Recipient Outcomes with Younger Donors Undergoing Living Donor Liver Transplantation.

Introduction The impact of donor age on liver transplantation is well known. Data on an appropriate donor age cut-off for living donor liver transplantation (LDLT) with a background of hepatitis C (HCV) is generally limited. The objective of this study was to determine whether limiting donor age to less than 35 years improved outcomes in patients with HCV-related end-stage liver disease (ESLD). Methods This was a retrospective review of 169 patients who underwent LDLT for HCV-related ESLD. The patients were divided into two groups based on whether they received grafts from donors ≤ 35 (Group 1) or > 35 (Group 2) years of age. Kaplan Meier curves were used to determine survival. Uni and multivariate analysis were performed to determine independent predictors of mortality. Results Mean donor age was 25.1 ± 5.2 and 40.1 ± 3.4 years (P < 0.0001). Early allograft dysfunction (EAD) was seen in 11.7% patients in Group 1 versus 29.6% in Group 2 (P = 0.02). A significant difference in mortality was present between the two groups, i.e., 33.3% versus 15.8% (P = 0.04). The estimated four-year overall survival (OS) was 78% and 64% (P = 0.03). Upon doing univariate analysis, the donor age (P = 0.04) and EAD (P = 0.006) were found to be significant variables for mortality. On multivariate analysis, EAD was the only independent predictor of mortality (Hazard ratio: 2.6; confidence interval: 1.1 - 5.8; P = 0.01). Conclusion Opting for younger donors (≤ 35 years) for HCV-related ESLD patients lowers the risk of EAD and improves overall survival.

Living Donor Liver Transplantation for Hepatocellular Carcinoma: A Single-Center Experience from Pakistan.

BACKGROUND: Living donor liver transplantation (LDLT) is an established treatment for patients with cirrhosis and hepatocellular carcinoma (HCC) within Milan criteria. Acceptable outcomes have been demonstrated in patients fulfilling extended criteria. Here, we share our experience with LDLT for patients with HCC within and beyond Milan criteria, with emphasis on poor prognostic factors. METHODS: We retrospectively reviewed patients who underwent LDLT between 2012 and 2017 and had HCC proven on explant liver histopathology. A total of 117 patients were included. Patients who died early after transplant (in <30 days) were excluded. For outcomes, patients were divided into prognostic groups. These groups were based on (1) alpha fetoprotein >600, (2) poor differentiation, and (3) the presence of lymphovascular invasion. Recurrence-free survival (RFS) was determined using Kaplan-Meier curves. RESULTS: Median age was 53 (30-73) years. Median follow-up was 20.3 (1-63.2) months. Median model for end stage liver disease (MELD) score was 19 (9-34). Of a total of 117 patients, 74 (63.2%) patients met Milan criteria. Recurrence rate was 12/117 (10.3%). Actuarial 5-year RFS was 88% and 82% (P = 0.3) in patients within and outside Milan criteria. There was no difference in 3-year RFS in patients with 0, 1, or 2 poor prognostic factors within Milan criteria (92%, 87%, and 75%, respectively; P = 0.3). However, a significant difference in RFS was seen in patients outside Milan criteria (92%, 93%, and 53%; P = 0.03). CONCLUSIONS: Patients within Milan criteria have acceptable RFS even in the presence of poor prognostic factors. However, the presence of two or more poor prognostic variables significantly impacts RFS of patients outside Milan criteria.

Living Donor Liver Transplantation for Acute on Chronic Liver Failure Based on EASL-CLIF Diagnostic Criteria.

BACKGROUND: The European association for the study of the liver and chronic liver failure consortium (EASL-CLIF) recently proposed diagnostic criteria for acute on chronic liver failure (ACLF). There is lack of data regarding liver transplant outcomes in ACLF patients based on these criteria. The objective of this study was to determine outcome following living donor liver transplantation (LDLT) in ACLF patients. METHODS: We retrospectively reviewed patients who underwent LDLT for ACLF based on European association for the study of the liver and chronic liver failure consortium (EASL-CLIF) diagnostic criteria (group 1) (N = 60) and compared them with ACLF patients who did not undergo transplantation (group 2) (N = 59). The primary outcome of interest was 30 day mortality. We also looked at one year survival in these patients. Survival was calculated using Kaplan-Meier curves and Log rank test was used to determine significance between variables. RESULTS: Median MELD scores for group 1 and 2 patients in ACLF grade 1 was 28 (20-38) and 31 (24-36), in ACLF grade 2 was 35 (24-42) and 36 (24-42) and in ACLF grade 3 was 36 (29-42) and 38 (32-52). For group 1 and 2, 30 day mortality in ACLF grade 1, 2 and 3 was 2/43(4.6%) versus 9/15(60%) (P < 0.001), 1/15 (6.6%) versus 13/19 (68.4%), 0/2 (0%) versus 20/25 (80%) (P < 0.001). Actuarial 1 year overall survival was 92% versus 11% (P < 0.001) in patients who underwent transplantation versus those who did not. One year survival in patients with grade 1 and 2 ACLF who received transplant versus medical treatment was 91% versus 13% and 93% versus 15% (P < 0.001) respectively. CONCLUSION: LDLT has excellent outcomes in patients with EASL-CLIF grade 1 and 2 ACLF. Without transplantation, ACLF patients have a very poor prognosis.

Living Donor Liver Transplantation in South Asia: Single Center Experience on Intermediate-Term Outcomes.

BACKGROUND: There is paucity of data on intermediate-term post liver transplant outcomes from South Asia. The objective of this study was to determine survival outcomes in patients who underwent living donor liver transplantation (LDLT) in a busy liver transplant center in Pakistan. METHODS: This study was a review of patients who underwent LDLT between 2012 and 2016. A total of 321 patients were included in this study. Early (within 90 days) and late (>90 days) morbidity and mortality was assessed. Estimated 1- and 4-year survival was determined. RESULTS: Median age was 48 (18-73) years. Male to female ratio was 4.5:1. Out of total 346 complications, 184 (57.3%) patients developed 276 (79.7%) complications in early post-transplant period, whereas there were 70 (21.3%) late complications. Most common early complication was pleural effusion in 46 (16.6%) patients. Biliary complications were the most common late complication and were seen in 31/70 (44.2%) patients. Overall 21.4% patients had a biliary complication. The 3-month mortality was 14%. The estimated 1- and 4-year OS for a MELD cutoff of 30 was 84.5 versus 72 and 80 versus 57% (P = 0.01). There was no donor mortality. CONCLUSION: Acceptable intermediate-term post-transplant outcomes were achieved with LDLT. There is a need to improve outcomes in high-MELD patients.

Failure to rescue in living donor liver transplantation: Patterns and predictors.

BACKGROUND: As a quality assessment tool, failure to rescue (FTR) has been employed in various surgical specialties. However, its role in liver transplantation has only recently been explored. To the best of our knowledge, role of FTR in living donor liver transplant (LDLT) has not been assessed previously. The objective of the current study was to determine failure to rescue (FTR) rate and it's predictors in an LDLT center. MATERIALS AND METHODS: We reviewed a prospectively maintained database of patients who underwent LDLT at our center between 2012 and 2016. Patients who experienced grade 3B or above complications on Clavien-Dindo grading were included in this study. Primary outcome of interest was FTR rate in these patients. FTR was defined as a preventable major complication followed by death within one year after transplantation. We also looked at independent predictors of FTR in our patients and a multivariate analysis was performed. RESULTS: Median age was 48.4(18-73) years. Male to female ratio was 3.3:1. Median MELD score was 17(6-42). The FTR rate in the current study was 52/131 (39.6%). Infectious complications were more common in the FTR group i.e. 22/32(68.8%) versus 10/32 (31.2%) (P < 0.0001). Biliary complications were more common in the non-FTR group i.e. 49/62 (79.1%) versus 13/62 (20.9%) (P < 0.0001). On multivariate analysis, there was a 60% increase in mortality following a major complication in the presence of early allograft dysfunction (Hazard ratio: 1.6, Confidence interval; 1.2-2.2, P = 0.002). A 40% reduction in FTR was seen in patients with a biliary complication versus other complications (Hazard ratio: 0.6, Confidence interval = 0.4-0.8, P = 0.009). CONCLUSION: Early allograft dysfunction and biliary complications are independent predictors of FTR in LDLT.

An Update on Endoscopic Management of Post-Liver Transplant Biliary Complications.

Biliary complications are the most common post-liver transplant (LT) complications with an incidence of 15%-45%. Furthermore, such complications are reported more frequently in patients who undergo a living-donor LT compared to a deceased-donor LT. Most post-LT biliary complications involve biliary strictures, bile leakage, and biliary stones, although many rarer events, such as hemobilia and foreign bodies, contribute to a long list of related conditions. Endoscopic treatment of post-LT biliary complications has evolved rapidly, with new and effective tools improving both outcomes and success rates; in fact, the latter now consistently reach up to 80%. In this regard, conventional endoscopic retrograde cholangiopancreatography remains the preferred initial treatment. However, percutaneous transhepatic cholangioscopy is now central to the management of endoscopy-resistant cases involving complex hilar or multiple strictures with associated stones. Many additional endoscopic tools and techniques-such as the rendezvous method, magnetic compression anastomosis , and peroral cholangioscopy-combined with modified biliary stents have significantly improved the success rate of endoscopic management. Here, we review the current status of endoscopic treatment of post-LT biliary complications and discuss conventional as well as the aforementioned new tools and techniques.

Assigning Treatment to HCC Patients for Transplantation: Utility of a New Decision-Making Tool.

BACKGROUND The Barcelona clinic liver cancer (BCLC) staging system is considered the standard of care for hepatocellular carcinoma (HCC) management. It has various limitations, including lack of second-line treatment options and combination therapy. We prospectively collected data on our HCC patients based on a new decision-making tool (NDT). The objective of this study was to determine the applicability of this tool and compare it with BCLC for treatment allocation, in particular with respect to liver transplantation. MATERIAL AND METHODS We retrospectively reviewed HCC patients who were managed based on an NDT that was developed in 2012. All patients whose treatment decision was based on this tool between 2012 and 2015 were included. Comparison was made with BCLC. Survival was compared for patients who underwent liver transplantation. RESULTS Based on the NDT, 406 (40.6%) patients were eligible for curative treatment versus only 22 (2.2%) patients based on BCLC. A total of 58 (5.8%) patients underwent liver transplant based on the NDT, while only 2 (0.2%) were transplantable based on BCLC. Estimated 3-year survival for transplanted patients based on the NDT was 73%. There were 41 (4.1%) stage C and 15 (1.5%) stage D BCLC patients who received transplant based on the NDT. Estimated 3-year survival for stage A, C, and D BCLC patients who received transplantation was 100%,72%, and 67%, respectively (P=0.6). CONCLUSIONS The NDT correctly identified a group of HCC patients for liver transplantation who would otherwise have received palliative treatment based on the BCLC algorithm.

Prognostication of Learning Curve on Surgical Management of Vasculobiliary Injuries after Cholecystectomy.

Background. Concomitant vascular injury might adversely impact outcomes after iatrogenic bile duct injury (IBDI). Whether a new HPB center should embark upon repair of complex biliary injuries with associated vascular injuries during learning curve is unknown. The objective of this study was to determine outcome of surgical management of IBDI with and without vascular injuries in a new HPB center during its learning curve. Methods. We retrospectively reviewed patients who underwent surgical management of IBDI at our center. A total of 39 patients were included. Patients without (Group 1) and with vascular injuries (Group 2) were compared. Outcome was defined as 90-day morbidity and mortality. Results. Median age was 39 (20-80) years. There were 10 (25.6%) vascular injuries. E2 injuries were associated significantly with high frequency of vascular injuries (66% versus 15.1%) (P = 0.01). Right hepatectomy was performed in three patients. Out of these, two had a right hepatic duct stricture and one patient had combined right arterial and portal venous injury. The number of patients who developed postoperative complications was not significantly different between the two groups (11.1% versus 23.4%) (P = 0.6). Conclusion. Learning curve is not a negative prognostic variable in the surgical management of iatrogenic vasculobiliary injuries after cholecystectomy.

Paediatric Living Donor Liver Transplantation: ASingle Centre Experience from Pakistan.

OBJECTIVE: To determine the outcomes of paediatric living donor liver transplantation (LDLT) recipients from Pakistan in terms of 90-day morbidity and mortality. STUDY DESIGN: Cohort study. PLACE AND DURATION OF STUDY: Shifa International Hospital, Islamabad, Pakistan, between April 2012 and April 2015. METHODOLOGY: All patients in paediatric age group (≤ 17 years) who underwent LDLT with a minimum follow-up of 3 months, were included. All grade 2 and above complications on Clavien-Dindo system were included as morbidity. The main outcome measure was 90-day morbidity and mortality. RESULTS: Fourteen paediatric LDLTs were performed. Median age of the recipients was 8.5 years ranging between 6 months and 17 years. Wilson's disease and cryptogenic cirrhosis were the most common etiologies (28.6% each). Acute liver failure was present in 5 (35.7%) patients. Overall 90-day morbidity and mortality was 71.4% and 14.2%; both were attributable to pulmonary infection. No difference was observed in morbidity (21.3% vs. 42.8%, p=0.3) and mortality rates (20% vs. 11%, p=1.0) between patients with acute and chronic liver failure. Estimated 3-year survival was 85%. CONCLUSION: Paediatric LDLT offers a promising treatment option for acute and chronic liver failure. Mortality was attributable to post-transplant pulmonary infections.

Survival advantage with para aortic lymphadenectomy in peri-ampullary cancer: A retrospective cohort study.

BACKGROUND: Metastatic para aortic lymph nodes (PALN) in patients with peri ampullary cancer entail poor prognosis. Role of curative surgery in these patients remains debatable. The objective of the current study was to evaluate outcome after extended pancreaticoduodenectomy (PD) in patients with and without positive PALN. METHODS: We reviewed 65 patients who underwent extended PD with PALN removal between 2011 and 2014. Patients were divided into two groups; those with positive PALN and those without. Patients were sub classified for pancreatic and non-pancreatic cancer. Outcome was determined based on median and estimated 3 year overall survival. RESULTS: Median age was 57 (32-85) years. PALN were involved in 15 (23%) patients. Overall 3 year survival for patients with and without positive PALN was 60% and 54% (P = 0.7). Significant difference in survival was present between patients with pancreatic cancer and positive PALN [9 (3-12) months] versus non-pancreatic cancers with positive PALN [17.5 (13-38) months] (P = 0.02). Four out of five patients with pancreatic cancer and positive PALN had survival >6 months and 3 out of these 5 patients were alive at the last follow up. CONCLUSION: Curative surgery may benefit some patients with pancreatic cancer and positive PALN and should be considered selectively.

Short Term Donor Outcomes After Hepatectomy in Living Donor Liver Transplantation.

OBJECTIVE: To determine the outcome of living-donor liver transplant (LDLT) donors from the first liver transplant program in Pakistan. STUDY DESIGN: Cohort study. PLACE AND DURATION OF STUDY: Shifa International Hospital, Islamabad, from April 2012 to August 2014. METHODOLOGY: A total of 100 live donors who underwent hepatectomy were included. Demographics, etiologies, graft characteristics and operative variables were retrospectively assessed. Outcome was assessed based on morbidity and mortality. RESULTS: Median donor age was 28 (17 - 45) years and median body mass index (BMI) was 24 kg/m2 (15 - 36). Male to female ratio was 1.5:1. Hepatitis B and C were the most common underlying etiologies and accounted for 79/100 (79%) of LDLT&#039;s. Overall, 93/100 (93%) donors donated a right lobe graft. Median estimated graft weight to recipient body weight (GW/BW) ratio was 1.03 (0.78 - 2). Standard arterial anatomy was present in 56% donors. The 90-day morbidity was 13/100 (13%) and overall morbidity was 17/100 (17%). Bile leak was encountered in 3 (3%) patients. There was no donor mortality. CONCLUSION: Acceptable short-term donor outcomes were achieved in an LDLT program in Pakistan with careful donor selection and planning.

Hepatocellular Carcinoma in Pakistan: National Trends and Global Perspective.

Hepatocellular carcinoma (HCC) ranks second amongst all causes of cancer deaths globally. It is on a rise in Pakistan and might represent the most common cancer in adult males. Pakistan contributes significantly to global burden of hepatitis C, which is a known risk factor for HCC, and has one of the highest prevalence rates (>3%) in the world. In the absence of a national cancer registry and screening programs, prevalence of hepatitis and HCC only represents estimates of the real magnitude of this problem. In this review, we present various aspects of HCC in Pakistan, comparing and contrasting it with the global trends in cancer care. There is a general lack of awareness regarding risk factors of HCC in Pakistani population and prevalence of hepatitis C has increased. In addition, less common risk factors are also on a rise. Majority of patients present with advanced HCC and are not eligible for definitive treatment. We have attempted to highlight issues that have a significant bearing on HCC outcome in Pakistan. A set of strategies have been put forth that can potentially help reduce incidence and improve HCC outcome on national level.

Fibroblast growth factor 9 is a novel modulator of negative affect.

Both gene expression profiling in postmortem human brain and studies using animal models have implicated the fibroblast growth factor (FGF) family in affect regulation and suggest a potential role in the pathophysiology of major depressive disorder (MDD). FGF2, the most widely characterized family member, is down-regulated in the depressed brain and plays a protective role in rodent models of affective disorders. By contrast, using three microarray analyses followed by quantitative RT-PCR confirmation, we show that FGF9 expression is up-regulated in the hippocampus of individuals with MDD, and that FGF9 expression is inversely related to the expression of FGF2. Because little is known about FGF9's function in emotion regulation, we used animal models to shed light on its potential role in affective function. We found that chronic social defeat stress, an animal model recapitulating some aspects of MDD, leads to a significant increase in hippocampal FGF9 expression, paralleling the elevations seen in postmortem human brain tissue. Chronic intracerebroventricular administration of FGF9 increased both anxiety- and depression-like behaviors. In contrast, knocking down FGF9 expression in the dentate gyrus of the hippocampus using a lentiviral vector produced a decrease in FGF9 expression and ameliorated anxiety-like behavior. Collectively, these results suggest that high levels of hippocampal FGF9 play an important role in the development or expression of mood and anxiety disorders. We propose that the relative levels of FGF9 in relation to other members of the FGF family may prove key to understanding vulnerability or resilience in affective disorders.

Is pancreaticodoudenectomy with vascular resection a safe procedure in developing country? Early outcomes and review of national literature.

INTRODUCTION: Safety of extended lymphadenectomy (EL) ± vascular resection in patients undergoing pancreaticoduodenectomy (PD) in resource limited settings is not well established. The objective of this study was to report outcomes of PD resection with EL ± vascular resection from Pakistan and review national literature. METHODS: Data of patients who underwent PD between 2011 and 2014 was reviewed. A total of 66 patients were included in the study. Primary outcome was 90 day morbidity and mortality. Secondary objective was 2 year overall survival. RESULTS: Median age was 57 (32-82) years. Majority patients had locally advanced (pT3/T4) tumors and nodal involvement i.e. 44 (71%) and 42 (67.8%). Mean number of excised lymph nodes and positive lymph nodes was 28.2 ± 12.8 (range 3-62) and 4.8 ± 6.9 (range 0-27) respectively. There were 13 vascular resections including 3 arterial resections. Overall 90 day morbidity was 31.8% and mortality was 3%. No difference in complication rate was observed in patients who did and did not undergo vascular resection i.e. 18% versus 34.5% (P = 0.1). Similarly, median survival was 11 (3-24) months and 11 (1-36) months and not significantly different (P = 0.5). CONCLUSION: In developing countries, extended lymphadenectomy with vascular resection can be safely performed with pancreaticoduodenectomy in specialized hepatobiliary units.

The travails of setting up a living donor liver transplant program: Experience from Pakistan and lessons learned.

Living donor liver transplantation (LDLT) is the only treatment option for patients with end-stage liver disease (ESLD) where cadaveric donors are not available. In developing countries, the inception of LDLT programs remains a challenge. The first successful liver transplantation program in Pakistan started transplantation in 2012. The objective of this study was to report outcomes of 100 LDLT recipients in a developing country and to highlight the challenges encountered by a new LDLT program in a resource-limited setting. We retrospectively reviewed recipients who underwent LDLT between April 2012 and August 2014. Demographics, etiology, graft characteristics, and operative variables were assessed. Outcome was assessed on the basis of morbidity and mortality. All complications of ≥ 3 on the Clavien-Dindo grading system were included as morbidity. Estimated 1-year survival was calculated using Kaplan-Meier curves, and a Log-rank test was used to determine the significance. Outcomes between the first 50 LDLTs (group 1) and latter 50 LDLTs (group 2) were also compared. Median age was 46.5 (0.5-72) years, whereas the median MELD score was 15.5 (7-37). The male to female ratio was 4:1. ESLD secondary to hepatitis C virus was the most common indication (73% patients). There were 52 (52%) significant (≥ grade 3) complications. The most common morbidities were bile leaks in 9 (9%) and biliary strictures in 14 (14%) patients. Overall mortality in patients who underwent LDLT for ESLD was 10.6%. Estimated 1-year survival was 87%. Patients who underwent transplantation in the latter period had a significantly lower overall complication rate (36% versus 68%; P = 0.01). Comparable outcomes can be achieved in a new LDLT program in a developing country. Outcomes improve as experience increases.

Quality of Life After Living Donor Hepatectomy for Liver Transplantation.

BACKGROUND: Living donor liver transplantation (LDLT) involves healthy individuals undergoing voluntary major hepatic resection. LDLT program only started in 2012 in Pakistan and its impact on donor's quality of life (QOL) post resection is not known. The objective of this study was to determine health-related QOL in donors who underwent hepatectomy in country's first liver transplant program. METHODS: A total of 60 donors who underwent hepatectomy between 2012 and 2014 with a minimum follow-up of 6 months were included in the study. Short form (SF-36) and Profile of mood states (POMS-65) was used to assess QOL. In addition scores were compared between patients who did and did not develop complications. RESULT: Mean time duration between hepatectomy and administration of questionnaire was 15 ± 5.1 months. Median age was 28 (19-45) years. Mean BMI was 24.4 ± 3.7. A total of 7 (11.6%) Grade 3 and above complications were observed in donors. Donors exceeded a score of 90 in 6 out of 8 evaluated categories on SF-36. The highest mean score was recorded for emotional role limitation 95.5 ± 17.1 and lowest for energy 84.8 ± 17.5. The mean score for anger was 6.6 ± 7.5. Donors also did well on the POMS vigor score with a mean of 22.7 ± 5. No significant difference in scores was observed between donors with and without complications for any of the categories except tension. Donors who developed complications post-operatively had a significantly low mean tension score of 1.5 versus 3.8 for donors without complications. CONCLUSION: Acceptable post donation QOL was achieved and surgical complications did not adversely affect SF-36 and POMS scores.

A subset of presympathetic-premotor neurons within the centrally projecting Edinger-Westphal nucleus expresses urocortin-1.

Numerous motivated behaviors require simultaneous activation of somatomotor and autonomic functions. We have previously characterized the organization of brain circuits that may mediate this integration. Presympathetic premotor neurons (PSPMNs) that are part of such circuits are distributed across multiple brain regions, which mediate stress-elicited behavioral and physiological responses, including the Edinger-Westphal nucleus (EW). Based on its connectivity and function, EW has recently been re-classified into a preganglionic (EWpg) and a centrally projecting (EWcp) population. Neurons within EWcp are the major source of urocortin 1 (Ucn-1), an analog of the corticotropin-releasing factor that binds the CRFR1 and CRFR2 receptors and has been implicated in mediating homeostatic responses to stress. We hypothesized that a subset of EWcp PSPMNs expresses Ucn-1. Utilizing dual-label immunofluorescence, we initially mapped the distribution of Ucn-1 and cholinergic neurons within EW in colchicine pre-treated rats. Based on this labeling we divided EWcp into three neuroanatomical levels. To examine connections of EWcp neurons to the gastrocnemius muscle and the adrenal gland, we next employed trans-synaptic tract-tracing in a second group of rats, utilizing two pseudorabies virus (PRV) recombinants that express unique reporter proteins. Using multi-label immunofluorescent staining, we identified the presence of Ucn-1-positive PSPMNs, dually labeled with PRV and present throughout the entire extent of EWcp and intermingled with Ucn-1 neurons infected with one or neither of the viral recombinants. Compared to rats pretreated with colchicine, we observed significantly fewer Ucn-1 neurons in animals that received PRV injections. Post hoc analyses revealed significantly fewer Ucn-1 neurons at the rostral level as compared to the caudal and middle levels. These data suggest functional and anatomic heterogeneity within EWcp; this organization may coordinate various aspects of stress-elicited and emotionally salient behaviors.