Staged laparoscopic orchiopexy of intra-abdominal testis: Spermatic vessels division versus traction? A multicentric comparative study.

BACKGROUND: Staged laparoscopic management of intra-abdominal testes using pedicular section is recognized as gold standard technique, successful in 85 % of cases for scrotal testicular position with less than 10 % testicular atrophy. Recently, Shehata proposed a new technique without pedicular division for these testes, using spermatic vessels traction, but did not provide a comparative study of the two techniques. OBJECTIVE: To evaluate the laparoscopic spermatic pedicular traction (Shehata technique, ST) for the treatment of intra-abdominal testis, as an alternative to gold standard pedicular section (2-stage Fowler-Stephens, FS). STUDY DESIGN: Intra-abdominal testes of 129 patients in two tertiary pediatric urology centers were managed laparoscopically (2011-2019) either by 2-stage FS orchidopexy or ST according to the surgeon preference. Testicular position and size were statistically compared. RESULTS: A total of 147 testes were pulled down by 80 ST and 67 FS, including 18 bilateral cases. Median (IQR) age at surgery was 24.2 (15.6-46.4) months (ST) and 18.3 (13.1-38.2) months (FS) (p = 0.094). Scrotal pulling-down of the testis was performed after a median (IQR) period of 2.3 (1.6-3.4) months (ST) and 6.1 (4.7-8.3) months (FS), respectively (p < 0.005). Although ST had collapsed in 17 cases (21.3 %), only one (1.3 %) redo procedure was required. After a median (IQR) follow-up of 22 (12-40) and 19 (8.75-37) months (p = 0.59), the testis was in the scrotum in 85 % and 81 % of ST and FS cases, respectively (p = 0.51). Testicular atrophy occurred in 10 % of ST and 13.4 % of FS (p = 0.61). Multivariate analysis using the propensity score analysis did not identify any difference between the two techniques. DISCUSSION: Our results seem to confirm that FS and ST achieve the same results regarding final testicular position and testicular atrophy rate, with a long-term follow-up. Our study supports pediatric surgeons to favor laparoscopic spermatic pedicular traction (ST) which preserves the testicular vascularization and may ensure better spermatogenesis after puberty. More details on the size and position of the testicle at the beginning of the first laparoscopy seem however essential to assess more accurately the outcomes of each surgical technique. Our outcomes will also be re-evaluated when our patients have reached puberty, from an exocrine and endocrine points of view. CONCLUSIONS: This study showed similar results after laparoscopic traction or section of spermatic vessels for intra-abdominal testis in a long-term follow-up, providing more evidence for the use of ST as a valuable alternative to FS.

What we learned from the Covid-19 first wave: a survey from Young Pediatric Urology Committee (YPUC) from ESPU.

BACKGROUND: The Corona virus still has a big impact on medical work. All medical specialties have been called to confront this unexpected event, even pediatric surgery. The objective of this study is to highlight the effect of pandemic on daily work of young pediatric surgeons during the Covid-19 first wave. METHODS: An online survey was sent via email by the Scientific Committee of YPUC in April 2020. The impact of Covid-19 was invested, by analyzing the results of answers received. The difference between young consultants and trainees (C and T) were examined to assess the effect of pandemic in 2 different categories. RESULTS: A total of 88 participants filled out the questionnaire. Guidelines around surgeries were well arranged: clear for 98% concerning triage with no difference between T and C; clear for 84% concerning pre-operative screening and for 81% concerning surgical dressing with a significance difference between T and C in understanding (p=0.07 and p=0.06). Forty-two respondents (48%) tested all surgical patients and the 20% operated patients positive for COVID-19. Thirteen (15%) were relocated to work in other divisions on different tasks, 12 were C. 86% of T did not participate in surgeries as much as before. CONCLUSIONS: The impact of the pandemic has been very significant for pediatric urologists and the difference between C and T confirm that the training could be impacted. After the first wave we should be careful on PPE, on pre-operative screening of surgical patients and we should protect the trainee learning curve.

TGR5 controls bile acid composition and gallbladder function to protect the liver from bile acid overload.

BACKGROUND & AIMS: As the composition of the bile acid (BA) pool has a major impact on liver pathophysiology, we studied its regulation by the BA receptor Takeda G protein coupled receptor (TGR5), which promotes hepatoprotection against BA overload. METHODS: Wild-type, total and hepatocyte-specific TGR5-knockout, and TGR5-overexpressing mice were used in: partial (66%) and 89% extended hepatectomies (EHs) upon normal, ursodeoxycholic acid (UDCA)- or cholestyramine (CT)-enriched diet, bile duct ligation (BDL), cholic acid (CA)-enriched diet, and TGR5 agonist (RO) treatments. We thereby studied the impact of TGR5 on: BA composition, liver injury, regeneration and survival. We also performed analyses on the gut microbiota (GM) and gallbladder (GB). Liver BA composition was analysed in patients undergoing major hepatectomy. RESULTS: The TGR5-KO hyperhydrophobic BA composition was not directly related to altered BA synthesis, nor to TGR5-KO GM dysbiosis, as supported by hepatocyte-specific KO mice and co-housing experiments, respectively. The TGR5-dependent control of GB dilatation was crucial for BA composition, as determined by experiments including RO treatment and/or cholecystectomy. The poor TGR5-KO post-EH survival rate, related to exacerbated peribiliary necrosis and BA overload, was improved by shifting BAs toward a less toxic composition (CT treatment). After either BDL or a CA-enriched diet with or without cholecystectomy, we found that GB dilatation had strong TGR5-dependent hepatoprotective properties. In patients, a more hydrophobic liver BA composition was correlated with an unfavourable outcome after hepatectomy. CONCLUSIONS: BA composition is crucial for hepatoprotection in mice and humans. We indicate TGR5 as a key regulator of BA profile and thereby as a potential hepatoprotective target under BA overload conditions. LAY SUMMARY: Through multiple in vivo experimental approaches in mice, together with a patient study, this work brings some new light on the relationships between biliary homeostasis, gallbladder function, and liver protection. We showed that hepatic bile acid composition is crucial for optimal liver repair, not only in mice, but also in human patients undergoing major hepatectomy.

Hepatoprotective impact of the bile acid receptor TGR5.

During liver repair after injury, bile secretion has to be tightly modulated in order to preserve liver parenchyma from bile acid (BA)-induced injury. The mechanisms allowing the liver to maintain biliary homeostasis during repair after injury are not completely understood. Besides their historical role in lipid digestion, bile acids (BA) and their receptors constitute a signalling network with multiple impacts on liver repair, both stimulating regeneration and protecting the liver from BA overload. BA signal through nuclear (mainly Farnesoid X Receptor, FXR) and membrane (mainly G Protein-coupled BA Receptor 1, GPBAR-1 or TGR5) receptors to elicit a wide array of biological responses. While a great number of studies have been dedicated to the hepato-protective impact of FXR signalling, TGR5 is by far less explored in this context. Because the liver has to face massive and potentially harmful BA overload after partial ablation or destruction, BA-induced protective responses crucially contribute to spare liver repair capacities. Based on the available literature, the TGR5 BA receptor protects the remnant liver and maintains biliary homeostasis, mainly through the control of inflammation, biliary epithelial barrier permeability, BA pool hydrophobicity and sinusoidal blood flow. Mouse experimental models of liver injury reveal that in the lack of TGR5, excessive inflammation, leaky biliary epithelium and hydrophobic BA overload result in parenchymal insult and compromise optimal restoration of a functional liver mass. Translational perspectives are thus opened to target TGR5 with the aim of protecting the liver in the context of injury and BA overload.

TGR5-dependent hepatoprotection through the regulation of biliary epithelium barrier function.

OBJECTIVE: We explored the hypothesis that TGR5, the bile acid (BA) G-protein-coupled receptor highly expressed in biliary epithelial cells, protects the liver against BA overload through the regulation of biliary epithelium permeability. DESIGN: Experiments were performed under basal and TGR5 agonist treatment. In vitro transepithelial electric resistance (TER) and FITC-dextran diffusion were measured in different cell lines. In vivo FITC-dextran was injected in the gallbladder (GB) lumen and traced in plasma. Tight junction proteins and TGR5-induced signalling were investigated in vitro and in vivo (wild-type [WT] and TGR5-KO livers and GB). WT and TGR5-KO mice were submitted to bile duct ligation or alpha-naphtylisothiocyanate intoxication under vehicle or TGR5 agonist treatment, and liver injury was studied. RESULTS: In vitro TGR5 stimulation increased TER and reduced paracellular permeability for dextran. In vivo dextran diffusion after GB injection was increased in TGR5-knock-out (KO) as compared with WT mice and decreased on TGR5 stimulation. In TGR5-KO bile ducts and GB, junctional adhesion molecule A (JAM-A) was hypophosphorylated and selectively downregulated among TJP analysed. TGR5 stimulation induced JAM-A phosphorylation and stabilisation both in vitro and in vivo, associated with protein kinase C-ζ activation. TGR5 agonist-induced TER increase as well as JAM-A protein stabilisation was dependent on JAM-A Ser285 phosphorylation. TGR5 agonist-treated mice were protected from cholestasis-induced liver injury, and this protection was significantly impaired in JAM-A-KO mice. CONCLUSION: The BA receptor TGR5 regulates biliary epithelial barrier function in vitro and in vivo through an impact on JAM-A expression and phosphorylation, thereby protecting liver parenchyma against bile leakage.

Bile acids and their receptors during liver regeneration: "Dangerous protectors".

Tissue repair is orchestrated by a finely tuned interplay between processes of regeneration, inflammation and cell protection, allowing organisms to restore their integrity after partial loss of cells or organs. An important, although largely unexplored feature is that after injury and during liver repair, liver functions have to be maintained to fulfill the peripheral demand. This is particularly critical for bile secretion, which has to be finely modulated in order to preserve liver parenchyma from bile-induced injury. However, mechanisms allowing the liver to maintain biliary homeostasis during repair after injury are not completely understood. Besides cytokines and growth factors, bile acids (BA) and their receptors constitute an insufficiently explored signaling network during liver regeneration and repair. BA signal through both nuclear (mainly Farnesoid X Receptor, FXR) and membrane (mainly G Protein-coupled BA Receptor 1, GPBAR-1 or TGR5) receptors which distributions are large in the organism, and which activation elicits a wide array of biological responses. While a number of studies have been dedicated to FXR signaling in liver repair processes, TGR5 remains poorly explored in this context. Because of the massive and potentially harmful BA overload that faces the remnant liver after partial ablation or destruction, both BA-induced adaptive and proliferative responses may stand in a central position to contribute to the regenerative response. Based on the available literature, both BA receptors may act in synergy during the regeneration process, in order to protect the remnant liver and maintain biliary homeostasis, otherwise potentially toxic BA overload would result in parenchymal insult and compromise optimal restoration of a functional liver mass.

The Bile Acid Receptor TGR5 and Liver Regeneration.

BACKGROUND: Most of the literature on the bile acid (BA) membrane receptor TGR5 is dedicated to its potential role in the metabolic syndrome, through its regulatory impact on energy expenditure, insulin and GLP-1 secretion, and inflammatory processes. While the receptor was cloned in 2002, very little data are available on TGR5 functions in the normal and diseased liver. However, TGR5 is highly expressed in Kupffer cells and liver endothelial cells, and is particularly enriched in the biliary tract [cholangiocytes and gallbladder (GB) smooth muscle cells]. We recently demonstrated that TGR5 has a crucial protective impact on the liver in case of BA overload, including after partial hepatectomy. KEY MESSAGES: TGR5-KO mice after PH exhibited periportal bile infarcts, excessive hepatic inflammation and defective adaptation of biliary composition (bicarbonate and chloride). Most importantly, TGR5-KO mice had a more hydrophobic BA pool, with more secondary BA than WT animals, suggesting that TGR5-KO bile may be harmful for the liver, mainly in situations of BA overload. As GB is both the tissue displaying the highest level of TGR5 expression and a crucial physiological site for the regulation of BA pool hydrophobicity by reducing secondary BA, we investigated whether TGR5 may control BA pool composition through an impact on GB. Preliminary data suggest that in the absence of TGR5, reduced GB filling dampens the cholecystohepatic shunt, resulting in more secondary BA, more hydrophobic BA pool and extensive liver injury in case of BA overload. CONCLUSIONS: In the setting of BA overload, TGR5 is protective of the liver through the regulation of not only secretory and inflammatory processes, but also through the control of BA pool composition, at least in part by targeting the GB. Thereby, TGR5 appears to be crucial for protecting the regenerating liver from BA overload.