Introduction

Cholangiocarcinoma (CCA) constitutes a heterogeneous group of epithelial malignancies that arise in the biliary tree. CCA is a very aggressive cancer and carries a poor prognosis¹. Furthermore, in view of the constant increase in its incidence and mortality in recent decades throughout the world, it represents a growing global health problem^1,2. CCAs are divided into three subtypes according to their anatomical site of origin: intrahepatic CCA (iCCA), perihilar (pCCA), and distal (dCCA). Specifically, iCCA is characterize by high intertumoral clinical-pathological and molecular heterogeneity, leading to an innovative histological classification approved by WHO (ICD-O-3.2), into small bile duct iCCA and large bile duct iCCA³. The molecular pathogenesis of iCCA is very intricate and involves multiple molecular networks: among them, the Hedgehog (Hh)^4,6 signaling pathway. Indeed, the Hh pathway plays an important role in many aspects of iCCA, such as tumor survival, proliferation, migration and EMT reprogramming⁵. The impact of innovative therapies on the survival of patients with iCCA is an ongoing area of investigation. Evidence on the pathogenetic role of Hh in iCCA implies the possibility of targeting this signaling pathway for therapeutic purposes in iCCA subtypes.

Aims & Methods

The aim of this study is to demonstrate the antitumor efficacy of a natural therapeutic compound, from an in-house library, that inhibits the Hh pathway in experimental models of human iCCA, in vitro, in established iCCA cell lines (CCLP1) and primary cell lines derived from small or large bile duct iCCA. The iCCA samples from resected specimens have been processed by mechanical and enzymatic digestion to obtain patient-derived primary cell lines. The effect of Glabrescione B (GlaB), a selective inhibitor of GLI1 (Hh downstream transcriptional factor), has been evaluated. The dose-dependent efficacy of GlaB [0, 1, 5, 10, 20, 50 μM] or hyaluronic acid (HA) nanohydrogel-encapsulated Glab [0, 0.5, 1, 5, 10 μM], have been evaluated by Trypan Blue Exclusion Test and MTS assay (cell viability), at different time points (24h, 48h, 72h, 96h). Its ability as inhibitor of Hh signaling pathway has been evaluated by Western Blot analysis. All experiments have been conducted in N.3 experimental replicates.

Results

Our research shows a dose-dependent and time-dependent reduction of cell proliferation by Trypan Blue Exclusion Test in all cell lines (p<0.05). The decrease already occurs at low concentrations and at 24-hour incubation (40-50%) and becomes more evident at higher concentrations and at 96-hour incubation (80-90%) (p<0.05). Likewise, at the protein level, Gli1 knockdown, in a dose and time-dependent manner, is demonstrated (p<0.05). MTS assays confirmed the cytotoxicity effect of GlaB at 20 μM and 50 μM (p<0.05). Therefore, we decided to pursue the study with lower concentrations (from 1 μM to 10 μM) capable of knocking down the cell viability by 50%. Thereafter, successful, and stable encapsulation of GlaB [0.5-10 μM] in HA nanohydrogel has been accomplished. Data showed a dose-dependent and time-dependent inhibitory activity of HA-encapsuled GlaB [0.5-10 μM] in all cell lines (p<0.05).

Conclusion

Aberrant Hh pathway activation is widely known to be closely related with the development and malignant progression of various human cancers. Preclinical experimental data denote that dysregulation of this pathway is a determinant of cholangiocarcinoma progression and invasiveness. The achievements of this study could lay the groundwork for pre-clinical studies of HA-encapsuled Glab in iCCA.

References

1. Banales JM. et al., Nat Rev Gastroenterol Hepatol. 2020 Sep;17(9):557-588. Epub 2020 Jun 30. PMID: 32606456; PMCID: PMC7447603.
2. Bertuccio P. et al., J Hepatol. 2019 Jul;71(1):104-114. Epub 2019 Mar 23. PMID: 30910538.
3. European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL-ILCA Clinical Practice Guidelines on Intrahepatic Cholangiocarcinoma. J Hepatol. 2023 Mar 22:S0168-8278(23)00185-X. Epub ahead of print. PMID: 37084797.
4. Riedlinger D. et al., J Hepatobiliary Pancreat Sci. 2014 Aug;21(8):607-15. Epub 2014 Apr 15. PMID: 24733827.
5. Cigliano A. et al., Expert Opin Ther Targets. 2017 May;21(5):471-483.1310842. Epub 2017 Mar 30. PMID: 28326864.
6. Razumilava N. et al., J Hepatol. 2014 Mar;60(3):599-605. Epub 2013 Nov 14. Erratum in: J Hepatol. 2014 Jul;61(1):185. PMID: 24239776; PMCID: PMC3944428.

Introduction

Endoscopic ultrasound-guided biliary drainage (EUS-BD) is reported to be useful as an alternative treatment for patients who are unable to undergo transpapillary bile duct drainage. EUS-hepaticogastrostomy (HGS), which involves a transgastric approach to the left intrahepatic bile duct, has been suggested as the first-line approach for EUS-BD because of a lower risk of bile leakage in patients with dilated intrahepatic bile ducts. However, there are few reports comparing the effectiveness and safety of EUS-BD procedures between EUS-HGS and EUS-HGS with antegrade stenting (EUS-AS+HGS).

Aims & Methods

Therefore, we compared the efficacy and safety of EUS-AS+HGS and EUS-HGS as drainage methods in EUS-BD. From April 2017 to December 2020, we retrospectively evaluated patients who underwent EUS-AS+HGS or EUS-HGS in our hospital for unresectable malignant biliary obstruction for which transpapillary biliary drainage had failed. We compared the time to recurrence of biliary obstruction (TRBO), overall survival, technical success rate, clinical success rate, adverse event rate, reintervention rate, and length of hospital stay between each procedure.

Results

A total of 68 patients, 22 in the EUS-AS+HGS group and 46 in the EUS-HGS group, were included in the study. In the EUS-HGS group, 38 patients underwent HGS only, while EUS-AS+HGS was attempted in another 8 patients who ultimately underwent EUS-HGS because of unsuccessful guidewire penetration. In the EUS-AS+HGS group, the TRBO was significantly longer, and the re-intervention rate significantly lower than in the EUS-HGS group (both p=0.03). However, there were no significant differences in technical success rate, overall survival, clinical success rate, adverse event rate, and length of hospital stay.

Conclusion

EUS-AS+HGS was superior to EUS-HGS regarding the length of biliary patency and re-intervention rate in patients with unresectable malignant biliary obstruction. The results suggest that EUS-AS+HGS is the preferred treatment when guidewire penetration of the biliary stricture is possible.

Introduction

Low-volume bowel preparation solutions, including 1 L polyethylene glycol plus ascorbate (PEG-A), have been developed to improve tolerability because of the low tolerability of high-volume polyethylene glycol agents. However, 1 L PEG-A still has its typical odor that is not pleasant for most patients. The oral sodium sulfate tablet (OST) is a new agent with simethicone as a preloaded component. OST may have the better tolerability because of little odor due to its tablet formula.

Aims & Methods

We aimed to investigate the efficacy, safety, and tolerability of OST compared to 1 L PEG-A. We randomized patients aged 18 years or older who underwent colonoscopy into the OST (group A) and 1 L PEG-A (group B) groups. Bowel preparation efficacy was assessed on the Boston bowel preparation scale (BBPS) and bubble scale. Bowel preparation success was defined as BBPS score ≥ 6. The bubble scores ranged from 0 to 3 per segment (total from 0 to 9), with a lower score indicating lower bubbles in the colonic lumen. Safety and tolerability were evaluated using a systematized questionnaire.

Results

A total of 171 patients (group A: 87, group B: 84) were included in the final analyses. The average BBPS score of group A was 8.0±1.3, which was similar to that of group B (7.7±1.4) (p=0.215). The proportion of patients showing bowel preparation success was 95.4% in the group A whereas that in the group B was 96.4% (p=0.736). The adenoma detection rate was also similar between groups A (59.6%) and B (41.9%) (p=0.087). The bubble scale in the group A was 0.2±0.9, which was significantly better that that of the group B (1.9±1.7) (p<0.001). All adverse events were mild in both groups. The group A showed lower frequency of nausea compared to the group B (14.9% vs. 38.1%, p=0.001). Overall satisfaction was better in the group A (8.1 ± 2.1 vs. 6.4 ± 2.8, p<0.001).

Conclusion

Although both OST and 1 L PEG-A were efficacious, safe, and tolerable for bowel preparation of colonoscopy, the OST showed fewer bubbles and slightly better tolerability.

Introduction

Bowel preparation is recognized as the most burdensome aspect of the whole colonoscopy procedure, sometimes even worse that the examination itself, and represents a major barrier to screening colonoscopy. Mannitol could significantly improve patient acceptability as it is rapid, requires a single dose, a low volume and has a pleasant taste. The SATISFACTION study compared oral mannitol 100g/750ml with standard split-dose 2L PEG-ASC (MoviPrep®).

Aims & Methods

The SATISFACTION Phase III study was an international, multicentre, randomized (1:1), parallel-group, endoscopist-blinded non inferiority trial. Primary endpoint was the proportion of patients with adequate bowel cleansing. Secondary endpoints concerned efficacy (adenoma detection rate, caecal intubation rate, time of evacuation), safety (intestinal gases concentration, haematobiological parameters, adverse events) and patient satisfaction. The study included 703 patients (352 treated with mannitol and 351 with PEG-ASC) undergoing elective colonoscopy.

Results

Mannitol was not inferior to PEG-ASC for proportion of patients with adequate cleansing (91.1% and 95.5% respectively; p value for the non-inferiority =0.0095). There was no significant difference for secondary efficacy endpoints. The profile of acceptability was significantly better in mannitol group for easy to use, taste, willingness to use (p<0.0001 for all parameters). The concentration of intestinal gases (H₂, CH₄) was similar in the two groups and well below those potentially critical.

Conclusion

Mannitol was not inferior to PEG-ASC for proportion of patients with adequate cleansing (91.1% and 95.5% respectively; p value for the non-inferiority =0.0095). There was no significant difference for secondary efficacy endpoints. The profile of acceptability was significantly better in mannitol group for easy to use, taste, willingness to use (p<0.0001 for all parameters). The concentration of intestinal gases (H₂, CH₄) was similar in the two groups and well below those potentially critical.

Disclosure

Prof. Gian Eugenio Tontini and Prof. Maurizio Vecchi received a consultant fee from NTC Pharma. Anna Orsatti is a current NTC Pharma employee

Introduction

Epstein-Barr virus (EBV) associated gastric cancer (GC) has been reported to be about 5-16% of all gastric cancers with good prognosis compared to EBV-negative GC. The aim of this study was to evaluate the clinicopathological characteristics of EBV-positive GC including survival analysis in the prospective observational cohort study in a tertiary hospital in South Korea.

Aims & Methods

Total 4,586 patients who underwent EBV in situ hybridization (EBV-ISH) testing among 14,613 patients diagnosed with GC were prospectively enrolled at Seoul National University Bundang Hospital from 2003 to 2023. Data including age, sex, smoking, cancer type and stage, tumor size and location, histologic type, molecular features (p53 expression and MSI), and survival information including causes of death were collected and analyzed.

Results

EBV-positive cancer group showed significant differences compared to EBV-negative cancer group. That is, they showed higher proportion of males (p<0.001), predominant presence in the proximal stomach (p<0.001), higher proportion of undifferentiated cancer (p<0.001), and lower cancer stage (p=0.004) (Table). In Cox multivariate analyses, age (HR 1.022, p<0.001), tumor size (HR 1.118, p<0.001) along with cancer stage (stage 2 HR 5.843, p<0.001; stage3 HR 15.570, p<0.001; stage4 HR 50.075, p<0.001, respectively) were significant risk factors for GC-specific mortality, while EBV positivity was inversely correlated (HR 0.537, p=0.023). In the survival analyses, EBV-positive cancer group showed statistically significant survival advantages over EBV-negative cancer group in both overall (p=0.016) and gastric cancer-specific survival (p=0.005)

Conclusion

EBV-positive GC group was associated with male sex, proximal location, poorly differentiated histology and lower cancer stage, and showed significantly better prognosis than EBV-negative gastric cancer. EBV might play a role in the gastric carcinogenesis to make less metastasis resulting in better survival.