Laparoscopic liver resection for living donation: Where do we stand?

In Western countries, living donor liver transplantation(LDLT) may represent a valuable alternative to deceased donor liver transplantation. Yet, after an initial peak of enthusiasm, reports of high rates of complications and of fatalities have led to a certain degree of reluctance towards this procedure especially in Western countries. As for living donor kidney transplantation, the laparoscopic approach could improve patient's tolerance in order to rehabilitate this strategy and reverse the current trend. In this setting however, initial concerns regarding patient's safety and graft integrity, need for acquiring surgical expertise in both laparoscopic liver surgery and living donor transplantation and lack of evidence supporting the benefits of laparoscopy have delayed the development of this approach. Similarly to what is performed in classical resectional liver surgery, initial experiences of laparoscopy have therefore begunwith left lateral sectionectomy,which is performed for adult to child living donation.In this setting,the laparoscopic technique is now well standardized,is associated with decreased donor blood loss and hospital stays and provides graft of similar quality compared to the open approach.On the other hand laparoscopic major right or left hepatectomies for adult-adult LDLT currently lack standardization and various techniques such as the full laparoscopic approach,the hand assisted approach and the hybrid approach have been reported.Hence,even-though several reports highlight the feasibility of these procedures,the true benefits of laparoscopy over laparotomy remain to be fully assessed.This could be achieved through standardization of the procedures and creation of international registries especially in Eastern countries where LDLT keeps on flourishing.

Role of colectomy in preventing recurrent primary sclerosing cholangitis in liver transplant recipients

AIM To study the published evidence on the impact of colectomy in preventing recurrent primary sclerosing cholangitis(r PSC). METHODS An unrestricted systematic literature search in Pub Med, EMBASE, Medline Ovid SP, ISI Web of Science, Lista(EBSCO) and the Cochrane library was performed on clinical studies investigating colectomy in liver transplantation(LT) recipients with and without r PSC in the liver allograft. Study quality was evaluated according to a modification of the methodological index for non-randomized studies(MINORS) criteria. Primary endpoints were the impact of presence, timing and type of colectomy on r PSC. Overall presence of inflammatory bowel disease(IBD), time of IBD diagnosis, posttransplant IBD and immunosuppressive regimen were investigated as secondary outcome.RESULTS The literature search yielded a total of 180 publications. No randomized controlled trial was identified. Six retrospective studies met the inclusion criteria of which 5 studies were graded as high quality articles. Reporting of IBD was heterogenous but in four publications, either inflammatory bowel disease, ulcerative colitis or in particular active colitis post-LT significantly increased the risk of r PSC. The presence of an intact(i.e., retained) colon at LT was identified as risk factor for r PSC in two of the high quality studies while four studies found no effect. Type of colectomy was not associated with r PSC but this endpoint was underreported(only in 33% of included studies).Neither tacrolimus nor cyclosporine A yielded a significant benefit in disease recurrence of primary sclerosing cholangitis(PSC).CONCLUSION The data favours a protective role of pre-/peri-LT colectomy in r PSC but the current evidence is not strong enough to recommend routine colectomy for r PSC prevention.

Early tacrolimus exposure does not impact long-term outcomes after liver transplantation

BACKGROUND Tacrolimus trough levels(TTL)during the first weeks after liver transplantation(LT)have been related with long-term renal function and hepatocellular carcinoma recurrence.Nevertheless,the significance of trough levels of tacrolimus during the early post-transplant period for the long-term outcome is under debate AIM To evaluate the effect of TTL during the first month on the long-term outcomes after LT.METHODS One hundred fifty-five LT recipients treated de novo with once-daily tacrolimus were retrospectively studied.Patients with repeated LT or combined transplantation were excluded as well as those who presented renal dysfunction prior to transplantation and/or those who needed induction therapy.Patients were classified into 2 groups according to their mean TTL within the first month after transplantation:≤10(n=98)and>10 ng/mL(n=57).Multivariate analyses were performed to assess risk factors for patient mortality.RESULTS Mean levels within the first month post-transplant were 7.4±1.7 and 12.6±2.2 ng/mL in the≤10 and>10 groups,respectively.Donor age was higher in the high TTL group 62.9±16.8 years vs 45.7±17.5 years(P=0.002)whilst mycophenolate-mofetil was more frequently used in the low TTL group 32.7%vs 15.8%(P=0.02).Recipient features were generally similar across groups.After a median follow-up of 52.8 mo(range 2.8-81.1),no significant differences were observed in:Mean estimated glomerular filtration rate(P=0.69),hepatocellular carcinoma recurrence(P=0.44),de novo tumors(P=0.77),new-onset diabetes(P=0.13),or biopsy-proven acute rejection rate(12.2%and 8.8%,respectively;P=0.50).Eighteen patients died during the follow-up and were evenly distributed across groups(P=0.83).Five-year patient survival was 90.5%and 84.9%,respectively(P=0.44),while 5-year graft survival was 88.2%and 80.8%,respectively(P=0.42).Early TTL was not an independent factor for patient mortality in multivariate analyses.CONCLUSION Differences in tacrolimus levels restricted to the first month after transplant did not result in significant differences in long-term outcomes of LT recipients.

Systematic comparison of experimental and human obstructive cholestasis reveals conservation of canonical pathway activation and biomarkers relevant for cholestatic liver disease

Cholelithiasis-induced cholestasis is one of the most common causes of hospitalization due to gastrointestinal disease,yet considerable knowledge gaps exist in the pathogenesis of this disease.This can partially be explained by inadequate characterization of experimental cholestasis models.Here,we compared the transcriptional profile of commonly used mouse models for obstructive cholestasis and benchmarked them to human disease to identify the model(s)best suited for cholelithiasis-induced cholestasis research and to uncover conserved mechanisms involved in human and murine cholestasis.

Nutritional issues in patients with obesity and cirrhosis

Obesity and metabolic syndrome are considered as responsible for a condition known as the non-alcoholic fatty liver disease that goes from simple accumulation of triglycerides to hepatic inflammation and may progress to cirrhosis.Patients with obesity also have an increased risk of primary liver malignancies and increased body mass index is a predictor of decompensation of liver cirrhosis.Sarcopenic obesity confers a risk of physical impairment and disability that is significantly higher than the risk induced by each of the two conditions alone as it has been shown to be an independent risk factor for chronicliver disease in patients with obesity and a prognostic negative marker for the evolution of liver cirrhosis and the results of liver transplantation.Cirrhotic patients with obesity are at high risk for depletion of various fat-soluble,water-soluble vitamins and trace elements and should be supplemented appropriately.Diet,physical activity and protein intake should be carefully monitored in these fragile patients according to recent recommendations.Bariatric surgery is sporadically used in patients with morbid obesity and cirrhosis also in the setting of liver transplantation.The risk of sarcopenia,micronutrient status,and the recommended supplementation in patients with obesity and cirrhosis are discussed in this review.Furthermore,the indications and contraindications of bariatric surgery-induced weight loss in the cirrhotic patient with obesity are discussed.

Laparoscopic liver resection:Wedge resections to living donor hepatectomy, are we heading in the right direction?

Despite inception over 15 years ago and over 3000 completed procedures, laparoscopic liver resection has remained mainly in the domain of selected centers and enthusiasts. Requirement of extensive open liver resection(OLR) experience, in-depth understanding of anatomy and considerable laparoscopic technical expertise may have delayed wide application. However healthy scepticism of its actual benefits and presence of a potential publication bias; concern about its safety and technical learning curve, are probably equally responsible. Given that a large proportion of our work, at least in transplantation is still OLR, we have attempted to provide an entirely unbiased, mature opinion of its pros and cons in the current invited review. We have dividedthis review into two sections as we believe they merit separate attention on technical and ethical grounds. The first part deals with laparoscopic liver resection(LLR) in patients who present with benign or malignant liver pathology, wherein we have discussed its overall outcomes; its feasibility based on type of pathology and type of resection and included a small section on application of LLR in special scenarios like cirrhosis. The second part deals with the laparoscopic living donor hepatectomy(LDH) experience to date, including its potential impact on transplantation in general. Donor safety, graft outcomes after LDH and criterion to select ideal donors for LLR are discussed. Within each section we have provided practical points to improve safety in LLR and attempted to reach reasonable recommendations on the utilization of LLR for units that wish to develop such a service.

Laparoscopic fenestration of pancreatic serous cystadenoma:Minimally invasive approach for symptomatic benign disease

Serous cystadenoma(SC) is a benign pancreatic cystic tumor. Surgical resection is recommended for symptomatic forms, but laparoscopic fenestration of large symptomatic macrocystic SC was not yet described in the literature. In this study, 3 female patients underwent laparoscopic fenestration for macrocystic SC(12-14 cm). Diagnosis was established via magnetic resonance imaging and endoscopic ultrasound, with intra-cystic dosage of tumors markers(ACE and CA19-9) in 2 patients. All patients were symptomatic and operated on 15-60 mo after diagnosis.Radiological evaluation showed constant cyst growth.Patients were informed about this new surgical modality that can avoid pancreatic resection. The mean operative time was 103 min(70-150 min) with one conversion.The post-operative course was marked by a grade A pancreatic fistula in one patient and was uneventful in the other two. The hospital stay was 3, 10, and 18 d, respectively. The diagnosis of macrocystic SC was histologically-confirmed in all cases. At the last followup(13-26 mo), all patients were symptom-free, and radiological evaluation showed complete disappearance of the cyst. Laparoscopic fenestration, as opposed to resection, should be considered for large symptomatic macrocystic SC, thereby avoiding pancreatic resection morbidity and mortality.

Anti-Inflammatory Pre-Treatment to Reduce Mobilization-Induced Liver Inflammation in Mice: Novel Model to Study Liver Injury

Background: Liver surgery requires mobilization of the liver resulting in injury. Mobilization is the predominant cause of hepatocyte damage during liver surgery and jeopardizes post-operative liver function. Previously, mobilization-induced liver injury was found to be associated with inflammation. So far, anti-inflammatory drugs to potentially prevent liver inflammation following liver mobilization were not tested. In this study, we aimed to establish an in vivo mouse model of mobilization-induced liver injury and to evaluate the effect of anti-inflammatory pre-treatment before liver mobilization on liver inflammation. Methods: To develop a mouse model for mobilization-induced liver injury, C57BL/6 mice (n = 8) underwent surgery during which the liver was mobilized by gentle manipulation of the lobes with cotton-wool applicators for 15 minutes. In two control groups, the liver was left alone or was subjected to laparotomy only. An additional group was added that received anti-TNF treatment (Infliximab) 2 days prior to surgery. Liver samples were obtained 2 hours after mobilization and liver inflammation was analyzed by histology and inflammatory gene expression. Results: Gentle liver mobilization resulted in acute liver inflammation as indicated by increased recruitment of inflammatory cells and elevated inflammatory gene expression compared to controls. Infliximab pre-treatment had no effect on the inflammatory response in the liver. Conclusion: Our current model provides an excellent opportunity to study the effects of pre-treatment with anti-inflammatory drugs on mobilization-induced liver inflammation. Further studies are needed to investigate whether anti-inflammatory mediators can be used to prevent liver inflammation.

Robotic-assisted esophagectomy: A literature review and our experience at a tertiary care centre

Esophageal cancer is a common cancer with a high case-related mortality worldwide,and radical resection offers the best survival.Initial reports have suggested that esophagus is an ideal organ which could benefit with robotic assistance.However,it remains to be seen whether robotic technology translates into better surgical outcomes and survival for the patients with esophageal cancer.We searched PubMed,Scopus and Google Scholar for English language articles.The search terms included minimally invasive esophagectomy or MIE,robotic-assisted esophagectomy,hybrid esophagectomy,robot-assisted minimal invasive esophagectomy or RAMIE,esophageal cancer,esophageal carcinoma.We review the development of robotic-assisted esophagectomy to focus on the surgical techniques and oncological clearance,and present a brief summary of our experience in this approach.Controlled trials will be required to establish the benefit of robotic-assisted esophagectomy,however the current literature points towards the safety and feasibility of this approach.

Liver transplantation for non-resectable colorectal metastases-an evolving paradigm in transplant oncology

A better understanding of colorectal liver metastasis(CRLM)onco-genomics and the improvement of systemic treatments,including targeted and immune therapies,have shifted the paradigm of CRLM prognosis over the past two decades.While 40%of the patients with colorectal cancers are likely to develop CRLM[and 50%of them to be non-resectable(nCRLM)],current oncologic management allows for the identification of a subset of CRLM patients with controlled diseases likely to highly benefit from curative resections and,perhaps,liver transplantation(LT).Indeed,the Norwegian SECA I trial in 2013(1)triggered a growing interest in LT as a curative treatment for non-resectable colorectal liver metastasis(nCRLM).This strategy is supported by several pilot studies reporting up to 80%of 5-year estimated overall survival(OS)after LT for CRLM,in contrast to the poor results obtained in the early 80’s series.

Impact of Living Donor Liver Transplantation on COVID-19 Clinical Outcomes from a Quaternary Care Centre in Delhi

Background and Aims:The anticipated fear of serious out-comes in coronavirus infected liver transplant recipients led to disruption of transplant services globally.The aim of our study was to analyze COVID-19 severity in transplant recipients and to compare the difference of COVID-19 clinical outcomes in early(<1 year)vs.late(>1 year)post-transplant period.Methods:41 post-living donor liver transplant recipients with COVID-19 infection were studied retrospectively from 1st April 2020 to 28th February 2021.Results:The median age was 49.00 years with a male preponderance(80.49%).Fif-teen patients had infection within 1 year of transplant and 26 were infected after 1 year of transplant.The overall median interval between transplantation and COVID-19 diagnosis was 816.00 days.Fever and malaise were the common presenting symptoms.The most common associated comorbidities were diabetes mellitus(65.85%)and hypertension(46.34%).The severity of illness was mild in 28(68.29%),moderate in 4(9.76%),severe in 6(14.63%)and critical in 3(7.32%).To identify associated risk factors,we divided our patients into less severe and more severe groups.Except for lymphopenia,there was no worsening of total bilirubin,transaminases,al-kaline phosphatase,and gamma-glutamyl transferase in the more severe group.Eight(19.51%)patients required inten-sive care unit admission and three(7.32%)died,while none suffered graft rejection.In recipients with early vs.late post-transplant COVID-19 infection,there were similar outcomes in terms of severity of COVID-19 illness,intensive care unit care need,requirement of respiratory support,and death.Conclusion:Living donor liver transplantation can be per-formed during the COVID-19 pandemic without the fear of poor recipient outcome in cases of unfortunate contraction of severe acute respiratory syndrome coronavirus-2.

Haemoxygenase modulates cytokine induced neutrophil chemoattractant in hepatic ischemia reperfusion injury

AIM To investigate the hepatic microcirculatory changes due to Haemoxygenase(HO),effect of HO inhibition on remote ischemic preconditioning(RIPC) and modulation of CINC.METHODS Eight groups of animals were studied- Sham,ischemia reperfusion injury(IRI) the animals were subjected to 45 min of hepatic ischemia followed by three hours of reperfusion,RIPC(remote ischemic preconditioning) + IRI group,remote ischemic preconditioning in sham(RIPC + Sham),PDTC + IR(Pyridodithiocarbamate,HO donor),Zn PP + RIPC + IRI(Zinc protoporphyrin prior to preconditioning),IR-24(45 min of ischemia followed by 24 h of reperfusion),RIPC+IR-24(preconditioning prior to. After 3 and 24 h of reperfusion the animals were killed by exsanguination and samples were taken. RESULTS Velocity of flow(160.83 ± 12.24 μm/s),sinusoidal flow(8.42 ± 1.19) and sinusoidal perfusion index(42.12 ± 7.28) in hepatic IR were lower(P < 0.05) in comparison to RIPC and PDTC(HO inducer). RIPC increased velocity of flow(328.04 ± 19.13 μm/s),sinusoidal flow(17.75 ± 2.59) and the sinusoidal perfusion index(67.28 ± 1.82)(P < 0.05). PDTC(HO induction) reproduced the effects of RIPC in hepatic IR. PDTC restored RBC velocity(300.88 ± 22.109 μm/s),sinusoidal flow(17.66 ± 3.71) and sinusoidal perfusion(82.33 ± 3.5) to near sham levels. Zn PP(HO inhibition) reduced velocity of flow of RBC in the RIPC group(170.74 ± 13.43 μm/s and sinusoidal flow in the RIPC group(9.46 ± 1.34). Zn PP in RIPC(60.29 ± 1.82) showed a fall in perfusion only at 180 min of reperfusion. Neutrophil adhesion in IR injury is seen in both postsinusoidal venules(769.05 ± 87.48) and sinusoids(97.4 ± 7.49). Neutrophil adhesion in RIPC + IR injury is reduced in both postsinusoidal venules(219.66 ± 93.79) and sinusoids(25.69 ± 9.08)(P < 0.05). PDTC reduced neutrophil adhesion in both postsinusoidal venules(89.58 ± 58.32) and sinusoids(17.98 ± 11.01)(P < 0.05) reproducing the effects of RIPC. Zn PP(HO inhibition) increased venular(589.04 ± 144.36) and sinusoidal neutrophil adhesion in preconditioned animals(121.39 ± 30.65)(P < 0.05). IR after 24 h of reperfusion increased venular and sinusoidal neutrophil adhesion in comparison to the early phase and was significantly reduced by RIPC. Hepatocellular cell death in IRI(80.83 ± 13.03),RIPC + IR(17.35 ± 2.47),and PTDC+IR(11.66 ± 1.17) Zn PP + RIPC + IR(41.33 ± 3.07) reduced hepatocellular death. Zn PP significantly increased hepatocellular death(P < 0.05 PTDC/RIPC vs Zn PP and IR). The CINC cytokine levels in sham(101.32 ± 6.42). RIPC + sham(412.18 ± 65.24) as compared to sham(P < 0.05). Hepatic IR(644.08 ± 181.24)(P < 0.05). RIPC CINC-1 levels in the early phase(401.62 ± 78.56). And PDTC(HO inducer) CINC-1 levels in hepatic IR(413.36 ± 63.06) were significantly lower. HO inhibition in preconditioned animals with Zinc protoporphyrin increased serum CINC levels(521.81 ± 74.9)(P < 0.05). The serum CINC levels were high in the late phase of hepatic IR(15306 ± 1222.04). RIPC reduced CINC levels in the late phase of IR(467.46 ± 26.06),P < 0.05.CONCLUSION RIPC protects hepatic microcirculation by induction of HO and modulation of CINC in hepatic IR.

COVID-19 in Liver Transplant Recipients-A Series with Successful Recovery

The severe acute respiratory syndrome corona virus-2 (referred to as SARS-CoV-2) pandemic had a great impact on public life in general as well as on populations with pre-existing disease and co-morbidities. Liver transplant and immunosuppressant medication predisposes to more severe disease and is often associated with poor outcome. The clinical features, disease course, treatment and process of modulating the immunosuppression is challenging. Here, we describe the clinical presentation, treatment and outcomes in six liver transplant recipients. Out of those six patients, three had mild, one had moderate and one had severe COVID-19, and one was asymptomatic. The immunosup-pression minimization or withdrawal was done based upon the clinical severity. Consideration of tocilizumab and/or convalescent plasma as well as antivirals i.e. remdesvir done in severe cases. The routine practice of prophylactic anti-coagulation, consideration of repurposed drugs (i.e. teico-planin and doxycycline), and watchful monitoring of asymptomatic recipients helped to achieve an uneventful recovery.