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Uterine transplant (UTx) is performed to address absolute uterine infertility in the presence of uterine agenesis, a non-functional uterus, or following a prior hysterectomy. Following the initial success of UTx resulting in a livebirth (2014) in Sweden, there are over 70 reported UTx surgeries resulting in more than 40 livebirths worldwide. Currently, UTx has been performed in over 10 countries. As UTx is transitioning from an "experimental procedure" to a clinical option, an increasing number of centers may contemplate a UTx program. This article discusses essential steps for establishment of a successful UTx program. These principles may be implemented in cis- and transgender UTx candidates.

We present a case of life-threatening refractory hypertension (rHTN) in a patient with stage 3b chronic kidney disease that was unresponsive to open surgical renal denervation (RDN) but responded to bilateral nephrectomy (BLN). Both RDN and BLN reduce the increased sympathetic activation in rHTN. However, RDN has yet to show reductions in blood pressure adequate for the average patient with rHTN, and BLN has thus far been reserved for patients with preexisting end-stage kidney disease (ESKD). Our case suggests that there are patients with rHTN that warrant consideration of BLN prior to developing ESKD.

Positive resection margins are associated with worse survival after surgery for adrenocortical carcinoma (ACC). We aimed to identify risk factors for positive margins post-resection.The NCDB was queried for ACC patients from 2006 to 2015. Patients with positive versus negative resection margins post-surgery were compared using Chi-square tests. Survival based on adjuvant treatment was assessed using Kaplan-Meier curves.1,973 patients with ACC were identified, 217 (11.0%) with positive margins. Multivariable analysis identified extra-adrenal extension (HR 4.92, p 0.001), lymph node metastases (HR 2.64, p = 0.001), and distant metastases (HR 1.53, p = 0.03) as risk factors for positive margins. No significant difference in margin status existed between patients who had an open versus minimally invasive procedure (p = 0.6). Positive margin patients receiving adjuvant radiation (p = 0.007) or combined chemo-radiation (p = 0.001) had the longest survival.No modifiable risk factors were identified, but patients with positive margins receiving adjuvant radiation or chemo-radiation had the longest survival.

Many current guidelines recommend nonoperative management for pancreatic neuroendocrine tumors2 cm. The objective of this study was to evaluate the utilization and outcomes of resection for these pancreatic neuroendocrine tumors in the United States.Using the National Cancer Database (2004-2014), 3,243 cases of T1 (≤2.0 cm) pancreatic neuroendocrine tumors were identified. Additional patient and tumor characteristics were examined. Multivariate models were used to identify factors that predicted resection and to assess patient survival after resection.75% of pancreatic neuroendocrine tumors measuring 0 to 1.0 cm and 80% of pancreatic neuroendocrine tumors measuring1.0 and ≤2.0 cm were resected. Eighty-four pancreatic neuroendocrine tumors were functional, of which 82% were resected. Variables influencing resection included positive lymph nodes, tumor in body or tail of pancreas, well or moderately differentiated tumors, and resection at academic medical centers (odds ratio 1.5-4.9). When controlling for other variables, patients with pancreatic neuroendocrine tumors 1 to 2 cm who underwent resection had a prolonged 5-year survival rate (hazard ratio 0.51, confidence interval 0.34-0.75) when compared with those who did not undergo resection. This survival benefit of resection was not found for pancreatic neuroendocrine tumors 0 to 1 cm (hazard ratio = 0.63, confidence interval 0.36-1.11).Contrary to many current recommendations, most patients with pancreatic neuroendocrine tumors ≤2.0 cm undergo surgical resection in the United States. A survival benefit was found for resection of pancreatic neuroendocrine tumors 1 to 2 cm, suggesting that current recommendations should perhaps be revised.

The objective of the study was to determine the long-term stricture rate of hepaticojejunostiomy (HJ) performed for benign disease, to compare stricture rates for transplant patients and non-transplant patients, and to compare the success rates of procedural and surgical treatment options. Hospital charts of 135 consecutive patients undergoing HJ between 1998 and 2016 were analyzed retrospectively. The primary outcome was stricture formation. Secondary outcomes were time to stricture diagnosis and success rates of various interventions. The anastomotic stricture rate was 13.3 per cent (18). The mean follow-up period was 4.3 years. The mean time to stricture diagnosis was 2.3 years. Stricture rates were similar between the transplant (19.2%) and nontransplant, non-Whipple group (13%). Strictures were treated with radiological intervention with a 44.4 per cent success rate; each required multiple interventions. Mortality from liver disease after failure of nonoperative management of HJ strictures reached 30 per cent (3). Five of ten patients who failed radiological intervention underwent HJ revision; the success rate was 80 per cent. Anastomotic strictures of HJ performed for benign disease occur in 13 per cent of patients and typically develop within 2.5 years postoperatively. Yet, given the dangerous sequelae of chronic biliary obstruction and potential delay in presentation, a follow-up is recommended for up to 10 years. When strictures occur, HJ revision should be considered early, after two failed radiological interventions.

Background Adrenocortical carcinoma (ACC) is a rare malignancy with a dismal prognosis. Two landmark trials published in 2007 and 2012 showed efficacy for adjuvant mitotane in resectable ACC and etoposide/doxorubicin/cisplatin plus mitotane for unresectable ACC, respectively. In this study, we used the National Cancer Database to examine whether treatment patterns and outcomes changed after these trials. Methods The National Cancer Database was used to examine treatment patterns and survival in patients diagnosed with ACC from 2006 to 2015. Treatment modalities were compared within that group and with a historical cohort (1985 to 2005). χ2 tests were performed, and Cox proportional hazards models were created. Results From 2006 to 2015, 2752 patients were included; 38% of patients (1042) underwent surgery alone, and 31% (859) underwent surgery with adjuvant therapy. Overall 5-year survival rates for all stages after resection were 43% (median, 41 months) in the contemporary cohort and 39% (median, 32 months) in the historical cohort. After 2007, patients who underwent surgery were more likely to receive adjuvant chemotherapy (P = 0.005), and 5-year survival with adjuvant chemotherapy improved (41% vs 25%; P = 0.02). However, survival did not improve in patients with unresectable tumors after 2011 compared with 2006 to 2011 (P = 0.79). Older age, tumor size ≥10 cm, distant metastases, and positive margins were associated with lower survival after resection (hazard ratio range: 1.39 to 3.09; P < 0.03). Conclusions Since 2007, adjuvant therapy has been used more frequently in patients with resected ACC, and survival for these patients has improved but remains low. More effective systemic therapies for patients with ACC, especially those in advanced stages, are desperately needed.

Venous thromboembolism (VTE) occurs at high incidence in abdominal cancer surgery; therefore, a 4-week postoperative VTE prophylaxis is advocated. However, most patients with neuroendocrine tumors (NETs) have more favorable prognoses. This study aimed to determine the incidence of VTE in patients with abdominal NETs, compare these rates to other abdominal malignancies, and identify VTE risk factors. The ACS-NSQIP database was queried to identify patients with abdominal NETs and other abdominal malignancies who underwent surgery from 2008 to 2015. A 30-day postoperative VTE incidence for each group was compared. Univariable and multivariable analyses were used to identify VTE risk factors. Of the 7226 operations for patients with benign (2154) and malignant (5072) abdominal NETs, 144 patients experienced a VTE without significant differences between groups. Subgroup analysis revealed a spectrum of VTE rates. Compared to VTE rates of other abdominal malignancies, patients with benign (1.1% vs. 2.4%, p

Background COVID‐19 epidemiologic studies comparing immunosuppressed and immunocompetent patients may provide insight into the impact of immunosuppressants on outcomes. Methods In this retrospective cohort study, we assembled kidney or kidney‐pancreas transplant recipients who underwent transplant from January 1, 2010, to June 30, 2020, and kidney or kidney‐pancreas waitlisted patients who were ever on the waitlist from January 1, 2019, to June 30, 2020. We identified laboratory‐confirmed COVID‐19 until January 31, 2021, and tracked its outcomes by leveraging informatics infrastructure developed for an outcomes research network. Results COVID‐19 was identified in 62 of 887 kidney or kidney‐pancreas transplant recipients and 20 of 434 kidney or kidney‐pancreas waitlisted patients (7.0% vs. 4.6%, p = .092). Of these patients with COVID‐19, hospitalization occurred in 48 of 62 transplant recipients and 8 of 20 waitlisted patients (77% vs. 40%, p = .002); intensive care unit admission occurred in 18 of 62 transplant recipients and 2 of 20 waitlisted patients (29% vs. 10%, p = .085); and 7 transplant recipients were mechanically ventilated and died, whereas no waitlisted patients were mechanically ventilated or died (11% vs. 0%, p = .116). Conclusions Our study provides single‐center data and an informatics approach that can be used to inform the design of multicenter studies.

Background The extent of liver resection for tumours is limited by the expected functional reserve of the future liver remnant (FRL), so hypertrophy may be induced by portal vein embolization (PVE), taking 6 weeks or longer for growth. This study assessed the hypothesis that simultaneous embolization of portal and hepatic veins (PVE/HVE) accelerates hypertrophy and improves resectability. Methods All centres of the international DRAGON trials study collaborative were asked to provide data on patients who had PVE/HVE or PVE on 2016–2019 (more than 5 PVE/HVE procedures was a requirement). Liver volumetry was performed using OsiriX MD software. Multivariable analysis was performed for the endpoints of resectability rate, FLR hypertrophy and major complications using receiver operating characteristic (ROC) statistics, regression, and Kaplan–Meier analysis. Results In total, 39 patients had undergone PVE/HVE and 160 had PVE alone. The PVE/HVE group had better hypertrophy than the PVE group (59 versus 48 per cent respectively; P = 0.020) and resectability (90 versus 68 per cent; P = 0.007). Major complications (26 versus 34 per cent; P = 0.550) and 90-day mortality (3 versus 16 per cent respectively, P = 0.065) were comparable. Multivariable analysis confirmed that these effects were independent of confounders. Conclusion PVE/HVE achieved better FLR hypertrophy and resectability than PVE in this collaborative experience.

Comparative COVID-19 epidemiologic studies between immunosuppressed and immunocompetent patients may provide insight into the impact of immunosuppressive medications on clinical outcomes. In this retrospective cohort pilot study, we determined the incidence and outcomes of COVID-19 in kidney or kidney-pancreas transplant recipients and kidney or kidney-pancreas waitlisted patients in our center. COVID-19 testing was performed in 63 of 537 kidney or kidney-pancreas transplanted patients, versus 43 of 383 kidney or kidney-pancreas waitlisted patients as of June 4, 2020 (12% versus 11%, p=0.81). COVID-19 was identified in 14 of 537 kidney or kidney-pancreas transplanted patients, versus 9 of 383 kidney or kidney-pancreas waitlisted patients (2.6% versus 2.3%, p=0.81). Hospitalization occurred in 11 of 14 transplanted patients, and 4 of 9 waitlisted patients with COVID-19 (79% versus 44%, p=0.18). Intensive care unit admission occurred in 5 of 14 transplanted patients, and 1 of 9 waitlisted patients with COVID-19 (36% versus 11%, p=0.34). Two transplanted patients with COVID-19 were mechanically ventilated and died, whereas no waitlisted patients with COVID-19 died or were mechanically ventilated. Our study provides preliminary data that can be used for power calculations to inform multicenter studies designed to validate these findings.

BACKGROUND Patient compliance with immunosuppressive therapy after transplant has impacts on both graft and patient outcomes. For diabetic end-stage renal disease (ESRD) patients who are undergoing evaluation for kidney transplantation in our program, hemoglobin A1c (HbA1c) level of >10% is used as a flag that the patient may be at risk for noncompliance and that more comprehensive psychosocial screening is needed prior to transplant. We evaluated the association between pre-transplant HbA1c level and post-transplant compliance, as no study to date has looked at this in the transplant population. MATERIAL AND METHODS The charts of 392 patients who received a kidney transplant at a single institution between July 2008 and June 2012 were retrospectively reviewed. One hundred and sixty-five diabetic patients who received a kidney transplant alone were included in the final analysis. Our predictive variable was HbA1c level greater than 7.7% based on previous reports in the diabetic population. Outcome measures were graft survival, rejection episodes, unexplained low immunosuppressant levels, and documented noncompliance. RESULTS There were no statistically significant differences between the HbA1c groups of ≤7.7% and >7.7% in outcomes of failed grafts (22.0% and 17.8%, p=0.2), rejection episodes (15.0% and 6.7%, p=0.3), unexplained low immunosuppressant level (46.6% and 37.9%, p=0.3), and documented noncompliance (25.0% and 16.7%, p=0.4). CONCLUSIONS In diabetic ESRD patients selected for renal transplantation, elevated pre-transplant HbA1c levels, defined as HbA1c >7.7%, are not predictive of post-transplant medication compliance. We advocate that this group of patients should not be denied transplant solely on their elevated pre-transplant HbA1c.

Techniques such as the use of nonpenetrating vascular clips for arteriovenous fistula (AVF) anastomotic creation have been developed in an effort to reduce fistula-related complications. However, the outcomes data for the use of clips have remained equivocal, and the cost evaluations to support their use have been largely theoretical. Therefore, the present study aimed to determine both the clinical and the cost outcomes of AVFs created with nonpenetrating vascular clips compared with the continuous suture technique during a 10-year period at a single institution.All patients undergoing AVF creation in the upper extremity from 2009 through 2018 were retrospectively analyzed. The patient demographics and AVF outcomes were collected and compared stratified by the surgical technique used. A cost analysis was performed of a subgroup of patients from 2013 to 2018.During the 10-year study period, 916 AVFs were created (79% using the continuous suture technique and 21% using nonpenetrating vascular clips). Patient demographics and comorbid conditions did not differ between the two groups, and no differences were present in maturation, primary patency, assisted primary patency, or complication rates between the two groups at 1 year. The suture group had a shorter time to maturation (4.3 months vs 5.5 months; P .01) and improved secondary patency compared with the clip group (77.13% vs 69.59%; P = .03) The cost analysis of the procedures revealed a significant difference in direct costs (suture, $1389.26 vs clip, $1716.51; P .01) and contribution margin (suture, $1770.19 vs clip, $1128.36; P .01) for the two groups.Both suture and clip techniques in AVF creation demonstrated equivalent rates of maturation, primary patency, assisted primary patency, and complications at 1 year with higher expense associated with the use of clips. Thus, in an effort to reduce the economic burden of healthcare in the United States, the findings from the present study support the preferential use of the standard polypropylene suture technique when creating upper extremity AVFs.

Background After portal vein ligation of 1 side of the liver, the other side regenerates at a slow rate. This slow growth may be accelerated to rapid growth by adding a transection between the 2 sides, i.e., performing portal vein ligation and parenchymal transection. We found that in patients undergoing portal vein ligation and parenchymal transection, portal vein hyperflow in the regenerating liver causes a significant reduction of arterial flow due to the hepatic arterial buffer response. We postulated that the reduction of arterial flow induces hypoxia in the regenerating liver and used a rat model to assess hypoxia and its impact on kinetic growth. Methods A rat model of rapid (portal vein ligation and parenchymal transection) and slow regeneration (portal vein ligation) was established. Portal vein flow and pressure data were collected. Liver regeneration was assessed in rats using computed tomography, proliferation with Ki-67, and hypoxia with pimonidazole and HIF-1α staining. Results The rat model confirmed acceleration of regeneration in portal vein ligation and parenchymal transection as well as the portal vein hyperflow seen in patients. Additionally, tissue hypoxia was observed after portal vein ligation and parenchymal transection, while little hypoxia staining was detected after portal vein ligation. To determine if hypoxia is a consequence or an inciting stimulus of rapid liver regeneration, we used a prolyl-hydroxylase blocker to activate hypoxia signaling pathways in the slow model. This clearly accelerated slow to rapid liver regeneration. Inversely, abrogation of hypoxia led to a blunting of rapid growth to slow growth. The topical application of prolyl-hydroxylase inhibitors on livers in rats induced spontaneous areas of regeneration. Conclusion This study shows that pharmacologically induced hypoxic signaling accelerates liver regeneration similar to portal vein ligation and parenchymal transection. Hypoxia is likely an accelerator of liver regeneration. Also, prolyl-hydroxylase inhibitors may be used to enhance liver regeneration pharmaceutically.

International audience; BACKGROUND:Liver hypertrophy induced by partial portal vein occlusion (PVL) is accelerated by adding simultaneous parenchymal transection ("ALPPS procedure"). This preclinical experimental study in pigs tests the hypothesis that simultaneous ligation of portal and hepatic veins of the liver also accelerates regeneration by abrogation of porto-portal collaterals without need for operative transection.METHODS:A pig model of portal vein occlusion was compared with the novel model of simultaneous portal and hepatic vein occlusion, where major hepatic veins draining the portal vein-deprived lobe were identified with intraoperative ultrasonography and ligated using pledgeted transparenchymal sutures. Kinetic growth was compared, and the portal vein system was then studied after 7 days using epoxy casts of the portal circulation. Portal vein flow and portal pressure were measured, and Ki-67 staining was used to evaluate the proliferative response.RESULTS:Pigs were randomly assigned to portal vein occlusion (n = 8) or simultaneous portal and hepatic vein occlusion (n = 6). Simultaneous portal and hepatic vein occlusion was well tolerated and led to mild cytolysis, with no necrosis in the outflow vein-deprived liver sectors. The portal vein-supplied sector increased by 90 ± 22% (mean ± standard deviation) after simultaneous portal and hepatic vein occlusion compared with 29 ± 18% after PVL (P < .001). Collaterals to the deportalized liver developed after 7 days in both procedures but were markedly reduced in simultaneous portal and hepatic vein occlusion. Ki-67 staining at 7 days was comparable.CONCLUSION:This study in pigs found that simultaneous portal and hepatic vein occlusion led to rapid hypertrophy without necrosis of the deportalized liver. The findings suggest that the use of simultaneous portal and hepatic vein occlusion accelerates liver hypertrophy for extended liver resections and should be evaluated further.

Background. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are commonly present with metastatic disease, and the liver is the most frequent metastatic site. Herein, we studied whether primary tumor site affects survival in patients with GEP-NETs and liver metastases (NELM). As a secondary endpoint, we studied whether extrahepatic disease and surgical resection impact survival in this patient population. Methods. Patients with NELM diagnosed from 2006 to 2014 were identified from the National Cancer Database. Kaplan-Meier curves and nested Cox proportional hazards were used to assess variables associated with survival. Results. 2947 patients with well- or moderately differentiated GEP-NETs and NELM met the inclusion criteria for this study. Patients with small bowel NETs survived the longest of all GEP-NETs with NELM (median not reached). Rectal and gastric NETs with NELM had the shortest survival (median 31 months). Patients with extrahepatic metastases who underwent any operation survived longer than those managed nonoperatively (median survival 38.7 months vs. 18.6 months, p=0.01). On multivariable analysis, operations on the primary tumor and distant metastatic site (HR 0.23-0.43 vs. no surgery), treatment at an academic/research hospital, Charlson comorbidity index of 0, no extrahepatic metastases, and younger age were associated with prolonged survival (p<0.01). Conclusions. Primary tumor site affects survival in patients with GEP-NETs and NELM. Surgical resection seems beneficial for all GEP-NETs with NELM, even in the presence of extrahepatic metastases.

Heat stroke is a multiple organ dysfunction syndrome of poorly understood pathogenesis. Exertional heat stroke with acute liver failure is a rarely reported condition. Liver transplant has been recommended as treatment in cases of severe liver dysfunction; however, there are only 5 described cases of long-term survival after this procedure in patients with heat stroke. Here, we present 2 cases of young athletes who developed heat stroke. Both patients developed acute liver failure and were listed for liver transplant. Liver function tests of one patient improved, and he was discharged on postoperative day 13. The other patient showed no signs of improvement and liver biopsy showed massive necrosis. The patient underwent combined kidney-liver transplant and was discharged on postoperative day 17. After a follow-up of longer than 6 years, both patients are doing well with normal liver function and no neurologic sequelae. We also reviewed all published cases of hepatic failure associated with heat stroke and found 9 published cases of liver transplant for heat stroke in the English literature. Conservative management appears to be justified in heat stroke-associated liver failure, even in the presence of accepted criteria for emergency liver transplant. If the liver does not show signs of recovery and hepatic decompensation progresses, liver transplant should be performed.

Patients with gastroenteropancreatic neuroendocrine tumors often present with stage IV disease. Primary tumor resection in these patients remains controversial. Herein, we studied the impact of primary tumor removal, identified variables associated with prolonged survival for each neuroendocrine tumor subtype, and determined factors that influence surgeons to perform primary tumor resection.Patients with metastatic gastroenteropancreatic neuroendocrine tumors diagnosed from 2004 to 2014 were identified from the National Cancer Database. Nested Cox proportional hazards and logistic regression models were used to assess variables associated with survival and primary resection.A total of 14,510 patients met inclusion criteria. On multivariable analysis, resection of the primary tumor and grade 1 or 2 tumors was associated with prolonged survival in all subtypes (P.001). Organ-specific variables associated with prolonged survival in patients undergoing primary tumor resection included the following: low grade for all organs; young age for pancreatic, small intestinal, colonic, and rectal neuroendocrine tumor; tumor size for colonic and rectal neuroendocrine tumor; and tumor location for colonic neuroendocrine tumor. Low tumor grade was found to be significantly associated with removal of the primary tumor across all organs.This study is the first suggesting that primary tumor resection is associated with prolonged survival for all gastro-entero-pancreatic NETs. Additional variables related to survival for each NET subtype were identified and might help select patients who benefit from primary tumor removal.

Statin use in patients listed for in kidney transplant is believed to be beneficial. However, the optimum statin dose for improved survival in this high-risk population is unknown. Our study aimed to determine the impact of prekidney transplant statin dosage on survival postkidney transplant. In this retrospective cohort study, we enrolled patients who underwent kidney transplant from January 2005 to September 2015 at Rush University Medical. Data on the statin use and intensity used before kidney transplant were obtained. The patient population was stratified into 2 groups based on prekidney transplant use of statins. Patients using any form of statin, without regard to the type and dose, were placed in the statin groups, whereas the rest were categorized as the no statin group. The statin group was further classified into low-intensity, moderate-intensity, and high-intensity statin subgroups based on the present atherosclerotic cardiovascular disease definition of statin intensity. The primary outcome was patient survival after kidney transplant. A total of 687 patients had data on statin use before kidney transplant were followed. Median follow-up time was 3.4 years (interquartile range 1.2 to 5.6 years). Multivariate analysis showed that the use of statins prekidney transplant was associated with improved survival postkidney transplant compared with prestatin group (Hazard ratio 0.56, confidence intervals 0.32 to 1.00, p = 0.05). When patients on statins were stratified by statin intensity, Kaplan-Meier survival analysis revealed a significant dose-dependent improvement in survival. Multivariate analysis showed that the relation between statin intensity and survival was maintained even after adjusting for confounder (hazard ratio 0.30, confidence intervals 0.18 to 0.51, p0.001). In conclusion, our data indicate statistically significant survival benefit in patients receiving high-intensity statin before kidney transplant.

Recent clinical data support an aggressive surgical approach to both primary and metastatic liver tumors. For some indications, like colorectal liver metastases, the amount of liver tissue left behind after liver resection has become the main limiting factor of resectability of large or multiple liver tumors. A minimal amount of functional tissue is required to avoid the severe complication of post-hepatectomy liver failure, which has high morbidity and mortality. Inducing liver growth of the prospective remnant prior to resection has become more established in liver surgery, either in the form of portal vein embolization by interventional radiologists or in the form of portal vein ligation several weeks prior to resection. Recently, it was shown that liver regeneration is more extensive and rapid, when the parenchymal transection is added to portal vein ligation in a first stage and then, after only one week of waiting, resection performed in a second stage (Associating Liver Partition and Portal vein ligation for Staged hepatectomy = ALPPS). ALPPS has rapidly become popular across the world, but has been criticized for its high perioperative mortality. The mechanism of accelerated and extensive growth induced by this procedure has not been well understood. Animal models have been developed to explore both the physiological and molecular mechanisms of accelerated liver regeneration in ALPPS. This protocol presents a rat model that allows mechanistic exploration of accelerated regeneration.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) induces more rapid liver growth than portal vein ligation (PVL). Transection of parenchyma in ALPPS may prevent the formation of collaterals between lobes. The aim of this study was to determine if abrogating the formation of collaterals through parenchymal transection impacted growth rate. Twelve Yorkshire Landrace pigs were randomized to undergo ALPPS, PVL, or “partial ALPPS” by varying degrees of parenchymal transection. Hepatic volume was measured after 7 days. Portal blood flow and pressure were measured. Portal vein collaterals were examined from epoxy casts. PVL, ALPPS, and partial ALPPS led to volume increases of the RLL by 15.5% (range 3–22), 64% (range 45–76), and 32% (range 18–77), respectively, with significant differences between PVL and ALPPS/partial ALPPS (p

Since the first attempt of pig-to-primate liver xenotransplantation (LXT) in 1968, survival has been limited. We evaluated a model utilizing α-1,3-galactosyltransferase knockout donors, continuous posttransplant infusion of human prothrombin concentrate complex, and immunosuppression including anti-thymocyte globulin, FK-506, methylprednisone, and costimulation blockade (belatacept, n = 3 or anti-CD40 mAb, n = 1) to extend survival. Baboon 1 remained well until postoperative day (POD) 25, when euthanasia was required because of cholestasis and plantar ulcers. Baboon 2 was euthanized following a seizure on POD 5, despite normal liver function tests (LFTs) and no apparent pathology. Baboon 3 demonstrated initial stable liver function but was euthanized on POD 8 because of worsening LFTs. Pathology revealed C4d positivity, extensive hemorrhagic necrosis, and a focal cytomegalovirus inclusion. Baboon 4 was clinically well with stable LFTs until POD29, when euthanasia was again necessitated by plantar ulcerations and rising LFTs. Final pathology was C4d negative and without evidence of rejection, inflammation, or thrombotic microangiopathy. Thus, nearly 1-mo rejection-free survival has been achieved following LXT in two of four consecutive recipients, demonstrating that the porcine liver can support life in primates for several weeks and has encouraging potential for clinical application as a bridge to allotransplantation for patients with acute-on-chronic or fulminant hepatic failure.

Introduction The decision for isolated kidney transplant (KT) vs. combined liver–kidney transplant (CLKT) in patients with end-stage renal disease (ESRD) with compensated cirrhosis remains controversial. We sought to determine outcomes of patients requiring listing for a liver transplant (LT) following either a cadaveric or living donor KT and compare these outcomes to similar patients receiving a CLKT. Methods Our dataset included the United Network for Organ Sharing (UNOS)/Standard Transplant and Analysis and Research (STAR) kidney files from 1987 to 2012 after being joined with the liver files from 2002 to 2012. Outcomes of patients who received a CLKT with an international normalized ratio (INR) ≤1 and total bilirubin ≤1 were compared to patients who received a primary KT and subsequently required listing for LT between zero and five yr or after five yr. Results For the three groups, 244 patients had a CLKT, 216 were wait-listed for LT between zero and five yr after KT (0–5 WL), and 320 were wait-listed five yr after KT (+5 WL). From the time of KT, the 0–5 WL group had significantly worse survival than the CLKT group and the +5 WL group. The +5 WL had the best survival of all groups. For the 0–5 WL group, 45% underwent LT and 40% died while waiting compared to the +5 WL group with 53% having LT and 26% died while waiting. At the time of LT, the 0–5 WL group had a higher model for end-stage liver disease (MELD) score, higher incidence of being in the ICU at the time of transplant, and higher incidence of requiring life support. From the time of LT, the CLKT trended toward better survival (p = 0.0549) than both the 0–5 WL and +5 WL groups, which had equivalent survival. Conclusion The 0–5 WL group is a higher risk group with poorer survival due to a higher incidence of dying on the waitlist. Better identification of patients with a high risk for hepatic decompensation following KT and agreement for regional exception for LT in the event of decompensation may improve utilization of organs and better survival for those patients.

Background Pig to baboon liver xenotransplantation typically results in severe thrombocytopenia and coagulation disturbances, culminating in death from hemorrhage within 9 days, in spite of continuous transfusions. We studied the contribution of anticoagulant production and clotting pathway deficiencies to fatal bleeding in baboon recipients of porcine livers. Methods By transplanting liver xenografts from α1,3-galactosyltransferase gene-knockout (GalT-KO) miniature swine donors into baboons as auxiliary organs, leaving the native liver in place, we provided the full spectrum of primate clotting factors and allowed in vivo mixing of porcine and primate coagulation systems. Results Recipients of auxiliary liver xenografts develop severe thrombocytopenia, comparable to recipients of conventional orthotopic liver xenografts and consistent with hepatic xenograft sequestration. However, baboons with both pig and native livers do not exhibit clinical signs of bleeding and maintain stable blood counts without transfusion for up to 8 consecutive days post-transplantation. Instead, recipients of auxiliary liver xenografts undergo graft failure or die of sepsis, associated with thrombotic microangiopathy in the xenograft, but not the native liver. Conclusion Our data indicate that massive hemorrhage in the setting of liver xenotransplantation might be avoided by supplementation with primate clotting components. However, coagulation competent hepatic xenograft recipients may be predisposed to graft loss related to small vessel thrombosis and ischemic necrosis.

Hepatic cysts encompass a spectrum of clinical etiologies but most are benign, occur rarely, and are usually asymptomatic. Symptomatic cysts may present with abdominal pain, hemorrhage, obstructive jaundice, or a consumptive coagulopathy. The optimal surgical management of hepatic cysts varies depending on the size and location of the lesion, but includes laparoscopic cyst fenestration,1 formal resection, enucleation, as well as liver transplantation.

Type 1 primary hyperoxaluria (PH1) causes renal failure, for which isolated kidney transplantation (KT) is usually unsuccessful treatment due to early oxalate stone recurrence. Although hepatectomy and liver transplantation (LT) corrects PH1 enzymatic defect, simultaneous auxiliary partial liver transplantation (APLT) and KT have been suggested as an alternative approach. APLT advantages include preservation of the donor pool and retention of native liver function in the event of liver graft loss. However, APLT relative mass may be inadequate to correct the defect. We here report the first case of native portal vein embolization (PVE) to increase APLT to native liver mass ratio (APLT/NLM-R). Following initial combined APLT-KT, both allografts functioned well, but oxalate plasma levels did not normalize. We postulated the inadequate APLT/NLM-R could be corrected by trans-hepatic native PVE. The resulting increased APLT/NLM-R decreased serum oxalate to normal levels within 1 month following PVE. We conclude that persistently elevated oxalate levels after combined APLT-KT for PH1 treatment, results from inadequate relative functional capacity. This can be reversed by partial native PVE to decrease portal flow to the native liver. This approach might be applicable to other scenarios where partial grafts have been transplanted to replace native liver function.

Purpose: Ureteroneocystostomy (UCN) is the most widely used urinary reconstruction technique during kidney transplantation. Disadvantages of this technique include a high incidence of hematuria and reflux, plus the potential for obstruction resulting from distal ureteral fibrosis. Pyeloureterostomy (PU) avoids these complications but increases the technical complexity. Methods: Between January 1990 and December 2005, 1066 adults patients underwent kidney transplantations; 768 patients (72.1%) had urinary reconstruction by PU and 298 (27.9%) underwent UNC. Results: Patients in the PU group underwent simultaneous ipsilateral native nephrectomy. The operative time was longer in the PU group compared with the UNC group: 210 � 36 min versus 182 � 24 min (P < 0.001). Overall surgical complications in the PU group were comparable to those in the UNC group (9.5% versus 12.3%). The urinary complication rate was also comparable in both groups: 3.2% (25 of 768) in the PU group and 5% (15 of 298) in the UNC group. However, urinary obstruction comprised 60% of urinary complications in the UNC group, compared with 32% in the PU group (P < 0.01). We treated most urinary complications non-operatively. However, 24% of patients (six of 25) in the PU group needed operative intervention or revision for ureteral reconstruction, compared with 46.6% (seven of 15) in the UNC group (P < 0.01). Conclusions: Pyeloureterostomy is a safe and effective method for urinary tract reconstruction in renal transplantation. Pyeloureterostomy should be part of every transplant surgeon’s armamentarium.

As patients with end-stage renal disease are receiving renal allografts at older ages, the number of male renal transplant recipients (RTRs) being diagnosed with prostate cancer (CaP) is increasing. Historically, the literature regarding the management of CaP in RTR's is limited to case reports and small case series. To date, there are no standardized guidelines for screening or management of CaP in these complex patients. To better understand the unique characteristics of CaP in the renal transplant population, we performed a literature review of PubMed, without date limitations, using a combination of search terms including prostate cancer, end stage renal disease, renal transplantation, prostate cancer screening, prostate specific antigen kinetics, immuno-suppression, prostatectomy, and radiation therapy. Of special note, teams facilitating the care of these complex patients must carefully and meticulously consider the altered anatomy for surgical and radiotherapeutic planning. Active surveillance, though gaining popularity in the general low risk prostate cancer population, needs further study in this group, as does the management of advance disease. This review provides a comprehensive and contemporary understanding of the incidence, screening measures, risk stratification, and treatment options for CaP in RTRs.

Cytomegalovirus (CMV)-seronegative kidney transplant (KTx) recipients of organs from CMV-seropositive donors (D+/R-) are at increased risk for CMV infection. Despite valganciclovir (VGCV) prophylaxis (900 mg daily for 200 days), late-onset CMV (LO-CMV) occurs at excessive rates. VGCV-associated cost and toxicities remain problematic.We retrospectively evaluated 50 D+/R- adult KTx recipients from August 2008 to August 2014 who received low-dose VGCV (450 mg daily) prophylaxis for an extended duration. The primary outcome was occurrence of CMV disease.All patients received depletion induction and underwent ABO-compatible KTx. Mean prophylaxis and follow-up durations were 22.8 and 40.7 months, respectively. Eight patients developed CMV: 5 breakthrough cases (1 case of colitis [2%] and 4 cases of infection [8%]) and 3 cases of LO-CMV (1 syndrome [2.9%] and 2 cases of infection [5.7%]). On logistic regression, longer duration of VGCV prophylaxis was protective against CMV infection or disease (P = .044; odds ratio, 1.12 [95% confidence interval, 1.03-1.29]). None of 19 recipients with prophylaxis for ≥12 months developed LO-CMV compared with 3 of 16 recipients with prophylaxis for 12 months (18.8%) (P = .086). Four patients had recurrence of CMV, and 1 patient developed resistance. CMV was not responsible for graft or patient loss and did not affect survival.Low-dose VGCV is an effective prophylaxis for D+/R- KTx recipients despite depleting induction. Longer prophylaxis is more protective, and receiving VGCV for ≥12 months nearly eradicated LO-CMV without increasing antiviral resistance.

Background. The PHS increased risk donor (IRD) is underutilized in liver transplantation. We aimed to examine the posttransplant outcomes in recipients of increased-risk organs.Methods. We analyzed 228,040 transplants in the Organ Procurement and Transplantation Network database from 2004 to 2013. Endpoints were graft failure and death. Results were controlled for demographics and comorbidities. Statistical analysis utilized Fisher’s test and logistic regression.Results. 58,816 patients were identified (5,534 IRD, 53,282 non-IRD). IRDs were more frequently male (69.2% versus 58.3%,p<0.001), younger (34 versus 39,p<0.001), and less likely to have comorbidities (p<0.001). Waitlist time was longer for IRD graft recipients (254 versus 238 days,p<0.001). All outcomes were better in the IRD group. Graft failure (23.6 versus 27.3%,p<0.001) and mortality (20.4 versus 22.3%,p=0.001) were decreased in IRD graft recipients. However, in multivariate analysis, IRD status was not a significant indicator of outcomes.Conclusion. This is the first study to describe IRD demographics in liver transplantation. Outcomes are improved in IRD organ recipients; however, controlling for donor and recipient comorbidities, ischemia time, and MELD score, the differences lose significance. In multivariate analysis, use of IRD organs is noninferior, with similar graft failure and mortality despite the infectious risk.

Kim K, Schuetz C, Elias N, Veillette GR, Wamala I, Varma M, Smith RN, Robson SC, Cosimi AB, Sachs DH, Hertl M. Up to 9-day survival and control of thrombocytopenia following GalT-KO swine liver xenotransplantation in baboons. Xenotransplantation 2012; 19: 256–264.. © 2012 John Wiley & Sons A/S. Abstract: Background: With standard miniature swine donors, survivals of only 3 days have been achieved in primate liver-transplant recipients. The recent production of alpha1,3-galactosyl transferase knockout (GalT-KO) miniature swine has made it possible to evaluate xenotransplantation of pig organs in clinically relevant pig-to-non-human primate models in the absence of the effects of natural anti-Gal antibodies. We are reporting our results using GalT-KO liver grafts. Methods: We performed GalT-KO liver transplants in baboons using an immunosuppressive regimen previously used by our group in xeno heart and kidney transplantation. Post-operative liver function was assessed by laboratory function tests, coagulation parameters and histology. Results: In two hepatectomized recipients of GalT-KO grafts, post-transplant liver function returned rapidly to normal. Over the first few days, the synthetic products of the donor swine graft appeared to replace those of the baboon. The first recipient survived for 6 days and showed no histopathological evidence of rejection at the time of death from uncontrolled bleeding, probably caused by transfusion-refractory thrombocytopenia. Amicar treatment of the second and third recipients led to maintenance of platelet counts of over 40 000 per μl throughout their 9- and 8-day survivals, which represents the longest reported survival of pig-to-primate liver transplants to date. Both of the last two animals nevertheless succumbed to bleeding and enterococcal infection, without evidence of rejection. Conclusions: These observations suggest that thrombocytopenia after liver xenotransplantation may be overcome by Amicar therapy. The coagulopathy and sepsis that nevertheless occurred suggest that additional causes of coagulation disturbance must be addressed, along with better prevention of infection, to achieve long-term survival.

Background The shortage in donor livers has led to increased use of allografts derived from donation after cardiac death (DCD). The compromised viability in these livers leads to inferior post-transplantation allograft function and survival compared with donation after brain death (DBD) donor grafts. In this study, we reconditioned DCD livers using an optimized normothermic machine perfusion system. Methods Livers from 12 Yorkshire pigs (20–30 kg) were subjected to either 0 min (WI-0 group, n = 6) or 60 min (WI-60 group, n = 6) of warm ischemia and 2 h of cold storage in UW solution, followed by 4 h of oxygenated sanguineous normothermic machine perfusion. Liver viability and metabolic function were analyzed hourly. Results Warm ischemic livers showed elevated transaminase levels and reduced ATP concentration. After the start of machine perfusion, transaminase levels stabilized and there was recovery of tissue ATP, coinciding with an increase in bile production. These parameters reached comparable levels to the control group after 1 h of machine perfusion. Histology and gross morphology confirmed recovery of the ischemic allografts. Conclusion Our data demonstrate that metabolic and functional parameters of livers with extended warm ischemic time (60 min) can be significantly improved using normothermic machine perfusion. We hereby compound the existing body of evidence that machine perfusion is a viable solution for reconditioning marginal organs.

BackgroundMany patients on hemodialysis do not have adequate anatomy for native arteriovenous fistulas. In these patients, synthetic conduits remain an alternative option for permanent hemodialysis access. We sought to compare the standard cuffed expanded polytetrafluoroethylene (ePTFE) graft with the bovine carotid artery (BCA) graft.MethodsThis was a prospective, randomized controlled trial that was set in an academic medical center. We enrolled 26 patients in the BCA group and 27 patients in the ePTFE group. Primary, assisted primary, and secondary patency were calculated using the Kaplan-Meier method. Complications were monitored and are reported.ResultsAlthough there was no significant difference in secondary patency rates, primary and assisted primary patency rates were significantly higher in BCA than in the ePTFE grafts (60.5% vs 10.1% and 60.5% vs 20.8% at 1 year, respectively). The BCA graft survival advantage was most profound in the upper arm grafts with significantly higher primary and assisted patency rates (P < .0001 and .0005, respectively). The total number of interventions (upper arm grafts) and total number of angioplasties (overall and upper arm) required to maintain patency were significantly fewer in the BCA group. The most common complication was graft thrombosis which occurred 0.34 ± 0.09 times per patient year in the BCA group compared to 0.77 ± 0.16 times per patient year in the ePTFE group, P = .01.ConclusionThe BCA graft is an excellent option for patients on hemodialysis that are not suitable for native arteriovenous fistulas, as these grafts required fewer interventions than the ePTFE grafts to maintain patency.

Donors after cardiac death present a significant pool of untapped organs for transplantation, and use of machine perfusion strategies has been an active focus area in experimental transplantation. However, despite 2 decades of research, a gold standard has yet to emerge for machine perfusion systems and protocols. Whole blood reperfusion has been used as a surrogate for organ transplantation, especially as a model for the short-term response posttransplantation, and for optimization of perfusion systems. Although it is known that there is a strong correlation between liver function in whole-blood reperfusion and survival, the exact nature of these correlations, and to what extent they can be considered as an indicator of viability for transplantation/recipient survival, remain unclear. In this work, we demonstrate that diluted whole-blood reperfusion can be used as a direct model for transplantation of ischemic rat liver grafts. Specifically, we show that recipient survival can be predicted based simply on the value of alanine aminotransferase during perfusion, providing quantitative criteria of viability for use in this animal model. These results indicate that in the rat model graft survival is highly correlated with hepatocellular damage.

The effect of the model for end-stage liver disease (MELD) system on the post-transplant survival of patients with hepatocellular carcinoma (HCC) has not been fully elucidated. Our objective is to review the results of liver transplantation (LT) for HCC at the Massachusetts General Hospital over a period of 12 years, with special emphasis on the effect of the MELD system. A retrospective review of 73 patients who underwent liver transplantation for HCC between 1995 and 2007. Outcome measures included demographics, tumor stage at explant, patient survival, and tumor recurrence. On pathologic review of the explanted liver, 12.3% of patients were classified as stage I; 42.5% as stage II, 21.9% as stage III, and 23.3% as stage IV. The overall actual survival rate was 85% at 1 year, 82% at 3 years, 73% at 5 years, and 66% at 10 years. Overall tumor recurrence was 11%. Survival rates were higher after the MELD system (5 year survival 60% before MELD vs. 85% after MELD). Recurrence decreased from 21% to 7.5%. We showed improved survival for HCC after LT over the last 12 years, and especially improved survival and decreased recurrence in the time since the implementation of the MELD system.

Orthotopic liver transplantation is the only available treatment for severe liver failure, but it is currently limited by organ shortage. One technical challenge that has thus far limited the development of a tissue-engineered liver graft is oxygen and nutrient transport. Here we demonstrate a novel approach to generate transplantable liver grafts using decellularized liver matrix. The decellularization process preserves the structural and functional characteristics of the native microvascular network, allowing efficient recellularization of the liver matrix with adult hepatocytes and subsequent perfusion for in vitro culture. The recellularized graft supports liver-specific function including albumin secretion, urea synthesis and cytochrome P450 expression at comparable levels to normal liver in vitro. The recellularized liver grafts can be transplanted into rats, supporting hepatocyte survival and function with minimal ischemic damage. These results provide a proof of principle for the generation of a transplantable liver graft as a potential treatment for liver disease.

Biliary adenofibroma and hepatobiliary mucinous cystic neoplasm are exceedingly rare tumors. To our knowledge, no case of co-existent biliary adenofibroma and mucinous cystic neoplasm has been previously reported. We present a patient who was diagnosed with both tumors concurrently. Both can present with abdominal pain, although some are diagnosed incidentally in asymptomatic patients. Imaging and tumor markers can be suggestive, but histologic examination is needed for definitive diagnosis. Both have a propensity for malignant transformation, thus complete surgical resection is the treatment of choice. Although rare, awareness of these tumors leads to earlier diagnosis and treatment.

A 58-year-old man was admitted to this hospital because of hepatitis C infection, hepatocellular carcinoma, and recurrent bleeding. Hemophilia had caused multiple hemarthroses, for which he had received blood products since infancy. Hepatocellular carcinoma was detected 8 months before admission; attempts at radiofrequency ablation had been complicated by hemorrhage and the failure to correct coagulation-test results with factor VIII. A surgical procedure was performed.