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In the last two decades there has been significant progress in research on and diagnosis of hepatocellular adenoma (HCA), resulting in the establishment of a molecular and immunohistological HCA classification. This review aims to fine-tune the current expertise in order to enhance the histopathological diagnostic possibilities, by refining issues that are already known, addressing diagnostic difficulties, and identifying still unknown aspects of HCA. We discuss novel methods to identify HCA subtypes, in particular the sonic hedgehog HCAs and the interpretation of glutamine synthetase patterns for the recognition of β-catenin-mutated HCAs. The major complications of HCAs, i.e. bleeding and malignant transformation, are considered, including the dilemmas of atypical and borderline lesions. HCAs in different clinical and geographical settings, e.g. pregnancy, cirrhosis and non-western countries, are also discussed. The natural history of the different HCA subtypes in relation to age, sex and risk factors is a feature that is still insufficiently investigated. This is also true for the risks of clinical bleeding and malignant transformation in association with HCA subtypes. As HCA is a relatively rare tumour, a multicentre and multidisciplinary approach across geographical boundaries will be the appropriate method to establish prospective programmes with which to identify, classify and manage HCAs, focusing on several aspects, e.g. aetiology, underlying liver disease, complications, regression, and growth. Updating what we know and identifying and addressing what we do not know matters for optimal patient management.

Background: Children with intestinal failure (IF) are at risk of loss of vascular access because of catheter-related venous thrombosis. Whether primary prophylactic anticoagulation is effective and safe in preventing catheter-related thrombosis is largely unknown. Our aim was to assess the incidences of catheter-related venous thrombosis and bleeding complications in children with IF receiving home parenteral nutrition (HPN) treated with primary prophylactic anticoagulation. Methods: All children, aged 0–18 years, treated with HPN at the Emma Children's Hospital/Amsterdam UMC were followed from January 2007 to July 2019. All patients were offered primary prophylactic anticoagulation from the start of HPN. The primary outcomes were catheter-related venous thrombosis and bleeding on prophylactic anticoagulation. Results: In total, 55 (76%) of 74 patients received primary prophylactic anticoagulation. The median age at the start of prophylaxis was 8.4 (interquartile range [IQR], 5.0–55.7) months. Patients were followed for a median of 31.2 (IQR, 10.7–53.5) months, with a total of 65,463 catheter days. The incidence of catheter-related thrombosis on prophylactic anticoagulation was 0.2 per 1000 catheter days. In total, the incidence of clinically relevant bleeding was 0.1 per 1000 catheter days. The median time to first event was 1268 (IQR, 149–2014) days for thrombosis and 389 (IQR, 227–2912) days for clinically relevant bleeding. Cumulative event-free survival after 5 years was 78% for thrombosis. Conclusions: Our study shows a low rate of catheter-related venous thrombosis and a slightly elevated rate of clinically relevant bleeding in children receiving HPN and primary prophylactic anticoagulation.

Objective To determine differences in clinical presentation and disease progression between patients with dementia due to AD with visually normal and abnormal EEG recordings. We hypothesized that patients with normal electroencephalographs (EEGs) are a representation of the heterogeneity of AD. We expected this group to have a phenotype with relatively predominant hippocampal atrophy, memory deficits, and a slower disease progression. Methods Patients were included based on diagnosis of dementia due to AD, positive amyloid and tau cerebrospinal fluid (CSF) biomarkers, and the availability of EEG recordings. Patients were categorized in groups of normal (N = 208) and abnormal (N = 336) EEG recordings based on visual assessment by experienced neurophysiologists. At baseline demographics, cognitive, MRI, and CSF measures were compared between groups. Cognitive data from follow‐up visits were assessed by linear mixed‐effects models (LMMs), and corrected for baseline value, sex, age, and educational level, to compare cognitive deterioration over time between groups. Results About 1 in 4.5 patients with AD dementia had a visually normal EEG and this group showed better overall cognitive performance compared to the abnormal group, where memory was the most prominent affected domain. The normal group showed less global and parietal but similar medial temporal atrophy. Follow‐up data showed a slower deterioration on all tested cognitive domains in the normal EEG group. Interpretation Patients with dementia due to AD and visually normal EEG recordings showed a milder clinical presentation and had a milder disease progression compared to patients with an abnormal EEG. These results provide evidence of clinical and biological heterogeneity within AD dementia.

BACKGROUND: In patients with non-severe hemophilia A, we lack detailed knowledge on the timing of treatment with factor VIII (FVIII) concentrates. This knowledge could provide information about the expected treatment timing in patients with severe hemophilia A treated with non-replacement therapies. OBJECTIVE: To assess the FVIII treatment history in patients with non-severe hemophilia A. METHODS: Patients with non-severe hemophilia (baseline FVIII activity [FVIII:C] 2-40 IU/dL) were included from the INSIGHT study. The primary outcome was median age at first FVIII exposure (ED1). In a subgroup of patients for whom more detailed information was available, we analyzed the secondary outcomes: median age at first 20 EDs, annualized bleeding rate for all bleeds (ABR), joint bleeds (AJBR), and major spontaneous bleeds (ASmBR). RESULTS: In the total cohort (n = 1013), median baseline FVIII activity was 8 IU/dL (interquartile range [IQR] 4-15) and the median age at ED1 was 3.7 years (IQR 1.4-7.7). Median age at ED1 rose from 2.5 years (IQR 1.2-5.7) in patients with FVIII:C 2-5 IU/dL to 9.7 years (IQR 4.8-16.0) in patients with FVIII:C 25-40 IU/dL. In the subgroup (n = 104), median age at ED1, ED5, ED10, and ED20 was 4.0 years (IQR 1.4-7.6), 5.6 years (IQR 2.9-9.3), 7.5 years (IQR 4.4-11.3), and 10.2 years (IQR 6.5-14.2), respectively. Median ABR, AJBR, and ASmBR were 1.1 (IQR 0.5-2.6), 0.3 (IQR 0.1-0.7), and 0 (IQR 0-0), respectively. CONCLUSION: This study demonstrates that in non-severe hemophilia A, the age at first FVIII exposure increases with baseline FVIII:C and that major spontaneous bleeds rarely occur. ispartof: JOURNAL OF THROMBOSIS AND HAEMOSTASIS vol:18 issue:12 pages:3203-3210 ispartof: location:England status: published

Hepatocellular adenomas (HCA) are rare benign tumors of the liver, occurring predominantly in females using oral contraceptives. Our case describes a 66-year-old woman presenting with a palpable mass in her upper abdomen. Contrast-enhanced computed tomography and magnetic resonance imaging showed a large exophytic mass protruding from the caudal border of liver segments IV and V, without visible metastases. Laparoscopic resection of the tumor and gallbladder was performed. Histopathological examination showed a hepatocellular carcinoma with areas of HNF1a-HCA (H-HCA). This case shows that malignant transformation is possible in H-HCA. We present our preoperative decision-making process, as well as the role of imaging techniques in this rare case.

Purpose We investigated in a single-center prospective trial (NCT03376386) the use of serial fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) to determine the boost dose and to guide boost segmentation in head and neck cancer. Methods and Materials Patients were eligible when treated with curative radiation therapy with or without systemic treatment for T2-4 squamous cell carcinoma of the hypopharynx, larynx, or oropharynx (20 patients in total). FDG-PET/CT scans were made at baseline and for redelineation and replanning at the end of weeks 2 and 4 of radiation therapy. The metabolically active part of the primary tumor received a 4 Gy boost on top of the 70 Gy baseline dose per partial metabolic response. The study would be considered feasible when ≥80% of adaptations were successful and no Common Terminology Criteria for Adverse Events grade ≥4 acute toxicity occurred. Results One patient received 70 Gy after complete metabolic response in week 2, and 12 patients received 78 Gy because of partial metabolic response at weeks 2 and 4. Seven patients received 74 Gy, either because of complete metabolic response at week 4 (n = 3) or a missed FDG-PET/CT (n = 4). The patients missed their FDG-PET/CT scans because they did not fast (n = 2) or at patients’ request (n = 2). In addition to the 4 missed FDG-PET/CT scans, 2 adaptive plans could not be finished successfully owing to logistical problems. In total, 85% of adaptations were completed correctly. No patient experienced grade ≥4 toxicity, and 40% had grade 3 dysphagia (tube feeding) during treatment. This decreased at 12 weeks posttreatment to 20%. Conclusions This prospective trial demonstrates the feasibility of serial FDG-PET/CT scans for dose escalation and patient selection.

Accurate identification of the underlying cause(s) of cognitive decline and dementia is challenging due to significant symptomatic overlap between subtypes. This study presents a multi-class classification framework for subjects with subjective cognitive decline, mild cognitive impairment, Alzheimer's disease, dementia with Lewy bodies, fronto-temporal dementia and cognitive decline due to psychiatric illness, trained on source-localized resting-state magnetoencephalography data. Diagnostic profiles, describing probability estimates for each of the 6 diagnoses, were assigned to individual subjects. A balanced accuracy rate of 41% and multi-class area under the curve value of 0.75 were obtained for 6-class classification. Classification primarily depended on posterior relative delta, theta and beta power and amplitude-based functional connectivity in the beta and gamma frequency band. Dementia with Lewy bodies (sensitivity: 100%, precision: 20%) and Alzheimer's disease subjects (sensitivity: 51%, precision: 90%) could be classified most accurately. Fronto-temporal dementia subjects (sensitivity: 11%, precision: 3%) were most frequently misclassified. Magnetoencephalography biomarkers hold promise to increase diagnostic accuracy in a noninvasive manner. Diagnostic profiles could provide an intuitive tool to clinicians and may facilitate implementation of the classifier in the memory clinic.

Intracranial hemorrhage (ICH) is a severe complication that is relatively common among patients with hemophilia. This systematic review aimed to obtain more precise estimates of ICH incidence and mortality in hemophilia, which may be important for patients, caregivers, researchers, and health policy makers. PubMed and EMBASE were systematically searched using terms related to “hemophilia” and “intracranial hemorrhage” or “mortality.” Studies that allowed calculation of ICH incidence or mortality rates in a hemophilia population ≥50 patients were included. We summarized evidence on ICH incidence and calculated pooled ICH incidence and mortality in 3 age groups: persons of all ages with hemophilia, children and young adults younger than age 25 years with hemophilia, and neonates with hemophilia. Incidence and mortality were pooled with a Poisson-Normal model or a Binomial-Normal model. We included 45 studies that represented 54 470 patients, 809 151 person-years, and 5326 live births of patients with hemophilia. In persons of all ages, the pooled ICH incidence and mortality rates were 2.3 (95% confidence interval [CI], 1.2-4.8) and 0.8 (95% CI 0.5-1.2) per 1000 person-years, respectively. In children and young adults, the pooled ICH incidence and mortality rates were 7.4 (95% CI, 4.9-11.1) and 0.5 (95% CI, 0.3-0.9) per 1000 person-years, respectively. In neonates, the pooled cumulative ICH incidence was 2.1% (95% CI, 1.5-2.8) per 100 live births. ICH was classified as spontaneous in 35% to 58% of cases. Our findings suggest that ICH is an important problem in hemophilia that occurs among all ages, requiring adequate preventive strategies.

Contains fulltext : 244007.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Persons with hemophilia and hepatitis C virus (HCV) infection have a lower health-related quality of life (HRQoL) than those never HCV infected. However, it is unknown whether HRQoL after HCV eradication is comparable to individuals never HCV infected. We aimed to compare HRQoL between HCV-cured and never chronically HCV-infected persons with hemophilia. METHODS: All persons with hemophilia in the Netherlands were invited for a nationwide study conducted in 2018-2019. For the current analysis, participants born before 1992 with data on HRQoL and HCV status were included. HCV status was collected from medical records. HRQoL was measured by RAND-36 questionnaire, with a minimally important difference set at 4.0 points. Multivariable linear regression was used to adjust for age, hemophilia severity, HIV status, and self-reported joint impairment. RESULTS: In total, 486 persons were eligible; 180 were HCV cured and 306 never chronically HCV infected. Compared with those never HCV infected, HCV-cured individuals were older (57 vs. 53 years), more often had severe hemophilia (67% vs. 21%), and reported more impaired joints (median 3 vs. 0). Compared with those never HCV infected, adjusted RAND-36 domain scores of HCV-cured individuals cured were lower on all RAND-36 domains except Pain, ranging from a difference of 4.5 (95% CI, -8.8 to -0.3) for Physical functioning to 11.3 (95% CI, -19.4 to -3.1) for Role limitations due to physical problems. CONCLUSION: Despite effective HCV treatment, HRQoL of HCV-cured persons with hemophilia is still lower than HRQoL of those never chronically HCV-infected on all RAND-36 domains. This implies that careful psychosocial follow-up and support are indicated.

Background: Legacy hemophilia-specific questionnaires are considered too long, show floor-/ceiling effects, and/or include irrelevant questions. Patient Reported Outcomes Measurement Information System (PROMIS) item banks, including Computer Adaptive Tests (CATs) and short forms, were designed for more efficient outcome assessment. Objectives: Evaluate the feasibility, measurement properties, and relevance of seven PROMIS CATs and two short forms in patients with hemophilia. Patients/Methods: In this cross-sectional study, Dutch adults with hemophilia completed nine PROMIS item banks electronically. Feasibility was assessed by number of items and floor/ceiling effects. Reliability was determined as the proportion of reliable scores (standard error ≤3.2). Construct validity was assessed by comparison with legacy instruments and expected differences between subgroups. Relevance of item banks was determined by proportions of limited scores. Results: Overall, 142 of 373 invited patients (mean age, 47 [range, 18-79], 49% severe hemophilia, 46% receiving prophylaxis) responded. Per CAT item bank, mean number of items answered varied from 5 (range, 3-12) to 9 (range, 5-12), with floor effects in pain interference (26% lowest scores) and depression (18% lowest scores). Construct validity and reliability were good for physical function, pain interference, satisfaction with social roles and activities, and fatigue. The CAT physical function showed the most limited scores (38%). The self-efficacy short forms showed ceiling effects (22%-28%) and no relation with the legacy instruments. Conclusions: The PROMIS CATs physical function, pain interference, satisfaction with social roles and activities, and fatigue are feasible, reliable, and valid alternatives to legacy instruments for patients with hemophilia, with few items and low floor-/ceiling effects.

Background The mechanism of synaptic loss in Alzheimer’s disease is poorly understood and may be associated with tau pathology. In this combined positron emission tomography (PET) and magnetoencephalography (MEG) study, we aimed to investigate spatial associations between regional tau pathology ([18F]flortaucipir PET), synaptic density (synaptic vesicle 2A [11C]UCB-J PET) and synaptic function (MEG) in Alzheimer’s disease. Methods Seven amyloid-positive Alzheimer’s disease subjects from the Amsterdam Dementia Cohort underwent dynamic 130-min [18F]flortaucipir PET, dynamic 60-min [11C]UCB-J PET with arterial sampling and 2 × 5-min resting-state MEG measurement. [18F]flortaucipir- and [11C]UCB-J-specific binding (binding potential, BPND) and MEG spectral measures (relative delta, theta and alpha power; broadband power; and peak frequency) were assessed in cortical brain regions of interest. Associations between regional [18F]flortaucipir BPND, [11C]UCB-J BPND and MEG spectral measures were assessed using Spearman correlations and generalized estimating equation models. Results Across subjects, higher regional [18F]flortaucipir uptake was associated with lower [11C]UCB-J uptake. Within subjects, the association between [11C]UCB-J and [18F]flortaucipir depended on within-subject neocortical tau load; negative associations were observed when neocortical tau load was high, gradually changing into opposite patterns with decreasing neocortical tau burden. Both higher [18F]flortaucipir and lower [11C]UCB-J uptake were associated with altered synaptic function, indicative of slowing of oscillatory activity, most pronounced in the occipital lobe. Conclusions These results indicate that in Alzheimer’s disease, tau pathology is closely associated with reduced synaptic density and synaptic dysfunction.

The aim of this study was to determine the extent to which the Tyme Wear smart shirt is as reliable and valid in detecting personalized ventilatory thresholds when compared to the Parvo Medics TrueOne 2400. In this validation study, 19 subjects were recruited to conduct two graded exercise test (GXT) trials. Each GXT trial was separated by seven to ten days of rest. During the GXT, gas exchange and heart rate data were collected by the TrueOne 2400 (TRUE) in addition to the ventilation data collected by the Tyme Wear smart shirt (S-PRED). Gas exchange data from TRUE was used to detect VT1 and VT2. TRUE and S-PRED VT1 and VT2 were compared to determine the reliability and validity of the smart shirt. Of the 19 subjects, data from 15 subjects were used during analysis. S-PRED exhibited excellent (ICC > 0.90) reliability for detection of VT1 and VT2 utilizing time point and workload and moderate (0.90 > ICC > 0.75 ) reliability utilizing heart rate. TRUE exhibited excellent reliability for detection of VT1 and VT2 utilizing time point, workload, and heart rate. When compared to TRUE, S-PRED appears to underestimate the VT1 workload (p > 0.05) across both trials and heart rate (p < 0.05) for trial 1. However, S-PRED appears to underestimate VT2 workload (p < 0.05) and heart rate (p < 0.05) across both trials. The result from this study suggests that the Tyme Wear smart shirt is less valid but is comparable in reliability when compared to the gold standard. Moreover, despite the underestimation of S-PRED VT1 and VT2, the S-PRED detected personalized ventilatory thresholds will provide an adequate training workload for most individuals. In conclusion, the Tyme Wear smart shirt provides easily accessible testing to establish threshold-guided training zones but does not devalue the long-standing laboratory equivalent.

The autonomic nervous system plays a role in a variety of liver regenerative and metabolic functions, including modulating bile secretion and cholangiocyte and hepatobiliary progenitors of the canals of Hering. However, the nature and location of nerves which link to the proximal biliary tree have remained uncertain. We investigate the anatomic relationship of nerves to the proximal biliary tree including the putative stem/progenitor cell niche of the canal of Hering. Using double immunostaining (fluorescence, histochemistry) to highlight markers of cholangiocytes (biliary-type keratins), nerves (S100, neurofilament protein, PGP9.5, tyrosine hydroxylase), and stellate cells (CRBP-1), we examined sections from normal adult livers from autopsy or surgical resections. There is extensive contact between nerves and interlobular bile ducts, bile ductules, and canals of Hering (CoH). In multiple serial sections from 4 normal livers, biliary-nerve contacts were seen in all of these structures and were more common in the interlobular bile ducts (78/137; 57%) than in the ductules and CoH (95/294; 33%) (p

OBJECTIVE: In clinical trials in Alzheimer's Disease (AD), an improvement of impaired functional connectivity (FC) could provide biological support for the potential efficacy of the drug. Electroencephalography (EEG) analysis of the SAPHIR-trial showed a treatment induced improvement of global relative theta power but not of FC measured by the phase lag index (PLI). We compared the PLI with the amplitude envelope correlation with leakage correction (AEC-c), a presumably more sensitive FC measure.METHODS: Patients with early AD underwent 12 weeks of placebo or treatment with PQ912, a glutaminylcyclase inhibitor. Eyes-closed task free EEG was measured at baseline and follow-up (PQ912 n = 47, placebo n = 56). AEC-c and PLI were measured in multiple frequency bands. Change in FC was compared between treatment groups by using two models of covariates.RESULTS: A significant increase in global AEC-c in the alpha frequency band was found with PQ912 treatment compared to placebo (p = 0.004, Cohen's d = 0.58). The effect remained significant when corrected for sex, country, ApoE ε4 carriage, age, baseline value (model 1; p = 0.006) and change in relative alpha power (model 2; p = 0.004).CONCLUSIONS: Functional connectivity in early AD, measured with AEC-c in the alpha frequency band, improved after PQ912 treatment.SIGNIFICANCE: AEC-c may be a robust and sensitive FC measure for detecting treatment effects.

BACKGROUND & AIMS: Bu Gu Zhi (BGZ) is a Chinese herb consumed mainly for osteoporosis treatment. Only small case series of BGZ-induced liver injury (BGZILI) have been reported. We describe the clinicopathological features and clinical course of BGZILI.METHODS: Patients diagnosed with drug-induced liver injury (DILI) at Beijing Friendship Hospital from 2005 to 2017 were reviewed. Clinical and follow-up data were analysed.RESULTS: Of the 547 DILI patients, 40 cases (7.3%) were attributed to BGZILI. About 34/40 (85.0%) patients were females with a median age of 63 (range, 54-70) years. The median latency period was 45 (range, 29-90) days. Patients commonly presented with loss of appetite (57.5%), dark urine (57.5%) and fatigue (55.0%). The median level of alanine aminotransferase and aspartate aminotransferase at BGZILI onset was 673.5 and 423.0 U/L respectively. Total bilirubin (TB) and direct bilirubin (DB) were 59.0 and 39.4 µmol/L respectively. The biochemical liver injury pattern was hepatocellular (92.5%), cholestatic (5.0%) and mixed (2.5%). They were categorized into 'mild' (N = 23, 57.5%), 'moderate' (6, 15.0%) or 'severe' (11, 27.5%) according to severity assessment by DILI network. The main histological injury pattern in 9/40 patients with liver biopsy was acute hepatitis with/without cholestasis. Median duration of follow-up was 26.3 months with recovery in 37 patients within 6 months. No patients died or required transplantation.CONCLUSIONS: BGZ-induced liver injury manifested more often as a hepatocellular injury pattern with mild to moderate hepatocellular damage. Most patients recovered after cessation of BGZ within 6 months, and none developed end-stage liver disease or died.

Background and aims Non-alcoholic fatty liver disease (NAFLD) commonly affects subjects with obesity, yet non-obese NAFLD is increasingly being recognized. We aimed to investigate the clinicopathological and genetic characteristics of non-obese NAFLD patients. Methods The clinical, histological and genetic data of 84 NAFLD patients with biopsy for abnormal liver function test were reviewed. Both NAS-CRN and SAF scoring systems were applied for histopathological evaluation. PNPLA3 and TMS6F2 genotyping were also performed. Results All of the 84 patients were histologically diagnosed with non-alcoholic steatohepatitis (NASH), with 36 of them (42.9%) being non-obese (BMI

Hepatocyte nuclear factor 1A (HNF1A) maturity-onset diabetes of the young (MODY) is a monogenetic, autosomal dominantly inherited form of diabetes. HNF1A-MODY is associated with HNF1A-inactivated hepatocellular adenoma (H-HCA) formation. Hepatocellular adenoma (HCA) are benign liver tumours and related complications are rare but serious: hepatic haemorrhage and malignant transformation. Guidelines recommend resection of all HCA in men and do not take any co-occurring metabolic disorders into account. We report a family with HCA preceding diabetes mellitus. Male index patient presented with numerous, irresectable HCA. After initial diagnostic and aetiologic uncertainty HNF1A germline mutation c.815G>A (p.Arg272His) was confirmed 8 years later. No HCA-related complications occurred. His diabetic mother was diagnosed with HCA after severe hepatic haemorrhage years before. HNF1A-MODY should be considered in (non-)diabetic (male) patients with H-HCA. We advocate liver biopsy and, if necessary, genetic analysis to precede any intervention for HCA in males and screening for HCA in HNF1A-MODY patients.

Objective: The aim of the current study was to determine the incidence of organ function preservation failure (OFPF) in patients with head and neck squamous cell carcinoma (HNSCC) treated by (chemo)radiotherapy and to identify its risk factors. Study Design: Retrospective cohort analysis. Setting: Tertiary cancer care center. Subjects and Methods: A single-center retrospective cohort analysis was done (n = 703) in which OFPF after (chemo)radiotherapy was assessed. OFPF was defined as local failure or pure functional failure in the absence of local failure because of major surgical intervention (total laryngectomy, commando resection, permanent tracheostomy) or feeding tube dependence >2 years. Results: OFPF occurred in 153 patients (21.8%). Reasons for OFPF were local failure in 103 patients (14.6%) and functional failure in 50 patients (7.2%). Evidence of functional failure included need for total laryngectomy (n = 9, 1.3%), commando resection (n = 2, 0.3%), permanent tracheostomy (n = 16, 2.3%), and/or long-term feeding tube for functional reasons (n = 23, 3.3%). In a Cox proportional hazards model, OFPF was worse for patients with T4 tumors (hazard ratio [HR]

Supplemental Digital Content is available in the text., Background. Ex situ normothermic machine perfusion (NMP) can be used to assess viability of suboptimal donor livers before implantation. Our aim was to assess the diagnostic accuracy of bile biochemistry for the assessment of bile duct injury (BDI). Methods. In a preclinical study, 23 human donor livers underwent 6 hours of end-ischemic NMP to determine biomarkers of BDI. Livers were divided into groups with low or high BDI, based on a clinically relevant histological grading system. During NMP, bile was analyzed biochemically and potential biomarkers were correlated with the degree of BDI. Receiver operating characteristics curves were generated to determine optimal cutoff values. For clinical validation, identified biomarkers were subsequently included as viability criteria in a clinical trial (n = 6) to identify transplantable liver grafts with low BDI. Results. Biliary bicarbonate and pH were significantly higher and biliary glucose was significantly lower in livers with low BDI, compared with high BDI. The following cutoff values were associated with low BDI: biliary bicarbonate greater than 18 mmol/L (P = 0.002), biliary pH greater than 7.48 (P = 0.019), biliary glucose less than 16 mmol/L (P = 0.013), and bile/perfusate glucose ratio less than 0.67 (P = 0.013). In the clinical trial, 4 of 6 livers met these criteria and were transplanted, and none developed clinical evidence of posttransplant cholangiopathy. Conclusions. Biliary bicarbonate, pH, and glucose during ex situ NMP of liver grafts are accurate biomarkers of BDI and can be easily determined point of care, making them suitable for the pretransplant assessment of bile duct viability. This may improve graft selection and decrease the risk of posttransplant cholangiopathy.

BACKGROUND & AIMS: Hepatocellular Adenomas (HCA) are rare, hormone driven, benign liver tumors. HCA >50mm are associated with hemorrhage and malignant transformation. Guidelines recommend cessation of oral contraceptive pills (OCP) for size reduction, however, it is currently unknown how HCA respond to cessation of OCP. We sought to investigate the effect of OCP cessation on HCA size.METHODS: A retrospective cohort study was performed including HCA patients who stopped OCP intake within six months of imaging between 2005-2018. Biometrics and hormonal medication use were evaluated with self-designed questionnaires. Response of the largest HCA was evaluated according to Response Evaluation Criteria in Solid Tumors (RECISTv1.1). Cox regression was performed for analysis of factors influencing HCA regression.RESULTS: Seventy-eight HCA patients were included, diagnosed at a median (IQR) age of 32 (26-41) years. Follow-up was 1.6 (0.4-2.9) years. HCA size at diagnosis ranged 10-167mm. After a median time of 1.3 (0.6 - 2.6) years after OCP cessation, 37.2% of HCA showed >30% regression, 5.1% complete regression, 56.4% stability, and 1.3% progression. No HCA induced complications were observed during follow-up. Cox regression analysis demonstrated a significant association of HCA size with rate of regression; 50≤HCA100mm (HR 8.3, 95% CI 3.3-21.6; pCONCLUSIONS: Ninety-eight percent of HCA remained stable or regressed after OCP cessation. A longer wait-and-see period was associated with a larger proportion of regressing HCA, without HCA related complications during follow-up. This article is protected by copyright. All rights reserved.

Purpose: Early detection of residual disease (RD) after (chemo)radiation for oropharyngeal (OPC) is crucial. Surveillance of neck nodes with FDG-PET/CT has been studied extensively, whereas its value for local RD remains less clear. We aim to evaluate the diagnostic value of post-treatment FDG-PET/CT in detecting local RD and the outcome of patients with local RD. Methods: A cohort (n = 352) of consecutively treated OPC patients at our institute between 2010 and 2017 was evaluated. Patients that underwent FDG-PET/CT at 3 months post-treatment (n = 94) were classified as having complete (CMR) or partial metabolic response (PMR). PMR was defined as visually detectable metabolic activity above the background of surrounding normal tissues. Primary endpoint was diagnostic accuracy in detecting local RD. Results: Local RD was seen in 19/352 patients (5%), all of them were HPV negative. The FDG-PET/CT had a sensitivity of 100% (8/8), specificity 85% (73/86), PPV 38% (8/21), NPV 100% (73/73), and accuracy 86%. Patients with local RD had significantly worse OS at 2 years, compared to those without (10 versus 88%, P < 0.001). In multivariable analysis, local RD remained a significant predictive factor for death with a hazard ratio of 11.9 (95% CI 5.8–24.3). The number of patients that underwent PET/CT increased over time (P < 0.001), whereas the number of patients that underwent EUA declined (P = 0.072). Conclusion: FDG-PET/CT has excellent performance for the detection of RD, with the sensitivity and negative predictive value approaching 100%. Due to these excellent results is examination under anaesthesia today in the vast majority of the PET-negative cases not necessary anymore.

Background There is a need to identify patients with haemophilia who have a very low or high risk of developing inhibitors. These patients could be candidates for personalized treatment strategies. Aims The aim of this study was to externally validate a previously published prediction model for inhibitor development and to develop a new prediction model that incorporates novel predictors. Methods The population consisted of 251 previously untreated or minimally treated patients with severe haemophilia A enrolled in the SIPPET study. The outcome was inhibitor formation. Model discrimination was measured using the C-statistic, and model calibration was assessed with a calibration plot. The new model was internally validated using bootstrap resampling. Results Firstly, the previously published prediction model was validated. It consisted of three variables: family history of inhibitor development, F8 gene mutation and intensity of first treatment with factor VIII (FVIII). The C-statistic was 0.53 (95% CI: 0.46-0.60), and calibration was limited. Furthermore, a new prediction model was developed that consisted of four predictors: F8 gene mutation, intensity of first treatment with FVIII, the presence of factor VIII non-neutralizing antibodies before treatment initiation and lastly FVIII product type (recombinant vs. plasma-derived). The C-statistic was 0.66 (95 CI: 0.57-0.75), and calibration was moderate. Using a model cut-off point of 10%, positive- and negative predictive values were 0.22 and 0.95, respectively. Conclusion Performance of all prediction models was limited. However, the new model with all predictors may be useful for identifying a small number of patients with a low risk of inhibitor formation.

OBJECTIVES: New markers are required to predict chemoradiation response in oropharyngeal squamous cell carcinoma (OPSCC) patients. This study evaluated the ability of magnetic resonance (MR) radiomics to predict locoregional control (LRC) and overall survival (OS) after chemoradiation and aimed to determine whether this has added value to traditional clinical outcome predictors.METHODS: 177 OPSCC patients were eligible for this study. Radiomic features were extracted from the primary tumor region in T1-weighted postcontrast MRI acquired before chemoradiation. Logistic regression models were created using either clinical variables (clinical model), radiomic features (radiomic model) or clinical and radiomic features combined (combined model) to predict LRC and OS 2-years posttreatment. Model performance was evaluated using area under the curve (AUC), 95 % confidence intervals were calculated using 500 iterations of bootstrap. All analyses were performed for the total population and the Human papillomavirus (HPV) negative tumor subgroup.RESULTS: A combined model predicted treatment outcome with a higher AUC (LRC: 0.745 [0.734-0.757], OS: 0.744 [0.735-0.753]) than the clinical model (LRC: 0.607 [0.594-0.620], OS: 0.708 [0.697-0.719]). Performance of the radiomic model was comparable to the combined model for LRC (AUC: 0.740 [0.729-0.750]), but not for OS prediction (AUC: 0.654 [0.646-0.662]). In HPV negative patients, the performance of all models was not sufficient with AUCs ranging from 0.587 to 0.660 for LRC and 0.559 to 0.600 for OS prediction.CONCLUSION: Predictive models that include clinical variables and radiomic tumor features derived from MR images of OPSCC better predict LRC after chemoradiation than models based on only clinical variables. Predictive models that include clinical variables perform better than models based on only radiomic features for the prediction of OS.

Contains fulltext : 237722.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Prophylactic replacement therapy (prophylaxis) in patients with haemophilia (PWH) requires lifelong, frequent (self)infusions. Prophylaxis effectiveness depends on adherence, and the drivers of treatment adherence among PWH are unclear. AIM: To quantify prophylaxis adherence and associations between adherence and patients' treatment attitudes and satisfaction in a large cohort of children and adults with haemophilia. METHODS: In a nationwide, cross-sectional, questionnaire-based study, PWH with complete information currently using prophylaxis were selected. Validated Hemophilia Regimen Treatment Adherence Scale-Prophylaxis (VERITAS-Pro; normalised score range: 0-100, optimum 0) measured treatment adherence; the Patient Activation Measure (PAM-13; total score range 0-100, optimum 100) measured activation of self-management; Hemophilia Patient Satisfaction Scale (Hemo-Sat; range 0-100, optimum 0) measured treatment satisfaction. Groups were compared according to age (children: 18 years) and adherence levels using non-parametric tests, and correlations were assessed using Spearman's rho. RESULTS: Among 321 participants (median age 33 years, interquartile range [IQR]:15-54 years), adherence was high (median VERITAS-Pro total score 17, 89% adherent) but worsened with age, with median scores of 5, 14 and 20 in children, adolescents, adults, respectively (p

Since the introduction of episodic and prophylactic treatments with safer factor concentrates, the life expectancy of people with haemophilia (PwH) has improved considerably. Ageing-related diseases such as cardiovascular disease (CVD) have also become more prevalent in PwH. This cross-sectional study aimed to evaluate CVD risk factors and estimate 10-year risk for CVD events among PwH. Male patients >= 30 years were interviewed and examined. Blood tests were performed at the local laboratory. Eighty-two patients were included, of whom 83% had haemophilia A and half had severe disease. Median age at study entry was 43.0 years (interquartile range [IQR], 36.0-51.3). Prevalence of obesity, systemic arterial hypertension (SAH) and diabetes mellitus were 16%, 60% and 16%, respectively. Hypertriglyceridaemia, hypercholesterolaemia and low HDL blood levels were present in 18%, 41% and 30% of patients, respectively. Metabolic syndrome was found in 37%. The Framingham Risk Score showed that 39% of PwH had a high risk of developing cardiovascular events in the following 10 years. We conclude that, in this cohort, PwH have a higher prevalence of SAH when compared with Brazilian men without haemophilia and about two-fifths have a high risk of developing a CVD event in the following 10 years.

Background: Patient-relevant health outcomes for persons with hemophilia should be identified and prioritized to optimize and individualize care for persons with hemophilia. Therefore, an international group of persons with hemophilia and multidisciplinary health care providers set out to identify a globally applicable standard set of health outcomes relevant to all individuals with hemophilia. Methods: A systematic literature search was performed to identify possible health outcomes and risk adjustment variables. Persons with hemophilia and multidisciplinary health care providers were involved in an iterative nominal consensus process to select the most important health outcomes and risk adjustment variables for persons with hemophilia. Recommendations were made for outcome measurement instruments. Results: Persons with hemophilia were defined as all men and women with an X-linked inherited bleeding disorder caused by a deficiency of coagulation factor VIII or IX with plasma activity levels

Contains fulltext : 237741.pdf (Publisher’s version ) (Open Access) INTRODUCTION: We conducted six cross-sectional nationwide questionnaire studies among all patients with hemophilia in the Netherlands from 1972 until 2019 to assess how health outcomes have changed, with a special focus on patients >50 years of age. METHODS: Data were collected on patient characteristics, treatment, (joint) bleeding, joint impairment, hospitalizations, human immunodeficiency virus and hepatitis C infections, and general health status (RAND-36). RESULTS: In 2019, 1009 patients participated, of whom 48% had mild, 15% moderate, and 37% severe hemophilia. From 1972 to 2019, the use of prophylaxis among patients with severe hemophilia increased from 30% to 89%. Their median annual bleeding rate decreased from 25 to 2 bleeds. Patients with severe hemophilia aged 40 years joint status did not improve. In 2019, 5% of all 1009 patients were positive for the human immunodeficiency virus. The proportion of patients with an active hepatitis C infection drastically decreased from 45% in 2001 to 2% in 2019 due to new anti-hepatitis C treatment options. Twenty-five percent had significant liver fibrosis even after successful therapy. Compared to the general male population, patients aged >50 years reported much lower scores on the RAND-36, especially on physical functioning. DISCUSSION/CONCLUSION: Our study shows that increased use of prophylactic treatment and effective hepatitis C treatment have improved joint health and nearly eradicated hepatitis C infection in patients with hemophilia in the Netherlands. However, patients still suffer from hemophilia-related complications, especially patients aged >50 years.

Background: Non-severe hemophilia A patients have a life-long inhibitor risk. Yet, no studies have analyzed risk factors for inhibitor development after 50 factor VIII (FVIII) exposure days (EDs). Objectives: This case-control study investigated treatment-related risk factors for inhibitor development in non-severe hemophilia A and assessed whether these risk factors were different for early versus late inhibitor development. Patients/Methods: Non-severe hemophilia A patients (FVIII:C 2%–40%) were selected from the INSIGHT study. Inhibitor-positive patients were defined as early (50EDs) cases and matched to 1–4 inhibitor-negative controls by year of birth, cumulative number of EDs, and center/country. We investigated treatment intensity during the last 10 EDs prior to inhibitor development. Intensive treatment was defined as: surgery, peak treatment (10 consecutive EDs), and high mean FVIII dose (>45 IU/kg/ED). Odds ratios (OR) were calculated by logistic regression. Results: Of 2709 patients, we analyzed 63 early and 26 late cases and 195 and 71 respectively matched controls. Peak treatment was associated with early and late inhibitor risk (crude OR 1.8, 95% confidence interval [CI] 1.0–3.4; 4.0, 95%CI 1.1–14.3). This association was slightly less pronounced after adjustment for mean FVIII dose. High mean FVIII dose was also associated with early and late inhibitor risk (crude OR 2.8, 95%CI 1.5–5.1; 4.5, 95%CI 1.2–16.6). Surgery increased inhibitor risk for early cases. This was less pronounced for late cases. Conclusions: Our findings suggest that intensive FVIII treatment remains a risk factor for inhibitor development in non-severe hemophilia A after more than 50 EDs. Therefore, persistent caution is required throughout the life-time treatment course.

BACKGROUND & AIMS: Non-anastomotic biliary strictures (NAS) are a major cause of morbidity after orthotopic liver transplantation (OLT). Although ischemic injury of peribiliary glands (PBGs) and peribiliary vascular plexus (PVP) during OLT has been associated with the later development of NAS, the exact underlying mechanisms remain unclear. We hypothesized that bile ducts of patients with NAS suffer from ongoing biliary hypoxia and lack of regeneration from PBG stem/progenitor cells.APPROACH & RESULTS: Forty-two patients, requiring retransplantation for either NAS (n=18), hepatic artery thrombosis (HAT; n=13) or non-biliary graft failure (controls; n=11), were included in this study. Histomorphologic analysis of perihilar bile ducts was performed to assess differences in markers of cell proliferation and differentiation in PBGs, microvascular density, and hypoxia. In addition, isolated human biliary tree stem cells (hBTSCs) were used to examine exo-metabolomics during in vitro differentiation toward mature cholangiocytes. Bile ducts of patients with NAS or HAT had significantly reduced indices of PBG mass, cellular proliferation and differentiation (mucus production, secretin receptor expression, primary cilia), reduced microvascular density, and increased PBG apoptosis and hypoxia marker expression, compared to controls. Metabolomics of hBTSCs during in vitro differentiation toward cholangiocytes revealed a switch from a glycolytic to oxidative metabolism, indicating the need for oxygen.CONCLUSIONS: NAS are characterized by a microscopic phenotype of chronic biliary hypoxia due to loss of microvasculature, resulting in reduced proliferation and differentiation of PBG stem/progenitor cells into mature cholangiocytes. These findings suggest that persistent biliary hypoxia is a key mechanism underlying the development of NAS after OLT.

Introduction: We report the routine application of magnetoencephalography (MEG) in a memory clinic, and its value in the discrimination of patients with Alzheimer's disease (AD) dementia from controls.Methods: Three hundred sixty-six patients visiting our memory clinic underwent MEG recording. Source-reconstructed MEG data were visually assessed and evaluated in the context of clinical findings and other diagnostic markers. We analyzed the diagnostic accuracy of MEG spectral measures in the discrimination of individual AD dementia patients (n = 40) from subjective cognitive decline (SCD) patients (n = 40) using random forest models.Results: Best discrimination was obtained using a combination of relative theta and delta power (accuracy 0.846, sensitivity 0.855, specificity 0.837). The results were validated in an independent cohort. Hippocampal and thalamic regions, besides temporal-occipital lobes, contributed considerably to the model.Discussion: MEG has been implemented successfully in the workup of memory clinic patients and has value in diagnostic decision-making.

Contains fulltext : 245086.pdf (Publisher’s version ) (Open Access) BACKGROUND: Treatment of patients with hemophilia has advanced over the past decades, but it is unknown whether this has resulted in a normal life expectancy in the Netherlands. OBJECTIVE: This observational cohort study aimed to assess all-cause and cause-specific mortality in patients with hemophilia in the Netherlands between 2001 and 2018 and to compare mortality and life expectancy with previous survival assessments from 1973 onward. PATIENTS/METHODS: All 1066 patients with hemophilia who participated in a nationwide survey in 2001 were followed until July 2018. RESULTS: Information on 1031 individuals (97%) was available, of whom 142 (14%) deceased during follow-up. Compared with the general Dutch male population, mortality of patients with hemophilia was still increased (standardized mortality ratio: 1.4, 95% confidence interval: 1.2-1.7). Intracranial bleeding and malignancies were the most common causes of death. Estimated median life expectancy of patients with hemophilia was 77 years, 6 years lower than the median life expectancy of the general Dutch male population (83 years). Over the past 45 years, death rates of patients with hemophilia have consistently decreased, approaching the survival experience of the general population. Over the past decades, mortality due to human immunodeficiency virus and hepatitis C virus infections has decreased, death due to intracranial hemorrhages has increased, and death due to ischemic heart disease has remained consistently low over time. CONCLUSIONS: Survival in patients with hemophilia in the Netherlands has improved over time but is still lower than that of the general population.

ObjectivesTwo-thirds of patients do not harbor lymph node (LN) metastases after neoadjuvant chemoradiotherapy (nCRT). Our aim was to explore under which circumstances a selective lymph node dissection (LND) strategy, which selects patients for LND based on the restaging results after nCRT, has added value compared with standard LND in esophageal cancer.DesignA decision tree with state-transition model was developed. Input data on short-term and long-term consequences were derived from literature. Sensitivity analyses were conducted to assess promising scenarios and uncertainty.SettingDutch healthcare system.ParticipantsHypothetical cohort of esophageal cancer patients who have already received nCRT and are scheduled for esophagectomy.InterventionsA standard LND cohort was compared with a cohort of patients that received selective LND based on the restaging results after nCRT.Main outcome measuresQuality-adjusted life years (QALYs), residual LN metastases and LND-related complications.ResultsSelective LND could have short-term benefits, that is, a decrease in the number of performed LNDs and LND-related complications. However, this may not outweigh a slight increase in residual LN metastases which negatively impacts QALYs in the long-term. To accomplish equal QALYs as with standard LND, a new surgical strategy should have the same or higher treatment success rate as standard LND, that is, should show equal or less recurrences due to residual LN metastases.ConclusionsThe reduction in LND-related complications that is accomplished by selecting patients for LND based on restaging results after nCRT seems not to outweigh a QALY loss in the long-term due to residual LN metastases. Despite the short-term advantages of selective LND, this strategy can only match long-term QALYs of standard LND when its success rate equals the success rate of standard LND.

Introduction: Chimerism after orthotopic liver transplantation (OLT) has largely been investigated in intrahepatic cellular constituents. However, little is known about chimerism in the extrahepatic and large intrahepatic bile ducts. Our aim was to evaluate the presence and extent of chimerism after OLT in the peribiliary glands (PBG) and the luminal epithelium of the large donor bile ducts.Methods: For this study, we examined six extrahepatic and large intrahepatic bile ducts from livers that were re-transplanted. In all cases there was a sex-mismatch between donor and recipient (female donor organ and male recipient), which allowed to discriminate between donor- and recipient-derived cells. Specimens from female to female transplants were used as negative controls and male to male transplants as positive controls. Fluorescence in situ hybridization (FISH) for Y and X chromosomes was performed and the percentage of XY positive cells was determined among biliary epithelial cells. Immunohistochemistry was used to correlate chimerism with histological features.Results: Cholangiocellular chimerism in all studied specimens ranged from 14 to 52%. The degree of chimerism was not associated with biliary damage. Marked chimerism was present at 5 days post-OLT. Ki-67-positivity was detected in 1-8% of the epithelial cells at the time of liver re-transplantation, and this correlated inversely with the degree of chimerism.Conclusion: Recipient-derived cholangiocytes are present in the large bile ducts of the donor liver after OLT. The presence of chimerism in the large bile ducts suggests that recipient-derived cells may play a role in biliary regeneration following ischemia-induced injury during OLT.

Background Patients with resected colorectal liver metastasis (CRLM) who display only the desmoplastic histopathological growth pattern (dHGP) exhibit superior survival compared to patients with any non-desmoplastic growth (non-dHGP). The aim of this study was to compare the tumour microenvironment between dHGP and non-dHGP. Methods The tumour microenvironment was investigated in three cohorts of chemo-naive patients surgically treated for CRLM. In cohort A semi-quantitative immunohistochemistry was performed, in cohort B intratumoural and peritumoural T cells were counted using immunohistochemistry and digital image analysis, and in cohort C the relative proportions of individual T cell subsets were determined by flow cytometry. Results One hundred and seventeen, 34, and 79 patients were included in cohorts A, B, and C, with dHGP being observed in 27%, 29%, and 15% of patients, respectively. Cohorts A and B independently demonstrated peritumoural and intratumoural enrichment of cytotoxic CD8+ T cells in dHGP, as well as a higher CD8+/CD4+ ratio (cohort A). Flow cytometric analysis of fresh tumour tissues in cohort C confirmed these results; dHGP was associated with higher CD8+ and lower CD4+ T cell subsets, resulting in a higher CD8+/CD4+ ratio. Conclusion The tumour microenvironment of patients with dHGP is characterised by an increased and distinctly cytotoxic immune infiltrate, providing a potential explanation for their superior survival.

Background & Aims: The SALVE Histopathology Group (SHG) developed and validated a grading and staging system for the clinical and full histological spectrum of alcohol-related liver disease (ALD) and evaluated its prognostic utility in a multinational cohort of 445 patients. Methods: SALVE grade was described by semiquantitative scores for steatosis, activity (hepatocellular injury and lobular neutrophils) and cholestasis. The histological diagnosis of steatohepatitis due to ALD (histological ASH, hASH) was based on the presence of hepatocellular ballooning and lobular neutrophils. Fibrosis staging was adapted from the Clinical Research Network staging system for non-alcoholic fatty liver disease and the Laennec staging system and reflects the pattern and extent of ALD fibrosis. There are 7 SALVE fibrosis stages (SFS) ranging from no fibrosis to severe cirrhosis. Results: Interobserver κ-value for each grading and staging parameter was >0.6. In the whole study cohort, long-term outcome was associated with activity grade and cholestasis, as well as cirrhosis with very broad septa (severe cirrhosis) (p, SCOPUS: ar.j, info:eu-repo/semantics/published

Background Although numerous electroencephalogram (EEG) studies have described differences in functional connectivity in Alzheimer’s disease (AD) compared to healthy subjects, there is no general consensus on the methodology of estimating functional connectivity in AD. Inconsistent results are reported due to multiple methodological factors such as diagnostic criteria, small sample sizes and the use of functional connectivity measures sensitive to volume conduction. We aimed to investigate the reproducibility of the disease-associated effects described by commonly used functional connectivity measures with respect to the amyloid, tau and neurodegeneration (A/T/N) criteria. Methods Eyes-closed task-free 21-channel EEG was used from patients with probable AD and subjective cognitive decline (SCD), to form two cohorts. Artefact-free epochs were visually selected and several functional connectivity measures (AEC(-c), coherence, imaginary coherence, PLV, PLI, wPLI) were estimated in five frequency bands. Functional connectivity was compared between diagnoses using AN(C)OVA models correcting for sex, age and, additionally, relative power of the frequency band. Another model predicted the Mini-Mental State Exam (MMSE) score of AD patients by functional connectivity estimates. The analysis was repeated in a subpopulation fulfilling the A/T/N criteria, after correction for influencing factors. The analyses were repeated in the second cohort. Results Two large cohorts were formed (SCD/AD; n = 197/214 and n = 202/196). Reproducible effects were found for the AEC-c in the alpha and beta frequency bands (p = 6.20 × 10−7, Cohen’s d = − 0.53; p = 5.78 × 10−4, d = − 0.37) and PLI and wPLI in the theta band (p = 3.81 × 10−8, d = 0.59; p = 1.62 × 10−8, d = 0.60, respectively). Only effects of the AEC-c remained significant after statistical correction for the relative power of the selected bandwidth. In addition, alpha band AEC-c correlated with disease severity represented by MMSE score. Conclusion The choice of functional connectivity measure and frequency band can have a large impact on the outcome of EEG studies in AD. Our results indicate that in the alpha and beta frequency bands, the effects measured by the AEC-c are reproducible and the most valid in terms of influencing factors, correlation with disease severity and preferable properties such as correction for volume conduction. Phase-based measures with correction for volume conduction, such as the PLI, showed reproducible effects in the theta frequency band.

Background Artifacts caused by respiratory motion or ventilation-induced chest movements are a major problem for thoracic MRI, as they can obscure important anatomical structures such as lymph node metastases. We compared image quality of routine breathhold with intermittent apnea during controlled mechanical ventilation of patients under general anesthesia as the ideal situation without respiratory motion in the detection and characterization of regional lymph nodes in esophageal cancer. Methods In this prospective study, 10 patients treated for esophageal cancer underwent ultrasmall superparamagnetic iron oxide (USPIO) enhanced MRI scans. Before neoadjuvant therapy, MRI scans were acquired with a routine breathhold technique. After neoadjuvant therapy, patients were scanned under general anesthesia immediately prior to surgery with controlled mechanical ventilation. The image quality was compared using a Likert scale questionnaire based on visibility of anatomical structures and image artifacts. Results MRI with controlled mechanical ventilation and prolonged controlled apnea of 4 min was safe and feasible. All cardio-respiratory monitoring parameters remained stable during the apnea phases. Mediastinal and upper abdominal lymph nodes down to 2 mm in size could be visualized with all sequences. All image quality criteria, including visibility of thoracic structures and regional lymph nodes were scored higher using the controlled ventilation sequences compared to the routine breathhold phase. Conclusion USPIO-enhanced MRI with controlled mechanical ventilation is superior to routine breathhold MRI in visualizing lymph nodes, which warrants new motion reduction techniques to use MRI for the detection of lymph node metastases in patients with esophageal cancer.

Objectives: In hemophilia A the presence of non-neutralizing antibodies (NNAs) against Factor VIII (FVIII) may predict the development of neutralizing antibodies (inhibitors) and accelerate the clearance of administrated FVIII concentrates. This systematic review aimed to assess: (1) the prevalence and incidence of NNAs in patients with congenital hemophilia without inhibitors and (2) the association between NNAs and patient and treatment characteristics. Methods: We conducted a search in MEDLINE, Embase, Web of Science and the Cochrane database. We included cross-sectional and longitudinal studies reporting on NNAs in patients with hemophilia A and B, who were inhibitor-negative at the start of the observation period. Data were extracted on: hemophilia type and severity, patient and treatment characteristics, NNA prevalence and incidence, NNA assays and inhibitor development. Two independent reviewers performed study selection, data extraction and risk of bias assessment, using adapted criteria of the Joanna Briggs Institute. Studies were classified as high-quality when ≥5/9 criteria were met. NNA assays were classified as high-quality when both quality criteria were met: (1) use of positive controls and (2) competition with FVIII to establish FVIII-specificity. We reported NNA prevalence and incidence for each study. The pooled NNA prevalence was assessed for well-designed studies in previously treated patients, employing high-quality NNA assays. Results: We included data from 2,723 inhibitor-negative patients with hemophilia A, derived from 28 studies. Most studies were cross-sectional (19/28) and none reported on NNAs in hemophilia B. Study design was of high quality in 16/28 studies and the NNA assay quality was high in 9/28 studies. Various NNA assays were used, predominantly ELISA (18/28) with different cut-off values. We found a large variety in NNA prevalence (Range, 0-100%). The pooled NNA prevalence in high-quality studies was 25% (95% CI, 16-38%). The incidence of new NNA development was reported in one study (0.01 NNA per person-exposure day). Conclusion: This systematic review identified studies that were heterogeneous in study design, patient population and NNA assay type, with NNA prevalence ranging from 0 to 100% in inhibitor-negative patients with hemophilia A. The pooled NNA prevalence was 25% in high-quality studies including only previously treated patients and performing high-quality NNA assays.

Introduction Tumor-targeted imaging is a promising technique for the detection of lymph node metastases (LNM) and primary tumors. It remains unclear which biomarker is the most suitable target to distinguish malignant from healthy tissue in esophageal adenocarcinoma (EAC). Objective We performed an immunohistochemistry study to identify viable tumor markers for tumor-targeted imaging of EAC. Methods We used samples from 72 patients with EAC to determine the immunohistochemical expression of ten potential tumor biomarkers for EAC (carbonic anhydrase IX [CA-IX], carcinoembryonic antigen [CEA], hepatic growth factor receptor, epidermal growth factor receptor, epithelial membrane antigen [EMA], epithelial cell adhesion molecule [EpCAM], human epidermal growth factor receptor 2 [HER-2], urokinase plasminogen activator receptor, vascular endothelial growth factor-A [VEGF-A], and VEGF receptor 2). Immunohistochemistry was performed on tissue microarrays of LNM (n = 48), primary EACs (n = 62), fibrotic tissues (n = 11), nonmalignant lymph nodes (n = 24), and normal esophageal and gastric tissues (n = 40). Tumor marker staining was scored on intensity and percentage of positive cells. Results EMA and EpCAM showed strong expression in LNM (> 95%) and primary EACs (> 95%). Significant expression was also observed for LNM and EAC using VEGF-A (85 and 92%), CEA (68 and 54%), and CA-IX (4 and 34%). The other tumor biomarkers showed expression of 0–15% for LNM and primary EAC. Except for VEGF-A, nonmalignant lymph node staining was scored as slight or absent. Conclusions High expression rates and correlation between LNM in EAC combined with low expression rates in healthy lymph nodes and esophagus tissues were observed for EpCAM and CEA, meaning these are promising targets for tumor-targeted imaging approaches for lymph nodes in patients with EAC. Electronic supplementary material The online version of this article (10.1007/s40291-020-00448-9) contains supplementary material, which is available to authorized users.

Background and Objective New treatments for haemophilia are under development or entering the market, including extended half-life products, designer drugs and gene therapy, thereby increasing treatment options for haemophilia. It is currently unknown how people with haemophilia decide whether to switch to a new treatment. Therefore, the objective of this study was to explore what factors may play a role when Dutch patients and parents of boys with moderate or severe haemophilia make decisions about whether to switch to a different treatment, and how disease and treatment characteristics may affect these decisions. This may aid clinical teams in tailored information provision and shared decision making. Methods We conducted interviews among adults with moderately severe or severe haemophilia and parents of young boys with severe haemophilia. We aimed to include participants from a variety of backgrounds in terms of involvement in the haemophilia community, age, treatment centre and treatments. Participants were recruited through the Netherlands Haemophilia Society and a haemophilia treatment centre. Semi-structured interviews were recorded and transcribed verbatim. Thematic content analysis was used to analyse the data. Results Twelve people with haemophilia and two mothers of boys with haemophilia were included. In general, participants reported to be satisfied with their current treatment. However, they considered ease of use of the medication (fewer injections, easier handling, alternative administration) an added value of new treatments. Participants were aware of the high cost of coagulation factor products and some expressed their concern about the Netherlands Haemophilia Society’s long-term willingness to pay for current and novel treatments, especially for increased usage due to high-risk activities. Participants also expressed their concerns about the short- and long-term safety of new treatments and believed the effects of gene therapy were not yet fully understood. Participants expected their treatment team to inform them when a particular new treatment would be suitable for them. Conclusions With the number of treatment options set to increase, it is important for healthcare providers to be aware of how patient experiences shape patients’ decisions about new therapies. Electronic supplementary material The online version of this article (10.1007/s40271-019-00395-6) contains supplementary material, which is available to authorized users.

Background: The aim of this study was to identify more accurate variables to improve prognostication of individual patients with colorectal liver metastases (CRLM). Clinicopathological characteristics only partly explain the large range in survival rates. Methods: MessengerRNA expression profiles of resected CRLM of two patient groups were analysed by mRNA sequencing: poor survivors (death from recurrent disease 60 months after surgery). Tumour and adjacent liver parenchyma samples were analysed. Results: MessengerRNA expression profiling of the tumour samples identified 77 genes that were differentially expressed between the two survival groups at a False Discovery Rate (FDR)

Objective: The aim of this study was to preliminarily evaluate an oral small molecule p38α kinase inhibitor in patients with early Alzheimer's disease (AD) for the effects on brain amyloid plaque load and episodic memory function, and to establish pharmacokinetic–pharmacodynamics correlations if any effects identified on these parameters. Methods: Sixteen patients with early AD received a highly selective p38α inhibitor (neflamapimod) for 84 days (12 weeks). To obtain a broad range of plasma drug exposures, subjects randomized to receive either 40 mg (n = 9) or 125 mg (n = 7) twice daily. Dynamic, 11C-PiB positron emission scans were performed at baseline and at Day 84 and quantitatively analyzed by reference parametric mapping. Episodic memory assessed as Wechsler Memory Scale (WMS) immediate and delayed recall composites. Result: In the 11C-PiB analyses there were no main group level effects, though in the prespecified responder analysis (>7% reduction in 11C-PiB signal) there were three responders in the 40 mg, and one in the 125 mg group. There were statistically significant increases from baseline in mean WMS immediate recall score and WMS delayed recall at both day 28 (P = 0.03 and P = 0.001) and day 84 (P = 0.001 and P < 0.001). Individual subject plasma drug concentration profiles were significantly positively correlated with the change in combined WMS immediate and delayed recall (P < 0.0001, r2= 0.70). Within-subject effect size was 0.59 for immediate recall and 0.67 for delayed recall. Interpretation: Selective p38α inhibition in patients with early AD may improve episodic memory and potentially impact β-amyloid production. These preliminary clinical findings support conduct of a longer duration placebo-controlled study, particularly to confirm the effects on episodic memory function.

Objectives: To study the prognostic value of abnormalities in baseline complete blood count in patients with oropharyngeal cancer (OPC) treated with (chemo) radiation. Methods and materials: The prognostic value of baseline complete blood count on outcome in 234 patients with OPC treated between 2010 and 2015 was examined in multivariate analysis together with other conventional prognostic variables including HPV-status, tumor stage, tumor and nodal size. Results: The 3-year overall survival (OS), disease-free survival (DFS), locoregional control (LRC), and distant control (DC) of the whole group were 74%, 64%, 79%, and 88%, respectively. Leukocytosis and HPV-status were the only significant prognosticators for OS and DFS at the multivariate analysis. Patients without leukocytosis had a significantly better DC compared to those with leukocytosis (92% and 70%, respectively, p

Introduction: Monitoring clinical outcome in persons with haemophilia (PWH) is essential in order to provide optimal treatment for individual patients and compare effectiveness of treatment strategies. Experience with measurement of activities and participation in haemophilia is limited and consensus on preferred tools is lacking. Aim: The aim of this study was to give a comprehensive overview of the measurement properties of a selection of commonly used tools developed to assess activities and participation in PWH. Methods: Electronic databases were searched for articles that reported on reliability, validity or responsiveness of predetermined measurement tools (5 self-reported and 4 performance based measurement tools). Methodological quality of the studies was assessed according to the COSMIN checklist. Best evidence synthesis was used to summarize evidence on the measurement properties. Results: The search resulted in 3453 unique hits. Forty-two articles were included. The self-reported Haemophilia Acitivity List (HAL), Pediatric HAL (PedHAL) and the performance based Functional Independence Score in Haemophilia (FISH) were studied most extensively. Methodological quality of the studies was limited. Measurement error, cross-cultural validity and responsiveness have been insufficiently evaluated. Conclusion: Albeit based on limited evidence, the measurement properties of the PedHAL, HAL and FISH are currently considered most satisfactory. Further research needs to focus on measurement error, responsiveness, interpretability and cross-cultural validity of the self-reported tools and validity of performance based tools which are able to assess limitations in sports and leisure activities.

INTRODUCTION: Dual hypothermic oxygenated machine perfusion (DHOPE) of the liver has been advocated as a method to reduce ischemia-reperfusion injury. This study aimed to determine whether DHOPE reduces IR injury of the bile ducts in DCD liver transplantation.MATERIALS AND METHODS: In a recently performed phase 1-trial, ten DCD livers were preserved with DHOPE after static cold storage (SCS) (www.trialregister.nl NTR4493). Bile duct biopsies were obtained at the end of SCS (before DHOPE; baseline) and after graft reperfusion in the recipient. Histological severity of biliary injury was graded according to an established semi-quantitative grading system. Twenty liver transplantations using DCD livers not preserved with DHOPE served as control.RESULTS: Baseline characteristics and the degree of bile duct injury at baseline (end of SCS) were similar between both groups. In controls, degree of stroma necrosis (P=0.002) and injury of the deep peribiliary glands (P=0.02) increased after reperfusion, compared to baseline. In contrast, in DHOPE preserved livers the degree of bile duct injury did not increase after reperfusion. Moreover, there was less injury of deep peribiliary glands (P=0.04) after reperfusion in the DHOPE group, compared to controls.CONCLUSION: This study suggests that DHOPE reduces ischemia-reperfusion injury of bile ducts after DCD liver transplantation. This article is protected by copyright. All rights reserved.

Gray matter networks are disrupted in Alzheimer's disease and related to cognitive impairment. However, it is still unclear whether these disruptions are associated with cognitive decline over time. Here, we studied this question in a large sample of patients with mild cognitive impairment with extensive longitudinal neuropsychological assessments. Gray matter networks were extracted from baseline structural magnetic resonance imaging, and we tested associations of network measures and cognitive decline in Mini–Mental State Examination and 5 cognitive domains (i.e., memory, attention, executive function, visuospatial, and language). Disrupted network properties were cross-sectionally related to worse cognitive impairment. Longitudinally, lower small-world coefficient values were associated with a steeper decline in almost all domains. Lower betweenness centrality values correlated with a faster decline in Mini–Mental State Examination and memory, and at a regional level, these associations were specific for the precuneus, medial frontal, and temporal cortex. Furthermore, network measures showed additive value over established biomarkers in predicting cognitive decline. Our results suggest that gray matter network measures might have use in identifying patients who will show fast disease progression.

Background Sleep bruxism is a phenomenon associated with masticatory muscle hyperactivity. While stretching of limb and trunk muscles has been extensively studied for musculoskeletal disorders, little is known about the effectiveness of stretching of masticatory muscles in the management of bruxism. Objective The aim of this study is to determine the effectiveness of stretching of the masticatory muscles for sleep bruxism. Methods Twenty four pain-free individuals with sleep bruxism were randomly assigned to either an intervention group or a control group. Both groups were given sleep hygiene advice and the intervention group additionally received muscle-stretching exercises for 10 days. Primary outcome measures, bruxism bursts and episodes per hour of sleep, were measured by ambulant polysomnography. Secondary outcome measures were among others pain-free active maximum mouth opening (MMO) and masseter pressure pain threshold (PPT). Results The number of bruxism episodes per hour of sleep increased more in the intervention group than in the control group (by 1.1 episodes, P = 0.066), as did the number of bruxism bursts per hour of sleep (by 8.6 bursts, P = 0.049). MMO and PPT increased significantly more in the intervention group (by 3.2 mm, P = 0.020; and by 1.0 kg/cm2 , P = 0.036, respectively). Conclusion Static stretching of the masticatory muscles resulted in a minor increase in sleep bruxism episodes (not significant) and bursts (significant). It also led to a significant increase in MMO and PPT. Therefore, masticatory muscle stretching was not effective in reducing sleep bruxism in the absence of pain and/or dysfunction.