Impact of a Patient Blood Management monitoring and feedback programme on allogeneic blood transfusions and related costs.

A Patient Blood Management programme was established at the University Hospital of Zurich, along with a monitoring and feedback programme, at the beginning of 2014 with a first analysis reported in 2015. Our study aimed to investigate the further impact of this Patient Blood Management monitoring and feedback programme on transfusion requirements and related costs. We included adult patients discharged between 2012 and 2017. A total of 213,882 patients underwent analysis: 66,659 patients in the baseline period (2012-2013); 35,309 patients in the year after the introduction of the Patient Blood Management monitoring and feedback programme (2014) and 111,914 patients in the continued sustainability period (2015-2017). The introduction of the Patient Blood Management monitoring and feedback programme reduced allogeneic blood product transfusions by 35%, from 825 units per 1000 hospital discharges in 2012 to 536 units in 2017. The most sustained effect was an approximately 40% reduction in red blood cell transfusions, from 535 per 1000 discharges to 319 units. Fewer patients were transfused in the periods after the introduction of the Patient Blood Management monitoring and feedback programme (6251 (9.4%) vs. 2932 (8.3%) vs. 8196 (7.3%); p < 0.001). Compared with 2012, the yearly OR for being exposed to any blood transfusion declined steadily after the introduction of the Patient Blood Management monitoring and feedback programme to 0.64 (95%CI 0.61-0.68; p < 0.001) in 2017. For patients requiring extracorporeal membrane oxygenation, transfusion requirements were also sustainably reduced. This reduction in allogeneic blood transfusions led to savings of 12,713,754 Swiss francs (£ 9,497,000 sterling; EUR 11,100,000; US$ 12,440,000) in blood product acquisition costs over 4 years. In-hospital mortality was not affected by the programme. The Patient Blood Management monitoring and feedback programme sustainably reduced transfusion requirements and related costs, without affecting in-hospital mortality.

Can hypothermic oxygenated perfusion (HOPE) rescue futile DCD liver grafts?

BACKGROUND: The new UK-DCD-Risk-Score has been recently developed to predict graft loss in DCD liver transplantation. Donor-recipient combinations with a cumulative risk of >10 points were classified as futile and achieved an impaired one-year graft survival of <40%. The aim of this study was to show, if hypothermic oxygenated perfusion (HOPE) can rescue such extended DCD livers and improve outcomes. METHODS: "Futile"-classified donor-recipient combinations were selected from our HOPE-treated human DCD liver cohort (01/2012-5/2017), with a minimum follow-up of one year. Main risk factors, which contribute to the classification "futile" include: elderly donors>60years, prolonged functional donor warm ischemia time (fDWIT > 30min), long cold ischemia time>6hrs, donor BMI>25 kg/m2, advanced recipient age (>60years), MELD-score>25points and retransplantation status. Endpoints included all outcome measures during and after DCD LT. RESULTS: Twenty-one donor-recipient combinations were classified futile (median UK-DCD-Risk-Score:11 points). The median donor age and fDWIT were 62 years and 36 min, respectively. After cold storage, livers underwent routine HOPE-treatment for 120 min. All grafts showed immediate function. One-year and 5-year tumor death censored graft survival was 86%. CONCLUSION: HOPE-treatment achieved excellent outcomes, despite high-risk donor and recipient combinations. Such easy, endischemic perfusion approach may open the door for an increased utilization of futile DCD livers in other countries.

Risk Assessment in High- and Low-MELD Liver Transplantation.

Allocation of liver grafts triggers emotional debates, as those patients, not receiving an organ, are prone to death. We analyzed a high-Model of End-stage Liver Disease (MELD) cohort (laboratory MELD score ≥30, n = 100, median laboratory MELD score of 35; interquartile range 31-37) of liver transplant recipients at our center during the past 10 years and compared results with a low-MELD group, matched by propensity scoring for donor age, recipient age, and cold ischemia time. End points of our study were cumulative posttransplantation morbidity, cost, and survival. Six different prediction models, including donor age x recipient MELD (D-MELD), Difference between listing MELD and MELD at transplant (Delta MELD), donor-risk index (DRI), Survival Outcomes Following Liver Transplant (SOFT), balance-of-risk (BAR), and University of California Los Angeles-Futility Risk Score (UCLA-FRS), were applied in both cohorts to identify risk for poor outcome and high cost. All score models were compared with a clinical-oriented decision, based on the combination of hemofiltration plus ventilation. Median intensive care unit and hospital stays were 8 and 26 days, respectively, after liver transplantation of high-MELD patients, with a significantly increased morbidity compared with low-MELD patients (median comprehensive complication index 56 vs. 36 points [maximum points 100] and double cost [median US$179 631 vs. US$80 229]). Five-year survival, however, was only 8% less than that of low-MELD patients (70% vs. 78%). Most prediction scores showed disappointing low positive predictive values for posttransplantation mortality, such as mortality above thresholds, despite good specificity. The clinical observation of hemofiltration plus ventilation in high-MELD patients was even superior in this respect compared with D-MELD, DRI, Delta MELD, and UCLA-FRS but inferior to SOFT and BAR models. Of all models tested, only the BAR score was linearly associated with complications. In conclusion, the BAR score was most useful for risk classification in liver transplantation, based on expected posttransplantation mortality and morbidity. Difficult decisions to accept liver grafts in high-risk recipients may thus be guided by additional BAR score calculation, to increase the safe use of scarce organs.

Liver transplantation for "very early" intrahepatic cholangiocarcinoma: International retrospective study supporting a prospective assessment.

UNLABELLED: The presence of an intrahepatic cholangiocarcinoma (iCCA) in a cirrhotic liver is a contraindication for liver transplantation in most centers worldwide. Recent investigations have shown that "very early" iCCA (single tumors ≤2 cm) may have acceptable results after liver transplantation. This study further evaluates this finding in a larger international multicenter cohort. The study group was composed of those patients who were transplanted for hepatocellular carcinoma or decompensated cirrhosis and found to have an iCCA at explant pathology. Patients were divided into those with "very early" iCCA and those with "advanced" disease (single tumor >2 cm or multifocal disease). Between January 2000 and December 2013, 81 patients were found to have an iCCA at explant; 33 had separate nodules of iCCA and hepatocellular carcinoma, and 48 had only iCCA (study group). Within the study group, 15/48 (31%) constituted the "very early" iCCA group and 33/48 (69%) the "advanced" group. There were no significant differences between groups in preoperative characteristics. At explant, the median size of the largest tumor was larger in the "advanced" group (3.1 [2.5-4.4] versus 1.6 [1.5-1.8]). After a median follow-up of 35 (13.5-76.4) months, the 1-year, 3-year, and 5-year cumulative risks of recurrence were, respectively, 7%, 18%, and 18% in the very early iCCA group versus 30%, 47%, and 61% in the advanced iCCA group, P = 0.01. The 1-year, 3-year, and 5-year actuarial survival rates were, respectively, 93%, 84%, and 65% in the very early iCCA group versus 79%, 50%, and 45% in the advanced iCCA group, P = 0.02. CONCLUSION: Patients with cirrhosis and very early iCCA may become candidates for liver transplantation; a prospective multicenter clinical trial is needed to further confirm these results. (Hepatology 2016;64:1178-1188).

Machine Perfusion of Donor Livers for Transplantation: A Proposal for Standardized Nomenclature and Reporting Guidelines.

With increasing demand for donor organs for transplantation, machine perfusion (MP) promises to be a beneficial alternative preservation method for donor livers, particularly those considered to be of suboptimal quality, also known as extended criteria donor livers. Over the last decade, numerous studies researching MP of donor livers have been published and incredible advances have been made in both experimental and clinical research in this area. With numerous research groups working on MP, various techniques are being explored, often applying different nomenclature. The objective of this review is to catalog the differences observed in the nomenclature used in the current literature to denote various MP techniques and the manner in which methodology is reported. From this analysis, we propose a standardization of nomenclature on liver MP to maximize consistency and to enable reliable comparison and meta-analyses of studies. In addition, we propose a standardized set of guidelines for reporting the methodology of future studies on liver MP that will facilitate comparison as well as clinical implementation of liver MP procedures.

Histopathological evidence of invasive gastric mucormycosis after transarterial chemoembolization and liver transplantation.

We describe a case of a 62-year-old diabetic woman with hepatocellular carcinoma due to chronic hepatitis B virus infection. Two weeks after orthotopic liver transplantation, endoscopy for massive upper gastrointestinal bleeding revealed a large necrotic area in the gastric fundus. The patient underwent emergency resection. Histopathologically, angioinvasive mold infection compatible with mucormycosis was diagnosed in a large area of necrosis, mimicking an atypically localized gastric ulcer. Foreign bodies originating from transarterial chemoembolization (TACE) performed 7 and 8 months earlier and 40 days before transplantation were identified in the submucosal tissue. The patient was treated with liposomal amphotericin B (LAB) for 5 weeks, followed by 7 weeks of posaconazole. Follow-up biopsies after 1 and 5 months confirmed successful treatment. Review of the radiological images of the TACE procedure showed that some of the TACE material had been diverted to the stomach via an accessory gastric branch originating from the left hepatic artery. TACE agents may be associated with chronic, refractory gastroduodenal ulcers. We hypothesize that the ischemic lesion was first colonized with presumed Mucorales mold and invasive growth was promoted by the posttransplantation immunosuppression. Careful exploration of extrahepatic collaterals during TACE may prevent this complication.

Hypothermic machine perfusion in liver transplantation.

Dynamic preservation strategies are a promising option to improve graft quality before transplantation, and to extend preservation time for either logistic or treatment reasons. In contrast to normothermic oxygenated perfusion, which intends to mimic physiological conditions in the human body, with subsequent clinical application for up to 24 hrs, hypothermic perfusion is mainly used for a relatively short period with protection of mitochondria and subsequent reduction of oxidative injury upon implantation. The results from two randomized controlled trials, where recruitment has finished are expected this year. Both ex situ perfusion techniques are increasingly applied in clinical transplantation including recent reports on viability assessment, which could open the door for an increased liver utilization in the future.

Alexis Carrel: genius, innovator and ideologist.

Alexis Carrel was a Frenchman from Lyon, who gained fame at the Rockefeller Institute in New York at the beginning of the 20th century. He was the first to demonstrate that arteriovenous anastomoses were possible. Alexis Carrel was awarded the Nobel Prize for his contributions to vascular surgery and transplantation in 1912. He was a versatile scientist, who made numerous discoveries from the design of an antiseptic solution to treat injuries during the First World War to tissue culture and engineering, and organ preservation, making him the father of solid organ transplantation. Together, with the famous aviator and engineer Charles Lindbergh, they were the first scientists capable of keeping an entire organ alive outside of the body, using a perfusion machine. Due to his many dubious ideas and his association with fascism in the 1930s and during the Second World War, many of his scientific achievements have been forgotten today and taken for granted.

Machine perfusion for 'marginal' liver grafts.

Due to the critical shortage of deceased donor grafts, clinicians are continually expanding the criteria for an acceptable liver donor to meet the waiting list demands. However, the reduced ischemic tolerance of those extended criteria grafts jeopardizes organ viability during cold storage. Machine perfusion has been developed to limit ischemic liver damage but despite its proven biochemical benefit, machine liver perfusion is not yet considered clinically due to its low practicability. In this review, we summarize our understanding of the role of machine perfusion in marginal liver preservation. The goal is to highlight advantages or disadvantages of current perfusion techniques and to explain the underlying mechanisms. We provide evidence for the need of a liver perfusion performance shortly before implantation, and point out promising designs.

Prognostic significance of urokinase-type plasminogen activator expression in squamous cell carcinomas of the esophagus.

In the present study, urokinase-type plasminogen activator (uPA) expression in 150 potentially curatively resected SCCs of the esophagus was analyzed immunohistochemically by means of a murine monoclonal antibody (American Diagnostica, Greenwich, CT) and correlated with survival. Altogether, 122 of the 150 tumors (81.3%) expressed different levels of uPA. Among the 122 uPA-positive tumors, 104 (85.2%) showed a weak staining intensity, and 18 (14.8%) showed a strong staining intensity. Among the uPA-positive tumors, 29 (23. 8%) tumors showed a uPA immunoreactivity in 6-25% of all tumor cells, 30 (24.6%) showed a uPA immunoreactivity in 26-50% of all tumor cells, 41 (33.6%) showed a uPA immunoreactivity in 51-75% of all tumor cells, and 22 (18.0%) showed a uPA immunoreactivity in 76-100% of all tumor cells. No significant correlation could be shown between the different patterns of uPA expression and various clinicopathological parameters, such as pT category, pN category, tumor size, histological grade, blood vessel invasion, lymphatic vessel invasion, and inflammatory response. Concerning the overall postoperative survival, no significant differences between uPA-positive and uPA-negative tumors could be verified. This also held true when different cut points in the percentage of uPA-positive tumor cells were used. In contrast, the intensity of uPA staining provided significant prognostic information in that patients with strongly uPA-positive tumors had a poorer outcome than patients with weakly uPA-positive or uPA-negative tumors. Moreover, as shown by stepwise multivariate Cox regression analysis, the intensity of uPA expression was an independent prognostic factor.

Expression of Bcl-X(L), an antiapoptotic member of the Bcl-2 family, in esophageal squamous cell carcinoma.

Bcl-X, a Bcl-2-related protein, is a potent antagonist of apoptosis in its long splice variant (Bcl-X(L)). The present study was performed to determine its expression in preneoplastic and neoplastic lesions of the esophagus, its correlation with other members of the Bcl-2 family, and its impact on the outcome of surgically treated esophageal cancer patients. Samples of normal esophageal squamous epithelium (n = 10), severe squamous cell dysplasias (n = 19), carcinomas in situ (n = 14), invasive squamous cell carcinomas (n = 172), and lymph node metastases (n = 21) were immunohistochemically analyzed for Bcl-X(L) expression using a polyclonal anti-Bcl-X(L) antibody. The immunostaining was evaluated according to a score system (0-12 points) based on the percentage of positive tumor cells and the relative immunostaining intensity. Cytoplasmic staining for Bcl-X(L) protein was invariably found in all cell layers of the normal esophageal squamous epithelium. In contrast, a considerable portion of preneoplastic and neoplastic lesions display a decreased Bcl-X(L) expression as compared with that in the normal esophageal epithelium. On comparison of the amount of Bcl-X(L) expression between the different types of lesions, however, no significant differences were found between severe squamous cell dysplasias (mean immunoreactive score +/- SD, 5.2 +/- 1.8), carcinomas in situ (5.2 +/- 2.2), invasive carcinomas (4.5 +/- 2.8), and lymph node metastases (4.2 +/- 2.6). In invasive carcinomas, Bcl-X(L) expression decreased continuously with decreasing tumor differentiation (P = 0.0001) and was also directly correlated with bcl-2-associated X protein expression (P = 0.0001). On the contrary, an inverse correlation was found between Bcl-X(L) expression and Bcl-2 protein expression (P = 0.0001). No correlation was found between Bcl-X(L) expression and the parameters pT category, pN category, and tumor size. In the univariate survival analysis, patients with low immunoreactive scores (< or = 4) of Bcl-X(L) expression in the tumor tissue showed lower 2-year and 5-year survival rates than patients with high immunoreactive scores (> 4; P = 0.0485). In multivariate survival analysis, however, only the parameters pN category and pT category, but not Bcl-X(L) expression, could be verified as independent prognostic factors. This tendency of decreasing levels of an antiapoptotic protein toward unfavorable outcome is supported by an increasing number of studies on the role of Bcl-2, another antiapoptotic protein, and must be interpreted against the backdrop of apoptosis as a result of the interaction of many cell death-promoting and protecting proteins.

Expression of p21WAF1 predicts outcome of esophageal cancer patients treated by surgery alone or by combined therapy modalities.

The p21WAF1 protein is an important regulator of the cell cycle. Its expression and prognostic significance were investigated immunohistochemically in samples of normal esophageal squamous epithelium (n = 10), severe squamous cell dysplasia (n = 20), carcinoma in situ (n = 14), permanent esophageal squamous cell carcinoma cell lines (n = 3), and invasive squamous cell carcinomas treated either by potentially curative resection (n = 172) or by combined modality therapy (radiochemotherapy +/- surgery; n = 38). Whereas p21WAF1 expression in the normal epithelium was restricted to a few cells adjacent to the basal cell layer, p21WAF1 overexpression was frequently found in preneoplasias and invasive carcinomas. Expression of p21WAF1 in invasive carcinomas was not correlated with tumor differentiation, pT category, or pN category. Among carcinomas treated by potential curative resection, univariate (P = 0.0025) and multivariate (P = 0.0081) survival analysis showed significant correlation of strong p21WAF1 expression (> or =50% p21WAF1-positive tumor cells) with poor overall survival. Univariate survival analysis (P = 0.0006) revealed the same prognostic influence in the group of patients treated by combined modality therapy. We conclude that overexpression of p21WAF1 protein is a frequent event in preneoplasias and neoplasias of the esophagus. Immunohistochemical examination of p21WAF1 expression may provide important prognostic information for decision-making in the treatment of patients with esophageal cancer.

Hypothermic Oxygenated Liver Perfusion: Basic Mechanisms and Clinical Application.

Dynamic preservation strategies such as hypothermic machine perfusion are increasingly discussed to improve liver graft quality before transplantation. This review summarizes current knowledge of this perfusion technique for liver preservation. We discuss optimization of perfusion conditions and current strategies to assess graft quality during cold perfusion. Next, we provide an overview of possible pathways of protection from ischemia-reperfusion injury. Finally, we report on recent clinical applications of human hypothermic machine liver perfusion.

Reduced oxidative stress during acellular reperfusion of the rat liver after hypothermic oscillating perfusion.

BACKGROUND: ATP resynthesis during reperfusion after liver preservation has been shown to be well correlated with the function of transplanted grafts. Nevertheless, the advantages of a cellular energy charge loading during the preservation period are yet not fully understood. This study evaluates the effects of different nucleotide levels at the end of preservation on metabolic changes and oxidative stress during reperfusion. METHODS: Two experimental groups were chosen reflecting different energy charge states after preservation: static cold storage for 10 hr and hypothermic oxygenated oscillating perfusion for 10 hr. In both experimental groups, normothermic ex vivo acellular reperfusion over 40 min was performed. A third group consisted of nonpreserved livers similarly reperfused for 40 min. Superoxide formation was detected by the superoxide dismutase inhibitable reduction of ferricytochrome c added to the normothermic perfusate. RESULTS: Superoxide formation and lipid peroxidation malondialdehyde were significantly lower during reperfusion after the energy charge loading before reperfusion by the hypothermic oscillating perfusion technique. However, oxygen radical formation, liver cell injury (lactate dehydrogenase [LDH] release), and TNFalpha release were significantly higher in energy charge-depleted groups (nonpreserved and cold stored livers). CONCLUSIONS: Hypothermic oscillating oxygenated perfusion led to the elevated energy charge during preservation and led to reduced oxygen radical formation as well as less lipid peroxidation during reperfusion, in contrast to cold stored livers and nonpreserved livers. This suggests a correlation between the energy charge before reperfusion and oxygen radical formation as well as liver injury at reperfusion.

Tumor vascularization and prognosis in squamous cell carcinomas of the esophagus.

Quantification of tumor vascularization has recently been shown to be a parameter of potential prognostic significance in various types of malignant tumors. To determine the prognostic value of tumor vascularization in esophageal cancer, tumor samples from 150 patients with squamous cell carcinoma of the esophagus and 10 samples of normal esophageal mucosa were stained immunohistochemically with the monoclonal antibody QBEND/10 (CD34), which recognises endothelial cells. Using light microscopy, the number of microvessels was counted in the areas with the highest microvessel density (MVD). The microvessel density was significantly higher in the normal esophageal mucosa (mean: 130/mm2) than in the tumor samples (mean: 69/mm2, p = 0.0001). Correlation of the MVD in the tumor tissue with other prognostic factors showed significantly lower microvessel counts in tumors with lymphatic-vessel invasion (p = 0.0076) and in high pT-stages (p = 0.0081). No significant correlation was found between the MVD and pN stage, tumor size, tumor grade, blood-vessel invasion and proliferative activity. In the univariate survival analysis no significant differences were found between poorly vascularized tumors and highly vascularized tumors. A Cox proportional hazard regression selected the parameters lymphatic-vessel invasion (p = 0.0001), pT stage (p = 0.0034) and pN stage (p = 0.0256) but not MVD as independent prognostic variables.

The prognostic significance of epidermal growth factor receptor expression in squamous cell carcinomas of the oesophagus.

EGFR expression in 150 potentially curative resected squamous cell carcinomas of the oesophagus was analyzed immunohistochemically and correlated with survival. Altogether, 124 of 150 (82.7%) tumours expressed different levels of EGFR. The percentage of tumour cells expressing EGFR varied greatly between the different tumours (median: 70%). 62 (50.0%) tumours showed weak and intense staining, respectively. Regarding the staining pattern 19 (15.3%) tumours showed exclusively membraneous immunoreactivity, 27 (21.8%) an exclusively cytoplasmic immunoreactivity and 78 (62.9%) a mixed staining pattern. No significant correlation however could be found between EGFR expression and various clinicopathologic parameters such as pT category, pN category, tumour size, histologic grade and blood vessel invasion. In univariate survival analysis, no correlation between EGFR expression and postoperative survival time was observed. In a forward multivariate Cox regression analysis only the parameters lymphatic-vessel invasion (p = 0.001), pT category (p = 0.0034) and pN category (p = 0.0256), but not the EGFR expression, could be verified as independent prognostic variables. In conclusion, the evaluation of the EGFR expression does not provide prognostic information for patients who underwent potentially curative resection for SCC of the oesophagus.