Constance M. Mobley's research while affiliated with Weill Cornell Medical College and other places

11173 Background: Increasing liver transplantation (LT) utilization has resulted in more and more patients with a history of a non-hepatobiliary malignancy. Rather than deny such patients a lifesaving therapy the benefits must be weighed against risk of tumor recurrence and de novo malignancies (DNM) post-LT, especially with the immunosuppression required. While data has been presented on outcomes of pre transplant malignancies (PTM) in kidney and heart transplants, LT data is lacking. Our aim is to characterize rates of recurrence, DNM, and overall survival (OS) post-LT at a single, high volume American center. Methods: This retrospective study at Houston Methodist Hospital included patients who underwent LT with known history of PTM. Data was extracted from electronic health records, and descriptive statistics performed. Institutional IRB approval is obtained. Results: Between 01/1999- 12/2022, 1617 LTs were performed at our institute. We identified 261 LT recipients with 297 PTM, including 91 non- and 206 hepatobiliary cancers (See Table). Follow-up period ranged from 1 to 23 years. Post-LT malignancies were observed in 66 patients, 25% of the study population. Tumor recurrences accounted for 44 (17%) cases, and DNM were seen in 22 (8%). The DNMs included skin non-melanoma (n=8 cases), head & neck (3), PTLD (2), prostate (2), renal (1), lung (1), CRC (1), pancreatic (1), gynecologic (2), and poorly differentiated (1). The OS rate at 1-, 5-years (excluding those less than 5 years follow-up and unknown), and at time of last follow-up were 86.6%, 60-65% and 70%, respectively. Patients with post-LT malignancies had lower OS compared to those without (46% vs. 77.7%). Conclusions: To our knowledge, this study is the first to assess post-LT outcomes in patients with PTM. This study of LT recipients with PTM demonstrates post-LT malignancy rates of 25%, including 17% with recurrences and 8% with DNM. The latter is within the previously reported range of 3-14% DNM in the general post-LT population and dominated by skin cancers. Post-LT OS is excellent in these recipients and comparable to all LT patients. However, OS is lower in those with post-LT malignancies, implying a possible role for increased cancer surveillance. Limitations include retrospective design and potential chart bias. Future work in this cohort will focus on immunosuppression effects for this high-risk population. [Table: see text]

Background The COVID-19 pandemic has led to an increase in SARS-CoV-2–test positive potential organ donors. The benefits of life-saving liver transplantation (LT) must be balanced against the potential risk of donor-derived viral transmission. Although emerging evidence suggests that the use of COVID-19–positive donor organs may be safe, granular series thoroughly evaluating safety are still needed. Results of 29 consecutive LTs from COVID-19–positive donors at a single center are presented here. Methods A retrospective cohort study of LT recipients between April 2020 and December 2022 was conducted. Differences between recipients of COVID-19–positive (n = 29 total; 25 index, 4 redo) and COVID-19–negative (n = 472 total; 454 index, 18 redo) deceased donor liver grafts were compared. Results COVID-19–positive donors were significantly younger (P = 0.04) and had lower kidney donor profile indices (P = 0.04) than COVID-19–negative donors. Recipients of COVID-19–positive donor grafts were older (P = 0.04) but otherwise similar to recipients of negative donors. Donor SARS-CoV-2 infection status was not associated with a overall survival of recipients (hazard ratio, 1.11; 95% confidence interval, 0.24-5.04; P = 0.89). There were 3 deaths among recipients of liver grafts from COVID-19–positive donors. No death seemed virally mediated because there was no qualitative association with peri-LT antispike antibody titers, post-LT prophylaxis, or SARS-CoV-2 variants. Conclusions The utilization of liver grafts from COVID-19–positive donors was not associated with a decreased overall survival of recipients. There was no suggestion of viral transmission from donor to recipient. The results from this large single-center study suggest that COVID-19–positive donors may be used safely to expand the deceased donor pool.

Background Solid organ transplant (SOT) recipients are at risk of bloodstream infections (BSIs) with MDR organisms (MDROs). Objectives To describe the epidemiology of BSI in the year after several types of SOT, as well as the prevalence of MDRO infections in this population. Methods We conducted a single-centre, retrospective study of kidney, liver, heart, and multi-organ transplantation patients. We examined BSIs ≤1 year from SOT and classified MDRO phenotypes for Staphylococcus aureus, enterococci, Enterobacterales, Pseudomonas aeruginosa and Candida spp. We compared BSI characteristics between SOT types and determined risk factors for 90 day mortality. Results We included 2293 patients [1251 (54.6%) kidney, 663 (28.9%) liver, 219 (9.6%) heart and 160 (7.0%) multi-organ transplant]. Overall, 8.5% of patients developed a BSI. BSIs were most common after multi-organ (23.1%) and liver (11.3%) transplantation (P < 0.001). Among 196 patients with BSI, 323 unique isolates were recovered, 147 (45.5%) of which were MDROs. MDROs were most common after liver transplant (53.4%). The most frequent MDROs were VRE (69.8% of enterococci) and ESBL-producing and carbapenem-resistant Enterobacterales (29.2% and 27.2% of Enterobacterales, respectively). Mortality after BSI was 9.7%; VRE was independently associated with mortality (adjusted OR 6.0, 95% CI 1.7–21.3). Conclusions BSI incidence after SOT was 8.5%, with a high proportion of MDROs (45.5%), especially after liver transplantation. These data, in conjunction with local antimicrobial resistance patterns and prescribing practices, may help guide empirical antimicrobial selection and stewardship practices after SOT.

Background Liver retransplantation (reLT) has historically had inferior survival relative to primary liver transplant (LT). To improve outcomes after reLT, researchers have identified factors predicting overall (OS) and/or graft survival (GS) after reLT. This systematic review and random effects meta-analysis sought to summarize this literature to elucidate the strongest independent predictors of post-reLT. Methods A systematic review was conducted to identify manuscripts reporting factors affecting survival in multivariable Cox proportional hazards analyses. Papers with overlapping cohorts were excluded. Results All 25 included studies were retrospective, and 15 (60%) were single-center studies. Patients on pre-transplant ventilation (HR, 3.11; 95% CI, 1.56–6.20; p = 0.001) and with high serum creatinine (HR, 1.46; 95% CI, 1.15–1.87; p = 0.002) had the highest mortality risk after reLT. Recipient age, Model for End-Stage Liver Disease score, donor age, and cold ischemia time >12 h also conferred a significant risk of post-reLT death (all p < 0.05). Factors affecting GS included donor age and retransplant interval (the time between LT and reLT; both p < 0.05). OS is significantly higher when the retransplant interval is ≤7 days relative to 8–30 days ( p = 0.04). Conclusions The meta-analysis was complicated by papers utilizing non-standardized cut-off values to group variables, which made between-study comparisons difficult. However, it did identify 7 variables that significantly impact survival after reLT, which could stimulate future research into improving post-reLT outcomes.

Unlabelled: Combined liver-lung transplantation is an uncommon, although vital, procedure for patients with simultaneous end-stage lung and liver disease. The utility of lung-liver transplant has been questioned because of initial poor survival outcomes, particularly when compared with liver-alone transplant recipients. Methods: A single-center, retrospective review of the medical records of 19 adult lung-liver transplant recipients was conducted, comparing early recipients (2009-2014) with a recent cohort (2015-2021). Patients were also compared with the center's single lung or liver transplant recipients. Results: Recent lung-liver recipients were older (P = 0.004), had a higher body mass index (P = 0.03), and were less likely to have ascites (P = 0.02), reflecting changes in the etiologies of lung and liver disease. Liver cold ischemia time was longer in the modern cohort (P = 0.004), and patients had a longer posttransplant length of hospitalization (P = 0.048). Overall survival was not statistically different between the 2 eras studied (P = 0.61), although 1-y survival was higher in the more recent group (90.9% versus 62.5%). Overall survival after lung-liver transplant was equivalent to lung-alone recipients and was significantly lower than liver-alone recipients (5-y survival: 52%, 51%, and 75%, respectively). Lung-liver recipient mortality was primarily driven by deaths within 6 mo of transplant due to infection and sepsis. Graft failure was not significantly different (liver: P = 0.06; lung: P = 0.74). Conclusions: The severity of illness in lung-liver recipients combined with the infrequency of the procedure supports its continued use. However, particular attention should be paid to patient selection, immunosuppression, and prophylaxis against infection to ensure proper utilization of scarce donor organs.

Background: The need for liver retransplantation (reLT) has increased proportionally with greater numbers of liver transplants (LTs) performed, use of marginal donors, degree of recipient preoperative liver dysfunction, and longer survival after LT. However, outcomes following reLT have been historically regarded as poor. Methods: To evaluate reLT in modern recipients, we retrospectively examined our single-center experience. Analysis included 1268 patients undergoing single LT and 68 patients undergoing reLT from January 2008 to December 2021. Results: Pre-LT mechanical ventilation, body mass index at LT, donor-recipient ABO incompatibility, early acute rejection, and length of hospitalization were associated with increased risk of needing reLT following index transplant. Overall and graft survival outcomes in the reLT cohort were equivalent to those after single LT. Mortality after reLT was associated with Kidney Donor Profile Index, national organ sharing at reLT, and LT donor death by anoxia and blood urea nitrogen levels. Survival after reLT was independent of the interval between initial LT and reLT, intraoperative packed red blood cell use, cold ischemia time, and preoperative mechanical ventilation, all previously linked to worse outcomes. Conclusions: These data suggest that reLT is currently a safer option for patients with liver graft failure, with comparable outcomes to primary LT.

Cirrhosis-related immune dysfunction is well recognized and may contribute to early mortality following liver transplant (LT). The purpose of the present study was to identify pre-transplant biomarkers of immune dysfunction (i.e., immune frailty) that might accurately predict risk of early mortality following LT. Patient plasma was collected immediately prior to LT (T 0 ) and analyzed via Luminex (N=279). On multivariate analysis, HCV IgG, Fractalkine, and MMP3 were significant predictors of 1yr post-LT mortality and were utilized to comprise a novel Liver Immune Frailty Index (LIFI). The LIFI stratifies LT recipients into -low, -moderate, and –high risk tertiles. One-year mortality was 1.4% for LIFI-low, 12.7% for LIFI-moderate, and 58.3% for LIFI-high. Internal validation through bootstrap resampling with 2000 replicates demonstrated the final LIFI model predicts early post-LT mortality with C-statistic=0.84. This novel index may identify patients at risk for persistent severe immune dysfunction and early mortality following LT.

Current scoring systems accurately predict risk of pre-liver transplant (LT) mortality but fall short in estimation of post-LT survival. This study seeks to identify biomarkers of pre-LT immune dysfunction that predict mortality following LT. From 10/1/13-3/23/21, 279 cirrhotic patients underwent assessment of plasma biomarker (Luminex) and clinical variables immediately prior to LT (T 0 ). Cox-proportional hazards modeling identified HCV IgG, Fractalkine, and MMP3 as multivariate predictors of 1-year mortality, with covariate selection by clinical importance and LASSO methodology. These were utilized to comprise the novel Liver Immune Frailty Index (LIFI), which stratifies recipients into -low, -moderate, and –high risk tertiles. One-year mortality was 1.4%, 12.7%, and 58.3% for LIFI-low, -moderate, and -high, respectively. Internal validation through bootstrap resampling with 2000 replicates demonstrates LIFI predicts early post-LT mortality with C-statistic=0.84 and Brier score of 0.04. LIFI may identify patients at risk for persistent severe immune dysfunction and early mortality following LT.

Cirrhosis-related immune dysfunction is well recognized and may contribute to early mortality following liver transplant (LT). The purpose of the present study was to identify pre-transplant biomarkers of immune dysfunction (i.e., immune frailty) that might accurately predict risk of early mortality following LT. Patient plasma was collected immediately prior to LT (T 0 ) and analyzed via Luminex (N = 279). On multivariate analysis, HCV IgG, Fractalkine, and MMP3 were significant predictors of 1 year post-LT mortality and were utilized to comprise a novel Liver Immune Frailty Index (LIFI). The LIFI stratifies LT recipients into -low, -moderate, and –high risk tertiles. One year mortality was 1.5% for LIFI-low, 13.2% for LIFI-moderate, and 63.3% for LIFI-high. Internal validation through bootstrap resampling with 2000 replicates demonstrated the final LIFI model predicts early post-LT mortality with C-statistic = 0.84. This novel index may identify patients at risk for persistent severe immune dysfunction and early mortality following LT.