A simplified regimen of targeted antifungal prophylaxis in liver transplant recipients: A single-center experience.

BACKGROUND: Invasive fungal infection (IFI) is a severe complication of liver transplantation burdened by high mortality. Guidelines recommend targeted rather than universal antifungal prophylaxis based on tiers of risk. METHODS: We aimed to evaluate IFI incidence, risk factors, and outcome after implementation of a simplified two-tiered targeted prophylaxis regimen based on a single broad-spectrum antifungal drug (amphotericin B). Patients presenting 1 or more risk factors according to literature were administered prophylaxis. Prospectively collected data on all adult patients transplanted in Turin from January 2011 to December 2015 were reviewed. RESULTS: Patients re-transplanted before postoperative day 7 were considered once, yielding a study cohort of 581 cases. Prophylaxis was administered to 299 (51.4%) patients; adherence to protocol was 94.1%. Sixteen patients developed 18 IFIs for an overall rate of 2.8%. All IFI cases were in targeted prophylaxis group; none of the non-prophylaxis group developed IFI. Most cases (81.3%) presented within 30 days after transplantation during prophylaxis; predominant pathogens were molds (94.4%). Only 1 case of candidemia was observed. One-year mortality in IFI patients was 33.3% vs 6.4% in patients without IFI (P = .001); IFI attributable mortality was 6.3%. At multivariate analysis, significant risk factors for IFI were renal replacement therapy (OR = 8.1) and re-operation (OR = 5.2). CONCLUSIONS: The implementation of a simplified targeted prophylaxis regimen appeared to be safe and applicable and was associated with low IFI incidence and mortality. Association of IFI with re-operation and renal replacement therapy calls for further studies to identify optimal prophylaxis in this subset of patients.

Presentation and management of mycotic pseudoaneurysm after kidney transplantation.

Pseudoaneurysms (PAs) developing at the site of vascular anastomosis after organ transplantation are a rare but serious complication. We report a series of 3 cases of PA observed in a single center over a period of 18 years. The mode of presentation was acute bleeding in 2 cases. In the third patient, who underwent combined kidney and pancreas transplantation, the PA on the renal graft was discovered by chance. Graft removal associated with iliac artery ligation and extra-anatomic femoro-femoral bypass represents the standard treatment. However, interposition of a venous homograft may allow preservation of inferior limb perfusion and possibly graft salvage.

Posthepatectomy liver failure after simultaneous versus staged resection of colorectal cancer and synchronous hepatic metastases.

BACKGROUND: Posthepatectomy liver failure (PHLF) is the third most frequent complication and the major cause of postoperative mortality after resection of colorectal cancer liver metastases (CRLM). In case of synchronous resectable CRLM, it is still unclear if surgical strategy (simultaneous versus staged resection of colorectal cancer and hepatic metastases) influences the incidence and severity of PHLF. The aim of this study was to evaluate the impact of surgical strategy on PHLF and on the early and long-term outcome. PATIENTS AND METHODS: Retrospective study on 106 consecutive patients undergoing hepatectomy for synchronous CRLM between 1997 and 2012. RESULTS: Of 106 patients, 46 underwent simultaneous resection and 60 had staged hepatectomy. The rate of PHLF was similar between groups (16.7% vs 15.2%; p=1) and subgroup analysis restricted to patients undergoing major hepatectomy confirmed this observation (31.8% vs 23.8%; p=0.56). Propensity-score analysis showed that preoperative total bilirubin level and the amount of intra-operative blood transfusion were independently associated with an increased risk of PHLF. Nevertheless, the risk of severe PHLF (grade B - C) was increased in patients who underwent simultaneous resection and major hepatectomy (OR: 4.82; p=0.035). No significant differences were observed in severe (Dindo - Clavien 3 - 4) postoperative morbidity (23.9% vs 20.0%; p=0.64) and survival (3 and 5-year survival: 55% and 34% vs 56% and 33%; p=0.83). CONCLUSIONS: The risk of PHLF is not associated with surgical strategy in the treatment of synchronous CRLM. Nevertheless, the risk of severe PHLF is increased in patients undergoing simultaneous resection and major hepatectomy.

Gravitational field-flow fractionation integrated with chemiluminescence detection for a self-standing point-of-care compact device in bioanalysis.

A "Point-Of-Care-Testing" (POCT) system relies on portable and simply operated self-standing analytical devices. To fulfill diagnostic requirements, the POCT system should provide highly sensitive simultaneous detection of several biomarkers of the pathology of interest (multiplexing) in a short assay time. One of the main unsolved issues in POCT device development is the integration of pre-analytical sample preparation procedures in the miniaturized device. In this work, an integrated POCT system based on gravitational field-flow fractionation (GrFFF) and chemiluminescence (CL) detection is presented for the on-line sample pre-analytical treatment and/or clean-up and analysis of biological fluids. As a proof of principle for the new GrFFF-CL POCT system, the automatic on-line analysis of plasma alkaline phosphatase activity, a biomarker of obstructive liver diseases and bone disorders, starting from whole blood samples was developed. The GrFFF-CL POCT system was able to give quantitative results on blood samples from control and patients with low sample volume (0.5 µL) and reagent consumption, short analysis time (10 minutes), high reproducibility and with a linear range of 50-1400 IU L(-1). The system can be easily applied to on-line prepare plasma from whole blood for other clinical biomarkers and for other assay formats, based on immunoassay or DNA hybridization.

How useful is the machine perfusion in liver transplantation? An answer from a national survey.

Machine perfusion (MP) has been shown worldwide to offer many advantages in liver transplantation, but it still has some gray areas. The purpose of the study is to evaluate the donor risk factors of grafts, perfused with any MP, that might predict an ineffective MP setting and those would trigger post-transplant early allograft dysfunction (EAD). Data from donors of all MP-perfused grafts at six liver transplant centers have been analyzed, whether implanted or discarded after perfusion. The first endpoint was the negative events after perfusion (NegE), which is the number of grafts discarded plus those that were implanted but lost after the transplant. A risk factor analysis for NegE was performed and marginal grafts for MP were identified. Finally, the risk of EAD was analyzed, considering only implanted grafts. From 2015 to September 2019, 158 grafts were perfused with MP: 151 grafts were implanted and 7 were discarded after the MP phase because they did not reach viability criteria. Of 151, 15 grafts were lost after transplant, so the NegE group consisted of 22 donors. In univariate analysis, the donor risk index >1.7, the presence of hypertension in the medical history, static cold ischemia time, and the moderate or severe macrovesicular steatosis were the significant factors for NegE. Multivariate analysis confirmed that macrosteatosis >30% was an independent risk factor for NegE (odd ratio 5.643, p = 0.023, 95% confidence interval, 1.27-24.98). Of 151 transplanted patients, 34% experienced EAD and had worse 1- and 3-year-survival, compared with those who did not face EAD (NoEAD), 96% and 96% for EAD vs. 89% and 71% for NoEAD, respectively (p = 0.03). None of the donor/graft characteristics was associated with EAD even if the graft was moderately steatotic or fibrotic or from an aged donor. For the first time, this study shows that macrovesicular steatosis >30% might be a warning factor involved in the risk of graft loss or a cause of graft discard after the MP treatment. On the other hand, the MP seems to be useful in reducing the donor and graft weight in the development of EAD.

Graft factors as determinants of postoperative delirium after liver transplantation.

Post-operative delirium (POD) is a frequent complication after surgery, occurring in 15-20% of patients. POD is associated with a higher complications rate and mortality. Literature on POD after liver transplantation (LT) is limited, with the few available studies reporting an incidence of 10-47%. The aim of this study was analyzing pattern, risk factors and clinical impact of POD after LT. Data on donor and recipient characteristics, postoperative course and POD of consecutive adult LT recipients from March 2016 to May 2018 were prospectively collected and retrospectively analyzed. Risk factors for POD were analyzed using univariable logistic regression and Lasso regression. Kaplan-Meier method was used for survival analysis. 309 patients underwent LT during study period; 3 were excluded due to perioperative death. Incidence of POD was 13.4% (n = 41). The median day of onset was 5th (IQR [4-7]) with a median duration of 4 days (IQR [3-7]). Several risk factors, related to the severity of liver disease and graft characteristics, were identified. Graft macrovesicular steatosis was the only factor independently associated with POD at multivariable analysis (OR 1.27, CI 1.09-1.51, p = 0.003). POD was associated with a higher rate of severe postoperative complications and longer intensive care unit and hospital stay, but did not significantly impact on patient and graft survival. Incidence of POD after LT is comparable to that observed after general surgery and graft factors are strongly associated with its onset. These results help identifying a subset of patients to be considered for preventive interventions.

Molecular adsorbent recirculating system (MARS) application in liver failure: clinical and hemodepurative results in 22 patients.

PURPOSE: Acute liver failure (ALF) and acute on chronic liver failure (ACLF) still show a poor prognosis. MARS was used in 22 patients with ALF or ACLF to prolong patient survival for liver function recovery or as a bridge to transplantation. DESIGN: Evaluation of depurative efficiency, biocompatibility, hemodynamics, encephalopathy (HE) and clinical outcome. PROCEDURES: During 71 five-hour sessions we evaluated (0', 60', 120', 180', 240', 300'): bilirubin, ammonia, cholic acid (CCA), chenodeoxycholic acid (CCDCA), leukocytes, platelets, hemoglobin and mean arterial pressure (MAP). Serum creatinine, electrolytes, cardiac output, cardiac index (bioimpedence) and HE (West Haven Criteria score) were evaluated at 0' and 300'. STATISTICAL METHODS AND OUTCOME MEASURES: Student's t-test for pre- vs. end-session values was used. For bilirubin and ammonia the correlation test was made between pre- and end-session values and between pre-session values and removal rates (RRS). MAIN FINDINGS: Survival was 90.9% at 7 days, 40.9% at 30 days. Pre- vs. end-session: bilirubin from 37.2 +/- 12.5 mg/dL to 24.9 +/- 8.9 mg/dL (p < 0.01), ammonia from 88.0 +/- 60.4 micromol/L to 43.6 +/- 32.9 micromol/L (p < 0.01), CCA from 42.8 +/- 21.0 micromol/L 18.2 +/- 9.8 micromol/L (p < 0.01), CCDCA from 26.3 +/- 6.3 micromol/L to 15.7+/-7.6 micromol/L (p<0.01). The correlation test between pre-session values of bilirubin and ammonia vs. RR S was respectively 0.32 (p = 0.01) and 0.30 (p = 0.04). Leukocytes, platelets and hemoglobin remained stable. MAP increased from 82.0 +/- 12.0 mmHg to 87.0 +/- 13.0 mmHg (p < 0.05), West Haven Criteria score decreased from 2.7 +/- 0.7 to 0.7 +/- 0.7 (p < 0.001). CONCLUSION: MARS treatment led in all patients to an improvement of clinical, hemodynamic and neurological conditions, with significant reduction in the hepatic toxins blood level. Treatment biocompatibility and tolerance were satisfactory.

The use of a biological preparation in the treatment of some gynaecological diseases.

A double-blind between-patient trial was carried out in 200 women suffering from dysfunctional menorrhagia (142) or from menorrhagia associated with uterine fibromyomatosis (58) to assess and compare the effectiveness of a polypeptide preparation ('Lysometra') and methylandrostendiol in reducing hyperoestrogenism and clinical symptoms. Three 20-day courses of intramuscular injections of either 2.5 ml 'Lysometra' or 5 mg methylandrostendiol were given to matched pairs of patients, with an 8-day interval between. Results, as assessed by absolute and percentage changes in total urine oestrogen levels and by overall clinical response of patients, showed that 'Lysometra' produced a statistically significant greater effect than methylandrostendiol. The biological preparation was well tolerated and no unwanted side-effects were reported.

Distal splenorenal shunt and insulin secretion, plasma glucagon, and glucose homeostasis in cirrhosis.

Over the 1st postoperative yr, distal splenorenal shunt (DSRS) in cirrhotic patients is followed by a reduction in portal perfusion resulting from a spontaneous opening of portal-systemic collaterals. This can influence plasma levels of insulin and glucagon. Fasting plasma glucose, insulin, C-peptide, and glucagon and their 5-h responses to a protein meal (which directly stimulates the hormone secretions) were measured before and 3 and 12 mo after DSRS in 10 cirrhotic patients. Hormone effectiveness and pancreatic alpha- and beta-cell sensitivities to ammonia (NH3), amino acids, and glucose were also calculated. Liver function and portal vein diameter were assessed before each study. Seven cirrhotic patients treated with injection sclerotherapy of esophageal varices served as a control group. Liver function did not deteriorate in either patient group. An increase in fasting glucagon (from 181 +/- 22 to 242 +/- 22 and 255 +/- 22 pg/ml, p = 0.02) and NH3 (from 57 +/- 8 to 84 +/- 11 and 97 +/- 14 micrograms/dl, p = 0.04) and a decrease in glucagon effectiveness (from 0.56 +/- 0.06 to 0.39 +/- 0.05 and 0.035 +/- 0.03, p = 0.047) and portal vein diameter (from 16.0 +/- 1.1 to 11.3 +/- 0.8 and 9.4 +/- 0.6 mm, p < 0.001) was found only in DSRS patients. The elevation in glucagon was correlated with that of NH3 at 3 mo (r = 0.83, p = 0.003) and with the reduction of portal vein diameter at 1 yr (r = -0.81, p = 0.005). In cirrhosis, DSRS does not influence insulin secretion or its plasma level and effectiveness.(ABSTRACT TRUNCATED AT 250 WORDS)

Liver transplantation for hepatocellular carcinoma within Milan Criteria in patients with Model for End-Stage Liver Disease score below 15: the impact of the etiology of cirrhosis on long-term survival.

BACKGROUND: Liver transplantation (OLT) is the gold standard therapy for patients with cirrhosis complicated by hepatocellular carcinoma (HCC) within Milan Criteria (MC). We evaluated the impact of the etiology of the underlying liver disease on long-term outcomes of patients undergoing OLT for HCC within MC having a Model for End-stage Liver Disease (MELD) score < 15. METHODS: From November 2002 to December 2009, we performed 203 primary OLTs from brain-dead donors in recipients with HCC and cirrhosis with biochemical MELD scores below 15. We excluded 31 patients outside MC on the explant pathology of the native liver. The remaining 172 were divided into 3 groups according to the etiology of the underlying cirrhosis: hepatitis C virus-positive (HCV+; n = 78; 45%), hepatitis B virus-positive (HBV+; n = 65; 38%) and other indications (n = 29; 17%). The groups were compared for donor and recipient features, donor-recipient match, and transplant variables. The study endpoint was long-term patient survival. RESULTS: The groups were similar, except for a greater prevalence of hepatitis B core antibody-positive grafts in the HBV+ group and less frequent HCC bridging procedures in the other indications group. After a median follow-up of 72 months, HCC recurrence was observed in 8 (4.7%) patients (6 HCV+, 2 other indications), 5 of whom died. Overall 5-year patient survival of 82%, revealed significant differences among groups: 98.3% in HBV+, 67.1% in HCV+, and 85.8% in other indications (HBV+ vs other indications: P = .01; HBV+ vs HCV+: P = .0001; HCV+ vs other indications: P = NS). In the HCV+ group, recurrent HCV hepatitis was the most frequent cause of death. Upon multivariate analysis, HBV positivity in the recipient was an independent predictor of better patient survival (hazard ratio = 0.10, 95% confidence interval 0.02-0.64, P = .013). CONCLUSIONS: Etiology of the underlying cirrhosis significantly influenced the long-term survival after OLT of patients with HCC within MC and MELD < 15. It should be taken into account in estimation of survival benefit.

Estimation of B-cell function by the urinary excretion rate of C-peptide in diabetic patients: comparison with C-peptide response to glucagon and to a mixed meal.

This study examined the relationship between the C-peptide response to intravenous glucagon and mixed meal stimulation and the 24 h urinary excretion rate of C-peptide and its urinary excretion during the glucagon test in nine control subjects, eighteen Type 1 (insulin-dependent) and twenty-two Type 2 (non-insulin-dependent) diabetic patients. Compared to controls (61.0 +/- 7.1 micrograms), the 24-h urine excretion rate of C-peptide was 8.2 +/- 3.1 micrograms (p less than 0.001) in Type 1 and 89.8 +/- 12.9 micrograms (p = NS) in Type 2 diabetic patients. C-peptide urinary excretion rate during the glucagon test was 6.92 +/- 1.11 micrograms, 0.42 +/- 0.10 microgram (p less than 0.001) and 6.47 +/- 1.13 micrograms (p = NS) respectively. Fasting serum C-peptide values were 1.53 +/- 0.16 ng/ml in controls, 0.42 +/- 0.09 ng/ml in Type 1 (p less than 0.0001) and 2.08 +/- 0.22 ng/ml in Type 2 diabetics (p = NS); C-peptide areas under the curve after glucagon stimulation were, respectively, 241.6 +/- 20.3 ng/ml, 29.2 +/- 5.9 ng/ml (p less than 0.0001) and 170.9 +/- 17.9 ng/ml (p less than 0.03) and after the meal test they were 204.7 +/- 15.6, 68.7 +/- 19.8 ng/ml (p less than 0.0001) and 265.5 +/- 32.9 ng/ml (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma clearances of branched-chain amino acids in control subjects and in patients with cirrhosis.

In an attempt to clarify the pathogenesis of the decreased branched-chain amino acid (BCAA) plasma concentrations in cirrhosis, the plasma clearances were measured in 7 patients with cirrhosis and in 7 age- and sex-matched control subjects. BCAA were given as prime-continuous infusions. The plasma clearances of valine, isoleucine, and leucine, calculated as infusion rate divided by steady state concentration, were low normal in cirrhotics despite hyperinsulinaemia, but different BCAA had different clearances (P less than 0.01). The endogenous basal appearance rates of BCAA, estimated by the basal concentrations multiplied by the plasma clearances, were lower in cirrhotics (P less than 0.025). The apparent theoretical volumes of distribution of BCAA, assessed by the ratio between the clearance and the concentration decay constant after infusion stop, were on average 67% of the total body weight, and were neither different among the three BCAA, nor between the two groups. The urea nitrogen synthesis rate did not increase significantly, suggesting that most of the infused BCAA nitrogen was taken up in peripheral tissues. The decreased concentration of BCAA in cirrhotics (394 +/- 81 mumol/l (mean +/- SD) in the present series vs 510 +/- 68 in controls; P less than 0.025) is not attributable to changes in plasma clearance. The most likely explanation is decreased afflux of BCAA into plasma.

Urinary excretion rate of C-peptide in fed and fasted obese humans.

The aim of the study was to evaluate the reliability of urinary excretion rate of C-peptide as a marker of B-cell function during fasting. Ten obese subjects of both sexes fasted for 5 days. Diurnal serum C-peptide was collected before and on the 5th day; morning serum samples (for glucose, insulin and C-peptide) and 12-h urine samples (7.00 to 19.00 h) were collected daily. Body weight decreased from 138.7 +/- 15.9 to 132.9 +/- 15.6 kg. Morning glucose, insulin (-40%) and C-peptide (-50%) fell significantly throughout the study. Mean diurnal C-peptide values were 2.19 +/- 0.69 nmol/l before and 0.60 +/- 0.19 nmol/l after fasting (P less than 0.0001) and its secretion rate was 909.4 +/- 297.9 and 244.4 +/- 83.9 nmol/12 h (P less than 0.005), respectively. Excretion rate of C-peptide fell progressively from basal (11.2 +/- 4.2 nmol/12 h) to a nadir value of 1.3 +/- 0.8 nmol/12 h (P less than 0.0005); similarly, the C-peptide to creatinine clearance ratio fell from 0.062 +/- 0.035 to 0.028 +/- 0.015 (P less than 0.05). These results indicate that fasting modifies renal metabolism of C-peptide thus creating several complications in the quantitative interpretation of urinary levels as an index of its secretion rate from the B-cell.