Cross-fellowship Inter-institutional Exchange: Answering the Call for Hepatopancreatobiliary Training Standardization.

OBJECTIVE: General surgery trainees interested in performing hepatopancreatobiliary (HPB) surgery can choose from multiple fellowship pathways, namely HPB, surgical oncology (SO), and abdominal transplant-HPB (TXP-HPB). Although focused on similar operations, each program offers distinct clinical and technical emphases. DESIGN: An annual inter-institutional exchange between TXP-HPB and SO fellowships, starting in 2014. SETTING AND PARTICIPANTS: TXP-HPB fellows from Washington University in St. Louis (WUSTL) and SO fellows from Memorial Sloan Kettering Cancer Center (MSKCC). RESULTS: About 14 fellows have participated in the exchange so far, 13 of whom responded to our survey. At MSKCC, TXP-HPB fellows performed a median of 24 cases, including 6 major pancreatic resections, 3 major hepatectomies, 4 hepatic artery infusion pump insertions, and 1 major biliary case. At WUSTL, SO fellows performed a median of 16 cases, including 5 liver transplants, 2 major pancreatic resections, 2 major hepatectomies, and 2 major biliary cases. About 92.3% of respondents stated they would repeat the rotation, with SO fellows emphasizing the exposure to vascular anastomoses and transplant-HPB fellows appreciating the oncologic focus. CONCLUSIONS: A monthlong inter-institutional exchange offers a unique opportunity to standardize and improve HPB education.

Liver Transplant Costs and Activity After United Network for Organ Sharing Allocation Policy Changes.

Importance: A new liver allocation policy was implemented by United Network for Organ Sharing (UNOS) in February 2020 with the stated intent of improving access to liver transplant (LT). There are growing concerns nationally regarding the implications this new system may have on LT costs, as well as access to a chance for LT, which have not been captured at a multicenter level. Objective: To characterize LT volume and cost changes across the US and within specific center groups and demographics after the policy implementation. Design, Setting, and Participants: This cross-sectional study collected and reviewed LT volume from multiple centers across the US and cost data with attention to 8 specific center demographics. Two separate 12-month eras were compared, before and after the new UNOS allocation policy: March 4, 2019, to March 4, 2020, and March 5, 2020, to March 5, 2021. Data analysis was performed from May to December 2022. Main Outcomes and Measures: Center volume, changes in cost. Results: A total of 22 of 68 centers responded comparing 1948 LTs before the policy change and 1837 LTs postpolicy, resulting in a 6% volume decrease. Transplants using local donations after brain death decreased 54% (P < .001) while imported donations after brain death increased 133% (P = .003). Imported fly-outs and dry runs increased 163% (median, 19; range, 1-75, vs 50, range, 2-91; P = .009) and 33% (median, 3; range, 0-16, vs 7, range, 0-24; P = .02). Overall hospital costs increased 10.9% to a total of $46 360 176 (P = .94) for participating centers. There was a 77% fly-out cost increase postpolicy ($10 600 234; P = .03). On subanalysis, centers with decreased LT volume postpolicy observed higher overall hospital costs ($41 720 365; P = .048), and specifically, a 122% cost increase for liver imports ($6 508 480; P = .002). Transplant centers from low-income states showed a significant increase in hospital (12%) and import (94%) costs. Centers serving populations with larger proportions of racial and ethnic minority candidates and specifically Black candidates significantly increased costs by more than 90% for imported livers, fly-outs, and dry runs despite lower LT volume. Similarly, costs increased significantly (>100%) for fly-outs and dry runs in centers from worse-performing health systems. Conclusions and Relevance: Based on this large multicenter effort and contrary to current assumptions, the new liver distribution system appears to place a disproportionate burden on populations of the current LT community who already experience disparities in health care. The continuous allocation policies being promoted by UNOS could make the situation even worse.

Quantifying the association of sperm DNA fragmentation with assisted reproductive technology outcomes: An umbrella review.

BACKGROUND: Systematic reviews and meta-analyses are instrumental in shaping clinical practice. However, their findings can sometimes be marred by discrepancies and potential biases, thereby diluting the strength of the evidence presented. Umbrella reviews serve to comprehensively assess and synthesise these reviews, offering a clearer insight into the quality of the evidence presented. In the context of the relationship between sperm DNA fragmentation (SDF) and assisted conception outcomes, there is a divergence in the literature. Some reviews suggest a clear cause-and-effect linkage, whereas others present conflicting or inconclusive results. OBJECTIVES: In this umbrella review we aimed to synthesise the evidence collated in systematic reviews and meta-analyses summarising the association of SDF with assisted reproductive technology (ART) outcomes. SEARCH STRATEGY: After preregistration (https://doi.org/10.17605/OSF.IO/6JHDP), we performed a comprehensive search of the PubMed, Scopus, Cochrane Library, Web of Science and Embase databases. We conducted a search for systematic reviews on the association between SDF and ART without any restrictions on language or publication date. SELECTION CRITERIA: Systematic reviews and meta-analyses assessing the association between SDF and ART outcomes were eligible. DATA COLLECTION AND ANALYSIS: We assessed the quality of the included reviews using AMSTAR 2 and ROBIS, and determined the degree of overlap of primary studies between reviews estimating the corrected covered area (CCA), adjusted for structural missingness. We evaluated the most recent reviews assessing the association of SDF with live birth, pregnancy, miscarriage, implantation, blastulation and fertilisation. The synthesis of evidence was harmonised across all included quantitative syntheses, re-estimating the odds ratio (eOR) in random-effects meta-analyses with 95% confidence intervals (95% CIs) and 95% prediction intervals (95% PIs). We categorised the evidence strength into convincing, highly suggestive, suggestive, weak or nonsignificant, according to the meta-analysis re-estimated P-value, total sample size, I2 statistic for heterogeneity, small study effect, excess significance bias and the largest study significance. MAIN RESULTS: We initially captured and screened 49 332 records. After excluding duplicate and ineligible articles, 22 systematic reviews, 15 of which were meta-analyses, were selected. The 22 reviews showed a moderate degree of overlap (adjusted CCA 9.2%) in their included studies (overall n = 428, with 180 unique studies). The 15 meta-analyses exhibited a high degree of overlap (adjusted CCA = 13.6%) in their included studies (overall n = 274, with 118 unique studies). AMSTAR 2 categorised the quality of evidence in 18 reviews as critically low and the quality of evidence in four reviews as low. ROBIS categorised all the reviews as having a high risk of bias. The re-estimated results showed that the association of SDF with live birth was weak in one and nonsignificant in four meta-analyses. Similarly, the association of SDF with pregnancy, miscarriage, implantation, blastulation and fertilisation was also weak or nonsignificant. The association of high SDF with different ART outcomes was also weak or nonsignificant for different interventions (IVF, ICSI and IUI) and tests. CONCLUSIONS: This umbrella review did not find convincing or suggestive evidence linking SDF with ART outcomes. Caution should be exercised in making any claims, policies or recommendations concerning SDF.

Liver Transplantation After Hepatic Artery Infusion Pump Therapy: Single-Center Experience and Technical Considerations.

BACKGROUND: Hepatic artery infusion pump (HAIP) therapy has become increasingly commonplace in the treatment of intrahepatic tumors. When combined with standard chemotherapy, HAIP therapy demonstrates a higher response rate than chemotherapy alone. Biliary sclerosis is observed in up to 22 % of patients, for whom no treatment has been standardized. This report describes orthotopic liver transplantation (OLT) both as a treatment for HAIP-induced cholangiopathy and as a possible definitive oncologic treatment after HAIP-bridging therapy. METHODS: A retrospective study reviewed patients who had undergone HAIP placement followed by OLT at the authors' institution. Patient demographics, neoadjuvant treatment, and postoperative outcomes were reviewed. RESULTS: Seven OLTs were performed for patients with prior HAIP placement. The majority were women (n = 6), and the median age was 61 years (range, 44.5-65.5 years). Transplantation was performed for five patients due to biliary complications secondary to HAIP and two patients because of residual tumor after HAIP therapy. All the OLTs had difficult dissections due to adhesions. Because of HAIP-induced damage, atypical arterial anastomoses were required in six patients (2 patients used a recipient common hepatic artery below the gastroduodenal artery takeoff; 2 patients used recipient splenic arterial inflow; 1 patient used the junction of the celiac and splenic arteries; and 1 patient used the celiac cuff). The one patient with standard arterial reconstruction experienced an arterial thrombosis. The graft was salvaged with thrombolysis. Biliary reconstruction was duct-to-duct in five cases and Roux-en-Y in two cases. CONCLUSIONS: The OLT procedure is a feasible treatment option for end-stage liver disease after HAIP therapy. Technical considerations include a more challenging dissection and an atypical arterial anastomosis.

An insight into synthesis and antitumor activity of citrate and gallate stabilizing gold nanospheres.

Both gallic and citrate are well-established antioxidants that show promise as new selective anti-cancer drugs. Gold nanoparticles (AuNPs) as well can be developed as flexible and nontoxic nano-carriers for anti-cancer drugs. This article evaluating the efficiency and biocompatibility of gallic acid and citrate capping gold nanoparticles to be used as anti-cancer drug. The biosafety and therapeutic efficiency of prepared nano-formulations were tested on Hela and normal BHK cell line. Gold nanospheres coated with citrate and gallate were synthesized via wet chemical reduction method. The prepared nano-formulations, citrate and gallate coated gold nanospheres (Cit-AuNPs and Ga-AuNPs), were characterized with respect to their morphology, FTIR spectra, and physical properties. In addition, to assess their cytotoxicity, cell cycle arrest and flow cytometry to measure biological response were performed. Cit-Au NPs and Ga-Au NPs were shown to significantly reduce the viability of Hela cancer cells. Both G0/G cell cycle arrest and comet assay results showed that genotoxic effect was induced in Hela cells by Cit-Au NPs and Ga-Au NPs. The results of this study showed that Cit-Au NPs and Ga-AuNPs inhibit the growth of metastatic cervical cancer cells, which could have therapeutic implications.

Patient Understanding of Chemotherapy and Goals of Care as Provided by Different Care Team Members.

Chemotherapy can be challenging and overwhelming for patients, but when patients are knowledgeable about chemotherapy, their comfort level, overall satisfaction, and coping improve. It is currently unknown whether patients prefer information about chemotherapy to be provided by specific care team members and whether demographic characteristics affect learning preferences. We developed a 31-question questionnaire that asked patients when chemotherapy information was discussed and who they wanted that information to come from. The questionnaire was given to 50 patients who had completed 1 cycle of chemotherapy. Patients were evenly distributed among age categories of 45 to 64 years, 65 to 74 years, and 75 years or older. Thirty participants (60%) were women, 33 (66%) had high school degrees, and 23 (46%) were receiving their first chemotherapy regimen. Sixty percent of patients best understood goals of care from oncologists, 70% wanted goals of care to come from oncologists, and 61% best understood and wanted to understand logistics of chemotherapy from oncologists. Sixty-six percent of patients understood adverse effects when they were explained by nursing staff, and 56% wanted explanations of adverse effects to come from nursing staff. Patients did not prefer a specific care team member or information source when receiving financial cost information. Patients often preferred to receive chemotherapy information from their oncologist; however, other members of the care team also provided information to patients in a way that was understood.

Genetic profiling of different phenotypic subsets of breast cancer stem cells (BCSCs) in breast cancer patients.

BACKGROUND: Breast cancer stem cells (BCSCs) have a crucial role in breast carcinogenesis, development, and progression. The aim of the current study is to characterize the BCSCs through the genetic profiling of different BCSCs phenotypic subsets to determine their related genetic pathways. METHODS: Fresh tumor tissue samples were obtained from 31 breast cancer (BC) patients for (1) Mammosphere culture. (2) Magnetic separation of the BCSCs subsets using CD24, CD44, and CD326 Microbeads. (3) Flow cytometry (FCM) assay using CD44, CD24, and EpCAM. (4) RT-PCR profiler Arrays using stem cell (SC) panel of 84 genes for four group of cells (1) CD44+/CD24-/EpCAM- BCSCs, (2) CD44+/CD24- /EpCAM+ BCSCs, (3) mammospheres, and (4) normal breast tissues. RESULTS: The BCSCs (CD44+/CD24-/EpCAM-) showed significant downregulation in 13 genes and upregulation in 15, where the CD44, GJB1 and GDF3 showed the maximal expression (P = 0.001, P = 0.003 and P = 0.007); respectively). The CD44+/CD24-/EpCAM+ BCSCs showed significant upregulation in 28 genes, where the CD44, GDF3, and GJB1 showed maximal expression (P < 0.001, P = 0.001 and P = 0.003; respectively). The mammospheres showed significant downregulation in 9 genes and a significant upregulation in 35 genes. The maximal overexpression was observed in GJB1 and FGF2 (P = 0.001, P = 0.001; respectively). The genes which achieved significant overexpression in all SC subsets were CD44, COL9A1, FGF1, FGF2, GDF3, GJA1, GJB1, GJB2, HSPA9, and KRT15. While significant downregulation in BMP2, BMP3, EP300, and KAT8. The genes which were differentially expressed by the mammospheres compared to the other BCSC subsets were CCND2, FGF3, CD4, WNT1, KAT2A, NUMB, ACAN, COL2A1, TUBB3, ASCL2, FOXA2, ISL1, DTX1, and DVL1. CONCLUSION: BCSCs have specific molecular profiles that differ according to their phenotypes which could affect patients' prognosis and outcome.

Long non-coding RNAs as novel prognostic biomarkers for breast cancer in Egyptian women.

Breast cancer (BC), the most common type of malignant tumor, is the leading cause of death, having the highest incidence rate among women. The lack of early diagnostic tools is one of the clinical obstacles for BC treatment. The current study was designed to evaluate a panel of long non-coding RNAs (lncRNAs) BC040587, HOTAIR, MALAT1, CCAT1, CCAT2, PVT1, UCA1, SPRY4-IT1, PANDAR, and AK058003-and two mRNAs (SNCG, BDNF) as novel prognostic biomarkers for BC. This study was ethically approved by the Institutional Review Board of the National Cancer Institute, Cairo University. Our study included 75 women recently diagnosed with BC and 25 healthy women as normal controls. Patients were divided into three groups: 24 with benign breast diseases, 28 with metastatic breast cancer (MBC, stage IV), and 23 with non-metastatic breast cancer (NMBC, stage III). LncRNA and mRNA expression levels were measured in patient plasma using quantitative real-time PCR. We found that 10 lncRNAs (BCO40587, HOTAIR, PVT1, CCAT2, PANDAR, CCAT1, UCA1, SPRY4-IT1, AK058003, and MALAT1) and both mRNAs demonstrated at least a 2-fold change in expression with a more than 95% probability of significance. BCO40587 and SNCG were significantly up-regulated in MBC and NMBC patients (3.2- and 4-fold, respectively) compared with normal controls. The expression of UCA1 was repressed by 1.78-fold in MBC and NMBC patients compared with those with benign diseases. SPRY4-IT1 was down-regulated by 1.45-fold in MBC patients compared with NMBC and benign disease patients. Up-regulation of lncRNAs plays an important role in BC development. SNCG and BCO40587 may be potential prognostic markers for BC.The organization number is IORG0003381 (IRB No: IRB00004025).

Her2/EGFR-PDGFR pathway aberrations associated with tamoxifen response in metastatic breast cancer patients.

BACKGROUND: Metastatic breast cancer (MBC) is a major health problem worldwide. Some patients improve on tamoxifen and others do not respond to treatment. Therefore, the aim of the current study is to assess genetic aberrations in the Her2/EGFR-PDGFR pathway associated with tamoxifen response in MBC patients. METHODS: This is a retrospective cohort study, including 157 hormone receptors positive, locally recurrent inoperable and/or MBC patients on tamoxifen treatment. Patients were categorized into 78 (49.7%) tamoxifen responders and 79 (50.3%) tamoxifen non-responder patients. Genetic aberrations of 84 genes involved in the Her2/EGFR-PDGFR pathway were assessed in the tumor tissue samples obtained from the patients using SA-Bioscience assay. The identified panel was correlated to patients' response to treatment, to detect the differentially expressed genes in tamoxifen responders and non-responders. RESULTS: One hundred twenty-three (78.3%) patients were estrogen receptor (ER) and progesterone receptor (PR) positive, 108 (68.8%) were ER only positive, and 78 (49.7%) were PR only positive. There were 56 genes overexpressed in the refractory group compared to responders. However, only five out of these 56 genes, Janus kinase 1 (JAK1), collagen type I alpha 1 (COL1A1), GRB2-associated binding protein 1 (GAB1), fibronectin-1 (FN1), and MAP kinase-interacting serine/threonine-protein kinase (MKNK1), showed statistical significance between the two groups. Patients with bone metastasis showed a better response to treatment compared to those with metastatic deposits in other sites such as visceral metastasis (P < 0.005). CONCLUSIONS: Genetic profiling using simple quantitative real-time polymerase chain reaction (qRT-PCR) protocols could be used to assess response to tamoxifen treatment in MBC patients. According to our data, a five-gene panel in the EGFR pathway (JAK1, COL1A1, GAB1, FN1 and MKNK1) could be used to categorize MBC patients into groups according to treatment response.

Consecutive versus concomitant follicle-stimulating hormone and highly purified human menopausal gonadotropin: A milder response but better quality.

OBJECTIVE: This study investigated the impact of two stimulation protocols using highly purified human menopausal gonadotropin (HP-hMG) on the endocrine profile, follicular fluid soluble Fas levels, and outcomes of intracytoplasmic sperm injection (ICSI) cycles. METHODS: This prospective clinical trial included 100 normal-responder women undergoing ovarian stimulation for ICSI; 55 patients received concomitant follicle-stimulating hormone (FSH) plus HP-hMG from the start of stimulation, while 45 patients received FSH followed by HP-hMG during mid/late follicular stimulation. The primary outcome was the number of top-quality embryos. The secondary outcomes were the number and percentage of metaphase II (MII) oocytes and the clinical pregnancy rate. RESULTS: The number of MII oocytes was significantly higher in the concomitant protocol (median, 13.0; interquartile range [IQR], 8.5-18.0 vs. 9.0 [8.0-13.0] in the consecutive protocol; p=0.009); however, the percentage of MII oocytes and the fertilization rate were significantly higher in the consecutive protocol (median, 90.91; IQR, 80.0-100.0 vs. 83.33 [75.0-93.8]; p=0.034 and median, 86.67; IQR, 76.9-100.0 vs. 77.78 [66.7-89.9]; p=0.028, respectively). No significant between-group differences were found in top-quality embryos (p=0.693) or the clinical pregnancy rate (65.9% vs. 61.8% in the consecutive vs. concomitant protocol, respectively). The median follicular fluid soluble Fas antigen level was significantly higher in the concomitant protocol (9,731.0 pg/mL; IQR, 6,004.5-10,807.6 vs. 6,350.2 pg/mL; IQR, 4,382.4-9,418.4; p=0.021). CONCLUSION: Personalized controlled ovarian stimulation using HP-hMG during the late follicular phase led to a significantly lower response, but did not affect the quality of ICSI.

Reviewing Patient-Reported Outcomes 1 Year after Orthotopic Liver Transplantation.

BACKGROUND: With improved survivorship in liver transplantation (LT), there is an emerging focus on functional recovery and health-related quality of life (HRQoL) after surgery. The present study aimed to assess HRQoL after LT using the Patient-Reported Outcomes Measurement Information System (PROMIS). STUDY DESIGN: This was a prospective analysis of LT recipients between 2020 and 2021. A total of 238 patients were contacted by phone at 3, 6, and 12 months postoperatively using the PROMIS 29-Profile. Scores were recorded and computed using the HealthMeasures Scoring Service. RESULTS: PROMIS was available for 174 patients at 3 (n = 58), 6 (n = 57), and 12 months (n = 59). Overall, mean PROMIS scores were 47.6 ± 3, 47.6 ± 3, and 47.6 ± 3 at 3, 6, and 12 months, respectively. Most domains improved postoperatively by 12 months except for anxiety and sleep disturbance measures. The lowest domain in the immediate postoperative period was physical functioning, but this had the closest return to normative population values. Pain interference was above the population reference during the initial postoperative period, improving by 12 months where they were below mean population values. Depression and fatigue scores improved by 6 months and appeared to stabilize by 12 months post-LT. Patients demonstrated increased social participation, and scores were remarkably higher than general population means at each timepoint. CONCLUSION: LT can impact physical, mental, and social health which, in this setting, remains largely unexplored using PROMIS instruments. We report that although overall patient well being can improve, some mental health domains require further consideration during the postoperative period.

Are Current National Review Board Downstaging Protocols for Hepatocellular Carcinoma Too Restrictive?

BACKGROUND: Liver transplantation (LT) is an effective strategy for patients with unresectable hepatocellular carcinoma (HCC). To qualify for standardized LT model for end-stage liver disease exception points, the United Network for Organ Sharing National Liver Review Board (NLRB) requires that the presenting and final HCC tumor burden be within the University of California San Francisco criteria, which were recently expanded (within expanded UCSF [W-eUCSF]). Current NLRB criteria may be too restrictive because it has been shown previously that the initial burden does not predict LT failure when tumors downstage to UCSF. This study aims to assess LT outcomes for HCC initially presenting beyond expanded UCSF (B-eUCSF) criteria in a large multicenter collaboration. STUDY DESIGN: Comparisons of B-eUCSF and W-eUCSF candidates undergoing LT at seven academic institutions between 2001 and 2017 were made from a multi-institutional database. Survival outcomes were compared by Kaplan-Meier and Cox regression analyses. RESULTS: Of 1,846 LT recipients with HCC, 86 (5%) met B-eUCSF criteria at initial presentation, with the remainder meeting W-eUCSF criteria. Despite differences in tumor burden, B-eUCSF candidates achieved comparable 1-, 5- and 10-year overall (89%, 70%, and 55% vs 91%, 74%, and 60%, respectively; p = 0.2) and disease-free (82%, 60%, and 53% vs 89%, 71%, and 59%, respectively; p = 0.07) survival to patients meeting W-eUCSF criteria after LT. Despite increased tumor recurrence in B-eUCSF vs W-eUCSF patients (24% vs 10%, p = 0.0002), post-recurrence survival was similar in both groups (p = 0.69). CONCLUSION: Transplantation for patients initially presenting with HCC B-eUSCF criteria offers a survival advantage similar to those with tumors meeting W-eUCSF criteria at presentation. The current NLRB policy is too stringent, and considerations to expand criteria should be discussed.

Estrogen Receptor Gene Polymorphism as a Possible Genetic Risk Factor for Treatment Response in ER-Positive Breast Cancer Patients.

Estrogen receptor-α (ESR1) single nucleotide polymorphisms (SNPs) have been related to breast cancer (BC) susceptibility. In this retrospective study we investigated ESR1 SNPs in association with survival and treatment response in BC patients. Seven ESR1 SNPs were genotyped using TaqMan probe assay in 100 formalin-fixed paraffin embedded blocks of Egyptian ER+BC patients. Log-binomial regression was used to assess the association of 5 ESR1 SNPs with relative risk of non-response to adjuvant-hormonal treatment. We compared the performance of five machine learning classification models for prediction of treatment response. Predictive models were developed using rs1801132, rs2228480, and rs9322354 that were significantly associated with increased risk for non-response along with the relevant clinical features. Survival analysis was performed to detect prognostic significance of ESR1 SNPs in ESR+BC patients. rs1801132 (C), rs2228480 (A), and rs9322354 (G) minor alleles significantly increased the risk of non-response to tamoxifen by more than 81, 84, and 117%, respectively, in ER+BC patients on anthracycline/anthracycline-taxanes-based chemotherapy. Multivariate Cox regression survival analysis revealed that rs1801132 (C) and large tumor size were independent predictors for poor survival outcome in ER+BC. The best response predictive model was a combination random forest, K-nearest neighbor, and decision tree having an area under the curve of 0.94 and an accuracy of 90.8%. Our proposed predictive model based on ESR1 rs1801132, rs2228480, and rs9322354 SNPs represents a promising genetic risk stratification for selection patients who could benefit from tamoxifen therapy in such a way that might facilitate personalized medicine required to improve ER+BC patients' outcome.

Improving Liver Graft Function Using CD47 Blockade in the Setting of Normothermic Machine Perfusion.

BACKGROUND: Toward the goal of using more livers for transplantation, transplant centers are looking to increase the use of organs from "marginal" donors. Livers from these donors, however, have been shown to be more susceptible to preservation and reperfusion injury. METHODS: Using a porcine model of donation after circulatory death, we studied the use of antibody-mediated CD47 blockade to further improve liver graft function undergoing normothermic machine perfusion. Livers from 20 pigs (5 per group) were brought under either 30 or 60 min of warm ischemia time followed by the administration of CD47 monoclonal antibody (CD47mAb) treatment or immunoglobulin G control antibodies and 6 h of normothermic extracorporeal liver perfusion. RESULTS: After 6 h of normothermic extracorporeal liver perfusion, CD47mAb-treated livers with 30 or 60 min warm ischemia time had significantly lower alanine transaminase levels and higher bile production compared with their respective control groups. Blockade of the CD47 signaling pathway resulted in significantly lower thrombospondin-1 protein levels, lower expression of caspase-3, and higher expression of phosphorylated extracellular signal-regulated kinase. CONCLUSIONS: These findings suggested that CD47mAb treatment decreases ischemia/reperfusion injury through CD47/thrombospondin-1 signaling downregulation and the presence of necrosis/apoptosis after reperfusion and could increase liver regeneration during normothermic perfusion of the liver.

Single-center experience of liver transplantation for perihilar cholangiocarcinoma.

BACKGROUND: Traditionally, curative resection was considered the cornerstone of treatment for perihilar cholangiocarcinoma. More recently, liver transplantation (LT) offered an alternative for patients with unresectable disease. The purpose of this study was to assess our experience with perihilar cholangiocarcinoma and LT. METHODS: A perihilar cholangiocarcinoma protocol was commenced in 2006 whereby diagnosed patients were enrolled onto an institutional registry for LT consideration. Data on patient progression and oncologic outcomes were assessed. RESULTS: Fifty-eight patients were initially enrolled onto the protocol and 38 proceeded to LT following neoadjuvant chemoradiation (mean age 55.6 ± 11.4 years). Mean time to LT was 3.7 ± 2 months and, among those transplanted, 14 (37%) had underlying primary sclerosing cholangitis (PSC). Thirteen (34%) patients developed malignant recurrence and there were no differences in disease recurrence between PSC (n = 3) and non-PSC (n = 10) patients (p = 0.32). Overall patient survival was 91%, 58% and 52% at 1-, 3- and 5-years corresponding with 81%, 52% and 46% graft survival, respectively. CONCLUSION: Rigorous patient selection and chemoradiation treatment algorithms can be highly effective in treating perihilar cholangiocarcinoma. For appropriately selected candidates, LT can provide a 52% 5-year survival for patients who would otherwise have no surgical treatment option.

NRF2 assessment in discarded liver allografts: A role in allograft function and salvage.

Antioxidant defence mechanisms, such as the nuclear factor-erythroid 2-related-factor-2 (NRF2) axis, are integral to oxidative stress responses and ischemic injury. Hepatic antioxidant capacity is contingent on parenchymal quality, and there is a need to develop new insights into key molecular mechanisms in marginal liver allografts that might provide therapeutic targets. This study examines the clinical relevance of NRF2 in donor livers and its response to normothermic machine perfusion (NMP). Discarded donor livers (n = 40) were stratified into a high NRF2 and low NRF2 group by quantifying NRF2 expression. High NRF2 livers had significantly lower transaminase levels, hepatic vascular inflammation and peri-portal CD3+ T cell infiltration. Human liver allografts (n = 8) were then exposed to 6-h of NMP and high NRF2 livers had significantly reduced liver enzyme alterations and improved lactate clearance. To investigate these findings further, we used a rat fatty-liver model, treating livers with an NRF2 agonist during NMP. Treated livers had increased NRF2 expression and reduced transaminase derangements following NMP compared to vehicle control. These results support the association of elevated NRF2 expression with improved liver function. Targeting this axis could have a rationale in future studies and NRF2 agonists may represent a supplemental treatment strategy for rescuing marginal donor livers.