The Effect of New Acuity Circle Policy on Simultaneous Liver and Kidney Transplantation in the United States.

Background: New deceased donor liver allocation policy using an acuity circle (AC)-based model was implemented on February 4th, 2020. The effect of AC policy on simultaneous liver-kidney transplantation (SLKT) remains unknown. The aim of this study was to assess the effect of AC policy on SLKT waitlist mortality, transplant probability, and post-transplant outcomes. Methods: Using the United Network for Organ Sharing database, 4908 adult SLKT candidates during two study periods, pre-AC (Aug-2017 to Feb-2020, N = 2770) and post-AC (Feb-2020 to Dec-2021, N = 2138) were analyzed. Outcomes included 90-day waitlist mortality, transplant probability, and post-transplant patient and graft survival. Results: Compared to pre-AC period, SLKT recipients during post-AC period had higher median model for end-stage liver disease (MELD) score (24 vs 23, P < 0.001), and less percentage of MELD exception (4.6% vs 7.7%, P = 0.001). The 90-day waitlist mortality was same, but the probability of SLKT increased in post-AC period (P < 0.001). Post-AC period also saw increased utilization of donation after cardiac death organs (11% vs 6.4%, P < 0.001) and decreased rates of transplantation among Black candidates (7.9% vs 13%). After risk adjustment, post-AC period was not associated with any significant difference in 90-day waitlist mortality (sub-distribution hazard ratio [sHR] 0.80; 95% CI 0.56-1.16, P = 0.24), and a higher 90-day probability of SLKT (sHR 1.68; 95% CI 1.41-1.99, P < 0.001). During post-transplant period, one-year patient survival, liver and kidney graft survival were comparable between two study periods. Conclusions: The AC liver allocation policy was associated with increased transplant probability of adult SLKT candidates without decreasing waitlist mortality, post-transplant patient survival, or liver and kidney graft survival.

The effects of acuity circle policy on racial disparity in liver transplantation.

BACKGROUND: A new deceased donor liver allocation policy using an acuity circle-based model was implemented with the goal of providing equitable access to liver transplantation. We assessed the effect of the acuity circle policy on racial disparities in liver transplantation by analyzing waitlist mortality, transplant probability, and post-transplant outcomes. METHODS: We conducted a retrospective analysis of 23,717 adult liver transplantation candidates listed during the pre-acuity circle period and 21,051 during the post-acuity circle period (N = 44,768) in the United Network for Organ Sharing database from February 2020 to December 2021. RESULTS: Acuity circle-policy implementation was not associated with any significant difference in 90-day waitlist mortality but increased the 90-day probability of all candidates. Implementation did not decrease 90-day waitlist mortality but increased the 90-day transplant probability for all patients. One-year patient and liver graft survival were comparable between the study periods for all recipients, but Black recipients had higher rates of 1-year post-liver transplantation mortality and liver graft failure in both periods. CONCLUSION: Although the implementation of the acuity circle policy is associated with an increase in transplant probability in White, Black, and Hispanic liver transplantation candidates, it did not change their waitlist mortality, nor did it lead to any improvement in the preexistent worse post-transplant outcomes in Black liver transplantation recipients.

Inferior outcomes of liver transplantation for hepatocellular carcinoma during early-COVID-19 pandemic in the United States.

BACKGROUND: Early in the coronavirus disease 2019 (COVID-19) pandemic, there was a significant impact on routine medical care in the United States, including in fields of transplantation and oncology. AIM: To analyze the impact and outcomes of early COVID-19 pandemic on liver transplantation (LT) for hepatocellular carcinoma (HCC) in the United States. METHODS: WHO declared COVID-19 as a pandemic on March 11, 2020. We retrospectively analyzed data from the United Network for Organ Sharing (UNOS) database regarding adult LT with confirmed HCC on explant in 2019 and 2020. We defined pre-COVID period from March 11 to September 11, 2019, and early-COVID period as from March 11 to September 11, 2020. RESULTS: Overall, 23.5% fewer LT for HCC were performed during the COVID period (518 vs 675, P < 0.05). This decrease was most pronounced in the months of March-April 2020 with a rebound in numbers seen from May-July 2020. Among LT recipients for HCC, concurrent diagnosis of non-alcoholic steatohepatitis significantly increased (23 vs 16%) and alcoholic liver disease (ALD) significantly decreased (18 vs 22%) during the COVID period. Recipient age, gender, BMI, and MELD score were statistically similar between two groups, while waiting list time decreased during the COVID period (279 days vs 300 days, P = 0.041). Among pathological characteristics of HCC, vascular invasion was more prominent during COVID period (P < 0.01), while other features were the same. While the donor age and other characteristics remained same, the distance between donor and recipient hospitals was significantly increased (P < 0.01) and donor risk index was significantly higher (1.68 vs 1.59, P < 0.01) during COVID period. Among outcomes, 90-day overall and graft survival were the same, but 180-day overall and graft were significantly inferior during COVID period (94.7 vs 97.0%, P = 0.048). On multivariable Cox-hazard regression analysis, COVID period emerged as a significant risk factor of post-transplant mortality (Hazard ratio 1.85; 95%CI: 1.28-2.68, P = 0.001). CONCLUSION: During COVID period, there was a significant decrease in LTs performed for HCC. While early postoperative outcomes of LT for HCC were same, the overall and graft survival of LTs for HCC after 180 days were significantly inferior.

Outcomes of Liver Transplantation Using Machine Perfusion in Donation after Cardiac Death vs Brain Death in the US.

BACKGROUND: Liver transplant (LT) outcomes using machine perfusion (MP) in donation after brain death (DBD) is promising, but the LT outcomes of MP in donation after cardiac death (DCD) is limited in the US. The aim of this study was to compare LT outcomes of MP between DCD and DBD. STUDY DESIGN: We analyzed data from the United Network for Organ Sharing between 2016 and 2021 among adult LT recipients. Propensity score matching was performed to assess the outcomes between DCD and DBD. RESULTS: A total of 380 LTs (295 from DBD and 85 from DCD) were performed using MP. When compared with DBD, DCD group had older median recipient age (61 vs 58 years, p = 0.03), higher prevalence of diabetes (41% vs 28%, p = 0.02), lower model for end-stage liver disease score (17 vs 22, p < 0.01), longer wait time (276 vs 143 days, p < 0.01) and younger median donor age (40 vs 51 years, p < 0.01). The most common primary diagnosis was alcohol-related liver disease, and hepatocellular carcinoma was more common in the DCD group (22% vs 13%). On survival analysis, 1-year overall/graft survivals (DCD 95.4% vs DBD 92.1%, p = 0.54; DCD 91.7% vs DBD 89.8%, p = 0.86) were the same. After propensity score matching, overall/graft survivals were the same. In Cox regression analysis, DCD was not an independent risk factor of mortality (hazard ratio 0.80; 95% CI 0.25 to 2.52; p = 0.70) and graft failure (hazard ratio 0.58; 95% CI 0.17 to 1.97; p = 0.38). CONCLUSIONS: In transplant recipients who underwent LT using MP, posttransplant outcomes of overall and graft survival were similar among DCD and DBD cohorts.

Trends and outcomes of liver transplantation among older recipients in the United States.

BACKGROUND: The average age of recipients and donors of liver transplantation (LT) is increasing. Although there has been a change in the indications for LT over the years, data regarding the trends and outcomes of LT in the older population is limited. AIM: To assess the clinical characteristics, age-related trends, and outcomes of LT among the older population in the United States. METHODS: We analyzed data from the United Network for Organ Sharing database between 1987-2019. The sample was split into younger group (18-64 years old) and older group (≥ 65 years old). RESULTS: Between 1987-2019, 155758 LT were performed in the United States. During this period there was a rise in median age of the recipients and percentage of LT recipients who were older than 65 years increased (P < 0.05) with the highest incidence of LT among older population seen in 2019 (1920, 23%). Common primary etiologies of liver disease leading to LT in older patients when compared to the younger group, were non-alcoholic steatohepatitis (16.4% vs 5.9%), hepatocellular carcinoma (14.9% vs 6.9%), acute liver failure (2.5% vs 5.2%), hepatitis C cirrhosis (HCV) (19.2 % vs 25.6%) and acute alcoholic hepatitis (0.13% vs 0.35%). In older recipient group female sex and Asian race were higher, while model for end-stage liver disease (MELD) score and rates of preoperative mechanical ventilation were lower (P < 0.01). Median age of donor, female sex, body mass index (BMI), donor HCV positive status, and donor risk index (DRI) were significantly higher in older group (P < 0.01). In univariable analysis, there was no difference in post-transplant length of hospitalization, one-year, three-year and five-year graft survivals between the two groups. In multivariable Cox-Hazard regression analysis, older group had an increased risk of graft failure during the five-year post-transplant period (hazard ratio: 1.27, P < 0.001). Other risk factors for graft failure among recipients were male sex, African American race, re-transplantation, presence of diabetes, mechanical ventilation at the time of LT, higher MELD score, presence of portal vein thrombosis, HCV positive status, and higher DRI. CONCLUSION: While there is a higher risk of graft failure in older recipient population, age alone should not be a contraindication for LT. Careful selection of donors and recipients along with optimal management of risk factors during the postoperative period are necessary to maximize the transplant outcomes in this population.

Fatal acute respiratory distress syndrome caused by blastomycosis after recent orthotopic liver transplantation in a non-endemic area.

In blastomycosis, immunosuppression such as that following solid organ transplantation appears to be a risk factor for the development of overwhelming lung infection fulfilling criteria for the acute respiratory distress syndrome. Our transplant center, located outside traditional endemic areas for Blastomyces spp, experienced a case of fatal acute respiratory distress syndrome secondary to blastomycosis pneumonia in a recipient of recent orthotopic liver transplantation. The patient expired despite support with veno-venous extracorporeal membrane oxygenation.

Does utilization of heart machine perfusion for donation after cardiac death transplantation affect outcomes of other abdominal transplanted organs?

INTRODUCTION: Machine perfusion of heart for donation after circulatory death (DCD) is being increasingly utilized. Current protocols for utilizing heart DCD's machine perfusion might prolong donor warm ischemic time for nonheart organs. The aim of this study was to analyze the effects of utilizing heart machine perfusion on liver and kidney transplants from the same donor. METHODS: We analyzed data of DCD donors from the United Network for Organ Sharing (UNOS) from January-2020 to September-2021 among two groups: donors with heart machine perfusion (HM) and without heart machine perfusion (NHM). Propensity score (PS) matching was performed to compare the short-term outcomes of liver and kidney transplants between two groups. RESULTS: Total of 102 liver and 319 kidney transplants were performed using organs from donors with HM. After PS matching, no statistically significant difference was seen in 1-year graft survival (GS) for both liver and kidney transplants between two groups (liver HM 90.6% vs. NHM 90.2%, p = .47; kidney HM 95.2% vs. NHM 92.9%, p = .40). There was no difference in the delayed graft function (DGF) rates in kidney transplantation (KT) (HM 42% vs. NHM 35%, p = .062). CONCLUSION: Utilization of heart machine perfusion in DCD donors had no significant impact on 1-year outcomes of liver and kidney transplantation.

Hospital-Acquired Conditions after Liver Transplantation.

Hospital-acquired conditions (HACs) are used to define hospital performance measures. Patient comorbidity may influence HAC development. The National Inpatient Sample database was used to investigate HACs for the patients who underwent liver transplantation. Multivariate analysis was used to identify HAC risk factors. We found a total of 13,816 patients who underwent liver transplantation during 2002-2014. Of these, 330 (2.4%) had a report of HACs. Most frequent HACs were vascular catheter-associated infection [220 (1.6%)], falls and trauma [66 (0.5%), catheter-associated UTI [24 (0.2%)], and pressure ulcer stage III/IV [22 (0.2%)]. Factors correlating with HACs included extreme loss function (AOR: 52.13, P < 0.01) and major loss function (AOR: 8.11, P = 0.04), hepatopulmonary syndrome (AOR: 3.39, P = 0.02), portal hypertension (AOR: 1.49, P = 0.02), and hospitalization length of stay before transplant (AOR: 1.01, P < 0.01). The rate of HACs for liver transplantation is three times higher than the reported overall rate of HACs for GI procedures. Multiple patient factors are associated with HACs, and HACs may not be a reliable measure to evaluate hospital performance. Vascular catheter-associated infection is the most common HAC after liver transplantation.

Unplanned readmission after outpatient laparoscopic cholecystectomy.

BACKGROUND: Readmission after surgery has been considered as a measure of quality of hospital and surgical care. This study aims to investigate unplanned readmission after laparoscopic cholecystectomy. METHODS: The NSQIP database was used to investigate 30 days unplanned readmission after laparoscopic cholecystectomy. Multivariate analysis was used to identify predictors of readmission. RESULTS: We found a total of 117,248 patients who underwent outpatient laparoscopic cholecystectomy during 2014-2016. Of these 3315 (2.8%) had unplanned readmission. Overall, 90% of readmitted patients were discharged after one day of hospitalization. Pain (14.07%) followed by unspecified symptoms including fever, nausea, vomiting, ileus was the most common reason for readmission. After adjustment, factors such as renal failure on dialysis (AOR: 2.26, P < 0.01), discharge to a facility (AOR: 1.93, P < 0.01), and steroid use for chronic condition (AOR: 1.51, P < 0.01), were associated with unplanned readmission. CONCLUSION: Overall, 2.8% of the patients undergoing outpatient laparoscopic cholecystectomy are readmitted to the hospital. Most of such patients are discharged after one day of hospitalization. Unspecified symptoms such as pain and vomiting were the most common reasons for readmission. Readmission strongly influences patients' comorbid factors and it is not a reliable measurement of quality of hospital and surgical care.

Divergent antioxidant capacity of human islet cell subsets: A potential cause of beta-cell vulnerability in diabetes and islet transplantation.

BACKGROUND: Type 1 and Type 2 diabetes mellitus (T1DM and T2DM) are caused by beta(ß)-cell loss and functional impairment. Identification of mechanisms of ß-cell death and therapeutic interventions to enhance ß-cell survival are essential for prevention and treatment of diabetes. Oxidative stress is a common feature of both T1DM and T2DM; elevated biomarkers of oxidative stress are detected in blood, urine and tissues including pancreas of patients with DM. Islet transplantation is a promising treatment for diabetes. However, exposure to stress (chemical and mechanical) and ischemia-reperfusion during isolation and transplantation causes islet loss by generation of reactive oxygen species (ROS). Human intracellular antioxidant enzymes and related molecules are essential defenses against ROS. Antioxidant enzyme levels including superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX) have been shown to be low in islet cells. However, little is known about the expression and function of antioxidant enzymes within islet cell subsets. We evaluated the expression of the key antioxidant enzymes in ß- and alpha(α)-cell and accessed effects of oxidative stress, islet isolation and transplantation on ß/α-cell ratio and viability in human islets. METHODS: Human pancreata from T1DM, T2DM and non-diabetic deceased donors were obtained and analyzed by confocal microscopy. Isolated islets were (I) transplanted in the renal sub-capsular space of streptozotocin-induced diabetic nude mice (in vivo bioassay), or (II) exposed to oxidative (H2O2) and nitrosative (NO donor) stress for 24 hrs in vitro. The ratio, % viability and death of ß- and α-cells, and DNA damage (8OHdG) were measured. RESULTS AND CONCLUSIONS: Catalase and GPX expression was much lower in ß- than α-cells. The ß/α-cell ratio fells significantly following islet isolation and transplantation. Exposure to oxidative stress caused a significantly lower survival and viability, with higher DNA damage in ß- than α-cells. These findings identified the weakness of ß-cell antioxidant capacity as a main cause of vulnerability to oxidative stress. Potential strategies to enhance ß-cell antioxidant capacity might be effective in prevention/treatment of diabetes.

Metastatic neuroendocrine tumor of the esophagus with features of medullary thyroid carcinoma.

A 41-year-old female presented with a pedunculated mass in the upper esophagus and bilateral lymphadenopathy. Biopsies suggested a neuroendocrine tumor, possibly carcinoid, and ensuing imaging revealed cervical lymph node metastases. The esophageal mass was removed endoscopically and discovered by pathologists to closely resemble medullary thyroid carcinoma (MTC) on immunohistochemistry staining. Following surgery, further work up demonstrated very high serum calcitonin levels, suggestive of medullary thyroid carcinoma, however the thyroid gland was normal on ultrasound. The patient underwent a neck dissection to remove the lymph node metastases and subsequently her calcitonin levels dropped to 0 ng/mL, indicating remission. It appears that the primary tumor was not in the thyroid, but in the cervical esophagus. The thyroid has appeared normal on multiple ultrasounds without any detectable nodules or masses. This is quite a unique case because this patient presented with a tumor resembling medullary carcinoma of the thyroid that presented as a pedunculated mass in the cervical esophagus. The actual final diagnosis of this mass in the cervical esophagus was neuroendocrine tumor (NET), consistent with a carcinoid tumor, not ectopic MTC. This case report highlights that calcitonin-secreting tumors outside the thyroid should not lead to erroneous recommendations for thyroidectomy.

Case of Six-Year Disease-Free Survival with Undifferentiated Carcinoma of the Pancreas.

Undifferentiated carcinoma of the pancreas (UDC) is rare and has a dismal prognosis. Here, we report a case of 6-year disease-free survival with a mixed type of UDC and UDC with osteoclast-like giant cells, with a high mitotic index as well as perineural, lymphatic, vessel, and diaphragmatic invasion. The patient underwent radical distal pancreatectomy and was subsequently treated with adjuvant chemotherapy using gemcitabine plus S-1 followed by maintenance chemotherapy with oral tegafur-uracil. The patient has been doing well with no evidence of recurrence for more than 6 years after surgery.

Application of Digital Image Analysis to Determine Pancreatic Islet Mass and Purity in Clinical Islet Isolation and Transplantation.

Pancreatic islet mass, represented by islet equivalent (IEQ), is the most important parameter in decision making for clinical islet transplantation. To obtain IEQ, the sample of islets is routinely counted under a microscope and discarded thereafter. Islet purity, another parameter in islet processing, is routinely assessed by estimation only. In this study, we validated our digital image analysis (DIA) system by using the software of Image Pro Plus and a custom-designed Excel template to assess islet mass and purity to better comply with current good manufacturing practice (cGMP) standards. Human islet samples (60 collected from a single isolation and 24 collected from 12 isolations) were captured as calibrated digital images for the permanent record. Seven trained technicians participated in determination of IEQ and purity by the manual counting method (manual image counting, Manual I) and DIA. IEQ count showed statistically significant correlations between the Manual I and DIA in all sample comparisons (r > 0.819 and p < 0.0001). A statistically significant difference in IEQ between Manual I and DIA was not found in all sample groups (p > 0.05). In terms of purity determination, statistically significant differences between assessment and DIA measurement were found in high-purity 100-µl samples (p < 0.005) and low-purity 100-µl samples (p < 0.001) of the single isolation. In addition, islet particle number (IPN) and the IEQ/IPN ratio did not differ statistically between Manual I and DIA. In conclusion, the DIA used in this study is a reliable technique to determine IEQ and purity. Islet sample preserved as a digital image and results produced by DIA can be permanently stored for verification, technical training, and information exchange among islet centers. Therefore, DIA complies better with cGMP requirements than the manual counting method. We propose DIA as a quality control tool to supplement the established standard manual method for islet counting and purity estimation.

ß-Cell differentiation of human pancreatic duct-derived cells after in vitro expansion.

ß-Cell replacement therapy is a promising field of research that is currently evaluating new sources of cells for clinical use. Pancreatic epithelial cells are potent candidates for ß-cell engineering, but their large-scale expansion has not been evidenced yet. Here we describe the efficient expansion and ß-cell differentiation of purified human pancreatic duct cells (DCs). When cultured in endothelial growth-promoting media, purified CA19-9(+) cells proliferated extensively and achieved up to 22 population doublings over nine passages. While proliferating, human pancreatic duct-derived cells (HDDCs) downregulated most DC markers, but they retained low CK19 and SOX9 gene expression. HDDCs acquired mesenchymal features but differed from fibroblasts or pancreatic stromal cells. Coexpression of duct and mesenchymal markers suggested that HDDCs were derived from DCs via a partial epithelial-to-mesenchymal transition (EMT). This was supported by the blockade of HDDC appearance in CA19-9(+) cell cultures after incubation with the EMT inhibitor A83-01. After a differentiation protocol mimicking pancreatic development, HDDC populations contained about 2% of immature insulin-producing cells and showed glucose-unresponsive insulin secretion. Downregulation of the mesenchymal phenotype improved ß-cell gene expression profile of differentiated HDDCs without affecting insulin protein expression and secretion. We show that pancreatic ducts represent a new source for engineering large amounts of ß-like-cells with potential for treating diabetes.