Transcript analysis of uterus transplant cervical biopsies using the Banff Human Organ Transplant panel.

Uterus transplantation is being more widely implemented in clinical practice. Monitoring of rejection is routinely done for cervical biopsies and is dependent on histopathological assessment, as rejections are clinically silent and nonhistological biomarkers are missing. Until this gap is filled, it is important to corroborate the histopathological diagnosis of rejection through independent methods such as gene expression analysis. In this study, we compared our previously published scoring system for grading rejection in uterus transplant cervical biopsies to the gene expression profile in the same biopsy. For this, we used the Banff Human Organ Transplant gene panel to analyze the expression of 788 genes in 75 paraffin-embedded transplant cervical biopsies with a spectrum of histologic findings, as well as in 24 cervical biopsies from healthy controls. We found that gene expression in borderline changes did not differ from normal transplants, whereas the genes with increased expression in mild rejections overlapped with previously published rejection-associated transcripts. Moderate/severe rejection samples showed a gene expression pattern characterized by a mixture of rejection-associated and tissue injury-associated genes and a decrease in epithelial transcripts. In summary, our findings support our proposed scoring system for rejection but argue against the treatment of borderline changes.

2-Step-Scores with optional nephropathology for the prediction of adverse outcomes for brain-dead donor kidneys in Eurotransplant.

BACKGROUND AND HYPOTHESIS: The decision for acceptance or discard of the increasingly rare and marginal brain-dead donor kidneys in Eurotransplant (ET) countries has to be made without solid evidence. Thus, we developed and validated flexible clinicopathological scores called 2-Step Scores for the prognosis of delayed graft function (DGF) and one-year death-censored transplant loss (1y-tl) reflecting the current practice of six ET countries including Croatia and Belgium. METHODS: The training set was n=620 for DGF and n=711 for 1y-tl, with validation sets n=158 and n=162. In step 1, stepwise logistic regression models including only clinical predictors were used to estimate the risks. In step 2, risk estimates were updated for statistically relevant intermediate risk percentiles with nephropathology. RESULTS: Step 1 revealed an increased risk of DGF with increased cold ischaemia time, donor and recipient BMI, dialysis vintage, number of HLA-DR mismatches or recipient CMV IgG positivity. On the training and validation set, c-statistics were 0.672 and 0.704, respectively. At a range between 18% and 36%, accuracy of DGF-prognostication improved with nephropathology including number of glomeruli and Banff cv (updated overall c statistics of 0.696 and 0.701, respectively).Risk of 1y-tl increased in recipients with cold ischaemia time, sum of HLA-A. -B, -DR mismatches and donor age. On training and validation sets, c-statistics were 0.700 and 0.769, respectively. Accuracy of 1y-tl prediction improved (c-statistics = 0.706 and 0.765) with Banff ct. Overall, calibration was good on the training, but moderate on the validation set; discrimination was at least as good as established scores when applied to the validation set. CONCLUSION: Our flexible 2-Step Scores with optional inclusion of time-consuming and often unavailable nephropathology should yield good results for clinical practice in ET, and may be superior to established scores. Our scores are adaptable to donation after cardiac death and perfusion pump use.

Results of the Cologne Corona Surveillance (CoCoS) project- a cross-sectional study: survey data on risk factors of SARS-CoV-2 infection, and moderate-to-severe course in primarily immunized adults.

BACKGROUND: Amidst the COVID-19 pandemic, vaccination has been a crucial strategy for mitigating transmission and disease severity. However, vaccine-effectiveness may be influenced by various factors, including booster vaccination, as well as personal factors such as age, sex, BMI, smoking, and comorbidities. To investigate the potential effects of these factors on SARS-CoV-2 infection and disease severity, we analyzed data from the third round of the Cologne Corona Surveillance (CoCoS) project, a large cross-sectional survey. METHODS: The study was conducted mid-February to mid-March 2022 in Cologne, Germany. A random sample of 10,000 residents aged 18 years and older were invited to participate in an online survey. Information on participants' demographics (age, sex), SARS-CoV-2 infections, vaccination status, smoking, and preexisting medical conditions were collected. The outcomes of the study were: (1) the occurrence of SARS-CoV-2 infection despite vaccination (breakthrough infection) and (2) the occurrence of moderate-to-severe disease as a result of a breakthrough infection. Cox proportional-hazards regression was used to investigate possible associations between the presence/absence of booster vaccination, personal factors and the occurrence of SARS-CoV-2 infection. Associations with moderate-to-severe infection were analyzed using the Fine and Gray subdistribution hazard model. RESULTS: A sample of 2,991 residents responded to the questionnaire. A total of 2,623 primary immunized participants were included in the analysis of breakthrough infection and 2,618 in the analysis of SARS-CoV-2 infection severity after exclusions due to incomplete data. The multivariable results show that booster vaccination (HR = 0.613, 95%CI 0.415-0.823) and older age (HR = 0.974, 95%CI 0.966-0.981) were associated with a reduced hazard of breakthrough infection. Regarding the severity of breakthrough infection, older age was associated with a lower risk of moderate-to-severe breakthrough infection (HR = 0.962, 95%CI0.949-0.977). Female sex (HR = 2.570, 95%CI1.435-4.603), smoking (HR = 1.965, 95%CI1.147-3.367) and the presence of chronic lung disease (HR = 2.826, 95%CI1.465-5.450) were associated with an increased hazard of moderate-to-severe breakthrough infection. CONCLUSION: The results provide a first indication of which factors may be associated with SARS-CoV-2 breakthrough infection and moderate-to-severe course of infection despite vaccination. However, the retrospective nature of the study and risk of bias in the reporting of breakthrough infection severity limit the strength of the results. TRIAL REGISTRATION: DRKS.de, German Clinical Trials Register (DRKS), Identifier: DRKS00024046, Registered on 25 February 2021.

Genomic ALK alterations in primary and relapsed neuroblastoma.

BACKGROUND: Genomic alterations of the anaplastic lymphoma kinase gene (ALK) occur recurrently in neuroblastoma, a pediatric malignancy of the sympathetic nervous system. However, information on their development over time has remained sparse. METHODS: ALK alterations were assessed in neuroblastomas at diagnosis and/or relapse from a total of 943 patients, covering all stages of disease. Longitudinal information on diagnostic and relapsed samples from individual patients was available in 101 and 102 cases for mutation and amplification status, respectively. RESULTS: At diagnosis, ALK point mutations occurred in 10.5% of all cases, with highest frequencies in stage 4 patients <18 months. At relapse, ALK alteration frequency increased by 70%, both in high-risk and non-high-risk cases. The increase was most likely due to de novo mutations, frequently leading to R1275Q substitutions, which are sensitive to pharmacological ALK inhibition. By contrast, the frequency of ALK amplifications did not change over the course of the disease. ALK amplifications, but not mutations, were associated with poor patient outcome. CONCLUSIONS: The considerably increased frequency of ALK mutations at relapse and their high prevalence in young stage 4 patients suggest surveying the genomic ALK status regularly in these patient cohorts, and to evaluate ALK-targeted treatment also in intermediate-risk patients.

Performance of Scores Predicting Adverse Outcomes in Procurement Kidney Biopsies From Deceased Donors With Organs of Lower-Than-Average Quality.

Several scores have been devised for providing a prognosis of outcomes after kidney transplantation. This study is a comprehensive test of these scores in a cohort of deceased donors with kidneys of lower-than-average quality and procurement biopsies. In total, 15 scores were tested on a retrospective cohort consisting of 221 donors, 223 procurement biopsies, and 223 recipient records for performance on delayed graft function, graft function, or death-censored graft loss. The best-performing score for DGF was the purely clinical Chapal score (AUC 0.709), followed by the Irish score (AUC 0.684); for graft function, the Nyberg score; and for transplant loss, the Snoeijs score (AUC 0.630) and the Leuven scores (AUCs 0.637 and 0.620). The only score with an acceptable performance was the Chapal score. Its disadvantage is that knowledge of the cold ischemia time is required, which is not known at allocation. None of the other scores performed acceptably. The scores fared better in discarded kidneys than in transplanted kidneys. Our study shows an unmet need for practical prognostic scores useful at the time of a decision about discarding or accepting deceased donor kidneys of lower-than-average quality in the Eurotransplant consortium.

Influence of patient sex on outcomes after pancreatic surgery: multicentre study.

BACKGROUND: Recent findings support the hypothesis of sex-related differences in inflammatory and immunological responses to trauma. The aim of this study was to address sex-specific aspects in patients who underwent pancreatic surgery. METHODS: This retrospective study used data from the German StuDoQ registry. Patients who underwent pancreatic surgery between 2010 and 2020 were stratified according to procedure (pancreatic head resection, distal pancreatectomy (DP), total pancreatectomy (TP)). Each cohort underwent propensity score matching (PSM) with the co-variables BMI, ASA, age, coronary heart disease (CHD), diabetes, hypertension with medication, and histology to level the distribution of co-morbidities between men and women. The main outcomes were morbidity and mortality. RESULTS: The total cohort consisted of 10 224 patients (45.3 per cent women). Men had higher ASA grades, and more often had CHD, diabetes, and hypertension with medication. Women had fewer overall complications (57.3 versus 60.1 per cent; P = 0.005) and a lower mortality rate (3.4 versus 4.9 per cent; P < 0.001). Rates of pancreatic surgery-specific complications, such as clinically relevant postoperative pancreatic fistula (POPF) (grade B/C: 14 versus 17 per cent; P < 0.001), delayed gastric emptying (grade B/C: 7.8 versus 9.2 per cent; P = 0.014), and postpancreatectomy haemorrhage (grade B/C: 7.1 versus 9.0 per cent; P < 0.001), were also lower in women. After PSM, 8358 patients were analysed. In the pancreatic head resection cohort (5318 patients), women had fewer complications (58.6 versus 61.4 per cent; P = 0.044), a lower in-hospital mortality rate (3.6 versus 6.1 per cent; P < 0.001), and less often had clinically relevant POPF (11.6 versus 16.2 per cent; P < 0.001). After DP, the clinically relevant POPF rate was lower in women (22.5 versus 27.3 per cent; P = 0.012). In the TP cohort, men more often developed intra-abdominal abscess requiring drainage (5.0 versus 2.3 per cent; P = 0.050). CONCLUSION: Women had favourable outcomes after pancreatic surgery.

Prevalence and potential relevance of hyperuricemia in pediatric kidney transplant recipients-a CERTAIN registry analysis.

BACKGROUND: Asymptomatic hyperuricemia is frequently observed in pediatric kidney transplant recipients; symptomatic hyperuricemia, however, is a rare complication. Only few data are available in this patient population. We, therefore, investigated the prevalence of hyperuricemia and its association with kidney transplant function and blood pressure in a multicenter cohort of pediatric kidney transplant recipients. METHODS: This is a retrospective, observational multicenter registry study. All pediatric kidney transplant recipients in the CERTAIN database with at least one documented serum uric acid level and a follow-up of 5 years posttransplant were eligible. We identified 151 patients with 395 measurements of serum uric acid. We calculated the prevalence of hyperuricemia, analyzed potential risk factors and clinical consequences such as elevated blood pressure and reduced estimated glomerular filtration rate (eGFR). Statistical analysis was performed using IBM SPSS Statistics 26. RESULTS: One hundred and ten of 395 (27.8%) serum uric acid levels were above 416 µmol/L (7.0 mg/dL), defined as the upper limit of normal. Univariate analysis showed a significant (p = .026) inverse association of serum uric acid with eGFR overtime. There was no significant association of serum uric acid concentrations with body mass index (z-score), blood pressure (z-score), or sex. No episodes of gout were documented. CONCLUSION: This study shows that hyperuricemia is present in a considerable number of patients sometime after pediatric kidney transplantation and is associated with lower eGFR. Whether hyperuricemia contributes to faster decline of graft function or to the overall cardiovascular risk of these patients remains to be elucidated.

Effect of creatinine metrics on outcome after transplantation of marginal donor kidneys.

INTRODUCTION: Predicting outcome after transplantation of marginal kidneys is a challenging task. Donor creatinine or estimated glomerular filtration rate (eGFR) are integral components of the respective risk scores. However, there is uncertainty on which of their values obtained successively during procurement is the most suitable. MATERIAL AND METHODS: This is a retrospective study of 221 adult brain death donors with marginal kidneys, transplanted in 223 recipients. We applied logistic regression analysis to investigate the association between initial (at hospital admission), nadir (lowest), zenith (highest) and terminal (at recovery) donor eGFR with primary non-function (PNF), delayed graft function (DGF), 3- and 12-month graft function and 1- and 3-year patient- and death-censored graft survival. RESULTS: In the multivariate analysis, admission, terminal, and the lowest donor eGFR could most accurately predict DGF. The respective ORs [95% CI] were: 0.875 [0.771-0.993], 0.818 [95% CI: 0.726-0.922] and 0.793 [0.689-0.900]. Although not being significant for DGF (OR 0.931 [95% CI: 0.817-1.106]), the highest eGFR was the best predictor of 3-month graft function (adjusted b coefficient 1.161 [95% CI: 0.355-1.968]). Analysis of primary nonfunction showed that determination of initial and the highest eGFR proved to be the best predictors. The respective ORs [95% CI] were: 0.804 [0.667-0.968] and 0.750 [0.611-0.919]. There were no differences in the risk associations of each of the four eGFR recordings with patient- and graft survival. CONCLUSION: The various eGFR recordings determined during the procurement process of marginal donors can predict PNF, DGF and 3- and 12-month graft function. Regarding short-term patient- and graft survival, there appears to be impacted by recipient factors rather than donor kidney function.

Genetic and environmental risk factors for reticular pseudodrusen in the EUGENDA study.

PURPOSE: The purpose of this study was to analyze genetic and nongenetic associations with reticular pseudodrusen (RPD) in patients with and without age-related macular degeneration (AMD). METHODS: This case-control study included 2,719 consecutive subjects from the prospective multicenter European Genetic Database (EUGENDA). Color fundus photographs and optical coherence tomography (OCT) scans were evaluated for the presence of AMD and RPD. Association of RPD with 39 known AMD polymorphisms and various nongenetic risk factors was evaluated. Stepwise backward variable selection via generalized linear models (GLMs) was performed based on models including the following: a) age, sex, and genetic factors and b) all predictors. Receiver operating characteristic (ROC) curves and the areas under the curve (AUCs) were determined. RESULTS: RPD were present in 262 cases (no AMD, n = 9 [0.7%; early/intermediate AMD, n = 75 [12.4%]; late AMD, n = 178 [23.8%]). ROC analysis of the genetic model including age, APOE rs2075650, ARMS2 rs10490924, CFH rs800292, CFH rs12144939, CFI rs10033900, COL8A1 rs13081855, COL10A1 rs3812111, GLI3 rs2049622, and SKIV2L rs4296082 revealed an AUC of 0.871. Considering all possible predictors, backward selection revealed a slightly different set of genetic factors, as well as the following nongenetic risk factors: smoking, rheumatoid arthritis, steroids, antiglaucomatous drugs, and past sunlight exposure; the results showed an AUC of 0.886. CONCLUSIONS: RPD share a variety of genetic and nongenetic risk factors with AMD. Future AMD grading systems should integrate RPD as an important risk phenotype.

Clinical and molecular characterization of patients with stage 4(M) neuroblastoma aged less than 18 months without MYCN amplification.

INTRODUCTION: The survival of children with stage 4(M) neuroblastoma without MYCN amplification and below the age of 18 months is considered better than the still dismal outcome of older high-risk neuroblastoma patients. This study analyzes the impact of clinical and molecular characteristics on the long-term outcome. PATIENTS AND METHODS: Clinical presentation, survival, and recurrence patterns of patients enrolled onto trials NB90, NB97, and NB2004 were retrospectively analyzed. Gene expression signatures based on RNA microarrays (TH10) were investigated if tumor material was available. RESULTS: Between 1990 and 2015, 177 patients with stage 4(M) MYCN nonamplified neuroblastoma aged less than 18 months at diagnosis were eligible. After a median follow-up of 9.7 years (IQR 5.0, 13.4), the proportions of 10-year event-free survival (EFS) and overall survival (OS) were 73% (95% confidence interval [CI] 67-79%) and 86% (95% CI 80-92%), respectively. Of the 27 neuroblastoma recurrences, 44% occurred in more than one site. Four additional patients presented histologically mature ganglioneuroma at recurrence. Six patients developed a secondary malignancy. The secondary 5-year EFS and OS of the 27 patients with neuroblastoma recurrence were 44% and 59%, respectively. TH10 gene expression signature was not prognostically predictive in the investigated subcohort. CONCLUSION: The outcome of patients with stage 4(M) neuroblastoma aged less than 18 months is favorable when treated with high-risk or otherwise intensive therapy. The development of secondary malignancies and the potential of maturation to ganglioneuroma call for a controlled stepwise reduction of treatment intensity.

The reliability of bone marrow cytology as response criterion in metastatic neuroblastoma.

BACKGROUND: The quantitative assessment of neuroblastoma cell content in bone marrow aspirates for response evaluation has been introduced recently. Data on the concordance of interobserver reports are lacking so far. METHODS: Investigators of seven European countries representing national reference or large oncological centers convened in 2016. They agreed to quantitatively assess routine bone marrow smears of the participating institutions and to discuss the discrepant results in joint meetings. RESULTS: From 2017 through 2019, three cytology rounds with 24, 28, and 28 bone marrow samples were run evaluating the representativity of the smears (yes/[restricted]/no) and the presence of tumor cells (yes/no and %). The comparison of the reports using κ (Fleiss) and α (Krippendorff) statistics demonstrated no robust reliabilities. The agreement on the representativity was moderate to poor, on the presence of tumor cells moderate to good, and on the percentage of tumor cells slight to moderate. Though the value of cytology is unquestioned to detect even tiny metastatic cells in bone marrow, the investigators unanimously agreed that a reliable quantification of the tumor cell content in bone marrow smears is unrealistic. For the key issue of representativity, a new practical definition was developed. CONCLUSION: For any work with bone marrow aspirates, the representativity of the material is of paramount importance. A practical definition is proposed. A reliable quantitative cytological assessment of tumor cell content in bone marrow aspirates is not feasible in metastatic neuroblastoma. Therefore, its use as response criterion should be reconsidered.

[Epidemiological Studies on the Association between Chronic Exposure to Road Traffic Noise and Blood Pressure: A Systematic Review with Meta-Analyses]. / Epidemiologische Studien zu chronischen Straßenlärm-Expositionen und dem Blutdruck: Ein systematischer Review mit Metaanalysen.

AIM: The aim of this study was to review epidemiological studies on the association between chronic exposures to road traffic noise and prevalence of arterial hypertension as well as blood pressure by using meta-analyses. METHODS: A systematic literature search in the databases Medline® and Web of science™ as well as the database OpenGrey was conducted to identify suitable studies, namely epidemiological observational studies assessing objective exposures to road traffic noise at the subject's home place with analysis of their potential associations with arterial hypertension or blood pressure. Whenever possible, overall effects for the different relationships were estimated with meta-analyses. For statistical analyses R for windows was used. RESULTS: A total of 31 eligible studies were identified. Meta-analyses were conducted for potential association between road traffic noise and prevalence of arterial hypertension in adults and for association with systolic and diastolic blood pressure in adults and children. There was a significant (p<0.01) increase of risk for arterial hypertension in adults when exposed to chronic road traffic noise with an increment of 7% per 5 dB(A). Overall effects for systolic blood pressure were positive but weak for children as well as adults without any statistical significance. For diastolic blood pressure there appeared to be no relationship with chronic exposure to road traffic noise in either of the two groups. CONCLUSION: Considering the multiple methodological limitations of studies examined as well as the high level of heterogeneity in all random effects models, the estimated overall effects must be interpreted with caution. To examine potential associations between road traffic noise and arterial hypertension or measured blood pressure appropriately, more prospective cohort studies are necessary with precise assessments of noise exposure as well as clinical endpoints and with adjustments for relevant cofactors.

Artificial intelligence and machine learning in nephropathology.

Artificial intelligence (AI) for the purpose of this review is an umbrella term for technologies emulating a nephropathologist's ability to extract information on diagnosis, prognosis, and therapy responsiveness from native or transplant kidney biopsies. Although AI can be used to analyze a wide variety of biopsy-related data, this review focuses on whole slide images traditionally used in nephropathology. AI applications in nephropathology have recently become available through several advancing technologies, including (i) widespread introduction of glass slide scanners, (ii) data servers in pathology departments worldwide, and (iii) through greatly improved computer hardware to enable AI training. In this review, we explain how AI can enhance the reproducibility of nephropathology results for certain parameters in the context of precision medicine using advanced architectures, such as convolutional neural networks, that are currently the state of the art in machine learning software for this task. Because AI applications in nephropathology are still in their infancy, we show the power and potential of AI applications mostly in the example of oncopathology. Moreover, we discuss the technological obstacles as well as the current stakeholder and regulatory concerns about developing AI applications in nephropathology from the perspective of nephropathologists and the wider nephrology community. We expect the gradual introduction of these technologies into routine diagnostics and research for selective tasks, suggesting that this technology will enhance the performance of nephropathologists rather than making them redundant.

Combination therapy with rifampicin or fosfomycin in patients with Staphylococcus aureus bloodstream infection at high risk for complications or relapse: results of a large prospective observational cohort.

OBJECTIVES: To investigate whether Staphylococcus aureus bloodstream infection (SAB) patients at high risk for complications or relapse benefit from combination therapy with adjunctive rifampicin or fosfomycin. METHODS: In this post hoc analysis, SAB patients with native valve infective endocarditis, osteoarticular infections or implanted foreign devices were included. The co-primary endpoints were all-cause 90 day mortality and death or SAB-related late complications within 180 days. To overcome treatment selection bias and account for its time dependence, inverse probability of treatment weights were calculated and included in marginal structural Cox proportional hazard models (MSCMs). RESULTS: A total of 578 patients were included in the analysis, of which 313 (54%) received combination therapy with either rifampicin (n = 242) or fosfomycin (n = 58). In the multivariable MSCM, combination therapy was associated with a better outcome, that is, a lower rate of death or SAB-related late complications within 180 days (HR 0.65, 95% CI 0.46-0.92). This beneficial effect was primarily seen in patients with implanted foreign devices, in which combination therapy was associated with a lower rate of death or SAB-related late complications within 180 days (HR 0.53, 95% CI 0.35-0.79) and a lower 90 day mortality (HR 0.57, 95% CI 0.36-0.91). Upon agent-specific stratification, we found no significant differences in outcomes between combination therapy containing rifampicin and fosfomycin; however, the number of patients in most subgroups was not large enough to draw firm conclusions. CONCLUSIONS: In patients with implanted foreign devices, combination therapy was associated with a better long-term outcome. Larger prospective studies are needed to validate these findings.

Correction: Long-term outcomes of the GPOH NB97 trial for children with high-risk neuroblastoma comparing high-dose chemotherapy with autologous stem cell transplantation and oral chemotherapy as consolidation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Long-term outcomes of the GPOH NB97 trial for children with high-risk neuroblastoma comparing high-dose chemotherapy with autologous stem cell transplantation and oral chemotherapy as consolidation.

BACKGROUND: This study was done to investigate the long-term event free and overall survival of high-dose chemotherapy followed by autologous stem cell transplantation (ASCT), compared to maintenance chemotherapy (MT). Patterns of recurrences and late sequelae of both arms were analysed. METHODS: A randomised open label trial was conducted nationwide during 1997-2004 in Germany and Switzerland. 295 patients with high-risk neuroblastoma were randomly assigned to high-dose chemotherapy with autologous stem cell transplantation (ASCT) or maintenance chemotherapy (MT) for consolidation. Analyses were done by intention-to-treat (ITT: ASCT/MT N = 149/146), as treated (AT: N = 110/102), and treated as randomised (TAR: N = 75/70). RESULTS: The event free survival was superior for the patients receiving ASCT compared to patients treated with MT in all three cohorts (hazard ratio [HR] for ITT 1.39, 95% confidence interval (CI) 1.05-1.85, P = 0.022, HR for AT 1.75, CI 1.24-2.47, P = 0.001; HR for TAR 2.07, CI 1.36-3.16, P = 0.001). Overall survival was also in favour of the ASCT groups (ITT: P = 0.075; AT: P = 0.017; TAR: P = 0.005). The frequencies of late sequelae were not different except for focal nodular hyperplasia of the liver observed more frequently in the ASCT arm. CONCLUSIONS: High-dose chemotherapy with autologous stem cell transplantation had a better long-term outcome compared to maintenance chemotherapy.

Metronomic therapy has low toxicity and is as effective as current standard treatment for recurrent high-risk neuroblastoma.

The metronomic therapy concept uses low doses of continuously applied chemotherapeutic, anti-angiogenetic, and immunomodulating drugs. Twenty patients with recurrent and 3 with refractory high-risk neuroblastoma were treated by the metronomic concept using celecoxib, cyclophosphamide, vinblastine, and etoposide for up to 24 months. The outcome was compared to 274 matched patients with a first recurrence from stage 4 neuroblastoma using the variables time from diagnosis to first recurrence, number of organs involved, and MYCN amplification. All were treated with dose-intensive conventional chemotherapy. The study patients experienced 1-3 recurrences and had 1-3 sites involved (osteomedullary, primary tumor, central nervous system, lymph nodes, liver, lungs) before the metronomic therapy started. Two patients in complete remission and three with active refractory disease following recurrence treatment were excluded from the outcome analysis. The curves for secondary event-free and overall survival demonstrated no significant differences. The toxicity was minimal except for ≥3 grade thrombocytopenia and leukopenia (all heavily pretreated). The treatment was realized in an outpatient setting. The metronomic approach is similarly effective as standard treatment in recurrent high-risk neuroblastoma, has low toxicity, and is applicable in an outpatient setting. A prospective study including propranolol as a fifth drug is underway.

Predicting outcomes after transplantation of deceased donor kidneys of marginal quality within the Eurotransplant service area.

INTRODUCTION: Kidneys of marginal quality are increasingly being used to overcome the shortage of donor organs. However, accurate prediction of outcome is needed to optimise the use of these kidneys. We aimed to test the performance of a recently proposed score consisting of delayed graft function (DGF), renal function recovery (RFR), and glomerular filtration rate (GFR) <30 ml/min per 1.73 m2 90 days after transplantation for risk assessment of patient and graft survival. MATERIAL AND METHODS: A total of 221 adult brain death donors with marginal kidneys, transplanted into 223 recipients within Eurotransplant were included in the analysis. Multivariable Cox proportional hazards models were constructed to assess death-censored and all-cause censored graft failure and recipient mortality at one and three years. RESULTS: Recipients with DGF had a higher risk of death-censored graft loss (HR, 95%CIs: 3.058 (1.195 - 7.825)). Recipients with a GFR <30ml/min/1.73m² at 90 days after transplantation had a higher risk of death censored and all-cause graft failure (HR, 95%CIs: 2.122 (1.129-3.990 and 2.122 (1.129 - 3.990)). None of the three components of the proposed score was associated with a higher risk of mortality. CONCLUSION: DGF and eGFR <30 ml/min/1.73m² but not RFR at 90 days predicted graft failure after transplantation of marginal kidneys. However, no combination of these factors was able to predict short-term patient and graft survival.

Acceptance and utilization of web-based self-help for caregivers of children with externalizing disorders.

BACKGROUND: Web-based self-help interventions for parents of children with ADHD and other externalizing disorders have been proven to be effective. In order to recommend individualized and optimized interventions, a better understanding of the acceptance and utilization of this innovative treatment approach is needed. Previous research has frequently employed subjective reports of utilization, but the validity of these studies may be limited. METHODS: Data from the German WASH study were used. Participants (n = 276) were randomly assigned to the intervention condition (a) web-based self-help or (b) web-based self-help with optional telephone-based support calls. Data collection took place at baseline (T1) and 12 weeks later (T2). Utilization data were tracked using a log file generated for each participant at T2. Prediction models were calculated using CART (Classification and Regression Trees), a method known mostly from the field of machine learning. RESULTS: Acceptance, of the intervention as defined in this paper was very high on objective (89.4% have taken up the intervention) and subjective measures (91.4% reported having used the intervention and 95.3% reported they would recommend the intervention to a friend). The average number of logins corresponded to recommendations. Predictors of acceptance and predictors of utilization were similar and included, e.g., child's externalizing symptoms, parental psychopathology, and above all additional telephone-based support by counselors. CONCLUSIONS: Through a detailed identification of acceptance and utilization, and the predictors thereof, we were able to gain a better understanding of the acceptance and utilization of web-assisted self-help for a parent management intervention in the treatment of children with ADHD and ODD. These findings can be used to recommend web-based interventions to particularly suitable families. It should be noted that some form of support is required for an intensive engagement with the content of the program. TRIAL REGISTRATION: The protocol of the study (German Clinical Trials Register DRKS00013456 conducted on January 3rd, 2018) was approved by the Ethics Committee of the University Hospital, Cologne.

Clinical and histopathological characteristics of acute kidney injury in a cohort of brain death donors with procurement biopsies.

BACKGROUND: Kidney biopsies are routinely used for diagnostic and prognostic purposes but their utility in the intensive care unit (ICU) setting is limited. We investigated the associations of clinical and histopathological risk factors with ICU-acute kidney injury (AKI) in donors with brain death (DBD) with kidneys of lower quality and procurement biopsies. METHODS: Overall, 221 donors with brain death, 239 biopsies and 197 recipients were included. The biopsies were reread and scored according to the Banff recommendations. Clinical and histopathological data were compared between donors with and without AKI defined by serum creatinine and by urine output. Logistic regression analysis was applied to identify independent clinical and histopathological risk factors for both phenotypes. Lastly, the impact of each AKI phenotype on outcome was explored. AKI was diagnosed based on the RIFLE (Risk, Injury, Failure, Loss of function, End-stage kidney disease) AKIN (Acute Kidney Injury Network) or KDIGO (Kidney Disease Improving Global Outcomes) criteria. RESULTS: Acute kidney injury occurred in 65% of donors based both upon serum creatinine and by urine output. Serum creatinine was able to better discriminate AKI. Multiorgan failure and severe AKI were captured by serum creatinine, and hemodynamic instability by urine output. Donors with serum creatinine-AKI showed lower chronic macrovascular scores, while donors with urine output-AKI had higher chronic microvascular and tubulointerstitial scores. Tubular injury was similar between the subgroups. Except for delayed graft function and one-year death-censored graft survival, the other short-term recipient outcomes were similar for both AKI phenotypes. CONCLUSION: Serum creatinine is more suitable than urine output for defining AKI in donors with brain death. There are distinct clinical risk factors for each AKI-ICU phenotype. Donor AKI phenotype does not predict the recipient´s prognosis. Kidney biopsies do not seem to confer any tangible benefit in defining AKI in donors with brain death.