Introduction

Prone is a common position for endoscopic retrograde cholangiopancreatography (ERCP). However, patients need to rotate their neck up to 90^O to the right along the procedure time, which might cause post-procedure neck sprain. Furthermore, patients with limited neck rotation may have difficulty during intubation of the endoscope. We designed a pillow to have only one elevated corner, this was put under the right shoulder, and the height of the pillow gradually sloped down to the other 3 corners. We hypothesize that the elevation of the right shoulder by the pillow makes thoracic rotation to compensate the cervical rotation and this would reduce neck sprain, from overstretching neck muscle, and facilitate endoscope intubation.

Aims & Methods

This randomized, controlled study aimed to evaluate the efficacy of the ergonomic wedge pillow for patients undergoing prone ERCP. Patients aged between 18-80 years who were indicated for ERCP at King Chulalongkorn Memorial Hospital were recruited. Patients with limited neck rotation less than 30-degree, severe cervical spine diseases, endotracheal intubated, or informed consent could not be obtained were excluded. The patients were randomized to undergo ERCP using pillow (study group) or without pillow (control group), in 1:1 fashion. Neck pain was reported by patients at baseline (before ERCP), and 1 hour, 1 day, and 7 days after ERCP. Scope intubation difficulty was rated by endoscopists. Patients’ and endoscopists’ satisfaction scores were recorded by using scales of 0-10.

Results

A total of 256 patients (122 women and 134 men) were randomized to study (128 patients), and control (128 patients) groups. The baseline characteristics and base-line neck pain scores were not different between two groups. The pillow group required less assisting shoulder lift during scope intubation (9% vs 22%, respectively) (p = 0.002). The requirement of nasopharyngeal airway insertion was not different between the two groups (13% vs 17%, respectively) (p = 0.385). After ERCP, neck pain was reported at 1 hour, 1 day, and 7 days after ERCP in 25%, 20%, and 0% in study group, and 31%, 31%, and 0% in control group, respectively. The incidence of neck pain at 1 day was significantly lower in pillow group than control group (p = 0.044), especially for moderate to severe neck pain (4% vs 11%, respectively) (p = 0.032). Endoscopists’ satisfaction scores were significantly higher in pillow group than control group (9.6 vs 8.9, respectively) (p < 0.001). There was a trend of higher patients’ satisfaction scores in pillow than control groups, 9.7 vs 9.5, respectively, however, this did not reach a statistical significance (p = 0.081).

Conclusion

The ergonomic, wedge-shaped pillow reduced the difficulty score of scope intubation and required less assisting shoulder lifting during scope intubation when compared with control. This pillow significantly reduced the incidence of neck sprain, especially for moderate-to-severe pain, at 1 day after prone ERCP. The pillow had a higher endoscopist’s satisfaction score and a trend toward higher patients’ satisfaction score.

Introduction

The clinical value of combined resection of important hepatic vessels in hilar cholangiocarcinoma remains controversial. We aimed to compare the short-term and long-term outcome of combined versus non-combined major vessel resection in patients undergoing radical resection for hilar cholangiocarcinoma.

Aims & Methods

This single centre retrospective cohort study of patients with hilar cholangiocarcinoma was conduct from January 2007 to December 2018. Patients who underwent radical re-resection were enrolled. The short-term and long-term clinical outcomes of the groups were compared after propensity score matching.

Results

A total of 310 patients were included. There was no statistically significant difference in perioperative clinical outcomes between VR group (PVR and AVR) and non-VR group after 1:2 PSM. Patients who received PVR had significantly longer OS (p=0.023) and DFS (p=0.010) compared to those in the non-PVR group. AVR group was associated with improved OS (p=0.036) and DFS (p=0.029) compared with non-AVR group following the curative-intent resection. The postoperative complications of combined VR would not worsen long-term survival for patients (OS: p=0.159; DFS: p=0.112).

Conclusion

Combined vascular resection (VR) would improve the long-term survival for patients with hilar cholangiocarcinoma. The postoperative complications of combined VR would not worsen long-term survival. Therefore, radical surgical resection should be actively performed in these patients.

Disclosure

The authors declare that they have no competing interests.

Introduction

Non-alcoholic steatohepatitis (NASH) is a chronic liver disease characterized by liver steatosis and inflammation which abnormal immune responses involved in pathogenesis, and there is no approved therapeutic drug. Rhein, one of the main bioactive components of Rheum palmatum, has exerted anti-inflammatory properties. However, the mechanism by which Rhein exerts beneficial effects against NASH is far from elucidated. Here, our study aimed to investigate the therapeutic effects of Rhein on liver steatosis and inflammation and elucidate the related mechanisms of immunoregulation.

Aims & Methods

Male C57BL/6 mice were given high-fat diet for 10 weeks to induce NASH, followed by Rhein suspension administration at a dose of 100mg/kg and 200mg/kg for 4 weeks. The therapeutic effect of NASH was estimated by body weight, liver weight, LW/BW, food intake, the liver appearance and the histological analysis of liver section stained with hematoxylin and eosin. The proportion of lymphocyte cells in the mesenteric lymph nodes (MLNs) was detected by flow cytometry.

Results

Our findings demonstrated that high-fat diet treatment resulted in severe liver inflammation and severe steatosis, while Rhein appreciably reverse these phenomenon, as evidenced by the reduction of body weight, liver wet weight, LW/BW, and liver size in mice. Histological analysis of liver section revealed that administration of Rhein exhibited improvement of severe steatosis, elimination of inflammatory cells and resolution of balloon-like changes when compared to mice in the HFD group. Interestingly, there were no significant differences in food intake among groups of mice, suggesting that the protective effect of Rhein is not achieved by inhibiting appetite. Mechanistically, flow cytometry analysis showed that higher Th1 and Th17 polarized response were detected in the MLN compartments in HFD-induced mice, evidenced by the detection of increased numbers of Th1 cells (CD3+CD4+IFN-γ+) and Th17 cells (CD3+CD4+IL-17+), and Rhein intervention showed significant decrease numbers of Th1 and Th17 in MLNs. In contrast, Rhein treatment significantly increased the numbers of Treg cells (CD3+CD4+Foxp3+) with anti-inflammatory effects in the MLN of NASH mice.

Conclusion

Our results provide novel insights into the protective role of Rhein in modulating the liver steatosis and inflammation, with therapeutic potential for immunology-targeted strategy in the treatment of NASH.

References

[1] Cheng L, Chen Q, Pi R, Chen J. A research update on the therapeutic potential of rhein and its derivatives. Eur J Pharmacol. 2021,899:173908. doi:10.1016/j.ejphar.2021.173908.
[2] Gebru YA, Gupta H, Kim HS, et al. T Cell Subsets and Natural Killer Cells in the Pathogenesis of Nonalcoholic Fatty Liver Disease. Int J Mol Sci. 2021,22(22):12190. doi:10.3390/ijms222212190

Disclosure

The authors declare that there are no conflicts of interest regarding the publication of this paper.

Introduction

The literature regarding the risk of progression to extrahepatic disease and clinical factors associated with the development of metastases in patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) is sparse.

Aims & Methods

We aimed to assess the incidence of extrahepatic recurrence and to identify clinically relevant risk factors for the development of metastases in patients with HCC treated with TACE as first-line treatment.
From the Italian Liver Cancer (ITA.LI.CA) database, data of 981 HCC patients undergoing TACE as first-line treatment were retrieved and retrospectively analyzed. Incidence of extrahepatic recurrence was compared between two groups according to the diameter of the largest liver lesion at the time of TACE (HCC ≤ 3 cm vs. HCC > 3 cm). Multivariate Cox regression was used to identify predictor of extrahepatic recurrence.

Results

During a median follow-up of 27.0 months (IQR, 13.2-49.0) the overall recurrence rate was 75.4%. Only 78/981 patients (8.0%) had an extrahepatic tumor localization at first recurrence (5.4% in the ≤3 cm group and 10.7% in the >3 group; p=0.002), while the overall extrahepatic recurrence rate was 26.0% (21.2% and 31.0% patients in the ≤3 cm and >3 cm groups, respectively; p=0.0006) (Figure 1). Compared to those with larger tumors, patients with HCC ≤ 3 cm had a significantly longer recurrence-free survival (12.0 [95% CI 10.7-13.3] vs. 9.7 [95% CI 8.2-11.2] months; p=0.02) and overall survival (52.5 [95% CI 45.5-59.4] vs. 34.7 [95% CI 30.7-38.7] months; p<0.0001). HCC size ≥ 3 cm, multifocality and AFP levels were independent predictors of extrahepatic recurrence.

Conclusion

Although the majority of patients treated with TACE do not develop metastases during their lifespan, knowledge of risk factors for extrahepatic recurrence (HCC size, multifocality, AFP levels) may help to assess patient prognosis and to identify patients deserving closer follow-up in order to start early systemic therapy.

Introduction

Cholangiocarcinoma (CCA) comprises a heterogeneous group of malignant tumors with poor prognosis. Etiopathogenesis remains obscure and it is urgent to find novel therapeutic targets in order to develop effective therapies. Krüppel-like factors (KLF) are a family of transcription factors involved in large variety of biological processes, including organogenesis, differentiation and cellular homeostasis. However, the role of KLFs during cholangiocarcinogenesis is yet to be unveiled.

Aims & Methods

Here, we investigated the role of KLF5 in cholangiocarcinogenesis and evaluated the therapeutic potential of its inhibition during CCA tumorigenesis. KLF5 expression was determined in human CCA tissues [Copenhagen (n=210), TCGA (n=36), Job (n=78), TIGER-LC (n=90) and San Sebastian cohorts (n=12)] and cell lines. KLF5^-/- CCA cells were generated by CRISPR/Cas9. Proteomic analyses were carried out by mass spectrometry and the functional effects of KLF5 genetic ablation or chemical inhibition with ML264 were evaluated in vitro and in vivo.

Results

KLF5 expression was upregulated in human CCA tissues from 5 different patient cohorts compared to surrounding normal liver tissue and/or normal bile ducts. Importantly, KLF5 upregulation was observed independently on tumor mutational background. High KLF5 levels correlated with lymph node invasion and worse overall survival, being an important prognostic factor. In vitro, KLF5 protein and mRNA levels were found upregulated in human CCA cells compared to normal human cholangiocytes. Proteomic analysis of KLF5^-/- CCA cells revealed that most of the altered pathways are related with the modulation of cell cycle, proliferation, survival and migration. In agreement, KLF5^-/- CCAcells displayed decreased cell proliferation, colony formation and migration while promoting cell cycle arrest at G1/S and apoptosis in vitro, when compared with CCA control cells. Instead, no signs of tumor development were evident after subcutaneous or orthotopic injection in a xenograft animal model of CCA. Likewise, pharmacological inhibition of KLF5 with ML264 hampered CCA cells proliferation and migration in vitro, halting the progression of cell cycle and blocking tumor growth in vivo in distinct animal models. Lastly, both genetic and pharmacological inhibition of KLF5 sensitized CCA cells to chemotherapy-induced apoptosis in vitro, and the combination of the standard of care chemotherapy (gemcitabine + cisplatin) and ML264 completely halted CCA tumor growth in mice. Accordingly, KLF5^-/-CCA cells displayed altered levels of several proteins related to chemoresistance when compared to control cells, that were shown to significantly correlate with KLF5 expression in human CCA tissues

Conclusion

Increased KLF5 is a general event in CCA, contributing to cancer progression by promoting cell survival and proliferation, as well as, chemoresistance. KLF5 inhibition with ML264 may represent a potential therapeutic strategy for CCA.