Outcomes of normothermic machine perfusion of liver grafts in repeat liver transplantation (NAPLES initiative).

BACKGROUND: Retransplantation candidates are disadvantaged owing to lack of good-quality liver grafts. Strategies that can facilitate transplantation of suboptimal grafts into retransplant candidates require investigation. The aim was to determine whether late liver retransplantation can be performed safely with suboptimal grafts, following normothermic machine perfusion. METHODS: A prospectively enrolled group of patients who required liver retransplantation received a suboptimal graft preserved via normothermic machine perfusion. This group was compared with both historical and contemporaneous cohorts of patient who received grafts preserved by cold storage. The primary outcome was 6-month graft and patient survival. RESULTS: The normothermic machine perfusion group comprised 26 patients. The historical (cold storage 1) and contemporaneous (cold storage 2) groups comprised 31 and 25 patients respectively. The 6-month graft survival rate did not differ between groups (cold storage 1, 27 of 31, cold storage 2, 22 of 25; normothermic machine perfusion, 22 of 26; P = 0.934). This was despite the normothermic machine perfusion group having significantly more steatotic grafts (8 of 31, 7 of 25, and 14 of 26 respectively; P = 0.006) and grafts previously declined by at least one other transplant centre (5 of 31, 9 of 25, and 21 of 26; P < 0.001). CONCLUSION: In liver retransplantation, normothermic machine perfusion can safely expand graft options without compromising short-term outcomes.

Liver transplantation is a life-saving procedure for many different diseases. In the UK, one in 10 patients awaiting transplant have had a previous liver transplant. These retransplant operations are complex, and the general belief is that a good-quality donor liver graft is required for best outcomes. However, there is a significant shortage of good-quality organs for liver transplantation, so many patients awaiting retransplantation spend longer on the waiting list. This study investigated whether a new technology, called normothermic machine perfusion, could be used to preserve lower-quality donor livers and have successful outcomes for patients undergoing retransplantation. Traditionally, good-quality livers are preserved in an ice box and the study compared the outcomes of these two different approaches. The aim was to prove that normothermic machine perfusion improves access to transplantation for this group of patients, without compromising outcomes. A group of patients who underwent retransplantation and received a lesser-quality liver preserved with normothermic machine perfusion was compared with two groups of patients who had received a transplant with traditional ice-box preservation. The complications, graft, and patient survival of the former group was compared with those in the latter two groups who underwent liver retransplantation with better-quality liver grafts. The rate of survival and adverse surgical outcomes were comparable between the groups of patients who received a liver preserved via traditional ice-box preservation, and those who received a lesser-quality liver preserved via normothermic machine perfusion. Normothermic machine perfusion can potentially expand the number of suitable donor livers available for retransplant candidates.

The effect of end-ischaemic normothermic machine perfusion on donor hepatic artery endothelial integrity.

BACKGROUND: Ex vivo normothermic machine liver perfusion (NMLP) involves artificial cannulation of vessels and generation of flow pressures. This could lead to shear stress-induced endothelial damage, predisposing to vascular complications, or improved preservation of donor artery quality. This study aims to assess the spatial donor hepatic artery (HA) endothelial quality downstream of the cannulation site after end-ischaemic NMLP. METHODS: Remnant HA segments from the coeliac trunk up to the gastroduodenal artery branching were obtained after NMLP (n = 15) and after static cold storage (SCS) preservation (n = 15). Specimens were fixed in 10% neutral buffered formalin and sectioned at pre-determined anatomical sites downstream of the coeliac trunk. CD31 immunohistostaining was used to assess endothelial integrity by a 5-point ordinal scale (grade 0: intact endothelial lining, grade 5: complete denudation). Endothelial integrity after SCS was used as a control for the state of the endothelium at commencement of NMP. RESULTS: In the SCS specimens, regardless of the anatomical site, near complete endothelial denudation was present throughout the HA (median scores 4.5-5). After NMLP, significantly less endothelial loss in the distal HA was present compared to SCS grafts (NMLP vs. SCS: median grade 3 vs. 4.5; p = 0.042). In NMLP specimens, near complete endothelial denudation was present at the cannulation site in all cases (median grade: 5), with significantly less loss of the endothelial lining the further from the cannulation site (proximal vs. distal, median grade 5 vs. 3; p = 0.005). CONCLUSION: Loss of endothelial lining throughout the HA after SCS and at the cannulation site after NMLP suggests extensive damage related to surgical handling and preservation injury. Gradual improved endothelial lining along more distal sites of the HA after NMLP indicates potential for re-endothelialisation. The regenerative effect of NMLP on artery quality seems to occur to a greater extent further from the cannulation site. Therefore, arterial cannulation for machine perfusion of liver grafts should ideally be as proximal as possible on the coeliac trunk or aortic patch, while the site of anastomosis should preferentially be attempted distal on the common HA.

Transarterial chemoembolization of hepatocellular carcinoma before liver transplantation and risk of post-transplant vascular complications: a multicentre observational cohort and propensity score-matched analysis.

BACKGROUND: Transarterial chemoembolization (TACE) in patients with hepatocellular cancer (HCC) on the waiting list for liver transplantation may be associated with an increased risk for hepatic artery complications. The present study aims to assess the risk for, primarily, intraoperative technical hepatic artery problems and, secondarily, postoperative hepatic artery complications encountered in patients who received TACE before liver transplantation. METHODS: Available data from HCC liver transplantation recipients across six European centres from January 2007 to December 2018 were analysed in a 1 : 1 propensity score-matched cohort (TACE versus no TACE). Incidences of intraoperative hepatic artery interventions and postoperative hepatic artery complications were compared. RESULTS: Data on postoperative hepatic artery complications were available in all 876 patients (425 patients with TACE and 451 patients without TACE). Fifty-eight (6.6 per cent) patients experienced postoperative hepatic artery complications. In total 253 patients who had undergone TACE could be matched to controls. In the matched cohort TACE was not associated with a composite of hepatic artery complications (OR 1.73, 95 per cent c.i. 0.82 to 3.63, P = 0.149). Data on intraoperative hepatic artery interventions were available in 825 patients (422 patients with TACE and 403 without TACE). Intraoperative hepatic artery interventions were necessary in 69 (8.4 per cent) patients. In the matched cohort TACE was not associated with an increased incidence of intraoperative hepatic artery interventions (OR 0.94, 95 per cent c.i. 0.49 to 1.83, P = 0.870). CONCLUSION: In otherwise matched patients with HCC intended for liver transplantation, TACE treatment before transplantation was not associated with higher risk of technical vascular issues or hepatic artery complications.

Lay Summary Patients with liver cancer may be treated with transarterial chemoembolization (TACE) during the period on the transplant waiting list. With TACE, chemotherapeutic coils are injected directly into the small arteries supplying the tumour, after which these vessels are closed. The aim of this therapy is to decrease the tumour size and slow down tumour growth. However, concerns are raised that manipulation of the main hepatic artery by TACE may cause damage to the artery itself. If this would result in problems during or after liver transplantation when the artery is connected to the artery supplying the donor liver, this may endanger the donor liver graft survival. The present study shows no increased risk in problems to connect the artery during liver transplantation after TACE treatment. Also, arterial complications after liver transplantation did not occur more frequently if patients had received TACE treatment. The authors therefore conclude that TACE treatment before liver transplantation could be considered a safe approach.

Heterotaxy syndrome with malrotation of the gut and interrupted vena cava does not preclude safe procurement of multivisceral graft.

We report the first successful procurement and transplantation of a multivisceral graft from a pediatric donor with polysplenic heterotaxy syndrome, including intestinal malrotation, midline liver with left-sided gallbladder and an interrupted inferior vena cava with azygous continuation. Procurement of the graft presented a surgical challenge in the presence of above anomalies. Modified approach to standard organ procurement and minor technical adaptation enabled successful transplantation. In an era of severe organ shortage of pediatric multivisceral grafts, a valuable organ offer should not lightly be declined for reasons of anatomic imperfections that might be overcome.

Prognostic value of insulin-like growth factor 1 and insulin-like growth factor binding protein 3 blood levels in breast cancer.

High circulating insulin-like growth factor 1 (IGF-1) levels are firmly established as a risk factor for developing breast cancer, especially estrogen positive tumors. The effect of circulating IGF-1 on prognosis once a tumor is established is unknown. The authors explored the effect of IGF-1 blood levels and of it's main binding protein, IGFBP-3, on overall survival and occurrence of second primary breast tumors in breast cancer patients, as well as reproductive and lifestyle factors that could modify this risk. Patients were accrued from six hospitals in the Netherlands between 1998 and 2003. Total IGF-1 and IGFBP-3 were measured in 582 plasma samples. No significant association between IGF-1 and IGFBP-3 plasma levels and overall survival was found. However, in a multivariate Cox regression model including standard prognostic variables high IGF-1 levels were related to worse overall survival in patients receiving endocrine therapy (HR = 1.37, 95% CI: 1.11, 1.69, P 0.004). These data at least indicate that higher IGF-1 levels, and as a consequence most likely IGF-1-induced signaling, are related to a less favorable overall survival in breast cancer patients treated with endocrine therapy. Interventions aimed at reducing circulating levels of IGF-1 in hormone receptor positive breast cancer may improve survival.

Treatment of breast cancer cells by IGF1R tyrosine kinase inhibitor combined with conventional systemic drugs.

AIM: Insulin-like growth factor-1 receptor (IGF1R) is a tyrosine kinase receptor mediating cell growth and survival of cancer cells. We studied responses to IGF1R tyrosine kinase inhibitor NVP-AEW541 combined with conventional systemic drugs in breast cancer cell lines of different clinical subtype. MATERIALS AND METHODS: Sensitivity to NVP-AEW541, single treatment and combinations with tamoxifen, trastuzumab, doxorubicin or paclitaxel, was tested in MCF7, SKBR3 and T47D cells. Cells were assayed for proliferation, cell death, cell cycle distribution and phosphorylation of proteins downstream of IGF1R. RESULTS: Treatment of NVP-AEW541 resulted in reduced proliferation, G-1 cell cycle arrest and reduced phosphorylation of protein kinase B (AKT) and extracellular-signal-regulated protein kinase (ERK). Sensitivity to IGF1R tyrosine kinase inhibition was low in T47D cells, despite their high IGF1R expression. NVP-AEW541 combined with trastuzumab had synergistic cytotoxic effects in T47D cells, and additive effects were shown in MCF7 and SKBR3 cells. Also, combination with doxorubicin had antagonistic effects in T47D cells. Doxorubicin caused up-regulation of phosphorylated ERK in T47D cells, which was not inhibited by NVP-AEW541. CONCLUSION: Antagonistic effects should be anticipated when IGF1R inhibitors are combined with conventional systemic drugs in a subset of breast tumors. Development of functional biomarkers predicting tumor response to tailored IGF1R therapy is warranted.

Characterization of the size and orientation of Na and Cl(2) nanocrystals in electron irradiated NaCl crystals by means of synchrotron radiation.

Samples of synthetic NaCl crystals have been exposed to doses of electron irradiation up to 10(-2) TGy (1 Trad) at about 100 °C, and studied subsequently at T = 95 K by means of synchrotron radiation (SR). In addition to the earlier established Kurdjumov-Sachs orientation relationship (K-S OR) for Na precipitates, the following OR is revealed between solid chlorine and the host NaCl crystal system: [Formula: see text], [Formula: see text]. The size and shape of the Cl(2) precipitates has been studied as a function of the amount of radiation damage (i.e. the concentrations of Na and Cl(2)).

Cognitive functioning in young and middle-aged unmedicated out-patients with major depression: testing the effort and cognitive speed hypotheses.

BACKGROUND: Cognitive deficits are common in major depressive disorder, but their nature is unclear. The effort hypothesis states that performance on effortful tasks is disproportionately impaired compared with the performance on automatic tasks. The cognitive speed hypothesis states that depression is characterized by cognitive slowness, which is a source of cognitive dysfunctioning. The present study investigated both theories in unmedicated adult depressive patients. It was also investigated whether the cognitive deficits can be attributed to more general physical illness-related factors or specifically to depressive disorder. METHOD: Thirty non-psychotic depressive out-patients were compared with 38 healthy control subjects and 25 patients with severe allergic rhinitis. The effects of group on more automatic and more effortful aspects of cognitive tasks measuring cognitive speed (Concept Shifting Task, Stroop Colour Word Test, Memory Scanning Test) and memory retrieval (Visual Verbal Learning Task, Verbal Fluency Test) were evaluated by MANCOVA. Age, sex, education and pre-morbid intelligence were treated as covariates. RESULTS: The depressive group had cognitive deficits in the automatic processing subtask of the Stroop, memory scanning and memory span. Performance on more effortful tasks was not impaired. CONCLUSIONS: Our results are more consistent with the cognitive speed hypothesis. Cognitive functioning in depressive disorder seems to be characterized by a reduced speed of information processing in automatic subtasks.

Salivary cortisol patterns and cognitive speed in major depression: a comparison with allergic rhinitis and healthy control subjects.

Few studies have investigated the relationship between cortisol and cognitive functions other than memory in depression. This study investigated daily salivary cortisol patterns (basal cortisol levels at 08:00, 16:00, and 21:00 h and flatness of the diurnal curve) in relation to cognitive speed and memory. Twenty-seven unmedicated outpatients with major depressive disorder (MDD) were compared with 36 healthy controls and with 20 allergic rhinitis patients, to determine whether effects should be ascribed to MDD or to more general disease-related processes. MDD patients were characterised by a flatter diurnal cortisol curve and by reduced cognitive speed. Flatter cortisol curves were associated with cognitive slowness. However, this relationship is unlikely to be causal; after control for depressive symptoms and group membership, flatness of the diurnal cortisol curve was no longer a significant predictor of cognitive slowness. Thus, MDD and related depressive symptoms appeared to be independently associated with altered cortisol secretory patterns and with decrements in cognitive speed.

Relationship between allergic rhinitis, disturbed cognitive functions and psychological well-being.

BACKGROUND: Symptomatic allergic rhinitis reduces quality of life as a result of the symptoms experienced and possibly as a result of impaired psychological well-being and cognitive functioning. Few investigations have measured cognitive functions objectively and it remains uncertain whether allergic rhinitis leads to an objective reduction in cognitive functions. OBJECTIVE: To evaluate the relationship between symptomatic allergic rhinitis, cognitive functions and psychological well-being. Differences between subjective and objective cognitive impairments were evaluated. METHODS: The cognitive functions (working memory, memory retrieval, speed of information processing and flexibility of information processing) and psychological well-being of 26 patients with symptomatic allergic rhinitis and 36 healthy controls matched for intelligence, education, age and sex were compared. The influence of education, intelligence, sex and age was considered. RESULTS: Overall, psychological well-being was significantly impaired in the patient group, as shown by higher scores in feelings of insufficiency, complaints of somatization, sleep disturbances and depressive feelings, whereas cognitive function was not. CONCLUSIONS: Allergic rhinitis was related to significantly impaired psychological well-being and to perceived impaired cognitive functioning. However, no significant objective impairment of cognitive functioning was found. Allergic patients may temporarily put more effort into sustaining performance, resulting in earlier exhaustion, which is not noticed during assessment but which impairs psychological well-being.

Children born small for gestational age: do they catch up?

Postnatal growth of 724 (423 premature, 301 full-term) small for gestational age infants (SGA, birth length less than the third length percentile (P3) for gestational age) was studied for the first 2 y of life. The study group consisted of all SGA infants who had been admitted over a period of 8 y at the Departments of Neonatology of three University Hospitals in The Netherlands with exclusion of infants with well defined causes for growth retardation, such as chromosomal disorders, syndromes, severe malformations, or complications during the neonatal period or later on. The aim of the study was to describe postnatal growth of SGA infants and to find predictive factors for catch-up growth > or = P3 during the first 2 y of life. The majority (around 85%) of the healthy SGA infants showed catch-up growth to a height > or = P3 during the first 2 y of life. The percentage of premature SGA infants with catch-up growth > or = P3 at 2 y of age (82.5%) was not significantly different from that of full-term SGA infants (87.5%). Birth length SDS was more sensitive than birth weight SDS in predicting catch-up > or = P3 in premature SGA infants. In contrast, birth weight SDS was the best predictor for catch-up > or = P3 in full-term SGA infants. Gestational age, multiple birth, and sex were not significantly associated with catch-up in height > or = P3.(ABSTRACT TRUNCATED AT 250 WORDS)

Day-to-day follow-up after a short oral treatment of acute vaginal candidosis with itraconazole.

Seventeen patients with acute vaginal candidosis were treated for 2 days with itraconazole (200 mg daily). During 5 days after the start of the treatment, patients were daily screened for the presence of Candida (culture and microscopy) and the presence of signs and symptoms. Four days after treatment, no Candida could be detected in smears of vaginal fluid and cultures from these patients. At that time leucorrhoea, pruritus, vulvitis, and erythema were strongly reduced but had not completely disappeared.