Introduction

Bile duct injury (BDI) is one of the serious complications of cholecystectomy procedures, which has a disastrous impact on long-term survival, health-related quality of life (QoL), health-care costs as well as high rates of litigation. The standard treatment of major BDI is hepaticojejunostomy (HJ). Surgical outcomes depend on many factors, including the severity of the injury, the surgeons' experiences, the patient's condition, and the reconstruction time. We aimed to assess the impact of reconstruction time and abdominal sepsis control on the reconstruction success rate.

Aims & Methods

This is a multicenter, multi-arm, parallel-group, randomized trial that included all consecutive patients treated with HJ for major post-cholecystectomy BDI from February 2014 to January 2022. Patients were randomized according to the time of reconstruction by HJ and abdominal sepsis control into group A (early reconstruction without sepsis control), group B (early reconstruction with sepsis control), and group C (delayed reconstruction). The primary outcome was successful reconstruction rate, while blood loss, HJ diameter, operative time, drainage amount, drain and stent duration, postoperative liver function tests, morbidity and mortality, number of admissions and interventions, hospital stay, total cost, and patient QoL were considered secondary outcomes.

Results

Three hundred twenty one patients from 3 centers were randomized into three groups. 44 patients were excluded from the analysis, leaving 277 patients for intention to treat analysis. With univariate analysis, older age, male gender, laparoscopic cholecystectomy, conversion to open cholecystectomy, failure of intraoperative BDI recognition, Strasberg E4 classification, uncontrolled abdominal sepsis, secondary repair, end-to-side anastomosis, diameter of HJ (< 8 mm), non-stented anastomosis, and major complications were risk factors for successful reconstruction. With multivariate analysis, conversion to open cholecystectomy, uncontrolled sepsis, secondary repair, the small diameter of HJ, and non-stented anastomosis were the independent risk factors for the successful reconstruction. Also, group B patients showed decreased admission and intervention rates, decreased hospital stay, decreased total cost, and early improved patient QoL.

Conclusion

Early reconstruction after abdominal sepsis control can be done safely at any time with comparable results for delayed reconstruction in addition to decreased total cost and improved patient QoL.

Introduction

The passive bending colonoscope (PBCS) has a passive bending section on the scope head that could make the scope advance deeply and smoothly without forming a walking-stick handle. Although the efficacy of PBCS as colonoscope has been presented^1-3, the utility in endoscopic retrograde cholangiopancreatography (ERCP) for the patients with surgically altered anatomy (SAA) has not been established. There is no large-scale studies exist to date and only a case series that described the effect of PBCS-ERCP for patients with SAA was reported⁴.

Aims & Methods

We performed a multicenter observational study to evaluate the outcome of PBCS-ERCP compared to balloon assisted enteroscope (BAE) ERCP that could expand the drainage options for SAA cases. This study involved 343 patients with SAA who underwent ERCP. Among them, 110 underwent PBCS-ERCP, while 233 underwent BAE-ERCP. Propensity score matching was applied and a final cohort of 210 (105 in each group) with well-balanced backgrounds (type of SAA, presence of stomach, presence of naïve papilla Vater, Age and sex) was analyzed. In this study, CF HQ290ZI (similar to CF-HQ190I) and PCF PQ260L (similar to PF-PH190L) (Olympus Medical Systems, Tokyo, Japan) were used as PBCS. As BAE, EI580BT double balloon enteroscope (Fujifilm, Tokyo, Japan) was used.We evaluated the success rate and time to reach the anastomosis or ampulla of Vater as a primary outcome. Other success rate (cannulation, completion of planned procedure) and incidence of adverse event was also analyzed as secondary outcome measure.

Results

The success rate for reaching was 91.4% (96/105) in PBCS and 90.5% (95/105) in BAE (odds ratio [95%CI]: 1.12, [0.44–2.89], p = .809). Mean required time to reach was 10.04 min. (SD, 9.62) in PBCS, 18.77 min. (SD, 13.21) in BAE and significantly shorter in PBCS (p < .001). The success rate to cannulate and complete the procedure was not significantly different (cannulation, 97.8% in the PBCS and 90.2% in the BAE, odds ratio [95%CI]: 4.88, [1.02–23.24], p = .062; completion, 88.6% in PBCS and 81.0% in BAE, odds ratio [95%CI]: 1.82, [0.84–3.95], p = .178), while the required time to cannulate and complete the procedure was significantly shorter in PBCS (cannulation, 2.7 min. (SD, 3.16) in PBCS, 7.13 min. (SD, 9.71) in BAE, p < .001; completion, 42.32 min. (SD, 25.15) in PBCS, 65.73 min. (SD, 31.23) in BAE, p < .001). The incidence of adverse event was significantly higher in BAE (20/105, 19.0%) than in PBCS (5/105, 4.8%) (p < .001).

Conclusion

PBCS-ERCP showed promising results for SAA cases with shorter procedure time and lower adverse event incidence compared to BAE-ERCP, despite no significant difference in success rates.

References

1. Mizukami T, Ogata H, Hibi T. "Passive-bending colonoscope" significantly improves cecal intubation in difficult cases. World J Gastroenterol 2012;18:4454-6.
2. Sato K, Shigiyama F, Ito S, et al. Colonoscopy using a small-caliber colonoscope with passive-bending after incomplete colonoscopy due to sharp angulation or pain. Surg Endosc 2013;27:4171-6.
3. Sato K, Ito S, Shigiyama F, et al. A prospective randomized study on the benefits of a new small-caliber colonoscope. Endoscopy 2012;44:746-53.
4. Nakaji S, Hirata N, Shiratori T, et al. Three successful cases of biliary tract disease with Roux-en-Y reconstruction treated by ERCP using PCF-PQ260L. JJBA 2014;28:89-94.(in Japanese)

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.