ABO-Incompatible Living Donor Liver Transplantation with Reduced Rituximab Dose: A Retrospective Analysis of 65 Patients - Can We Fast-Track Liver Transplant Surgery and Improve Long-Term Survival?

BACKGROUND ABO-incompatible (ABO-i) living donor liver transplantation (LDLT) is a feasible alternative for donor liver allograft in emergency situations, especially in Asia, where deceased-donor organs remain scarce. The reported outcomes of ABO-i LDLT after optimal desensitization are comparable to those of ABO-compatible LDLT. In this retrospective study, we found improved outcomes after ABO-i LDLT with a low-dose rituximab in combination with double-filtration plasmapheresis (DFPP) and prophylactic antibiotic therapy. MATERIAL AND METHODS Between January 2006 and December 2018, a total of 65 recipients underwent ABO-i LDLT surgeries at our center. The study cohort consisted of 50 recipients (Era III) who underwent ABO-i LDLT using the recently updated desensitization protocol, which included rituximab 200 mg intravenous injection once a week prior to LDLT, 4 sessions of DFPP in all patients, and prophylactic antibiotics for 3 months. RESULTS The 3-year overall survival rate achieved in ABO-i LDLT patients was 72.7% (66.6% for Era I and 33.3% for Era II patients). In the study population, 11 patients developed complications due to infection. Five of these patients (10%) died due to overwhelming sepsis. Four patients (8%) were diagnosed with multiple strictures and diffusely scattered dilatation of intrahepatic bile ducts on computed tomography, without vascular complications. Three of them had evidence of antibody-mediated rejection (AMR). CONCLUSIONS Our experience shows that the ABO-i LDLT protocol of lowered rituximab combined with pre-transplant sessions of plasmapheresis and a quadruple immunosuppressive regimen can be effective in chronic liver failure patients with clinical urgency in the absence of an ABO-compatible donor. Fast-tracking the use of ABO-i LDLT is feasible in patients with an acute liver failure (ALF) and can safely increase the donor liver pool, with an acceptable outcome.

De Novo Malignancy After Heart, Kidney, and Liver Transplant: A Nationwide Study in Taiwan.

OBJECTIVES: In the Asian population, patterns and risk factors for de novo malignancies after solid-organ transplant are not well understood. MATERIALS AND METHODS: Insurance claims from Taiwan's National Health Institute Research Database from 1997 to 2011 revealed 687 deceased-donor heart transplant recipients, 5038 kidney transplant recipients (50% living related-donor, 50% deceased-donor transplants), and 2127 liver transplant recipients (mainly living related-donor transplants, 30% deceased-donor transplants). During the follow-up period, rates of malignancy incidence were calculated with standardization based on national age, sex, and year-specific incidence. We used multivariate regression analyses to determine risk factors of posttransplant de novo malignancies. RESULTS: Compared with the general population, several de novo cancers were more common posttransplant (P < .05): lung cancer (2.6-fold), non-melanoma skin cancer (5.8-fold), and non-Hodgkin lymphoma (5.4-fold) in heart recipients; transitional cell carcinoma (31.4-fold), renal cell carcinoma (37.3-fold), and non-Hodgkin lymphoma (3.6-fold) in kidney recipients; and gastric cancer (3.0-fold) and lymphatic-hematopoietic malignancy (4.5-fold) in liver recipients. Independent risk factors for posttransplant malignancy in kidney transplant recipients were increased age, female, hepatitis B virus, and mycophenolate use (adjusted hazard ratio 1.5; 95% confidence interval, 1.2-1.8; P < .001). In liver transplant recipients, old age was an independent risk factor. Kidney transplant recipients without diabetes or hypertension had higher risk of transitional cell carcinoma (adjusted hazard ratio 3.0; 95% confidence interval, 2.1-4.4; P < .001) and renal cell carcinoma (adjusted hazard ratio 1.9; 95% confidence interval, 1.1-3.3; P < .05). CONCLUSIONS: Regional endemic epidemiologic factors play significant roles in the development of de novo cancers, particularly in kidney transplant recipients due to causes of renal failure other than diabetes and hypertension. Each regional organ transplant program should tailor and establish its surveillance protocol based on epidemiologic data. However, the type and intensity of surveillance require further and long-term investigations in this patient cohort.

Effect of Oligomeric Proanthocyanidin on the Antioxidant Status and Lung Function of Patients with Chronic Obstructive Pulmonary Disease.

BACKGROUND/AIM: Evidence exists that oxidative stress and oxidative damage play a pivotal role in chronic obstructive pulmonary disease (COPD). Oligomeric proanthocyanidins (OPCs) extracted from grape seeds have been shown to exhibit antioxidant capabilities greater than those of vitamin C and E. The objective of this study was to evaluate the effects of OPCs on antioxidant status and lung function in patients with COPD. PATIENTS AND METHODS: Patients were supplemented with 150 mg/day OPC (n=13) orally or with a placebo (n=14) for 8 weeks in a randomized double-blind clinical design. Changes in anthropometric values, lung function, oxidative state, and lipid profiles were assessed after OPC or placebo treatment for 8 weeks. RESULTS: The results showed that OPC supplementation significantly reduced the concentration of malondialdehyde, superoxide dismutase, and total cholesterol (TC)/high-density lipoprotein cholesterol (HDL-C) ratio. The concentration of HDL-C significantly increased in the OPC-treated group. The plasma triglyceride, TC and low-density lipoprotein cholesterol values and the activities of catalase and glutathione peroxidase also decreased, but did not significantly differ between the OPC- and placebo-treated groups. Lung function was not significantly different between the two groups after 8 weeks. CONCLUSION: OPC supplementation was effective in increasing the antioxidant capacity, in addition to improving the lipid profiles in patients with COPD.

Effects of Nutritional Intervention on the Survival of Patients with Cardiopulmonary Failure Undergoing Extracorporeal Membrane Oxygenation Therapy.

BACKGROUND/AIM: This study aimed to examine the effects of nutritional intervention on the prognosis of patients with cardiopulmonary failure undergoing extracorporeal membrane oxygenation (ECMO) therapy in Taiwan. MATERIALS AND METHODS: An institutional review board-approved retrospective study was conducted on patients receiving ECMO therapy in the intensive care unit of the China Medical University Hospital, Taiwan, from January 2013 to December 2013. The study included 102 patients with cardiopulmonary failure receiving ECMO therapy. RESULTS: The data indicated that higher survival rates were closely related to lower age and APACHE II scores among the patients. In addition, compared to patients who deceased, those who survived had a higher total calorie intake. Most patients could tolerate bolus feeding and polymeric formulas. Furthermore, patients who underwent nutritional therapy with nutritional goals greater than 80% achieved a better outcome and lower mortality than other patients. CONCLUSION: Early nutritional intervention could benefit patients undergoing ECMO, and those who reached the delivery goal of 80% had significantly better outcomes than other patients. Enteral feeding can begin early and was well tolerated by patients receiving ECMO therapy. Following individual nutrition goals is critical for better outcomes, and this analysis might be useful in establishing individualized nutrition goals for oriental population when caring for critically ill patients.

Living Donor Liver Transplantation in Acute Liver Failure Patients with Grade IV Encephalopathy: Is Deep Hepatic Coma Still an Absolute Contraindication? A Successful Single-Center Experience.

BACKGROUND The prognosis of the patients of acute liver failure (ALF) with onset of hepatic coma is often dismal. ALF is a well-accepted indication for liver transplantation (LT) and has markedly improved the prognosis of these patients. However, its role in ALF patients with onset of hepatic coma has never been elucidated before. The aim of our study was to analyze the outcome in patients of ALF with hepatic coma who underwent LT. MATERIAL AND METHODS From January 2002 to December 2015, a total of 726 liver transplantations were done at China Medical University Hospital, Taiwan. The hospital database of 59 recipients that underwent LT for ALF was analyzed. Eleven ALF patients with the onset of hepatic coma (grade IV encephalopathy) requiring mechanical ventilatory support were retrospectively analyzed. The patients were sub-grouped in 2 groups depending on the timing of LT after the onset of hepatic coma: Group A had LT within 48 h of onset of coma (n=7) and Group B had LT after 48 h of onset of coma (n=4). RESULTS The study cohort (group A and B) comprised 8 males and 3 females, with an average age of 39.63±13.95 years (range, 13 to 63). Ten patients received living donor liver transplantation (LDLT) and deceased donor liver transplantation (DDLT) was done in 1 recipient. All the patients in group A had complete neurological recovery and were extubated within 48 h after LT, whereas extubation was delayed for various reasons for group B patients. At a mean follow up of 36 months (range, 20 to 76 months), the overall survival of all the recipients (group A and B) was 72%. Three-year survival for Group A (n=7) was 85% and for Group B (n=4) it was 50%. There were no acute rejection episodes. CONCLUSIONS LT is an acceptable modality of treatment for patients of ALF with new onset of hepatic coma. Neurological recovery is expected in all patients if LT can be done within 48 h of onset of hepatic coma without increasing the risk of morbidity. Due to shortage of deceased donor organs in Asia, LDLT can be used proactively, with a success rate comparable to that of non-ALF patients undergoing LT.

Plasma exosomal miR-223 expression regulates inflammatory responses during cardiac surgery with cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) induces inflammatory responses, and effective endogenous homeostasis is important for preventing systemic inflammation. We assessed whether plasma exosomal microRNAs in patients undergoing cardiac surgery with CPB are involved in the regulation of inflammatory responses. Plasma samples were isolated from CPB patients (n = 21) at 5 specified time points: pre-surgery, pre-CPB and 2 hours (h), 4 h and 24 h after CPB began. Plasma TNF-α expression was increased after CPB began compared to that in the pre-surgery samples. Plasma IL-8 and IL-6 expression peaked at 4 h after CPB began but was downregulated at 24 h. The number of plasma exosomes collected at 2 h (55.1 ± 8.3%), 4 h (63.8 ± 10.1%) and 24 h (83.5 ± 3.72%) after CPB began was significantly increased compared to that in the pre-CPB samples (42.8 ± 0.11%). These exosomes had a predominantly parental cellular origin from RBCs and platelets. Additionally, the plasma exosomal miR-223 levels were significantly increased after CPB began compared to those in the pre-CPB samples. Further, exosomal miR-223 from plasma collected after CPB began downregulated IL-6 and NLRP3 expression in the monocytes. Here, we present the novel findings that increased plasma exosomal miR-223 expression during cardiac surgery with CPB might play homeostatic roles in downregulating inflammatory responses through intercellular communication.

Extracorporeal Membrane Oxygenation Support for Rituximab-Induced Acute Respiratory Distress Syndrome in an ABO-Incompatible Living Donor Liver Transplant Recipient: Successful Management of a Rare Complication and a Review of the Literature.

BACKGROUND Rituximab is commonly used to reduce the agglutinin titer in ABO-incompatible liver transplant recipients. Although well-tolerated, rituximab infusion therapy may result in severe pulmonary adverse effects such as drug-induced pneumonitis, leading to acute respiratory distress syndrome (ARDS), which has a high mortality rate. Management of such rare cases in an ABO-incompatible patient has never been described before. Herein, we present successful use of extracorporeal membrane oxygenation (ECMO) support for rituximab-induced ARDS in an ABO-incompatible living donor liver transplantation (LDLT) recipient. CASE REPORT A 57-year-old man patient presented with acute-on-chronic hepatic failure. Due to worsening clinical condition and unavailability of a deceased donor organ, ABO-incompatible LDLT was considered. The patient received rituximab therapy and plasmapheresis 1 week before the transplantation to reduce the B cell count. However, he suddenly developed acute respiratory distress-like symptoms, with a chest X-ray suggesting organized pneumonia. Infectious etiology was excluded as evidenced from negative sputum and blood culture, which were repeated after 48 h. LDLT was performed and ECMO support was instituted in the immediate postoperative period due to worsening of the ARDS. The pulmonary signs improved, with a chest X-ray showing clear lung fields on the 5th postoperative day. The patient recovered well and was discharged with normal liver functions in the 4th postoperative month. CONCLUSIONS This is first reported experience of successful use of ECMO in an ABO-incompatible liver transplant recipient with rituximab-induced ARDS. This experience shows the feasibility and effectiveness of ECMO support in liver transplant recipients with poor respiratory functions.

Assessing the Safety of Expanded Polytetrafluoroethylene Synthetic Grafts in Living Donor Liver Transplantation: Graft Migration Into Hollow Viscous Organs - Diagnosis and Treatment Options.

BACKGROUND Our recent studies have highlighted the importance and safety of backtable venoplasty for middle hepatic vein (MHV) and inferior right hepatic veins (IRHV) reconstruction using expanded polytetrafluoroethylene (ePTFE) vascular grafts. In this study, we aim to analyze the complications associated with ePTFE graft use and discuss the management of the rare, but, potentially life threatening complications directly related to ePTFE conduits. MATERIAL AND METHODS From January 2012 to October 2015 a total of 397 patients underwent living donor liver transplantation (LDLT). The ePTFE vascular grafts were used during the backtable venoplasty for outflow reconstruction in 262 of the liver allografts. Recipients who developed ePTFE-related complications were analyzed. RESULTS ePTFE-related complications developed in 1.52% (4/262) of the patients. One patient (0.38%) developed complete thrombosis with sepsis at 24 months post-transplantation and died due to multiorgan failure. Three patients (1.1%) developed graft migration into the second portion of the duodenum, without overt peritonitis. Surgical exploration and ePTFE graft removal was done in all the patients. One patient died due to overwhelming sepsis. CONCLUSIONS ePTFE graft migration into the duodenum causing perforation is a new set of complications that has been recently described in LDLT and can be treated effectively by surgical removal of the infected vascular graft and duodenal perforation closure. Despite of such complications, in our experience, ePTFE use in LDLT continues to have wide safety margin, with a complication rate of only 1.52%.

Hepatic artery reconstruction in living donor liver transplantation using surgical loupes: Achieving low rate of hepatic arterial thrombosis in 741 consecutive recipients-tips and tricks to overcome the poor hepatic arterial flow.

The reconstruction of the hepatic artery (HA) is the most complex step in living donor liver transplantation (LDLT) because of the smaller diameter of the artery and the increased risk of HA-related complications. Because of the smaller diameter of the HA, many centers use a microsurgical technique with interrupted sutures for arterial anastomosis. The aim of our study was to retrospectively investigate the outcomes after HA reconstruction performed under magnifying loupes using the "parachute technique." From August 1, 2002 to August 31, 2016, LDLT was performed in 766 recipients. HA reconstruction for the initial 25 LDLT surgeries was performed using a microsurgery technique (era 1). From May 2007 until the end date, HA reconstruction was performed in 741 recipients by a "parachute technique" under surgical loupes (era 2). HA reconstruction was performed using surgical loupes in 737 adults (male:female, 526:211) and 4 pediatric patients (male:female, 3:1). The average diameter of the donor graft HA was 2.8 mm (range, 1-6.5 mm). The most notable factor in this era was the quick HA anastomosis procedure with a mean time of 10 ± 5 minutes (range, 5-30 minutes). In era 2, 9 (1.21%) patients developed hepatic artery thrombosis (HAT), whereas 2 patients developed nonthrombotic HA-related complications. Extra-anatomic HA reconstruction was performed in 14 patients due to either primary HA anastomosis failure or a poor caliber recipient HA. The use of magnifying surgical loupes to perform HA reconstruction is safe, feasible, and yields a low incidence of HA-related complications. The "parachute technique" for HA reconstruction can achieve a speedy reconstruction without increasing the risk of HAT. Liver Transplantation 23 887-898 2017 AASLD.

Reconstruction of Isolated Inferior Right Hepatic Vein(s) in Right Lobe Living Donor Liver Transplantation Using Polytetrafluoroethylene Grafts: A New Feasible Concept, Technique of 'Bridging Conduit Venoplasty' and Outcomes.

BACKGROUND Right lobe living donor liver transplantation (LDLT) remains the most common form of liver transplantation in Asia. However, reconstruction of the venous outflow in a right liver allograft may pose technical difficulties if hepatic venous variations are present. Recently, much emphasis has been given to the reconstruction of large and multiple inferior right hepatic veins (IRHVs). The method of reconstructive technique, type of vascular grafts, and the outcome after the procedure have been a point of debate. In this report we discuss the IRHV reconstruction techniques using expanded polytetrafluoroethylene (ePTFE) vascular grafts and the outcomes after such reconstruction. MATERIAL AND METHODS Out of 262 right liver allografts that underwent venous reconstruction using ePTFE vascular grafts, IRHVs required either venoplasty or second inferior vena cava (IVC) anastomosis in 99 recipients. Depending upon type of IRHV reconstruction, the recipients were divided in 2 groups: Group A (n=52): IRHV venoplasty using ePTFE graft, and group B (n=47): Direct IRHV-to-IVC anastomosis. The outcome after LDLT was compared for these 2 groups. RESULTS The ePTFE venoplasty group had significantly shorter warm ischemia time as compared to the direct to IVC anastomosis group (p<0.01, 95% confidence interval -10.96 to -2.92). There were no thrombotic complications in either group of recipients; 4.2% of the recipients from group B developed hepatic venous stenosis but with no clinical deterioration; and 1 patient from group A developed ePTFE graft migration in the second portion of the duodenum that required surgical exploration. CONCLUSIONS The IRHVs drain a considerable portion of the posterior sector of right liver allografts and thus must be reconstructed. Use of ePTFE vascular grafts for IRHV venoplasty is a safe and feasible concept that facilitates the outflow reconstruction of liver allografts.

Outflow reconstruction for right liver allograft with multiple hepatic veins: "V-plasty" of hepatic veins to form a common outflow channel versus 2 or more hepatic vein-to-inferior vena cava anastomoses in limited retrohepatic space.

Outflow reconstruction in living donor liver transplantation (LDLT) is certainly difficult in limited retrohepatic space with using right liver grafts with venous anomalies. Venoplasty of the inferior right hepatic veins (IRHVs) and middle hepatic vein (MHV) reconstruction using synthetic grafts to form a common outflow channel or a second venocaval anastomosis are available options. We aim to compare outcomes of LDLT recipients who underwent outflow reconstruction with a "V-Plasty" technique and outcomes of patients who underwent a second venocaval anastomosis. Out of 325 recipients who underwent LDLT from March 2011 to September 2014, 45 received right liver allografts that were devoid of MHV with multiple draining IRHVs (2 or more). Group A (n = 16) comprised the recipients with outflow reconstruction with a V-Plasty, and group B (n = 29) included the recipients with a second venocaval anastomosis. Group A recipients (male:female, 10:6; median age, 50.5 years) had a mean Model for End-Stage Liver Disease score of 14.7, whereas for group B recipients (male:female, 20:9; median age, 52.0 years) it was 17.2. The mean IRHV diameter for group A and B grafts was 8.3 mm each. Mean warm ischemia time for group A was significantly lower (25.2 minutes) as compared to group B recipients (34.6 minutes) with P < 0.001. The 2-month patency rates of vascular grafts were 100% for group A recipients with no evidence of thrombosis. In conclusion, the V-Plasty technique of MHV and IRHV reconstruction to form a common outflow is a new concept that proves to be a safe and feasible alternative for second venocaval anastomosis.

"V-Plasty" technique using dual synthetic vascular grafts to reconstruct outflow channel in living donor liver transplantation.

BACKGROUND: The reconstruction of outflow is a crucial step in living donor liver transplantation. This study describes a suitable technique that uses synthetic vascular conduits in presence of multiple draining veins of right lobe of liver and the outcome of the recipients to evaluate safety of using multiple synthetic grafts. METHODS: From March 2011 to September 2014, 325 patients underwent right lobe living donor liver transplantation. Expanded polytetra-fluoroethylene (ePTFE) grafts were used in total 155 of the liver allografts. Among these, 16 liver grafts required dual ePTFE grafts to reconstruct the outflow due to presence of multiple hepatic veins. RESULTS: The mean diameters for venous branches of segment 5 (V5) and 8 (V8) were 5 mm (range, 4-8 mm) and 7 mm (range, 5-9 mm). The mean diameter of inferior right hepatic veins was 8 mm (7-10 mm). All the recipients who received the right liver with dual ePTFE grafts showed satisfactory inflow and outflow immediately after reconstruction as measured by Doppler flowmetry. Postoperative ultrasonographic studies showed no disturbances in outflow. Protocol dynamic computed tomography performed in the second postoperative month showed 100% patency rates of the artificial grafts. At median follow-up of 24 months graft survival was achieved in 88%, whereas the patency rates of the ePTFE grafts were 100%. CONCLUSION: The use of "V-Plasty" technique using dual artificial vascular grafts is a safe and feasible technique in the presence of various allograft venous anomalies & ensures a single venous channel for outflow reconstruction. Our study also suggests that ePTFE graft may be a useful interposition material without serious complications.

Outcome of frozen elephant trunk technique for acute type A aortic dissection: as systematic review and meta-analysis.

Acute aortic dissections of Stanford type A require emergency surgery repair and present challenges to surgeons. The frozen elephant technique is one of several approaches used to treat aortic arch dissection. The purpose of this meta-analysis was to investigate the clinical effectiveness of the frozen elephant technique for treating acute type A aortic dissection.Medline, Cochrane, Google Scholar, and ClinicalTrials.gov databases were searched up to March 31, 2014, for studies that assessed the use of frozen elephant trunk technique for treating acute type A aortic dissection. The primary outcome was in-hospital mortality. Secondary outcomes included rate of stroke, spinal cord injury, renal failure, and reoperations for bleeding.Eleven studies were included in the analysis that encompassed 881 patients. The mean age ranged from 45.4 to 66.8 years, and the proportion of the population that was male ranged from 45 to 85%. The overall in-hospital mortality rate was 8%. The rate of stroke, spinal cord injury, renal failure, and frequency of reoperations for bleeding were 3, 4, 5, and 5, respectively. Sensitivity analysis indicates that the findings are robust and there was no publication bias.These findings indicate that the frozen elephant techniques does not bring unacceptable mortality or morbidity risk for treating acute type A aortic dissection.

Impact of LPS-induced cardiomyoblast cell apoptosis inhibited by earthworm extracts.

Dilong is an earthworm extract with a dense nutritional content, widely used in Chinese herbal medicine to remove stasis and stimulate wound healing. Earthworm extracts are traditionally used by indigenous people throughout the world. How this Dilong inhibits Lipopolysaccharide (LPS)-induced cardiomyoblast cell apoptosis is still unclear. This study investigates the Dilong extract effect on LPS-induced apoptosis in H9c2 cardiomyoblast cells. LPS (1 µg/ml) administration for 24 h induced apoptosis in H9c2 cells. Cell apoptosis was detected using MTT, LDH, TUNEL assay and JC-1 staining. Western blot analysis was used to detect pro-apoptotic and anti-apoptotic proteins. Dilong extract totally blocked the LPS impact, leading to the activation of anti-apoptotic proteins, Bcl-2 and Bcl-xL, stabilized the mitochondria membrane and down-regulated the extrinsic and intrinsic pro-apoptotic proteins, TNF-α, active caspase-8, t-Bid, Bax, active caspase-9 and active caspase-3. Dilong could potentially serve as a cardio protective agent against LPS-induced H9c2 cardiomyoblast cell apoptosis.

"Single Oval Ostium Technique" using Polytetrafluoroethylene Graft for Outflow Reconstruction in Right Liver Grafts with venous Anomalies in Living Donor Liver Transplantation.

Right lobe living donor liver transplantation form a major source of liver allografts in Asia because of the scarcity of deceased donation. However, the transplant surgeons often face challenges while managing right lobe liver allografts due to variations in vascular anatomy. Such variations have led the transplant team to adopt modifications in existing techniques of inflow and outflow reconstruction. One of such variations is presence of multiple draining inferior right hepatic veins (IRHVs). This hepatic venous anomaly pose a lot of technical difficulties in the outflow reconstruction as second and/or third anastomosis to inferior vena cava is not always possible in limited retrohepatic space. Herein, we describe the "Single oval ostium technique" using dual synthetic vascular grafts ensuring a common outflow channel for all the hepatic veins.