Taner, Timucin

Background & Aims: Liver transplantation (LT) remains the only cure for severe polycystic liver disease (PLD). However, LT indications and strategies vary across Europe, resulting in (unwanted) practice variation and unequal access to care for patients with PLD. This study aimed to (1) identify existing PLD-specific LT criteria across European countries, (2) assess which criteria are considered relevant by specialist, and (3) map the variation in liver-kidney transplant strategies among patients with autosomal dominant polycystic kidney disease (ADPKD). Methods: National PLD-specific LT criteria were collected, and if unavailable ERN RARE-Liver representatives from that country were asked to provide information. An online survey was conducted amongst hepatologists, LT surgeons, and nephrologists managing patients with PLD. The survey assessed relevant LT indications/listing requirements, clinical case evaluations, and explored preferences for liver-kidney transplantation in patients with ADPKD. Results: Defined LT criteria for patients with PLD were available in only 8 of the 17 assessed countries and showed substantial variation. Sixty-nine clinicians (43 hepatologists, 15 surgeons, 11 nephrologists), predominantly from LT centers (75.4%), completed the survey. Key LT indications were recurrent liver cyst infections (78.3%), significant impaired quality of life (75.4%), and severe malnutrition (75.4%). In ADPKD simultaneous liver-kidney transplantation (SLK) was preferred by 40.4% of respondents, primarily due the favorable immunological profile (47.6%) and prevention of renal failure (33.3%). In contrast, those favoring a liver-first approach (30.8%), followed by sequential kidney transplant, highlighted the potential harm to the kidney graft during SLK (62.5%). Conclusions: Uniform PLD-specific LT criteria in Europe are lacking. While recurrent liver cyst infections, decreased quality of life, and malnutrition are widely recognized as crucial LT indications, they are insufficiently reflected in existing criteria, contributing to unequal access to LT. Moreover, considerable variation exists in liver-kidney transplantation for ADPKD patients, with a current lack of evidence to support one approach over another.

Abstract Reconstructing gene expression atlases for human tissues is challenging due to limited access to healthy samples from live donors. Neurologically deceased donors often show ischemic changes, while tissues near diseased regions may have altered gene expression. The liver, with its unique regenerative capacity, allows analysis from live healthy donors (LHDs). Using spatial transcriptomics (Visum, Visium HD and MERFISH), we analyzed 16 liver samples: eight from young LHDs and eight from patients with liver pathology, sampling ‘adjacent normal’ tissue. LHD livers displayed significant gene expression differences from ‘adjacent normal’ tissues. Hepatocytes exhibited marked zonation along the porto-central axis of liver lobules, with key functions pericentrally shifted compared to other mammals. Our atlas identified dynamic programs in early steatotic hepatocytes, showing transitions from lipid uptake in low-lipid regions to insulin hypersensitivity in high-lipid regions. This study presents a spatial gene expression reference for the healthy human liver and insights into hepatocyte adaptations in steatosis.

Background The Scientific Registry for Transplant Recipients (SRTR) publishes outcomes of all transplant centres in the USA two times a year. The outcomes are publicly available and used by insurance payers and patients to assess the performance of a programme. Poor performance can result in temporary suspension or termination of a transplant programme. The estimated 1-year survival hazard ratio (EHR) is an important metric publicly reported by the SRTR. Problem The EHR at our institution was 1.13, indicating a graft loss rate that was 13% higher than the national average. Methods/INTERVENTION We defined an improvement in this metric as achieving an EHR of <1.0. Our balance measure was maintaining similar liver transplant volumes and avoiding limiting access to transplant. Using a causality tree, we identified there was no ‘real time’ assessment of programme risk or objective metric to assess this. An affinity diagram was used to determine high and intermediate risk factors for mortality and graft loss and, using a REDCap form (a web application used to manage our database) to track actual and potential complications, we calculated a weekly ‘risk metric’ that was introduced at multidisciplinary selection conference meetings. Results We remeasured our EHR at each interval release of the SRTR outcomes and found it to be 0.98 and 0.65 after implementing the ‘risk metric.’ During the intervention period, annual liver transplant volume remained above the baseline measure. Conclusion By implementing a ‘risk metric’ to prospectively assess the risk of a low EHR at transplant selection committee meetings, we were able to reduce the EHR well below the national average without limiting access to liver transplants.

ABSTRACT Background and Objectives Hepatic epithelioid hemangioendothelioma (HEHE) is an uncommon vascular neoplasm characterized by variable clinical behavior. Our aim was to describe the therapeutic approach for HEHE at diagnosis and define clinicopathological characteristics associated with tumor progression and long‐term survival. Methods This is a retrospective study that includes patients with HEHE who received treatment at Mayo Clinic Rochester between 1984 and 2023. Results Eighty patients were included in the study (median age: 44 years; 62.5% female), 24 underwent liver transplantation, 26 underwent liver resection, and 30 were managed medically. The 3‐year overall survival rates were 86.7%, 80.9%, and 51.1%, respectively. Notably, 26 patients had extrahepatic metastases at the time of diagnosis, four (16.7%) in the transplantation group, four (15.4%) in the resection group, and 18 (69.2%) in the nonsurgical group. On multivariable modeling, bone metastasis was independently associated with long‐term mortality (HR 6.3, p < 0.001) while lung metastasis and surgical intervention were not associated with long‐term mortality (HR 0.8, p = 0.8; HR 1.1, p = 0.9, respectively). Conclusion Bone metastasis emerged as a strong predictor of poor survival. Hence, aggressive surgical intervention may not be advantageous in patients with skeletal metastases but can still be offered for those with other extrahepatic metastases.

Mesenchymal stem/stromal cells (MSCs) facilitate repair in experimental diabetic kidney disease (DKD). However, the hyperglycemic and uremic milieu may diminish regenerative capacity of patient-derived therapy. We hypothesized that DKD reduces human MSC paracrine function. Adipose-derived MSC from 38 participants with DKD and 16 control subjects were assessed for cell surface markers, trilineage differentiation, RNA sequencing (RNA-seq), in vitro function (coculture or conditioned medium experiments with T cells and human kidney cells [HK-2]), secretome profile, and cellular senescence abundance. The direction of association between MSC function and patient characteristics were also tested. RNA-seq analysis identified 353 differentially expressed genes and downregulation of several immunomodulatory genes/pathways in DKD-MSC versus Control-MSC. DKD-MSC phenotype, differentiation, and tube formation capacity were preserved, but migration was reduced. DKD-MSC with and without interferon-γ priming inhibited T-cell proliferation greater than Control-MSC. DKD-MSC medium contained higher levels of anti-inflammatory cytokines (indoleamine 2,3-deoxygenase 1 and prostaglandin-E2) and prorepair factors (hepatocyte growth factor and stromal cell–derived factor 1) but lower IL-6 versus control-MSC medium. DKD-MSC medium protected high glucose plus transforming growth factor-β–exposed HK-2 cells by reducing apoptotic, fibrotic, and inflammatory marker expression. Few DKD-MSC functions were affected by patient characteristics, including age, sex, BMI, hemoglobin A1c, kidney function, and urine albumin excretion. However, senescence-associated β-galactosidase activity was lower in DKD-MSC from participants on metformin therapy. Therefore, while DKD altered the transcriptome and migratory function of culture-expanded MSCs, DKD-MSC functionality, trophic factor secretion, and immunomodulatory activities contributing to repair remained intact. These observations support testing of patient-derived MSC therapy and may inform preconditioning regimens in DKD clinical trials.

Metabolic syndrome (MetS) profoundly changes the contents of mesenchymal stem cells and mesenchymal stem cells–derived extracellular vesicles (EVs). The anti-inflammatory TGF-β (transforming growth factor-β) is selectively enriched in EVs from Lean but not from MetS pigs, but the functional impact of this endowment remains unknown. We hypothesized that Lean-EVs more effectively induce regulatory T cells in injured kidneys. Five groups of pigs (n=7 each) were studied after 16 weeks of diet-induced MetS and unilateral renal artery stenosis (RAS; MetS+RAS). Two groups of MetS+RAS were treated 4 weeks earlier with an intrarenal injection of either Lean-EVs or MetS-EVs. MetS+RAS had lower renal volume, renal blood flow, and glomerular filtration rate than MetS pigs. Compared with Lean-EVs, MetS-EVs were less effective in improving renal function and decreasing tubular injury and fibrosis in MetS+RAS. Lean-EVs upregulated TGF-β expression in stenotic kidney and increased regulatory T cells numbers more prominently. Furthermore, markedly upregulated anti-inflammatory M2 macrophages reduced proinflammatory M1 macrophages, and CD8 + T cells were detected in stenotic kidneys treated with Lean-EVs compared with MetS-EVs, and renal vein levels of interleukin-1β were reduced. In vitro, coculture of Lean-EVs with activated T cells led to greater TGF-β-dependent regulatory T cells induction than did MetS-EVs. Therefore, the beneficial effects of mesenchymal stem cells–derived EVs on injured kidneys might be partly mediated by their content of TGF-β signaling components, which permitting increased Treg preponderance. Modulating EV cargo and transforming their functionality might be useful for renal repair.

Background. Anesthetic management of orthotopic liver transplantation (OLT) can be challenging. Management involves responding to sudden hemodynamic shifts, addressing instability, and performing ongoing volume assessment. To best prepare for these perturbations, various monitors are used intraoperatively. We sought to explore the impact of transesophageal echocardiography (TEE) and pulmonary artery catheter (PAC) use on outcomes of patients undergoing OLT. Methods. We retrospectively reviewed records of patients who underwent OLT at a single institution and included all who were monitored intraoperatively with TEE alone, PAC alone, or both methods concurrently (TEE + PAC). We determined whether these groups had differences in length of hospitalization (primary outcome), 30-day mortality rate, and other outcomes. Results. Three hundred eighteen liver transplant operations were included in the study. Patients in the TEE + PAC group had the shortest median length of hospitalization (TEE + PAC, 8.6 days; TEE, 10.3; PAC, 9.1; P = 0.04). The TEE + PAC group also had the lowest 30-day mortality rate (TEE + PAC, n = 1 [1.3%]; TEE, n = 5 [12.8%]; PAC, n = 7 [3.5%]; P = 0.009). However, the TEE + PAC group also had the highest rate of a new postoperative need for dialysis (TEE + PAC, n = 8 [10.3%]; TEE, n = 2 [5.1%]; PAC, n = 1 [0.5%]; P < 0.001). Conclusions. Compared with either TEE alone or PAC alone, intraoperative monitoring with TEE + PAC during OLT was associated with the shortest length of hospitalization and lowest 30-day mortality rate. Transplant anesthesiologists should be aware of the potential benefit on patient mortality and hospital length of stay with concurrent intraoperative TEE + PAC monitoring and the increased need for new postoperative dialysis.

Abstract Abstract 2692 Background: Massive splenomegaly is occasionally encountered in patients with Non-Hodgkin's Lymphoma (NHL) and can be associated with abdominal symptoms, anemia and thrombocytopenia. The spleen may also be a primary focus of the disease itself. Splenectomy offers the benefit of localized treatment of the disease as well as relief of symptoms from splenomegaly and associated cytopenias. The safety and long term clinical outcomes of splenectomy for massive splenomegaly (>1500 gm) in patients with various histologies of NHL was analyzed. Methods: Data was obtained from clinical records of 90 patients with a diagnosis of NHL who underwent a splenectomy at Mayo Clinic Rochester from January 1998 to December 2007. Demographics, previous treatments, histology, post- surgical complications were collected and analyzed for the entire cohort. Additionally, median overall survival, improvement in symptoms, anemia and thrombocytopenia were analyzed by NHL type. Results: Median age at splenectomy was 67 years (range 42–84 yrs.) and 56 (62%) of patients were male. Average time from diagnosis to splenectomy was 3 months (range 0–217 months). Splenectomy was the first treatment in 56 (62%) patients; the other 34 patients were treated with chemotherapy with an average of two previous regimens. Most patients had involvement outside of the spleen, 65 (72%) with concurrent bone marrow involvement and 35 (50%) with lymph node involvement. Various different NHL histologies were represented: marginal zone (MZ) (34%), mantle cell (MC) (26%), diffuse large B-cell lymphoma (DLBCL) (10%), follicular (FL) (11%), lymphoplasmacytic (LP) (6%) and T cell NOS (4%). With a median follow-up time of 25 months, the median overall survival differed by histology type of NHL (Table 1). Indolent lymphomas such as FL, LP and MZ had more favorable survival compared with more aggressive lymphomas such as DLBCL and T cell NOS. Splenectomy was safe and well tolerated with only one treatment related death. There were no reported post-splenectomy septic events. Two patients did develop a portal vein thrombosis. 95% of patients had relief in pressure and abdominal symptoms post-splenectomy. With the exception of patients with DLBCL and T-cell NHL, a majority of patients had improvement in anemia and thrombocytopenia related to splenomegaly (Table 2). Conclusions: This represents the largest reported series of patients with lymphoma treated with splenectomy. Our results indicate that median overall survival after splenectomy is determined by the underlying type of NHL. Patients with LP, FL, MZ and MCL have a favorable outcomes following splenectomy. Splenectomy remains a safe and effective treatment option for massive splenomegaly in selected patients during the course of their disease management. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 2848 Background: Massive splenomegaly (MS) (>1500 grams) is a rare and overtly symptomatic manifestation of myelofibrosis. While splenectomy may provide palliation, the procedure may be technically difficult and lead to high operative risks. We retrospectively analyzed myelofibrosis patients who underwent splenectomy for MS to analyze complications and outcomes. Methods: Retrospective chart review of all patients with myelofibrosis at our institution who underwent splenectomy for MS between 1998 and 2006 was performed. MS was defined as post-operative spleen weight measured to be more than 1500 grams. A total of 63 patients with MS had splenectomy for palliation of pressure symptoms or transfusion requiring cytopenias during that time period. Kaplan Meier statistics and log rank test were used for survival analysis. Results: Mean age of the study patients was 64.9 ± 9.5 years and 56% of those were males. Commonest pre-splenectomy symptoms were left upper quadrant abdominal discomfort (85.7%), fatigue (81%), early satiety (76.2%), anorexia (54%) and weight loss (39.7%). Packed red blood cell and platelet transfusions were required pre-operatively in 36/63 (57.1%) and 10/63 (15.9%) of patients, respectively. Median spleen weight was 2805 (range 1540 – 13085) grams. Perioperative complications occurred in 15 patients (23.8%) including infection (= 4 patients [6.3 %]), thrombosis (= 6 patients [9.5%]), or bleeding (= 9 patients [14.3%]), 2 of which (3.2% of all patients) were fatal. Median post-splenectomy survival (PSS) of these patients was 16.4 (0–110) months and 5 year PSS was 20%. Excluding patients lost to follow up, 43/55 (78.2%), 33/55 (60%) and 26/54 (48.1%) patients were alive at 6 months, 1 year and 2 years after splenectomy, respectively. At 1 year, out of 33 alive patients, 24 (72.7%) patients had relief of pressure symptoms. Out of 36 patients who were red cell transfusion dependent pre-splenectomy, 13 were alive and 6/13 (46.2%) patients were transfusion independent at 1 year. Similarly, out for 10 patients requiring platelet transfusions pre-operatively, 5 were alive and 3/5 (60%) were transfusion independent after 1 year follow up. PSS after splenectomy for MS was decreased in patients that required pre-operative packed red cell transfusions (median 9.3 months vs. 32.1 months, p= 0.033) (Fig 1), but not affected by other factors including age (>64 years), pre-operative thrombocytopenia (<100 × 109/uL), prolonged operative time (>90 minutes) or larger spleen size (>2800 grams). Conclusions: Splenectomy is relatively safe and effective palliative treatment for pressure related symptoms and refractory cytopenias related to MS in patients with myelofibrosis. Pre-operative anemia requiring red cell transfusions may predict advanced disease and is associated with inferior PSS. Disclosures: No relevant conflicts of interest to declare.