Thromboelastography profiles for controlled circulatory death donors: Validating the role of heparin.

Controlled donation after circulatory death (cDCD) liver transplants are associated with increased ischemic-type biliary complications. Microvascular thrombosis secondary to decreased donor fibrinolysis may contribute to bile duct injury. We hypothesized that cDCD donors are hypercoagulable with impaired fibrinolysis and aim to use thromboelastography to characterize cDCD coagulation profiles.

Intraoperative autologous transfusion and oncologic outcomes in liver transplantation for hepatocellular carcinoma: a propensity matched analysis.

BACKGROUND: Intraoperative autologous transfusion (IAT) of salvaged blood is a common method of resuscitation during liver transplantation (LT), however concern for recurrence in recipients with hepatocellular carcinoma (HCC) has limited widespread adoption. METHODS: A review of patients undergoing LT for HCC between 2008 and 2018 was performed. Clinicopathologic and intraoperative characteristics associated with inferior recurrence-free (RFS) and overall survival (OS) were identified using Kaplan-Meier analysis and uni-/multi-variable Cox proportional hazards modeling. Propensity matching was utilized to derive clinicopathologically similar groups for subgroup analysis. RESULTS: One-hundred-eighty-six patients were identified with a median follow up of 65 months. Transplant recipients receiving IAT (n = 131, 70%) also had higher allogenic transfusions (median 5 versus 0 units, P < 0.001). There were 14 recurrences and 46 deaths, yielding an estimated 10-year RFS and OS of 89% and 67%, respectively. IAT was not associated with RFS (HR 0.89/liter, P = 0.60), or OS (HR 0.98/liter, P = 0.83) pre-matching, or with RFS (HR 0.97/liter, P = 0.92) or OS (HR 1.04/liter, P = 0.77) in the matched cohort (n = 49 per group). CONCLUSION: IAT during LT for HCC is not associated with adverse oncologic outcomes. Use of IAT should be encouraged to minimize the volume of allogenic transfusion in patients undergoing LT for HCC.

Patency for autologous vein is superior to cadaveric vein in portal-mesenteric venous reconstruction.

BACKGROUND: Portal venous reconstruction (PVR) is often needed during resection of hepatopancreato-biliary (HPB) malignancies. Primary repair (PR), autologous vein (AV), or cryopreserved cadaveric vein (CCV) are frequently utilized, however relative patency is not well studied. METHODS: All patients undergoing PVR between 2007-2019 at our center were identified. 3-year primary patency (PP), overall survival (OS), and survival-adjusted patency (SAP) were evaluated with Kaplan-Meier and Cox proportional hazards modeling. RESULTS: One-hundred-twenty patients were identified with a median follow-up of 11 months. PR, AV, and CCV reconstruction were used in 28 (23%), 35 (29%), and 57 (48%) patients, respectively, with two (7%), four (11%), and 29 (51%) thromboses, respectively. 3-year PP was greater for both primary repair (90%) and AV (83%) compared to CCV (33%, both p<0.001). On multivariable analysis, CCV had worse 3-year PP (HR 7.89, p=0.005) and SAP (HR 2.09, p=0.02) compared to PR; AV reconstruction had equivalent oncologic and patency-related outcomes to PR (p>0.4 for both comparisons). CONCLUSIONS: Primary patency for PR and AV reconstruction is superior to CCV for PVR during resection of HPB malignancies. AV conduit should be the preferred choice of reconstruction when PR is not achievable. Surgeons should only use CCV when factors preclude PR/AV reconstruction.

Graft-versus-host disease after liver transplantation is associated with bone marrow failure, hemophagocytosis, and DNMT3A mutations.

Graft-versus-host disease after liver transplantation (LT-GVHD) is rare, frequently fatal, and associated with bone marrow failure (BMF), cytopenias, and hyperferritinemia. Given hyperferritinemia and cytopenias are present in hemophagocytic lymphohistiocytosis (HLH), and somatic mutations in hematopoietic cells are associated with hyperinflammatory responses (clonal hematopoiesis of indeterminate potential, CHIP), we identified the frequency of hemophagocytosis and CHIP mutations in LT-GVHD. We reviewed bone marrow aspirates and biopsies, quantified blood/marrow chimerism, and performed next-generation sequencing (NGS) with a targeted panel of genes relevant to myeloid malignancies, CHIP, and BMF. In all, 12 marrows were reviewed from 9 LT-GVHD patients. In all, 10 aspirates were evaluable for hemophagocytosis; 7 had adequate DNA for NGS. NGS was also performed on marrow from an LT cohort (n = 6) without GVHD. Nine of 10 aspirates in LT-GVHD patients showed increased hemophagocytosis. Five (71%) of 7 with LT-GVHD had DNMT3A mutations; only 1 of 6 in the non-GVHD LT cohort demonstrated DNMT3A mutation (p = .04). Only 1 LT-GVHD patient survived. BMF with HLH features was associated with poor hematopoietic recovery, and DNMT3A mutations were over-represented, in LT-GVHD patients. Identification of HLH features may guide prognosis and therapeutics. Further studies are needed to clarify the origin and impact of CHIP mutations on the hyperinflammatory state.

Degree of biliary tract violation during treatment of gallbladder adenocarcinoma is independently associated with development of peritoneal carcinomatosis.

BACKGROUND: Gallbladder cancer (GBC) is often incidentally diagnosed after cholecystectomy. Intra-operative biliary tract violations (BTV) have been recently associated with development of peritoneal disease (PD). The degree of BTV may be associated with PD risk, but has not been previously investigated. METHODS: We reviewed patients with initially non-metastatic GBC treated at our institution from 2003 to 2018. Patients were grouped based on degree of BTV during their treatment: major (e.g., cholecystotomy with bile spillage, n = 27, 29%), minor (e.g., intra-operative cholangiogram, n = 18, 19%), and no violations (n = 48, 55%). Overall survival (OS) and peritoneal disease-free survival (PDFS) were evaluated with Kaplan-Meier and Cox proportional hazards modeling. RESULTS: Ninety-three patients were identified; the median age was 64 years (range 31-87 years). Seventy-six (82%) were incidentally diagnosed. The median follow-up was 23 months; 20 (22%) patients developed PD. The 3-year PDFS for patients with major, minor, and no BTV was 52%, 83%, and 98%, respectively (major vs. none: p < 0.001; minor vs. none: p < 0.01). BTV was not associated with 5-year OS (HR 1.53, p = 0.16). CONCLUSION: Increasing degree of BTV is associated with higher risk of peritoneal carcinomatosis in patients with GBC and should be considered during preoperative risk stratification. Reporting biliary tract violations during cholecystectomy is encouraged.

Impact of center volume and the adoption of laparoscopic donor nephrectomy on outcomes in pediatric kidney transplantation.

Reports for pediatric kidney transplant recipients suggested better outcomes for ODN compared to LDN. Contemporary outcomes stratified by donor type and center volume have not been evaluated in a national dataset. UNOS data (2000-2014) were analyzed for pediatric living donor kidney transplant recipients. The primary outcome was GF; secondary outcomes were DGF, rejection, and patient survival. Live donor nephrectomies for pediatric recipients decreased 30% and transitioned from ODN to LDN. GF rates did not differ for ODN vs LDN (P = .24). GF was lowest at high volume centers (P < .01). Donor operative approach did not contribute to GF. LDN was associated with less rejection than ODN (OR 0.66, CI 0.5-0.87, P < .01). Analysis of the 0- to 5-yr recipient group showed no effect of ODN vs LDN on GF or rejection. For the contemporary era, there was no association between DGF and LDN in the 0- to 5-yr group (OR 1.12, CI 0.67-1.89, P = .67). Outcomes of kidney transplants in pediatric recipients following LDN have improved since its introduction and LDN should be the approach for live donor nephrectomy regardless of recipient age. The association between case volume and improved outcomes highlights future challenges in organ transplantation.

The fate of anti-HLA antibodies following liver transplantation.

Introduction: Liver transplant recipients may have pre-formed anti-HLA antibodies directed to mismatched HLA of the liver donor (donor specific antibodies, DSA) or not directed to the liver donor (non-donor specific, non-DSA). We observed the fate of these antibodies (DSA and non-DSA) at 12 months after transplant. Methods: Patients transplanted between 4/2015 and 12/2018 (N = 216) who had anti-HLA antibody measurements at both transplant and 12 months posttransplant (N = 124) and with DSAs at transplant (N = 31) were considered informative for a paired analysis of the natural history of DSA and non-DSA following liver transplantation. Results: Class I DSAs and non-DSAs decreased between transplant and 12 months; however, Class I DSAs essentially disappeared by 12 months while Class I non-DSAs did not. Anti-HLA Class II DSAs performed differently. While there was a significant drop in values between transplant and 12 months, these antibodies mostly persisted at a low level. Discussion: Our study demonstrated a significant difference in the kinetics of DSA compared to non-DSA following liver transplantation, most profoundly for anti-HLA Class I antibodies. Class I DSAs were mostly absent at 12 months while Class II DSAs persisted, although at lower levels. The mechanisms of reduction in anti-HLA antibodies following liver transplantation are not completely understood and were not pursued as a part of this study. This detailed analysis of Class I and Class II DSAs and non-DSAs represents and important study to explore the change in antibodies at one year from liver transplantation.

Biliary complications adversely affect patient and graft survival after liver retransplantation.

Inferior outcomes are consistently observed for recipients of liver retransplantation (re-LT) versus recipients of primary transplants. Few studies have examined the incidence and impact of biliary complications (BCs) on outcomes after re-LT. The aim of this study was to compare patient and graft survival for re-LT recipients with BCs (BC(+) ) and re-LT recipients without BCs (BC(-) ). Additional aims were to determine the impact of biliary reconstruction on the incidence of BCs and to identify risk factors for BCs after re-LT. A single-center, retrospective analysis of all re-LT recipients over a decade was performed. Univariate analyses were performed, and survival was compared with the log-rank method. A multivariate Cox regression analysis was performed to determine independent predictors of death and graft failure. The BC rate was 20.9% (n = 23) for 110 re-LT cases. The average follow-up was 55 months. The survival rates for BC(-) recipients at 3 months and 1, 3, and 5 years were 95.3%, 91.7%, 85.4%, and 80.9%, respectively, whereas BC(+) patients had survival rates of 64.3%, 49.7%, 34.8%, and 29.8%, respectively (P < 0.001, log-rank). The graft survival rates at 3 months and 1, 3, and 5 years were 92.0%, 88.5%, 82.4%, and 78.0%, respectively, for the BC(-) group and 60.9%, 43.5%, 30.4%, and 26.1%, respectively, for the BC(+) group (P < 0.001, log-rank). BCs, a length of stay ≥ 12 days, and donor age were strongly associated with death and graft failure in a regression analysis, whereas retransplant indications other than chronic rejection and recurrent disease also affected graft failure. In conclusion, BCs significantly affected both patient and graft survival, with an increased risk of death and graft loss among BC(+) recipients. Early recognition, appropriate interventions, and preventative measures for BCs are critical in the clinical management of re-LT recipients.

Anatomic considerations in the surgical resection of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and is a common cause of cancer death worldwide. Treatment of HCC usually consists of combinations of locoregional therapy, surgical resection, orthotopic liver transplantation, and in advanced cases, systemic chemotherapy. The best rates of cure are achieved with surgical resection or orthotopic liver transplantation in well-selected patients. The success of surgical resection depends on the adequacy of the extent of resection, balanced with the need to preserve functional hepatic parenchyma. Nonanatomic resection for HCC has been proposed as a surgical technique to maximize residual liver mass, but has been shown by some to yield inferior oncologic outcomes compared with formal anatomic resection. This review discusses relevant surgical anatomy of the liver, classifications of hepatic resection, and the current literature regarding outcomes of anatomic and nonanatomic resection of the liver.

Safety and efficacy of preoperative right portal vein embolization in patients at risk for postoperative liver failure following major right hepatectomy.

BACKGROUND: Right portal vein embolization (RPVE) has been utilized with or without segment IV (RPVE + IV) prior to hepatectomy to induce hypertrophy and prevent liver insufficiency in patients with a predicted future liver remnant (FLR) of ≤30% or cirrhosis. METHODS: Records of patients who underwent RPVE during 2006-2010 were retrospectively reviewed. Patient demographics, operative outcomes and complications were analysed. Computed tomography-based volumetrics were performed to determine FLR volume and degree of hypertrophy. Patients were stratified by segment IV embolization. Short-term outcomes following RPVE and liver resection are reported. RESULTS: A total of 23 patients were identified. Ten patients underwent RPVE and 13 underwent RPVE + IV. The RPVE procedure resulted in a 38% increase in FLR volume. Liver volumes, hypertrophy rates and outcomes were similar in both groups. Rates of operative complications in the RPVE and RPVE + IV groups were similar at 50% and 54%, respectively, and most complications were minor. Complication rates as a result of embolization were 30% in the RPVE group and 31% in the RPVE + IV group. One patient underwent modified operative resection as a result of a complication of RPVE. CONCLUSIONS: Right portal vein embolization (±segment IV) is a safe and effective modality to increase FLR volume. Post-embolization complications and short-term outcomes after resection are acceptable and are similar in both RPVE and RPVE + IV.

The Changing Liver Transplant Recipient: From Hepatitis C to Nonalcoholic Steatohepatitis and Alcohol.

Hepatitis C virus has historically been the leading indication for liver transplant, followed by nonalcoholic steatohepatitis (NASH) and alcoholic liver disease. Severe alcoholic hepatitis has become a growing indication for liver transplant, and overall alcohol use rates continue to increase in the United States. Rates of obesity and NASH in the United States continue to increase and are expected to place increasing demand on liver transplant infrastructure. In the current absence of robust pharmacologic therapy for NASH, the use of bariatric procedures and surgeries is being explored, as are other innovative approaches to curtail this upward trend.

Neoadjuvant chemotherapy is associated with improved survival in patients undergoing hepatic resection for intrahepatic cholangiocarcinoma.

BACKGROUND: The impact of neoadjuvant chemotherapy (NAC) on overall and recurrence-free survival (OS, RFS) in resectable intrahepatic cholangiocarcinoma (ICC) is poorly characterized. We sought to investigate the association of NAC with oncologic outcomes in ICC. METHODS: We identified n = 52 patients with ICC undergoing hepatectomy from 2004 to 2017. Oncologic outcomes were analyzed using Kaplan-Meier and multivariate Cox proportional hazard modeling. RESULTS: The median patient age was 64-years. NAC was administered in ten (19%) patients, most commonly with gemcitabine-cisplatin (n = 8, 80%). Median RFS and OS were 15 months. and 49 months, respectively. Controlling for stage and margins, NAC was independently associated with improved OS (HR 0.16, P = 0.01) but not RFS (HR 0.54, P = 0.27). NAC was not associated with major post-operative complications (P = 0.25) or R1 margins (P = 0.58). CONCLUSION: NAC in ICC may hold oncologic benefits beyond downstaging borderline resectable disease, such as identifying patients with favorable biology who are more likely to benefit from resection.

Detection of Tumor Multifocality in Resectable Intrahepatic Cholangiocarcinoma: Defining the Optimal Pre-operative Imaging Modality.

BACKGROUND: Multiple tumor foci (MTF) in intrahepatic cholangiocarcinoma (ICC), including satellitosis and true multifocality, is a known negative prognostic factor and can inform pre-operative decision-making. Lack of standardized pre-operative liver staging practices may contribute to undiagnosed MTF and poor outcomes. We sought to investigate the sensitivity of different cross-sectional imaging modalities for MTF at our institution. METHODS: We identified n = 52 patients with ICC who underwent curative-intent resection from 2004 to 2017 in a multidisciplinary hepato-pancreato-biliary cancer program. Timing and modality of pre-operative imaging were recorded. Blinded review of imaging was performed and modalities were evaluated for false-negative rate (FNR) in detecting MTF, satellitosis, and true multifocality. RESULTS: Forty-one (79%) patients underwent CT and 20 (38%) underwent MRI prior to hepatectomy. MTF was pre-operatively identified in six (12%) patients. An additional seven patients had MTF discovered on final surgical pathology, despite a median interval from CT/MRI to surgery of 20 days. On blinded review the FNR of MRI compared to CT for multifocality was 0% vs. 38%, 50% vs 80% for satellitosis, and 22% vs 46% for MTF as a whole. CONCLUSION: CT is inadequate for pre-operative diagnosis of MTF in resectable ICC, even when performed within 30 days of hepatectomy. We recommend liver-protocol MRI as the standard pre-operative imaging modality in non-metastatic ICC.

Increased vascular endothelial growth factor transcription in residual hepatocellular carcinoma after open versus laparoscopic hepatectomy in a small animal model.

BACKGROUND: Vascular endothelial growth factor (VEGF) is overexpressed in hepatocellular carcinoma (HCC), and findings have shown that its upregulation in these tumors has an impact on tumor growth. The authors hypothesized that compared with open liver resection, laparoscopic hepatectomy would result in a decreased local angiogenic response in residual tumor cells. METHODS: Right- and left-lobe hepatomas were induced in Buffalo rats via laparoscopically guided subcapsular injection of Morris hepatoma cells. After 1 week, the animals were randomized to laparoscopic or open left lateral hepatectomy. In 14 days after resection, the rats were killed, the residual right lobe tumors were measured, and tissue was procured for RNA extraction. Transcript levels of VEGF messenger RNA (mRNA) were quantified with reverse transcriptase-polymerase chain reaction (RT-PCR), and VEGF serum levels were measured by enzyme-linked immunoassay (ELISA) both before resection and at the time of tissue harvest. RESULTS: None of the animals had development satellite liver lesions or distant metastases in the abdomen or thorax. The median residual tumor volume was 320 mm(3) in the open group compared with 180 mm(3) in the laparoscopic group (p = 0.164). The animals that underwent open resection had a 1.3-fold increase in VEGF mRNA transcript levels compared with the laparoscopic resection group (p = 0.008). The serum VEGF levels were not significantly different between the laparoscopic and open groups at baseline (open tumor resection [OR], 23.7 +/- 12.0 pg/ml; laparoscopic tumor resection [LR], 30.7 +/- 15.5 pg/ml; p = 0.334) nor at the time of tissue harvest (OR, 19.9 +/- 19.6 pg/ml; LR, 26.9 +/- 34.5 pg/ml; p = 0.549). CONCLUSIONS: Laparoscopic hepatic resection produces decreased VEGF mRNA expression in residual hepatoma cells compared with open resection. Decreased stimulation of angiogenesis promoters in the tumor microenvironment after minimally invasive liver resection may contribute to a lower residual disease burden and ultimately lead to a lower recurrence rate.

Correction to: Yttrium-90 Radioembolization for BCLC Stage C Hepatocellular Carcinoma Comparing Child-Pugh A Versus B7 Patients: Are the Outcomes Equivalent?

The name of one of the co-authors was slightly misspelled. Kristian Enestvedt is listed currently as "Kristian K. Enestvedt" and should be listed instead as "C. Kristian Enestvedt."

Perioperative outcomes of laparoscopic transhiatal inversion esophagectomy compare favorably with those of combined thoracoscopic-laparoscopic esophagectomy.

AIMS: Wide acceptance of laparoscopic esophagectomy has been hampered by the technical difficulty of the procedure and inconsistent improvements in morbidity and mortality. Most case series have utilized a combined thoracoscopic-laparoscopic approach (TLE), but laparoscopic inversion esophagectomy (LIE), a method of transhiatal esophagectomy, has been proposed as an alternative. Inversion esophagectomy simplifies retraction and improves exposure during the mediastinal dissection; however, no previous studies have directly compared LIE outcomes with those of the combined approach. METHODS: Between July 2003 and March 2008, 70 consecutive patients underwent minimally invasive esophagectomy by LIE (N = 40) or TLE (N = 30). Data for all patients were collected prospectively and stored in a relational database. Recorded outcome measures included operative time, blood loss, length of hospital stay, intensive care unit stay, and perioperative complications. RESULTS: There were no significant differences in patient age, gender, body mass index (BMI), or American Society of Anesthesiologists (ASA) class between the groups, but LIE patients had lower stage of esophageal cancer, and were less likely to have received induction chemoradiotherapy than TLE patients. Patients undergoing LIE had significantly lower operative time (398 vs. 537 min, p < 0.001), intraoperative blood loss (100 vs. 200 ml, p < 0.001), and overall length of stay (9 vs. 14 days, p = 0.003) compared with TLE patients. LIE yielded a median of 10 lymph nodes removed compared with 13 for TLE (p = 0.016). Atrial arrhythmia and postoperative pneumonia were less common in LIE patients than in TLE patients, occurring in 17.5% vs. 27.1% (p = 0.036), and in 7.5% vs. 15.7% of cases (p = 0.029), respectively. CONCLUSION: LIE provides safe and effective approach to minimally invasive esophagectomy for patients with early esophageal cancer and high-grade dysplasia. Compared with TLE, inversion esophagectomy requires less operative time and has lower operative blood loss and length of hospital stay. LIE may also result in fewer perioperative cardiac and pulmonary complications compared with TLE. Based on these results, we reserve TLE for more advanced esophageal cancer and those undergoing preoperative radiochemotherapy.

Hepatic resection of solitary HCC in the elderly: A unique disease in a growing population.

BACKGROUND: Management of elderly patients with solitary hepatocellular carcinoma (sHCC) is challenging with perceived clinicopathologic differences driving treatment options. We sought to determine factors predictive of disease control and survival after hepatic resection of sHCC in elderly patients. METHODS: We identified n = 45 elderly patients (³≥65 yo) with sHCC treated with hepatic resection alone from our prospective database from 2003-16. Clinicopathologic data were analyzed and survival was assessed from the time of hepatic resection. RESULTS: The median age was 75-years-old. Less than half of patients (47%) had viral hepatitis. At resection, the median Child-Pugh score was A6, median tumor size 5 cm, and mean AFP of 1050 (ng/mL). Major hepatectomy was performed in 23 patients (51%) with R0 resection achieved in 96%. Two patients (4%) had Grade III complications with no mortalities at 30 days and one death (2%) at 90-days. After R0 resection 44% (n = 20) had intrahepatic recurrence at a median of 32 months (95% CI: 15-46) with 20% (n = 9) developing extrahepatic recurrence at a median of 78 months (95% CI: 78-.). The median survival was 72 months (95% CI: 30-108 months). For patients with at least 3 years of follow-up, the 1-, 3-, and 5-year overall survival was 74%, 59%, and 50%, respectively. Mortality was associated with higher AFP and lower Prognostic Nutritional Index (PNI). CONCLUSION: Carefully selected elderly patients with sHCC appear to have unique disease that is amenable to hepatic resection with low morbidity and mortality with excellent overall and recurrence-free survival.

The evaluation of esophageal adenocarcinoma using dynamic contrast-enhanced magnetic resonance imaging.

Although neoadjuvant chemoradiation eradicates esophageal adenocarcinoma in a substantial proportion of patients, conventional imaging techniques cannot accurately detect this response. Dynamic contrast-enhanced magnetic resonance imaging is an emerging approach that may be well suited to fill this role. This pilot study evaluates the ability of this method to discriminate adenocarcinoma from normal esophageal tissue. Patients with esophageal adenocarcinoma and control subjects underwent scanning. Patients treated with neoadjuvant therapy underwent pre- and postchemoradiation scans. Parameters were extracted for each pixel were Ktrans (equilibrium rate for transfer of contrast reagent across the vascular wall), ve (volume fraction of interstitial space), and taui (mean intracellular water lifetime). Five esophageal adenocarcinoma patients and two tumor-free control subjects underwent scanning. The mean Ktrans value was 5.7 times greater in esophageal adenocarcinoma, and taui is 2.0 times smaller, than in the control subjects. Ktrans decreased by 11.4-fold after chemoradiation. Parametric maps qualitatively demonstrate a difference in Ktrans. DCE MRI of the esophagus is feasible. Ktrans, a parameter that has demonstrated discriminative ability in other malignancies, also shows promise in differentiating esophageal adenocarcinoma from benign tissue. The determination of Ktrans represents an in vivo assay for endothelial permeability and thus may serve as a quantitative measure of response to induction chemoradiation.