Introduction

Recently, liquid-liquid phase separation (LLPS) of transcription factor has been found to play a critical role in the development of tumors [1-3]. Meanwhile, Forkhead box C1 (FOXC1), a transcription factor protein with intrinsically disordered regions (IDRs), is related with the prognosis of gastric cancer [4]. However, whether FOXC1 could undergo LLPS and whether FOXC1 involved in the development of gastric has not been studied until now.

Aims & Methods

Therefore, we aimed to investigate whether FOXC1 could undergo LLPS and the potential role of FOXC1 in gastric cancer. We analyzed different expression gene of gastric cancer samples from The Cancer Genome Atlas dataset and the sequencing results of our own samples. The protein sequence prediction website (Disprot - Database of Protein Disorder) was used to predict the IDRs of FOXC1. Besides, fluorescence recovery after photobleaching (FRAP) and cellular immunofluorescence were used to explore whether FOXC1 could undergo LLPS. What’s more, cell proliferation assay, cell apoptosis assay and cell migration assay were utilized to investigate the potential role of FOXC1 in gastric cancer.

Results

In the different expression gene analysis of the TCGA database and our own data, it was found that the expression level of FOXC1 in gastric cancer was significantly higher than that of paracancer tissue (Figure 1 A-B), which was proved by RTq-PCR (Figure 1 C). Knockdown of FOXC1 in gastric cancer cell resulted in decreased proliferation (Figure 2A), decreased migration (Figure 2B), and increased apoptosis (Figure 2C). In the prediction of protein structure, it can be found that the IDRs region of FOXC1 accounts for more than 50% (Figure 3). After the fluorescence bleaching of the droplet formed by FOXC1 with AcGFP in AGS cell, the fluorescence gradually recovers within a few minutes (Figure 4C). What’s more, endogenous FOXC1 could form puncta with irregular distribution in nuclear (Figure 4D), which also proves that FOXC1 can undergo LLPS.

Conclusion

Overall, knockdown of FOXC1 in gastric cancer cell can inhabit the development of gastric cancer by decreasing proliferation and migration, increasing apoptosis. FOXC1 can also undergo LLPS in vitro and in vivo. Therefore, we speculate that FOXC1 may promote the development of gastric cancer through LLPS.

References

[1] Kondo H, Mishiro K, Iwashima Y, Qiu Y, Kobayashi A, Lim K, Domoto T, Minamoto T, Ogawa K, Kunishima M, Hazawa M, Wong RW. Discovery of a Novel Aminocyclopropenone Compound That Inhibits BRD4-Driven Nucleoporin NUP210 Expression and Attenuates Colorectal Cancer Growth. Cells. 2022 Jan 18;11(3):317. doi: 10.3390/cells11030317. PMID: 35159127; PMCID: PMC8833887.
[2] Boeynaems S, Alberti S, Fawzi NL, et al, Polymenidou M, Rousseau F, Schymkowitz J, Shorter J, Wolozin B, Van Den Bosch L, Tompa P, Fuxreiter M. Protein Phase Separation: A New Phase in Cell Biology. Trends Cell Biol. 2018 Jun;28(6):420-435. doi: 10.1016/j.tcb.2018.02.004. Epub 2018 Mar 27. PMID: 29602697; PMCID: PMC6034118.
[3] Peng Q, Tan S, Xia L, et al. Phase separation in Cancer: From the Impacts and Mechanisms to Treatment potentials. Int J Biol Sci. 2022 Aug 1;18(13):5103-5122. doi: 10.7150/ijbs.75410. PMID: 35982902; PMCID: PMC9379413.Liu Z, Li L, Li X, Hua M,
[4] Xu Y, Shao QS, Yao HB, Jin Y, Ma YY, Jia LH. Overexpression of FOXC1 correlates with poor prognosis in gastric cancer patients. Histopathology. 2014 Jun;64(7):963-70. doi: 10.1111/his.12347. Epub 2014 Feb 12. PMID: 24329718.

Introduction

Sedation is commonly used during upper gastrointestinal (UGI) endoscopy to improve tolerability. We have previously reported an association between increased sedation use and lower rates of post endoscopy upper GI cancer. We have analysed sedation practices for diagnostic upper GI endoscopy in the National Endoscopy Database (NED).

Aims & Methods

The aim of this study was to examine endoscopy practice in the UK and quantify variation in sedation use during diagnostic endoscopy. Diagnostic endoscopies performed between 01/01/2019 and 29/02/2020 were analysed from NED data. Logistic regression analysis examined associations with sedation use and procedures abandoned due to tolerability.

Results

314,725 (51%) UGI endoscopies involved sedation: midazolam alone 36%; combined midazolam + fentanyl 14%; midazolam + pethidine 0.9%. In patients over the age of 70, during 11 887 of 206 386 endoscopies (5.8%), more than the recommended 2.5mg of midazolam was given (mean 3.4mg (SD±0.76)), including 3320 in which fentanyl was co-prescribed (mean 67.0mcg (SD±29.1)).

Sedation use was associated with: compared to gastroenterologists, clinical endoscopists OR 0.57 (95% CI 0.56-0.58), surgeons OR 0.65 (95% CI 0.64-0.66), SAS doctors 0.65 (95% CI 0.64-0.66); younger patients; males OR 0.60 (95% CI 0.59-0.61); afternoon lists OR 0.98 (95% CI 0.97-0.99) and weekends (OR 0.88 (95% CI 0.87-0.90); compared with routine endoscopy, urgent 1.22 (95% CI 1.21-1.23) and surveillance OR 0.91 (95% CI 0.88-0.94).

Sedation + opioid was most frequently used by gastroenterologists, but less by others: clinical endoscopists OR 0.26 (95% CI 0.25-0.27); surgeons OR 0.26, (95% CI 0.25-0.27); and SAS doctors 0.33 (95% CI 0.32-0.34).

3499 endoscopies were abandoned due to poor tolerance: age mean 59.1 (SD±17.1), female 59%, no sedation 57%, midazolam only 32% and midazolam + opioid 10%. This was associated with: surgeons OR 1.29 (95% CI 1.07-1.53) and clinical endoscopists OR 1.39 (95% CI 1.19-1.62), compared to gastroenterologists; addition of opioids OR 0.66 (95% CI 0.59-0.73); and no sedation OR 1.32 (CI 95% 1.23-1.40).

Conclusion

There is lower use of sedation overall, and combined midazolam and opioid particularly, among endoscopists other than consultant gastroenterologists, despite improved tolerability and reduced abandoned procedures. Sedation is used less in afternoons and at weekends, which may relate to recovery requirements and staffing.

Introduction

In the eighth edition of the TNM classification, clinical stage (cStage) and pathological stage after neoadjuvant chemotherapy (ypStage) were newly defined for gastric cancer. However, cStage after prior chemotherapy (ycStage) has not yet been defined.

Aims & Methods

This study aimed to validate ypStage and construct ycStage after preoperative chemotherapy in gastric cancer from the viewpoint of survival outcomes. One hundred-eighty-seven patients who planned to undergo gastrectomy with curative intention after preoperative chemotherapy were enrolled. Survival outcomes stratified by ypStage and ycStage was evaluated. ycStage was evaluated by extrapolating TNM cStage. In addition, macroscopic type, tumor size, histological type, and tumor marker (CEA/CA19-9) after chemotherapy were selected as other prognostic factors. These staging system and variables were evaluated by univariate and multivariable analysis. Harrell’s concordance index (C-index: time dependent area under the curve) was used to evaluate predictive ability.

Results

Gastrectomy was not performed in 14 patients (7.5%) due to incurable factors during operation. Remaining 173 patients underwent surgery. Residual tumor was R0: 148 cases (85.5%), R1: 17 cases (9.8%), R2: 19 cases (4.6%), respectively. ypStage: The survival distribution of ypStage was assessed in 173 patients who underwent gastrectomy. The 5-year survival rates (ysr) for ypStage I (n = 36), II (n = 55), III (n = 60), and IV (n = 22) were 82.3%, 76.5%, 42.7%, and 14.1%, respectively. There were significant differences between II/III (P=0.001) and between III/IV (P=0.009), respectively. There was a tendency for there to be a difference in survival between I/II (P=0.087). The C-index of ypStage was 0.713 (standard error: se=0.027). ycStage constructed by ordinal TNM factor: The survival distribution of ycStage, ycT, and ycN was assessed in all 187 patients. The 5-ysr for ycStage I (n = 12), II (n = 39), III (n = 90), and IV (n = 46) were 54.7%, 57.5%, 61.0%, and 40.6%, respectively. The predictive ability was poor with C-index of 0.533 (se=0.031). The 5-ysr for ycT1 (N=9): 66.7%, ycT2 (N=16): 64.2%, ycT3 (N=27): 60.6%, ycT4 (N=135): 52.0%, respectively. There were no significant differences between ycT1/2 (P=0.734) and between ycT2/3 (P=0.872). The 5-ysr for ycN0 (N=55): 45.9%, ycN1 (N=55): 59.3%, ycN2 (N=54): 68.2%, ycN3 (N=23): 36.4%, respectively. The survival outcomes among cN0, cN1 and N2 are completely reversed. Other preoperative prognostic factors: In univariate analysis histological type (P=0.703), macroscopic type (P=0.125), and CA19-9 (P=0.296) were not significant prognostic factors, but tumor size [<80mm (n=117): 5-ysr; 64.6% vs. >80mm (n=70): 34.2%, P<0.001] and CEA [(negative (n=152): 5-ysr; 59.2% vs. positive (n=35): 33.0%, P<0.001)] were significant prognostic factors. Multivariate Cox proportional hazard model selected tumor size (P<0.001) and CEA (P=0.007) as independent prognostic variables. Construction of proposal ycStage: A new proposal stage was constructed from the results of multivariate analysis. ycStageI: size<80mm and CEA-negative, ycStageII: size<80mm and CEA-positive, ycStageIII: size>80mm and CEA-negative, ycStageIV: size>80mm and CEA-positive. The 5-ysr for new proposal ycStage I (n = 94), II (n = 26), III (n = 52), and IV (n = 15) were 71.3%, 54.0%, 37.0%, and 20.0%, respectively. The C-index of new proposal ycStage was 0.662 (se=0.029). It is significant higher value than that of ycStage constructed by ordinal TNM factor.

Conclusion

The predictive ability of the ypStage, on the basis of TNM factors, considered favorable. However, survival separation was poor for both ycT and ycN. Thus, ycStage based on ordinal TNM did not have the perspective of survival outcome prediction. Proposal ycStage constructed by tumor diameter and CEA may be recommended.

Disclosure

The first author (Etsuro Bando) received honorarium from Johnson & Johnson, Medtronic plc, Intuitive Surgical G.K., KAKEN PHARMACEUTICAL CO., LTD, and
DAIICHI SANKYO COMPANY, LIMITED.

Introduction

Congenital hepatic fibrosis (CHF) is a rare autosomal recessive disease derived from biliary dysgenesis secondary to ductal plate malformation; it often coexists with Caroli’s disease, von Meyenburg complexes, autosomal dominant polycystic kidney disease (ADPKD), and autosomal recessive polycystic kidney disease (ARPKD). Congenital hepatic fibrosis (CHF) and Caroli syndrome has varied clinical presentations with or without renal involvement.

Aims & Methods

Our study aimed to describe the clinical manifestations and natural history of children with CHF and Caroli with or without renal involvement. Retrospective data from January 2022 to January 2024 was collected and analyzed.

Results

Twenty-three children (Caroli=7, CHF=16) were enrolled male predominance (76%) was noted. Consanguinity was noted in 76% and 23% had affected siblings. Median age at initial presentation was two years and abdominal distension was the most common presentation (47.6%) followed by variceal bleeding (23.8%), cholangitis (14.2%), incidental diagnosis (9.5%) and pancytopenia (4.76%). Median age at presentation and diagnosis was later with variceal bleeding at 5.6 years compared with children with abdominal distension who presented at 18 months respectively (p=0.0001). Renal involvement was present in 76% of the children. Autosomal Recessive Polycystic Kidney Disease (ARPKD) was the most common renal manifestation noted. Of them, 18% had developed Chronic Kidney Disease (CKD). All Caroli cases (100%) had renal involvement. There was no statistical difference in the age of presentation of CHF with or without renal involvement (p=0.5998). Growth faltering was noted in 52% of children. Statistical analysis revealed no significant difference in the likelihood of developing portal hypertension among children with either congenital hepatic fibrosis (CHF) or Caroli disease, regardless of renal involvement. Portal hypertension was seen in 76%. Only one child had variceal bleeding on follow up.

Conclusion

Abdominal distension, organomegaly, variceal bleeding, and cholangitis are frequently observed clinical manifestations in both congenital hepatic fibrosis (CHF) and Caroli disease. Interestingly, while renal involvement is more prevalent in Caroli disease compared to CHF, there doesn't appear to be a direct correlation between renal involvement and the severity of hepatic manifestations or growth faltering in affected children. This underscores the complexity of these conditions and the need for tailored management approaches that address both hepatic and renal complications.

References

1. Srinath, Arvind, and Benjamin L Shneider. “Congenital hepatic fibrosis and autosomal recessive polycystic kidney disease.” Journal of pediatric gastroenterology and nutrition vol. 54,5 (2012): 580-7. doi:10.1097/MPG.0b013e31824711b7
2. Gunay-Aygun M, Font-Montgomery E, Lukose L, Tuchman Gerstein M, Piwnica-Worms K, Choyke P, Daryanani KT, Turkbey B, Fischer R, Bernardini I, Sincan M, Zhao X, Sandler NG, Roque A, Douek DC, Graf J, Huizing M, Bryant JC, Mohan P, Gahl WA, Heller T. Characteristics of congenital hepatic fibrosis in a large cohort of patients with autosomal recessive polycystic kidney disease. Gastroenterology. 2013 Jan;144(1):112-121.e2. doi: 10.1053/j.gastro.2012.09.056. Epub 2012 Oct 3. PMID: 23041322; PMCID: PMC4162098.

Introduction

Aims & Methods

Results

Conclusion

Disclosure

Introduction

In Hungary, the population-based colorectal carcinoma (CRC) screening programme was introduced at the end of 2018, shortly before the start of the COVID-19 pandemic.

Aims & Methods

The aim of our retrospective cohort study was to evaluate the impact of two presumably opposing causal factors, COVID-19 pandemic and population-based screening, on the incidence and clinical characteristics of CRC. All patients with newly diagnosed CRC from 2014 to 2023 were included and categorized into pre-pandemic (confirmed between 2014-2019), pandemic (confirmed in 2020-2021) and post-pandemic (confirmed in 2022-2023) groups. The extended pre-pandemic period was required to assess the impact of the screening programme, further dividing it into screening-affected (2015, 2016, and 2019) and unaffected (2014, 2017, 2018) subgroups.

Results

A total of 2803 patients were diagnosed with CRC during the study period. The annual number of CRC cases was significantly lower in the pandemic subgroup compared to the pre-pandemic screened and post-pandemic subgroups (254/year, 295/year and 295/year, p=0.009). In addition, in the pandemic subgroup, the incidence rates of CRCs detected at localized stage were significantly lower compared to the other three groups (36.61%, 50.85%, 46.35% and 49.49%, p<0.001). Statistically significant difference in the rate of T1 tumors was only observed between the pandemic and the post-pandemic subgroups (7.09% and 12.20%, p=0.026). In the pandemic period, the annual number of colonoscopies decreased by 64.31% compared to the pre-pandemic period overall, however, the post-pandemic period (n=4574) saw a modest 8.70% increase relative to the pre-pandemic period, offering only partial compensation for the shortage experienced during the pandemic. Furthermore, the annual number of colonoscopies in the extended pre-pandemic subgroup with screening was higher by 20.06% compared to the pre-pandemic subgroup without screening (4591 examinations/year vs 3824 examinations/year) and it was almost the same as the post-pandemic subgroup (4574 examinations/year). Substantially fewer examinations were required to detect a CRC in the pandemic group compared to the pre-pandemic overall and post-pandemic groups (10.67, 15.56, 13.97 and 15.50 examinations, respectively), but within the extended pre-pandemic group, there was no relevant difference between the two subgroups in the mean number of colonoscopies required to detect a CRC (15.56 vs. 13.97).

Conclusion

Our study confirmed the negative impact of COVID-19 pandemic on the CRC epidemiology. The newly introduced population-based CRC screening has only been able to partially compensate this negative effect during pandemic period, however, was moderately compensated by during the pandemic period, but in the post-pandemic period it caused a favorable change in the clinical features of CRC. Our study demonstrates both the effectiveness of the screening programme and that by introducing non-invasive pre-screening of patients (e.g. iFOBT) in a pandemic situation, it can reduce its negative public health impact.

Introduction

The Crohn’s Disease Activity Index (CDAI) is a widely used research tool used to quantify CD patient’ symptoms, evaluate the severity of CD and to determine treatment outcomes.^​

Aims & Methods

The objective of this study was to assess any nuances in treating CD patients with active disease (CDAI score >150), who have remained on the same advanced therapy (biologics/ novel oral molecules) for more than 6 months. The Ipsos CD Therapy Monitor, a multi-centre online medical chart review study of patients with CD was conducted between July – September 2023 among UK, FR, DE, IT & ES gastroenterologists practicing across hospital and private practices. Physicians were screened for practice duration and patient volume. Charts of patients prescribed with advanced therapy were included in the analysis.

Results

208 sampled physicians collectively reported 373 CD patients who were recorded as being on the same advanced therapy for more than 6 months. 286 reported patients were deemed in remission (CDAI score ≤ 150) and 87 patients recorded with active disease (CDAI score >150). Looking at reported CD patient co-morbidities, metabolic conditions were more common in patients with active disease vs those in remission (24% vs 19%)

When looking at extra-intestinal manifestations (EIMs) between the two patient groups, patients with active disease were more likely to experience EIMs vs those in remission.

Table 1: EIMs in reported CD patients (% patients)

Conclusion

Comparisons in this study cohort highlighted that active disease in CD patients, as determined by the CDAI score, is associated with a higher number of patient co-morbidities and a greater likelihood of extra-intestinal manifestations; this indicates a more severe or complicated disease burden. As additional development products with new mechanisms of action become available in gastroenterology, non-TNF therapy usage may grow over time to provide more holistic and individualised treatment strategies for CD patients. Further investigation using comparator cohort is warranted.

References

[1] Use of the Crohn’s disease activity index in clinical trials of biological agents, Hugh James Freeman https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2725371/

Disclosure

No