secretion is suggested as a safer approach to minimise conventional side effects. This strategy may potentially limit the direct action on pancreatic β-cells; however, chronic use may lead to beneficial outcomes.
We developed a novel small-molecule agent as an oleoyl-lysophosphatidylinositol derivative that stimulates intestinal glucagon-like peptide-1 (GLP-1) secretion by coupling with gut receptors at the orthosteric site.

Aims & Methods

The present study was designed to investigate the chronic impact of novel GPR119 agonist agent ps297 alone and in combination with Sitagliptin on liver health in high-fat diet (HFD)-induced obese mice.
Five-week-old healthy male C57BL6/J mice were fed with HFD for 20 weeks. Normal control mice were maintained on a standard chow diet. A dose-escalation protocol was followed during the treatment phase. Oral administration of the test compound commenced with an initial dose of 10 mg/kg/day for the first week, followed by weekly dose escalations of 10 mg/kg for the subsequent ten weeks until reaching a maximum dose concentration of 90 mg/kg/day. Sitagliptin was gavaged at a fixed dose of 20 mg/kg/day. Vehicle control mice received an equal volume of 0.25% carboxymethyl cellulose in water.
After ten weeks of treatment, blood samples were collected from each 4-hour fasted mice. Biochemical parameters including plasma glucose, triglycerides (TG), cholesterol (CHO), alanine aminotransferase (ALT), and aspartate transaminase (AST) were analysed using an automated analyser. Plasmatic concentrations of metabolic hormones were determined in a multiplex assay platform. Hepatic TG, CHO, and hydroxyproline concentrations were determined in frozen liver tissue samples by colourimetric assay. Liver histology was studied in tissue stored in 10% neutral buffered formalin. Hepatic ballooning was assessed in hematoxylin and eosin-stained sections, imaged using a slide scanner.

Results

Ten-week co-administration of compound ps297 with sitagliptin resulted in higher plasmatic GLP-1 levels compared to the HFD control arm, which led to a significant (p<0.05) reduction in fasting plasma glucose levels in this group. Moreover, combination group exhibited a significant reduction in liver weights (p<0.0001), plasma CHO (p<0.05), ALT (p<0.0001), and AST (p<0.01) levels. Furthermore, combination treatment showed a significant reduction in hepatic TG (p<0.0001) and CHO (p<0.001) concentrations compared to the HFD control group. Elevated hepatic hydroxyproline levels in HFD control mice were attenuated by combination treatment. Additionally, the hepatic ballooning score was found to be significantly reduced in the combination treatment mice.

Conclusion

Sitagliptin combination of ps297, improved glucose homeostasis in HFD-fed obese mice. Additionally, a prominent improvement in liver health status was observed in this group, as evident by reductions in liver weight, plasma liver enzymes, hepatic TG and CHO, and hydroxyproline levels. These findings were further supported by liver histological examination. The overall findings suggest the pharmacological potential of the GPR119 agonist compound ps297 in combination with gliptins to alleviate fatty liver disease, warranting further molecular investigation in disease-specific animal models.

References

Paternoster S, Simpson PV, Kokh E, Kizilkaya HS, Rosenkilde MM, Mancera RL, Keating DJ, Massi M, Falasca M. Pharmacological and structure-activity relationship studies of oleoyl-lysophosphatidylinositol synthetic mimetics. Pharmacol. Res. 172 (2021) 105822.

Bahirat UA, Shenoy RR, Talwar R, Goel RJ, Nemmani KVS. Co-administration of APD668, a G protein-coupled receptor 119 agonist and linagliptin, a DPPIV inhibitor, prevents progression of steatohepatitis in mice fed on a high trans-fat diet. Biochem Biophys Res Commun 495 (2018) 1608-1613

Disclosure

MF and MM are inventors of a patent related to oleoyl-LPI mimetics. Curtin University received funding from Little Green Pharma Pty Ltd. to support MF to conduct the submitted work. LW is a paid employee of Little Green Pharma Pty Ltd. No other relationships or activities that could appear to have influenced the submitted work.

Introduction

High-risk human papillomavirus (hr-HPV) has been associated with a subset of Barrett’s dysplasia (BD) and oesophageal adenocarcinoma (OAC).^1,2,3,4 The L1 major capsid protein has been closely linked to disease regression and is a prognostic factor in HPV driven cancers of the cervix and anus.​^5,6​​​​ The progression of cervical intraepithelial neoplasia to invasive cancer is accompanied by a loss of viral L1 capsid protein expression.

Aims & Methods

Thus, in a retrospective, cross-sectional study, we investigated L1 protein expression in HPV-positive patients representing the oesophageal squamous (controls) [Group1]-Barrett’s metaplasia [Group 2]-low-grade dysplasia [Group 3]-high-grade dysplasia [Group 4]-adenocarcinoma [Group 5] sequence. L1 protein immuno-histochemical staining was correlated with p16 overexpression and E6/E7 mRNA in-situ hybridization. The association between the 5 patient groupings and L1 expression was analysed using the Chi-square test. Multivariable logistic regression was undertaken to investigate the above association with adjustment of potential confounders (age, gender, BMI, ever smoked and excess alcohol). Adjusted odds ratio (95% CI) was calculated.​​​​​

Results

^​​​​​​Of 116 HPV DNA-positive patients [(age range: 19-90, mean (SD), 63.2 (13.5)], 88 males and 28 females), 73 (62.9%) were genotype 16, 37 (31.9%) genotype 18 and 6 (5.2%) were genotype 6. L1 nuclear staining was observed in 64 individuals. L1 expression was detected in 84.9% (28/33) of controls; 94.1% (16/17) of BO patients; 50% (7/14) of LGD subjects; 38.1% (8/21) of HGD individuals and 16.1% (5/31) of OAC patients; [adjusted P < 0.0001]. Conversely, p16 was present in 9.1% (3/33) of controls, 17.7% of BO (3/17), 57.1% (8/14) in LGD individuals, 61.9% (13/21) of HGD patients and 64.5% (20/31) of OAC subjects [p<0.0001]. Corresponding figures for E6/E7 mRNA positivity was 6.1% (2/33), 23.5% (4/17), 28.6% (4/14), 38.1% (8/21) and 45.2% (14/31) respectively [p=0.008]. Expression of HPV-L1 and p16 or L1 and E6/E7 mRNA was largely mutually exclusive.

Conclusion

HPV L1 capsid expression is incrementally lost with increasing oesophageal disease severity as in viral driven anal and cervical lesions. Utility of L1 alone or in combination with p16/E6/E7 mRNA in stratifying HPV-positive oesophageal lesions for treatment should be further explored.

References

1. Rajendra S, Wang B, Snow ET, et al. Transcriptionally active human papillomavirus is strongly associated with Barrett’s dysplasia and esophageal adenocarcinoma. Am J Gastroenterol 2013;108:1082–1093.
2. Rajendra S, Yang T, Xuan W, et al. Active human papillomavirus involvement in Barrett's dysplasia and oesophageal adenocarcinoma is characterized by wild-type p53 and aberrations of the retinoblastoma protein pathway. Int J Cancer. 2017;141(10):2037-2049.
3. Li X, Gao C, Yang Y, et al. Systematic review with meta-analysis: the association between human papillomavirus infection and oesophageal cancer. Aliment Pharmacol Ther. 2014;39(3):270-281.
4. Rajendra, S., W. Xuan, N. Merrett, et al. Survival Rates for Patients With Barrett High-grade Dysplasia and Esophageal Adenocarcinoma With or Without Human Papillomavirus Infection. JAMA Netw Open. 2018; 1: e181054.
5. Choi YS, Kang WD, Kim SM, et al. Human papillomavirus L1 capsid protein and human papillomavirus type 16 as prognostic markers in cervical intraepithelial neoplasia 1. Int J Gynecol Cancer 2010;20(2):288-293.
6. Hernandez J, Elahi A, Siegel E, Coppola D, Riggs B, Shibata D. HPV L1 capsid protein detection and progression of anal squamous neoplasia Am J Clin Pathol 2011; 135: 436-41.

Disclosure

None

Introduction

Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most common chronic liver disease in recent years. However, medications to improve MAFLD has no standard. Several potential agents have been widely investigated for the treatment of MAFLD. Pemafibrate, a selective peroxisome proliferator-activated receptor-α modulator, has been reported to improve dyslipidemia. Sodium-glucose cotransporter-2 inhibitor (SGLT2i) is an oral antidiabetes drug that promotes glucose excretion into the urine. These medications have potential therapeutic effects on MAFLD.

Aims & Methods

This retrospective study aimed to evaluate the effects of long-term administration of pemafibrate plus SGLT2i in patients with dyslipidemia and type 2 diabetes complicated by MAFLD. Transient elastography (FiboScan; Echosens, Paris, France) was used for liver stiffness measurement (LSM) and assessment of the controlled attenuation parameter (CAP). In total, 594 patients with dyslipidemia and type 2 diabetes complicated by MAFLD started pemafibrate plus SGLT2i treatment between 2019 and 2020 at our hospital. Pre- and post-treatment transient elastography data were compared.

Results

Following 3 years of pemafibrate plus SGLT2i treatment, the median LSM significantly decreased from 10.1 kPa to 6.4 kPa (P < 0.001) and the median CAP significantly decreased from 321 dB/m to 219 dB/m (P < 0.001), in spite of no significant reductions of the studied patients’ weight. Moreover, serum parameters, including hemoglobin A1c, alanine aminotransferase, and gamma-glutamyl transferase, significantly decreased over the study period.

Conclusion

The findings of our study confirm that long-term administration of pemafibrate plus SGLT2i can improve hepatic fibrosis by ameliorating hepatic steatosis and inflammation in patients with dyslipidemia and type 2 diabetes complicated by MAFLD.

References

Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol. 2008; 48(5): 835-847.
Yamashita S, Masuda D, Matsuzawa Y. Clinical Applications of a Novel Selective PPARα Modulator, Pemafibrate, in Dyslipidemia and Metabolic Diseases. J Atheroscler Thromb. 2019; 26(5): 389-402.
Mantovani A, Petracca G, Csermely A, et al. Sodium-Glucose Cotransporter-2 Inhibitors for Treatment of Nonalcoholic Fatty Liver Disease: A Meta-Analysis of Randomized Controlled Trials. Metabolites. 2020; 11(1): 22.
Murakami K, Sasaki Y, Asahiyama M, et al. Selective PPARα Modulator Pemafibrate and Sodium-Glucose Cotransporter 2 Inhibitor Tofogliflozin Combination Treatment Improved Histopathology in Experimental Mice Model of Non-Alcoholic Steatohepatitis. Cells. 2022;11(4):720.

Clinical Case Summary

Introduction: Ustekinumab (UST), a human interleukin-12/23 monoclonal antibody, is approved for the treatment of moderate to severe Crohn’s disease (CD) and ulcerative colitis (UC). Some patients may lose response to standard maintenance therapy. Optimization strategies, such as dose escalation and intravenous (IV) re-induction, have been explored in CD, but scarcely studied in UC.
Clinical Case: A 61-year-old woman, with grade III obesity, hypertension, and peripheral venous insufficiency, diagnosed with UC and associated peripheral arthropathy, was initially treated with high-dose corticosteroids (CTS) for a severe exacerbation. She developed CTS dependence and suffered an osteoporotic fracture.
A combined therapy with methotrexate and an accelerated infliximab (IFX) induction regimen was initiated, but a severe exacerbation occurred after the second induction dose. Despite an early third dose, clinical, biochemical and endoscopic (Mayo score 3) activity persisted.
The patient was swapped to UST with maintenance therapy every 4 weeks. After IV infusion, free-CTS clinical and biochemical (fecal calprotectin (FC) <10 ug/g) remission were achieved, but, over time, there was a loss of response, with a FC 4817 ug/g.
Given the initial positive response to IV UST infusion and insights from CD studies, a 520mg IV UST re-induction followed by 4-week maintenance dose was administered. Eight months later, the patient remains in free-CTS clinical remission, with improved arthralgia, biochemical remission (FC 80 ug/g) and endoscopic response.
Conclusions: This case highlights the potential efficacy of IV UST re-induction in recapturing remission in refractory UC. While recognized in CD, UST re-induction may prove beneficial for UC patients with loss of response to standard UST therapy, serving as an alternative before swapping. Further exploration through randomized, multicenter studies is crucial to assess the efficacy and safety of this strategy in UC patients.