Non-colorectal liver metastases: A review of interventional and surgical treatment modalities.

Liver metastases (LM) occur in up to 90% either simultaneously with the diagnosis of the primary tumor or at a later time-point. While resection of colorectal LM and resection or transplantation of neuroendocrine LM is part of a standard therapy with a 5-year patient survival of up to 80%, resection of non-colorectal and non-neuroendocrine LM is still discussed controversially. The reason for it is the significantly lower survival benefit of all different tumor entities depending on the biological aggressiveness of the tumor. Randomized controlled trials are lacking. However, reviews of case series with ≥100 liver resections are available. They show a 5-year patient survival of up to 42% compared to only <5% in patients without treatment. Risk factors for poor survival include the type of primary tumor, a short interval between resection of the primary tumor and liver resection, extrahepatic manifestation of the tumor, number and size of the LM, and extent of liver resection. Overall, it has recently been shown that a good patient selection, the technical advances in surgical therapy and the use of a risk score to predict the prognosis lead to a significantly better outcome so that it is no longer justified not to offer liver resection to patients with non-colorectal, non- endocrine LM. Since modern therapy of LM is multimodal, the optimal therapeutic approach is decided individually by a multidisciplinary team consisting of visceral surgeons, oncologists, interventional radiologists and radiologists as part of a tumor board.

[Update: Immunosuppression in organ transplantation]. / Update: Immunsuppression bei Organtransplantationen.

Immunosuppression is an essential prerequisite for successful transplantation. In order to reduce the sometimes-considerable side effects, combination therapies with different agents are used. This article aims to provide an up-to-date overview of immunosuppression after liver and kidney transplantation.

Pulmonary vascular disease and exercise hemodynamics in chronic liver disease.

BACKGROUND & AIMS: Portopulmonary hypertension (POPH) and hepatopulmonary syndrome (HPS) are severe pulmonary vascular complications of chronic liver disease and strongly associated with morbidity and mortality. The prevalence of these complications is relatively high in patients evaluated for liver transplantation, however it is virtually unknown in patients with stable chronic liver disease. METHODS: We assessed the pulmonary hypertension (PH) and HPS prevalence in a prospective registry study of our liver out-patient clinic in a tertiary center. Between 2011 and 2016, consecutive patients with cirrhosis or non-cirrhotic portal hypertension were prospectively enrolled after written informed consent. We excluded patients with acute decompensation of liver disease and other causes of PH like severe chronic heart or lung diseases and chronic thromboembolic PH. HPS was diagnosed using contrast enhanced echocardiography and blood gas analysis. Patients were screened for PH using an algorithm implementing severity of dyspnea, echocardiography, cardiopulmonary exercise testing and exercise echocardiography employing a threshold of systolic pulmonary arterial pressure (SPAP) = 50 mmHg at peak exercise. If the algorithm indicated an increased PH risk, patients were invited for invasive investigations by means of right heart and hepatic vein catheter. We defined POPH as resting mPAP≥21 mmHg and PVR>3WU and PAWP<15 mmHg, mild PH as resting mPAP = 21-24 mmHg, and exercise PH as mPAP>30 mmHg and TPR >3 WU at peak exercise. RESULTS: Two-hundred-five patients were enrolled (male 75%; cirrhosis 96%; median age 57 yrs). Sixty-seven patients (33%) fulfilled HPS criteria but only two (1.0%) for severe (PaO2:50-60 mmHg) or very severe HPS (PaO2<50 mmHg). In 18/77 patients (23%) undergoing exercise echocardiography, SPAP at peak exercise exceeded 50 mmHg. Finally, n = 3 (1.5%) patients were invasively diagnosed with POPH, n = 4 (2.9%) with mild PH and n = 2 with exercise PH. CONCLUSION: In chronic liver disease, excluding acute decompensation and other causes of PH, POPH and severe HPS are rare findings while mild to moderate HPS and mild PH or exercise PH are more frequent.

Implementation of a mobile application for outpatient care after liver transplantation.

Background: In the face of the Covid-19 pandemic and the need for social distancing new therapeutic tools like mobile health applications might gain in importance for outpatient care. Objective of the present study was to assess if and to what extent the implementation of a free available transplant application in a cohort of liver transplant recipients was possible. Methods: Patients of the aftercare program at the Department of Transplant Surgery Graz in June 2016 were first asked to complete a survey concerning knowledge about mobile health and their management of everyday life. After using the application for 2 months a second survey evaluated whether the implementation of the application in the daily routine was achievable. Results: Among 135 patients, 124 (91.9%) agreed to participate. Seventy-one (57.3%) owned a mobile device with which they could use the application, 42 patients (33.8%) decided to try it out for 2 months. The majority stated that the application supported them for therapy management and surveillance of vital parameters. Successful implementation of the application has been reached in 57.1% of patients after 2 months testing period. Conclusion: The technical prerequisites are only partially met and should be improved. Older patients need extensive support and motivation.

COVID-19 Pandemic Stress-Induced Somatization in Transplant Waiting List Patients.

Background: The coronavirus disease 2019 (COVID-19) pandemic has resulted in widespread socioeconomic restrictions including quarantine, social distancing and self-isolation. This is the first study investigating the psychological impact of the pandemic on patients waiting for liver or kidney transplantation, a particularly vulnerable group. Methods: Twenty-seven patients on the transplantation waiting list and 43 healthy controls took part in an online survey including the Beck Depression Inventory (BDI-2), the Brief Symptom Inventory-18 (BSI-18), the Pittsburgh Sleep Quality Index (PSQI), the Alcohol Use Identification Test (AUDIT-C), the 12-item Operationalized Psychodynamic Diagnosis Structure Questionnaire (OPD-SQS) and a questionnaire to determine cognitions and beliefs, attitude and fear related to COVID-19. Results: BSI-18 Somatization was increased in waiting list patients compared to controls. Correlation analyses indicated a relationship between Somatization and the fear of contracting the coronavirus in the patient group; however this association was weak. In patients and controls, other psychologicial symptoms (depression, anxiety) correlated highly with emotional distress due to social distancing. There were no differences between patients and controls in depression scores and sleep disturbances. Alcohol consumption and personality structure were not related to COVID-19 fears. Conclusion: In times of the first lockdown during the COVID-19 pandemic, patients on the transplantation waiting list have high somatization symptoms associated with COVID-19 fears. As vulnerable group, they need psychological counseling to improve mental well-being during times of crisis.

Framework for Solid-Organ Transplantation During COVID-19 Pandemic in Europe.

INTRODUCTION: Since the effect of the COVID-19 pandemic on solid-organ transplantation (SOT) is unclear, an online survey on the specific framework of leading European transplant centers (n=155) in 31 European countries was conducted between April 24 and May 15, 2020. METHODS: A questionnaire was designed to collect information on restrictions on SOT, protective measures,(non)governmental information policies, and individual opinions on how to deal with SOT during COVID-19. RESULTS: The response rate was 37.4% (58 of 155). Overall, 84.5% reported an effect of COVID-19 on SOT in Europe. In 49% of these, limited capacity was mentioned, and in 51% the reason for restricted resources was strategic preparedness. As a result, SOT was totally or partially suspended for several weeks. In sum, 93.1% of centers implemented protective measures against COVID-19. Nongovernmental information policies were felt to be adequate in 90%. Continuation of transplant activities was desired by 97% of centers. CONCLUSION: The results of this survey suggested a need for more ICU capacity during COVID-19, in order to guarantee adequate and timely treatment of other patient cohorts in surveyed countries.

Health-related quality of life, workability, and return to work of patients after liver transplantation.

BACKGROUND: Health-related quality of life (HrQoL) and workability are related parameters to measure success of therapy. Both have been insufficiently explored in patients after liver transplantation (LT). Particularly little is known about patients' attitude to return to work, employment status before LT, and how frequently there is any employment at any time after LT. METHODS: This is a single-center retrospective cohort study including 150 adult outpatients after LT. Liver transplantations had been performed between 1993 and 2018. The study was carried out from February to July 2018. The exclusion criteria were combined transplantations, positive screening for current alcohol abuse, and anxiety or depression. To evaluate HrQoL and fitness to work, the patients were tested using the Short Form 36, the Chronic Liver Disease Questionnaire, and the Work Ability Index. KEY RESULTS: The return rate of sufficiently filled-in questionnaires was 46.8% (66 patients). The mean age of patients was 59.9 years (SD=10.8), ranging from 25 to 78 years old. HrQoL was partly comparable to the normal population. Workability sum scores with a mean value of 31.61 (SD 9.79) suggested moderate workability at present. While only 28.8% of respondents were ever employed after LT, 45.5% currently wished to work or would have wished to work. CONCLUSIONS: HRQL seems to be partly similar to population data, and subjective workability seems to be moderate in patients after LT. Despite a positive attitude to return to work in almost half of respondents, a lower rate of actual return to work was found in this study.

The Graz Liver Allocation Strategy-Impact of Extended Criteria Grafts on Outcome Considering Immunological Aspects.

Background: Transplant centers are forced to use livers of extended criteria donors for transplantation due to a dramatic organ shortage. The outcome effect of extended donor criteria (EDCs) remains unclear. Thus, this study was designed to assess the impact of EDCs on outcome including immunological aspects after liver transplantation (LT). Patients and Methods: Between November 2016 and March 2018, 49 patients (85.7% male) with a mean age of 57 ± 11 years underwent LT. The impact of EDCs on outcome after LT was assessed retrospectively using both MedOcs and ENIS (Eurotransplant Network Information System). Results: About 80% of grafts derived from extended criteria donors. Alanine aminotransferase/aspartate aminotransferase (AST/ALT) levels elevated more than three times above normal values in organ donors was the only significant risk factor for primary dysfunction (PDF) and primary non-function (PNF)/Re-LT and early non-anastomotic biliary strictures (NAS). Balance of risk (BAR) score did not differ between EDC and non-EDC recipients. PDF (14.3% of all patients) and PNF (6.1% of all patients) occurred in 23.1% of EDC-graft recipients and in 10.0% of non-EDC-graft recipients (RR 2.31, p = 0.663). The 90-day mortality was 3.6%. There was no difference of early non-anastomotic biliary tract complications and biopsy proven rejections (BPR). There was no correlation of PDF/PNF with BPR and NAS, respectively; however, 66.7% of the patients with BPR also developed early NAS (p < 0.001). Conclusion: With the Graz liver allocation strategy, excellent survival can be achieved selecting livers with no more than 2 not outcome-relevant EDCs for patients with MELD >20. Further, BPR is associated with biliary complications.

A prospective, randomized, single-blind, multicentre, phase III study on organ preservation with Custodiol-N solution compared with Custodiol® solution in organ transplantation (kidney, liver and pancreas).

BACKGROUND: Organ preservation before transplantation is still a challenge. Both the University of Wisconsin and Bretschneider's histidine-tryptophan-ketoglutarate (HTK; Custodiol®) solution are standard for liver, kidney and pancreas preservation. Organ preservation with both solutions is comparable; recently, however, Custodiol® solution has been modified to Custodiol-N according to the needs of today. Thus, our study was defined to study its effect in clinical transplantation. METHODS: Patients undergoing kidney transplantation (n = 412) (including approximately 30 combined kidney-pancreas) or liver transplantation (n = 202) receive grafts that have been cold stored in either Custodiol® or Custodiol-N to demonstrate noninferiority of Custodiol-N regarding both graft function and graft injury after transplantation. DISCUSSION: Preclinical data have clearly shown that Custodiol-N is superior to Custodiol® in cold static organ preservation via mechanisms including inhibition of hypoxic cell injury, cold-induced cell injury and avoidance of adverse effects during warm exposure to the solution. Further clinical safety data on Custodiol-N for cardioplegia are available. Thus, this study was designed to compare Custodiol® with Custodiol-N for the first time in a prospective, randomized, single-blinded, multicentre, phase III clinical transplantation trial. TRIAL REGISTRATION: Eudra-CT, 2017-002198-20. Registered on 28 November 2018.

PRevention of INCisional hernia after liver transplantation (PRINC trial): study protocol for a randomized controlled trial.

BACKGROUND: Incisional hernia is a common complication after liver transplantation with an incidence of 5 to 46%. Concerning non-transplant patients, a recently published meta-analysis describes a reduction of the incidence of incisional hernia of up to 85% due to prophylactic mesh replacement in elective, midline laparotomy. The aim of our study is to show a reduction of the incidence of incisional hernia after liver transplantation with minimal risk for complication. METHODS/DESIGN: This is an unblinded, randomized controlled trial comparing time to incisional hernia over a period of 12 months between patients undergoing liver transplantation and standardized abdominal closure with or without prophylactic placement of Phasix™ (Bard - Davol Inc., Warwick, RI, USA) mesh in an onlay position. As we believe that the mesh intervention is superior to the standard procedure in reducing the incidence of hernia, this is a superiority trial. DISCUSSION: The high risk for developing incisional hernia following liver transplantation might be reduced by prophylactic mesh placement. Immunosuppressed patients are at high risk for developing surgical-site infections. We chose a mesh which has anti-inflammatory properties and is fully resorbed after 18 months. TRIAL REGISTRATION: ClinicalTrials.gov, ID: 03222102 . Registered retrospectively on 17 July 2018. Protocol version 1.4, 7 October 2018.

Both sarcopenia and frailty determine suitability of patients for liver transplantation-A systematic review and meta-analysis of the literature.

Liver grafts are allocated based on both urgency and utility. Due to a tremendous shortage of suitable organs for liver transplantation (LT), a careful selection of suitable recipients is of utmost importance. While the sickest first principle for organ allocation based on MELD score goes along with poor utility, other parameters reflecting the general health condition like frailty and sarcopenia might be essential to detect suitable patients for the waiting list. Thus, this study was designed to evaluate both frailty and sarcopenia in LT. A systematic review of the literature on sarcopenia and frailty measurements in liver transplant recipients was performed. Thirteen of 238 studies were selected for full paper review. Six of the studies investigating the impact of frailty on waitlist mortality were subjected to a meta-analysis. Despite the different methodologies to assess sarcopenia, reports showed that sarcopenia was highly related to waitlist mortality with a sum of all that highly favored negative outcome in case of sarcopenia. The existing literature clearly underlines that frailty and sarcopenia are important to determine in LT candidates. One unique index for transplant candidates reflecting frailty should be developed and be used as a standard in all transplant centers to facilitate comparability.

Measurement of breath ammonia for detection of patients with chronic kidney disease.

BACKGROUND: In a healthy individual, ammonia is converted to urea in the liver. Urea is then transported through the bloodstream and then excreted into the urine by the kidneys. In patients with chronic kidney disease (CKD), the accumulated urea is degraded by salivary urease into ammonia, which is then excreted by breathing. Breath ammonia can therefore be used for detecting the increased nitrogen-bearing wastes. In our pilot study, an electrochemical sensor was used to measure and analyze breath ammonia in healthy volunteers and patients with CKD. PATIENTS AND METHODS: In our study, 8 patients with CKD (stages 4 and 5) and 6 healthy volunteers were enrolled. All participants were nonsmokers and without pulmonary or liver disease. One controlled breath sample was collected from each participant. Immediately after the sample was collected, a gas analyzer was used for measuring breath ammonia in our participants. RESULTS: Mean creatinine value of CKD patients was 455.2 ± 294.1 µmol/L and 62.1 ± 7.5 µmol/L for healthy volunteers. Breath ammonia levels (3.32 ± 2.19 ppm vs. 0.49 ± 0.08 ppm; p = 0.003) and measured electric current (4.33 ± 0.25 mA vs. 4.01 ± 0.01 mA; p = 0.003) were significantly higher in the CKD group. CONCLUSIONS: The results of our pilot study show that breath monitoring of ammonia can be a simple, useful, fast, and noninvasive tool for detection of advanced kidney impairment.
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CT perfusion imaging of the liver and the spleen in patients with cirrhosis: Is there a correlation between perfusion and portal venous hypertension?

OBJECTIVES: To correlate hepatic and splenic CT perfusion parameters with hepatic venous pressure gradient (HVPG) measurements in patients with cirrhosis. METHODS: Twenty-one patients with cirrhosis (males, 17; females, 4; mean ± SD age, 57 ± 7 years) underwent hepatic and splenic perfusion CT on a 320-detector row volume scanner as well as invasive measurement of HVPG. Different CT perfusion algorithms (maximum slope analysis and Patlak plot) were used to measure hepatic arterial flow (HAF), portal venous flow (PVF), hepatic perfusion index (HPI), splenic arterial flow (SAF), splenic blood volume (SBV) and splenic clearance (SCL). Hepatic and splenic perfusion parameters were correlated with HVPG, and sensitivity and specificity for detection of severe portal hypertension (≥12 mmHg) were calculated. RESULTS: The Spearman correlation coefficient was -0.53 (p < 0.05) between SAF and HVPG, and -0.68 (p < 0.01) between HVPG and SCL. Using a cut-off value of 125 ml/min/100 ml for SCL, sensitivity for detection of a HVPG of ≥12 mmHg was 94%, and specificity 100%. There was no significant correlation between hepatic perfusion parameters and HVPG. CONCLUSION: CT perfusion in patients with cirrhosis showed a strong correlation between SCL and HVPG and may be used for detection of severe portal hypertension. KEY POINTS: • SAF and SCL are statistically significantly correlated with HVPG • SCL showed stronger correlation with HVPG than SAF • 125 ml/min/100 ml SCL-cut-off yielded 94 % sensitivity, 100 % specificity for severe PH • HAF, PVF and HPI showed no statistically significant correlation with HVPG.

The chronic kidney disease epidemiology collaboration equation combining creatinine and cystatin C accurately assesses renal function in patients with cirrhosis.

BACKGROUND: Accurate measurement of renal function in cirrhotic patients is still challenging. To find the best test for the determination of the true glomerular filtration rate (GFR) in cirrhotic patients this study prospectively compared measured (m)GFR, the gold standard, with estimated (e)GFR using equations based on serum levels of creatinine and cystatin C. METHODS: GFR was measured by sinistrin clearance using the bolus method in 50 patients with cirrhosis (Child Turcotte Pugh score A, B and C) and 24 age-matched healthy subjects as controls. Measured (m)GFR was compared to eGFR using bias, accuracy 10 % and 30 %, as well as correlation coefficients. RESULTS: Creatinine-based equations generally overestimated GFR in patients with cirrhosis and showed a bias (average difference between mGFR and eGFR) of -40 (CG), -12 (MDRD) and -9 (CKD-EPI-Cr) ml/min/1.73 m(2). Cystatin C-based equations underestimated GFR, especially in patients with Child Turcotte Pugh score C (bias 17 ml/min/1.73 m(2)for CKD-EPI-CysC). Of these equations, the CKD-EPI equation that combines creatinine and cystatin C (CKD-EPI-Cr-CysC) showed a bias of 0.12 ml/min/1.73 m(2) as compared to measured GFR. CONCLUSIONS: The CKD-EPI equation that combines serum creatinine and cystatin C measurements shows the best performance for accurate estimation of GFR in cirrhosis, especially at advanced stages.

The Effect of Mammalian Target of Rapamycin Versus Calcineurin Inhibitor-based Immunosuppression on Measured Versus Estimated Glomerular Filtration Rate After Orthotopic Liver Transplantation.

INTRODUCTION: Mammalian target of rapamycin (mTOR) inhibitors have been proposed to preserve renal function in patients after orthotopic liver transplantation (OLT) based on estimated glomerular filtration rate (eGFR). The presented study evaluated their effect on renal function in comparison to calcineurin inhibitors (CNIs) defined by measured GFR. METHODS: Renal function was measured in patients on mTOR-based (n=28) or on CNI-based (n=51) immunosuppression after OLT by performing inulin clearance (IC) as well as eGFR based on the Modification of Diet in Renal Disease (MDRD4) Study and the chronic kidney disease epidermiology (CKD-EPI) formula at baseline, 6, 12, 18, and 24 months. Statistical analysis was performed by using analysis of variance and serial measurement testing. RESULTS: The MDRD4 and the IC values differed significantly at study inclusion in both groups (mTOR and CNI group, P=0.001), whereas the CKD-EPI and the IC values did not. Estimated GFR by the MDRD4 results declined throughout the study period in patients on CNI and in patients on mTOR (CNI, 81 vs. 61 mL/min/1.73 m(2), P=0.01; 82 vs. 60 mL/min/1.73 m(2), P=0.01), whereas CKD EPI and measured GFR did not change throughout the study period in the CNI. CONCLUSION: The use of eGFR especially the MDRD-based formula, in OLT patients, leads to incorrect interpretation of their renal function.

Effectiveness of porcine dermal collagen in giant hernia closure in patients with deleterious fascia constitution after orthotopic liver transplantation.

Incisional hernias (IHs) occur universally after orthotopic liver transplantation (OLT). This study aimed to investigate the effectiveness of porcine dermal collagen (PDC) as a closing aid in giant hernias after OLT in a prospective trial. If direct closure (DC) was not feasible due to the hernia size and abdominal wall constitution, a PDC mesh was implanted. All patients from the PDC and DC groups were followed prospectively for 24 months. IH recurrence rates served as the primary endpoint, and the development of infections and wound healing disorders served as the secondary endpoints. Recurrence rate was 21% (4/19) in DC patients and 12% (2/16) in PDC patients (P = 0.045). Implant site infections occurred in five of PDC and one of DC patients (P < 0.05). All of them were managed with antibiotics; two of the PDC patients required surgical drainage. Histological analysis of PDC mesh biopsies indicated good angiogenesis and integration of the PDC into the abdominal wall. PDC was effective in our study for incisional hernia repair, and our results compared favourably with those of patients in whom direct hernia closure was feasible.