Early postnatal high-dose fat-soluble enteral vitamin A supplementation for moderate or severe bronchopulmonary dysplasia or death in extremely low birthweight infants (NeoVitaA): a multicentre, randomised, parallel-group, double-blind, placebo-controlled, investigator-initiated phase 3 trial.

BACKGROUND: Vitamin A plays a key role in lung development, but there is no consensus regarding the optimal vitamin A dose and administration route in extremely low birthweight (ELBW) infants. We aimed to assess whether early postnatal additional high-dose fat-soluble enteral vitamin A supplementation versus placebo would lower the rate of moderate or severe bronchopulmonary dysplasia or death in ELBW infants receiving recommended basic enteral vitamin A supplementation. METHODS: This prospective, multicentre, randomised, parallel-group, double-blind, placebo-controlled, investigator-initiated phase 3 trial conducted at 29 neonatal intensive care units in Austria and Germany assessed early high-dose enteral vitamin A supplementation (5000 international units [IU]/kg per day) or placebo (peanut oil) for 28 days in ELBW infants. Eligible infants had a birthweight of more than 400 g and less than 1000 g; gestational age at birth of 32+0 weeks postmenstrual age or younger; and the need for mechanical ventilation, non-invasive respiratory support, or supplemental oxygen within the first 72 h of postnatal age after admission to the neonatal intensive care unit. Participants were randomly assigned by block randomisation with variable block sizes (two and four). All participants received basic vitamin A supplementation (1000 IU/kg per day). The composite primary endpoint was moderate or severe bronchopulmonary dysplasia or death at 36 weeks postmenstrual age, analysed in the intention-to-treat population. This trial was registered with EudraCT, 2013-001998-24. FINDINGS: Between March 2, 2015, and Feb 27, 2022, 3066 infants were screened for eligibility at the participating centres. 915 infants were included and randomly assigned to the high-dose vitamin A group (n=449) or the control group (n=466). Mean gestational age was 26·5 weeks (SD 2·0) and mean birthweight was 765 g (162). Moderate or severe bronchopulmonary dysplasia or death occurred in 171 (38%) of 449 infants in the high-dose vitamin A group versus 178 (38%) of 466 infants in the control group (adjusted odds ratio 0·99, 95% CI 0·73-1·55). The number of participants with at least one adverse event was similar between groups (256 [57%] of 449 in the high-dose vitamin A group and 281 [60%] of 466 in the control group). Serum retinol concentrations at baseline, at the end of intervention, and at 36 weeks postmenstrual age were similar in the two groups. INTERPRETATION: Early postnatal high-dose fat-soluble enteral vitamin A supplementation in ELBW infants was safe, but did not change the rate of moderate or severe bronchopulmonary dysplasia or death and did not substantially increase serum retinol concentrations. FUNDING: Deutsche Forschungsgemeinschaft and European Clinical Research Infrastructures Network (ECRIN).

Trends of mortality rate in patients with congenital heart defects in Germany-analysis of nationwide data of the Federal Statistical Office of Germany.

BACKGROUND: Congenital heart defects (CHD) are still associated with an increased morbidity and mortality. The aim of this study was to analyze trends of mortality rates in patients with CHD between 1998 and 2018 in Germany. METHODS: Data of registered deaths with an underlying diagnosis of CHD were used to evaluate annual mortality between 1998 and 2018. Polynomial regressions were performed to assess annual changes in CHD-associated mortality rates by age groups. RESULTS: During the 21-year study period, a total of 11,314 deaths were attributed to CHD with 50.9% of deaths in infants (age < 1 year) and 28.2% in neonates (age ≤ 28 days). The most frequent underlying CHDs associated with death were hypoplastic left heart syndrome (n = 1498, 13.2%), left ventricular outflow tract obstruction (n = 1009, 8.9%), atrial septal defects (n = 771, 6.8%), ventricular septal defects (n = 697, 6.2%), and tetralogy of Fallot (n = 673, 5.9%), and others (n = 6666, 58.9%). Among all patients, annual CHD-related mortality rates declined significantly between 1998 and 2010 (p < 0.0001), followed by a significant annual increase until 2018 (p < 0.0001). However, mortality rates in 2018 in all ages were significantly lower than in 1998. CONCLUSION: Mortality in CHD patients decreased significantly between 1998 and 2010, but a substantial number of deaths still occurred and even significantly increased in the last 3 years of the observation period particularly in neonates and infants. This renewed slight increase in mortality rate during the last years was influenced mainly by high-risk neonates and infants. Assessment of factors influencing the mortality rate trends in association with CHD in Germany is urgently needed. Obligatory nationwide registration of death cases in relation to surgical and catheter interventions in CHD patients is necessary to provide additional valuable data on the outcome of CHD.

How to improve initial diagnostic accuracy of kidney tumours in childhood?-A non-invasive approach.

Non-invasive differentiation of paediatric kidney tumours is particularly important in the SIOP-RTSG protocols, which recommend pre-operative chemotherapy without histological confirmation. The identification of clinical and tumour-related parameters may enhance diagnostic accuracy. Age, metastases, and tumour volume (TV) were retrospectively analysed in 3306 patients enrolled in SIOP/GPOH 9, 93-01, and 2001 including Wilms tumour (WT), congenital mesoblastic nephroma (CMN), clear cell sarcoma (CCSK), malignant rhabdoid tumour of the kidney (MRTK), and renal cell carcinoma (RCC). WT was diagnosed in 2927 (88.5%) patients followed by CMN 138 (4.2%), CCSK 126 (3.8%), MRTK 58 (1.8%) and RCC 57 (1.7%). CMN, the most common localized tumour (71.6%) in patients younger than 3 months of age, was diagnosed earliest and RCC the latest (median age [months]: 0 and 154, respectively) both associated with significantly smaller TV (median TV [mL]: 67.2 and 45.0, respectively). RCC occurred in >14% of patients older than 120 months or older than 84 months with TV <100 mL. Receiver operating characteristic analyses discriminated WT from CMN, RCC and MRTK regarding age (AUC = 0.976, 0.929 and 0.791) and TV (AUC = 0.768, 0.813 and 0.622). MRTK had the highest risk of metastasis (37.9%) despite young age, whereas the risk of metastasis increased significantly with age in WT. Age and TV at diagnosis can differentiate WT from CMN and RCC. MRTK must be considered for metastatic tumours at young age. Identification of CCSK without histology remains challenging. Combined with MRI-characteristics, including diffusion-weighted imaging, and radiomics and liquid biopsies in the future, our approach allows optimization of biopsy recommendations and prevention of misdiagnosis-based neoadjuvant treatment.

An Observational Case-Control Study on Parental Age and Childhood Renal Tumors.

Despite excellent outcomes, many open questions remain about Wilms tumor (WT). Influences and risk factors for tumorigenesis, as well as tumor aggressiveness and recurrence, are not fully understood. Parental age plays a role in various childhood diseases and is also discussed as a risk factor for childhood cancer. We analyzed both maternal and paternal age at birth as risk factors for the occurrence of Wilms and non-Wilms tumors in children and investigated whether older maternal or paternal age is associated with a higher tumor incidence. During 1990 and 2019 we collected data from 3991 patients from the multicenter studies SIOP9/GPO, SIOP 93-01/GPOH, and SIOP 2001/GPOH, of whom maternal and paternal age was available in 2277 cases. Data from the Federal Statistical Office containing live births in Germany from 1990-2019 served as a comparative database. For maternal age at birth, the control data yielded 22,451,412 cases and for paternal age yielded 19,046,314 cases. Comparing maternal and paternal ages of the study patients with those of the control data, we confirmed that higher parental age is not correlated with the incidence of renal tumors in childhood. Mean ages of fathers and mothers in patients and the control cohort increased between 1991 and 2019 (fathers: 30.28 vs. 34.04; mothers: 27.68 vs. 29.79 in the patient group and 31.29 vs. 34.23 and 28.88 vs. 32.67 in the control group, respectively) without higher numbers of patients with kidney cancer over time. No influence was found for the subtype of cancer nor for syndromes. In addition, overall survival of patients is independent of the year of diagnosis and the age of the parents but depends on histology type and stage in WT.

Associations between baseline heart rate and blood pressure and time to events in heart failure with reduced ejection fraction patients: Data from the QUALIFY international registry.

AIMS: A high resting heart rate (RHR) and low systolic blood pressure (SBP) are a risk factor and a risk indicator, respectively, for poor heart failure (HF) outcomes. This analysis evaluated the associations between baseline RHR and SBP with outcomes and treatment patterns in patients with HF and reduced ejection fraction (HFrEF) in the QUALIFY (QUality of Adherence to guideline recommendations for LIFe-saving treatment in heart failure surveY) international registry. METHODS AND RESULTS: Between September 2013 and December 2014, 7317 HFrEF patients with a previous HF hospitalization within 1-15 months were enrolled in the QUALIFY registry. Complete follow-up data were available for 5138 patients. The relationships between RHR and SBP and outcomes were assessed using a Cox proportional hazards model and were analysed according to baseline values as high RHR (H-RHR) ≥75 bpm versus low RHR (L-RHR) <75 bpm and high SBP (H-SBP) ≥110 mmHg versus low SBP (L-SBP) <110 mmHg and analysed according to each of the following four phenotypes: H-RHR/L-SBP, L-RHR/L-SBP, H-RHR/H-SBP and L-RHR/H-SBP (reference group). Compared to the reference group, H-RHR/L-SBP was associated with the worst outcomes for the combined primary endpoint of cardiovascular death and HF hospitalization (hazard ratio [HR] 1.83, 95% confidence interval [CI] 1.51-2.21, p < 0.001), cardiovascular death (HR 2.70, 95% CI 1.69-4.33, p < 0.001), and HF hospitalization (HR 1.62, 95% CI 1.30-2.01, p < 0.001). Low-risk patients with L-RHR/H-SBP achieved more frequently ≥50% of target doses of angiotensin-converting enzyme inhibitors (ACEIs) and beta-blockers (BBs) than the other groups. However, 48% and 46% of low-risk patients were not well treated with ACEIs and BBs, respectively (≤50% of target dose or no treatment). CONCLUSION: In patients with HFrEF and recent hospitalization, elevated RHR and lower SBP identify patients at increased risk for cardiovascular endpoints. While SBP and RHR are often recognized as barriers that deter physicians from treating with high doses of recommended drugs, they are not the only reason leaving many patients suboptimally treated.

Meta-Analysis of European Clinical Trials Characterizing the Healthy-Adult Serum 25-hydroxyvitamin D Response to Vitamin D Supplementation.

To obtain reliable data that allow health authorities to re-evaluate recommendations for oral vitamin D uptake, we conducted a meta-analysis to investigate the impact of supplementation on serum 25-hydroxyvitamin D (25(OH)D) levels in healthy adults in Europe. Of the publications identified (n = 4005) in our literature search (PUBMED, through 2 January 2022), 49 primary studies (7320 subjects, 73 study arms) were eligible for inclusion in our meta-analysis. The risk of bias was assessed using the Cochrane RoB tool based on seven categories, according to which each study is rated using three grades, and overall was rated as rather low. The median duration of intervention was 136.78 days (range, 1088 days); the mean weighted baseline 25(OH)D concentration and mean age were 33.01 vs. 33.84 nmol/L and 46.8 vs. 44.8 years in the vitamin D and placebo groups, respectively. Using random-effects models, 25(OH)D levels were increased by 36.28 nmol/L (95% CI 31.97-40.59) in the vitamin D group compared to the placebo, with a relative serum increment of 1.77 nmol/L per 2.5 µg of vitamin D daily. Notably, the relative serum 25(OH)D increment was affected by various factors, including the dosage and baseline serum 25(OH)D concentration, decreasing with increasing vitamin D doses and with increasing baseline serum levels. We estimate that supplementation in all healthy adults in Europe with appr. 25 µg of vitamin D (1000 IU) daily would raise serum 25(OH)D levels in 95% of the population to ≥50 nmol/L. Our work provides health authorities with reliable data that can help to re-evaluate recommendations for oral vitamin D supplementation.

Standardized Treatment and Diagnostic Approach to Reduce Disease burden in the early postoperative phase in children with congenital heart defects-STANDARD study: a pilot randomized controlled trial.

To explore the effect of a daily goal checklist on pediatric cardiac intensive care unit (PCICU) length of stay (LOS) after congenital heart surgery. This study is a prospective randomized single-center study. Group characteristics were as follows: STANDARD group: n = 30, 36.7% female, median age 0.9 years; control group: n = 33, 36.4% female, median age 1.1 years. Invasive ventilation time, STAT categories, mean vasoactive-inotropic score (VIS)24h, maximal (max.) VIS24h, mean VIS24-48h, max. VIS24-48h, VIS category, number of sedatives, analgesics, diuretics, number of deployed diagnostic modalities, morbidities, and mortality did not differ between both groups. Median PCICU LOS was 96.0 h (STANDARD group) versus 101.5 h (control group) (p = 0.63). In the overall cohort, univariate regression analysis identified age at surgery (b = -0.02), STAT category (b = 18.3), severity of CHD (b = 40.6), mean VIS24h (b = 3.5), max. VIS24h (b = 2.2), mean VIS24-48h (b = 6.5), and VIS category (b = 13.8) as significant parameters for prolonged PCICU LOS. In multivariate regression analysis, age at surgery (b = -0.2), severity of CHD (b = 44.0), and mean VIS24h (b = 6.7) were of significance. Within the STANDARD sub-group, univariate regression analysis determined STAT category (b = 32.3), severity of CHD (b = 70.0), mean VIS24h (b = 5.0), mean VIS24-48h (b = 5.9), number of defined goals (b = 2.6), number of achieved goals (b = 3.3), number of not achieved goals (b = 10.8), and number of unevaluated goals (b = 7.0) as significant parameters for prolonged PCICU LOS. Multivariate regression analysis identified the number of defined goals (b = 2.5) and the number of unevaluated goals (b = -3.0) to be significant parameters.   Conclusion: The structured realization and recording of daily goals is of advantage in patients following pediatric cardiac surgery by reducing PCICU LOS. What is known: • Communication errors are the most frequent reasons for adverse events in intensive care unit patients. • Improved communication can be achieved by discussion and documentation of the patients' goals during daily rounds. What is new: • In the overall cohort age at surgery, severity of congenital heart defect and mean vasoactive inotropic score within the first 24 hours had significant impact on pediatric cardiac intensive care unit (PCICU) length of stay (LOS). • In the intervention group, the number of defined goals and the number of unevaluated goals were significant parameters for prolonged PCICU LOS.

Recipient-Reported Reactogenicity of Different SARS-CoV-2 Vaccination Regimens among Healthcare Professionals and Police Staff in Germany.

The rapid availability of effective vaccines against SARS-CoV-2 was key during the COVID-19 pandemic. However, vaccine hesitancy and relatively low vaccine coverage rates among the general population and particularly vulnerable populations such as healthcare staff reduced the potential benefits of these vaccines. During the early phase of the pandemic, fear of vaccine-related adverse events was common among individuals who refused vaccination. Between March and May 2021, we comparatively assessed the self-reported reactogenicity of different SARS-CoV-2 prime-boost regimens using mRNA-based (BNT162b2 and mRNA-1273) and vector-based vaccines (ChAdOx1 nCoV-19) in (a) healthcare workers (HCW), and (b) police staff from southwest Germany. The majority of participants (71.8%; 1564/2176) received a homologous vaccination. Among HCW, 75.0% were female, whereas 70.0% of police staff were male. The most frequently reported reactions following the first vaccine administration were pain at the injection site (77.94%; 1696/2176), tiredness (51.75%; 1126/2176), and headache (40.44%; 880/2176), which were more commonly reported by HCW as compared to police staff. In homologous, mRNA-based and heterologous vaccination schedules, more reactions were reported after the second vaccine dose. We conclude that the frequency and intensity of self-perceived vaccine reactogenicity may differ between specific population groups and might be mitigated by tailored communication strategies.

Assessment of an umbilical venous catheter dwell-time of 8-14 days versus 1-7 days in very low birth weight infacts (UVC - You Will See): a pilot single-center, randomized controlled trial.

BACKGROUND: Umbilical venous catheters (UVCs) are used for central vascular access in preterm infants, but controversy exits with regard to the optimum dwell-time. PATIENTS AND METHODS: Prospective, randomized controlled trial at a level III University neonatal intensive care unit (NICU), comparing a UVC dwell-time of 1-7 days (control group) to 8-14 days (intervention group) in very low birth weight (VLBW) infants. PRIMARY OUTCOME PARAMETER: Number of infants requiring additional peripherally inserted central catheters (PICC) after removal of UVC. SECONDARY OUTCOME PARAMETERS: Total number of central lines (CL = UVC and PICCs) until time point of full enteral feeds (130-160 mL/kg/d), total number of intravenous vascular catheters, number of CL-associated complications (infection, thrombosis/emboli, organ injury, secondary CL dislocation), number of X-rays for assessment of CL positioning, and days of therapy (DOT) (teicoplanin) for CL-associated blood stream infections (CLABSI). RESULTS: Of 116 patients screened for eligibility, 63 patients were enrolled - control group: 31 infants, mean gestational age (GA) 280 weeks (standard deviation (SD) 2.6 weeks), mean birth weight (BW) 988.9 g (SD 322.0 g); intervention group: 32 infants, mean GA 285 weeks (SD 3.0 weeks), mean BW 1078.9 g (SD 324.6 g). In the control group, 28 infants required additional PICCs versus 16 in the intervention group (p < 0.001); total number of CLs: control group n = 58 versus intervention group n = 28; p < 0.001, and the total number of venous vascular devices was also significantly higher in the control group (109 versus 61; p = 0.04). No significant differences were seen with regard to CL-associated complications (p = 0.09). The number of X-rays for assessment of correct CL-position significantly lower in the intervention group (144 versus 96; p = 0.03). In the intervention group, length of hospital stay was significantly shorter (88.1 (SD: 35.3 days) versus 68.1 (SD: 32.6 days); p = 0.03) and GA significantly lower at discharge from the hospital (404: SD: 33 weeks) versus 385: SD: 25 weeks; p = 0.02. No differences existed with regard to neonatal morbidities and mortality at 36 weeks gestational age. CONCLUSIONS: A longer UVC dwell-time of up to 14 days significantly decreased the number of painful invasive vascular procedures and radiation exposure, and shortened the length of the hospital stay. The findings of our pilot study should be confirmed in a larger, multi-center RCT with the primary focus on catheter-associated complications.

Impact of Time to Surgery on Outcome in Wilms Tumor Treated with Preoperative Chemotherapy.

(1) Background: Wilms tumor (WT) treated preoperatively is cured in over 90% of cases. However, how long preoperative chemotherapy can be given is unknown. (2) Methods: 2561/3030 patients with WT (age < 18 years) treated between 1989 and 2022 according to SIOP-9/GPOH, SIOP-93-01/GPOH, and SIOP-2001/GPOH are retrospectively analyzed to assess the risk of time to surgery (TTS) for relapse-free survival (RFS) and overall survival (OS). (3) Results: TTS was calculated for all surgeries, with the mean being 39 days (38.5 ± 12.5) for unilateral tumors (UWT) and 70 days (69.9 ± 32.7) for bilateral disease (BWT). Relapse occurred in 347 patients, of which 63 (2.5%) were local, 199 (7.8%) were metastatic, and 85 (3.3%) were combined. Moreover, 184 patients (7.2%) died, 152 (5.9%) due to tumor progression. In UWT, recurrences and mortality are independent of TTS. For BWT without metastases at diagnosis, the incidence of recurrence is less than 18% up to 120 days and increases to 29% after 120 days, and to 60% after 150 days. The risk of relapse (Hazard Ratio) adjusted for age, local stage, and histological risk group increases to 2.87 after 120 days (CI 1.19-7.95, p = 0.022) and to 4.62 after 150 days (CI 1.17-18.26, p = 0.029). In metastatic BWT, no influence of TTS is detected. (4) Conclusions: The length of preoperative chemotherapy has no negative impact on RFS or OS in UWT. In BWT without metastatic disease, surgery should be performed before day 120, as the risk of recurrence increases significantly thereafter.

Epileptic Status in a PEDiatric cohort (ESPED) requiring intensive care treatment: A multicenter, national, two-year prospective surveillance study.

OBJECTIVE: The aim of this study was to provide seizure etiology, semiology, underlying conditions, and out-of- and in-hospital diagnostics, treatment, and outcome data on children with out-of- or in-hospital-onset status epilepticus (SE) according to the International League Against Epilepsy definition that required admission to the pediatric intensive care unit (PICU) for ≥4 hours. METHODS: This prospective national surveillance study on SE in childhood and adolescence was conducted over 2 years (07/2019-06/2021). RESULTS: This study examined 481 SE episodes in 481 children with a median age of 43 months (1 month to 17 years 11 months), of which 46.2% were female and 50.7% had a previous seizure history. The most frequent acute SE cause was a prolonged, complicated febrile seizure (20.6%). The most common initial seizure types were generalized seizures (49.9%), focal seizures (18.0%), and unknown types (12.1%); 40.5% of patients suffered from refractory SE and 5.0% from super-refractory SE. The three most common medications administered by nonmedically trained individuals were diazepam, midazolam, and antipyretics. The three most frequent anti-seizure medications (ASMs) administered by the emergency physician were midazolam, diazepam, and propofol. The three most common ASMs used in the clinical setting were midazolam, levetiracetam, and phenobarbital. New ASMs administered included lacosamide, brivaracetam, perampanel, stiripentol, and eslicarbazepine. Status epilepticus terminated in 16.0% in the preclinical setting, 19.1% in the emergency department, and 58.0% in the PICU; the outcome was unknown for 6.9%. The median PICU stay length was 2 (1-121) days. The median modified Rankin scale was 1 (0-5) on admission and 2 (0-6) at discharge. New neurological deficits after SE were observed in 6.2%. The mortality rate was 3.5%. SIGNIFICANCE: This study provides current real-world out-of- and in-hospital data on pediatric SE requiring PICU admission. New ASMs are more frequently used in this population. This knowledge may help generate a more standardized approach.

Umbilical venous catheter- and peripherally inserted central catheter-associated complications in preterm infants with birth weight < 1250 g : Results from a survey in Austria and Germany.

BACKGROUND AND OBJECTIVE: Umbilical venous catheters (UVC) and peripherally inserted central catheters (PICC) are commonly used in preterm infants but have been associated with a number of serious complications. We performed a survey in Austria and Germany to assess the use of UVCs and PICCs in preterm infants with a birth weight < 1250 g and associated rates of catheter-related adverse events. METHODS: Electronic survey of participating centers of the NeoVitaA trial. Main outcome parameter was the reported rates of UVC- and PICC-associated complications (infection, thrombosis, emboli, organ injury, arrhythmia, dislocation, miscellaneous). RESULTS: In total, 20 neonatal intensive care units (NICU) providing maximal intensive care in Austria and Germany (level I) were contacted, with a senior neonatologist response rate of 12/20 (60%). The reported rates for UVC with a dwell time of 1-10 days were bacterial infection: 4.2 ± 3.4% (range 0-10%); thrombosis: 7.3 ± 7.1% (0-20%); emboli: 0.9 ± 2.0% (0-5%); organ injury: 1.1 ± 1.9% (0-5%); cardiac arrhythmia: 2.2 ± 2.5% (0-5%); and dislocation: 5.4 ± 8.7% (0-30%); and for PICCs with a dwell time of 1-14 days bacterial infection: 15.0 ± 3.4% (range 2.5-30%); thrombosis; 4.3 ± 3.5% (0-10%); emboli: 0.8 ± 1.6% (0-5%); organ injury: 1.5 ± 2.3% (0-5%); cardiac arrhythmia: 1.5 ± 2.3% (0-5%), and dislocation: 8.5 ± 4.6% (0-30%). CONCLUSION: The catheter-related complication rates reported in this survey differed between UVCs and PICCs and were higher than those reported in the literature. To generate more reliable data on this clinically important issue, we plan to perform a large prospective multicenter randomized controlled trial investigating the non-inferiority of a prolonged UVC dwell time (up to 10 days) against the early change (up to 5 days) to a PICC.

Surgical Factors Influencing Local Relapse and Outcome in the Treatment of Unilateral Nephroblastoma.

OBJECTIVE: This study aims to identify factors associated with the occurrence of local relapse (LR) after treatment for unilateral nephroblastoma. BACKGROUND: Despite the fact that LR is rare (~5%) its adverse impact on the need for relapse treatment and outcome (40%-80% overall survival) cannot be neglected. Identifying the causative factors may improve initial treatment to achieve better local control. METHODS: Altogether 2386 patients with unilateral nephroblastoma prospectively enrolled over a period of 32 years (1989-2020) by the German Society for Pediatric Oncology and Hematology (SIOP-9/GPOH, SIOP-93-01/GPOH and SIOP-2001/GPOH) were retrospectively analyzed. Hazard ratios (HR) of LR were calculated for sex, age, size, local staging, histology, type of removal, rupture, lymph node (LN) removal using univariate and multivariate Cox models. RESULTS: Age >48 months, tumor volume >500 mL, histology and LN extent of removal were identified as significant risk factors for LR [HR: 1.68, P =0.018, confidence interval (CI): 1.09-2.58; HR: 1.84, P =0.015, CI: 1.13-3.00; HR: 3.19, P <0.001, CI: 2.03-5.00; HR: 2.26, P =0.002, CI: 1.36-3.576]. LR occur significantly more often in Stage I and II, even if no LN are removed. The risk of metastases is significantly increased after local recurrence (HR: 11.5, P <0.001, CI: 7.11-18.60). LR is associated with a subsequent 18.79-fold increased risk of death (HR: 18.79, P <0.001, CI: 2.07-5.28). CONCLUSIONS: Several factors are responsible for the occurrence of LR. Surgical ones, like LN sampling allow further reduction of LR and consequently a better outcome of patients with unilateral nephroblastoma.

Ultrasound-based "CEUS-Bosniak"classification for cystic renal lesions: an 8-year clinical experience.

PURPOSE: Renal cysts comprise benign and malignant entities. Risk assessment profits from CT/MRI imaging using the Bosniak classification. While Bosniak-IIF, -III, and -IV cover complex cyst variants, Bosniak-IIF and -III stand out due to notorious overestimation. Contrast-enhanced ultrasound (CEUS) is promising to overcome this deficit but warrants standardization. This study addresses the benefits of a combined CEUS and CT/MRI evaluation of renal cysts. The study provides a realistic account of kidney tumor boards' intricacies in trying to validate renal cysts. METHODS: 247 patients were examined over 8 years. CEUS lesions were graded according to CEUS-Bosniak (IIF, III, IV). 55 lesions were resected, CEUS-Bosniak- and CT/MRI-Bosniak-classification were correlated with histopathological diagnosis. Interobserver agreement between the classifications was evaluated statistically. 105 lesions were followed by ultrasound, and change in CEUS-Bosniak-types and lesion size were documented. RESULTS: 146 patients (156 lesions) were included. CEUS classified 67 lesions as CEUS-Bosniak-IIF, 44 as CEUS-Bosniak-III, and 45 as CEUS-Bosniak-IV. Histopathology of 55 resected lesions revealed benign cysts in all CEUS-Bosniak-IIF lesions (2/2), 40% of CEUS-Bosniak-III and 8% of CEUS-Bosniak-IV, whereas malignancy was uncovered in 60% of CEUS-Bosniak-III and 92% of CEUS-Bosniak-IV. Overall, CEUS-Bosniak-types matched CT/MRI-Bosniak types in 58% (fair agreement, κ = 0.28). CEUS-Bosniak resulted in higher stages than CT/MRI-Bosniak (40%). Ultrasound follow-up of 105 lesions detected no relevant differences between CEUS-Bosniak-types concerning cysts size. 99% of lesions showed the same CEUS-Bosniak-type. CONCLUSION: The CEUS-Bosniak classification is an essential tool in clinical practice to differentiate and monitor renal cystic lesions and empowers diagnostic work-up and patient care.

Quality of life and sexual function in patients aged 35 years or younger undergoing hysterectomy for benign gynecologic conditions: A prospective cohort study.

OBJECTIVE: To evaluate how hysterectomy performed for benign gynecologic pathologies affects the quality of life and sexual function of patients aged 35 years or younger, and if outcomes differ according to the surgical technique. METHODS: Seventy-three patients who underwent total laparoscopic hysterectomy (TLH), supracervical laparoscopic hysterectomy (SLH), or vaginal hysterectomy (VH) for benign uterine disorders between April 2014 and June 2020 at the Department of Gynecology and Obstetrics, Saarland University Hospital, Homburg, Germany, were enrolled in this prospective observational cohort study. Quality of life and sexual function were assessed preoperatively and 6 months postoperatively using standardized validated questionnaires: the European Quality of Life Five-Dimension Scale (EQ-5D) and the Female Sexual Function Index (FSFI). RESULTS: Thirty-three (45%) patients underwent TLH, 25 (34%) underwent SLH, and 15 (21%) patients underwent VH. The median preoperative EQ-5D score, FSFI score, and EQ-5D visual analog scale were 0.9 (range 0.62-1), 19.25 (range 2.4-27.4), and 50 (range 0-100); postoperative scores were 1 (range 0.61-1), 24.15 (range 3.9-29.3), and 90 (range 30-100), respectively (P ≤ 0.001). Postoperative scores were significantly higher than preoperative scores, with no significant difference according to the surgical technique. CONCLUSION: Hysterectomy for benign indication in women aged 35 years or less significantly improved the patients' quality of life and sexual function with no differences regarding the surgical technique. CLINICAL TRIAL REGISTRATION: The study was registered in the German trial registry (no. DRKS00005622).

Human papillomavirus vaccination of girls in the German model region Saarland: Insurance data-based analysis and identification of starting points for improving vaccination rates.

In Germany, the incidence of cervical cancer, a disease caused by human papillomaviruses (HPV), is higher than in neighboring European countries. HPV vaccination has been recommended for girls since 2007. However, it continues to be significantly less well received than other childhood vaccines, so its potential for cancer prevention is not fully realized. To find new starting points for improving vaccination rates, we analyzed pseudonymized routine billing data from statutory health insurers in the PRÄZIS study (prevention of cervical carcinoma and its precursors in women in Saarland) in the federal state Saarland serving as a model region. We show that lowering the HPV vaccination age to 9 years led to more completed HPV vaccinations already in 2015. Since then, HPV vaccination rates and the proportion of 9- to 11-year-old girls among HPV-vaccinated females have steadily increased. However, HPV vaccination rates among 15-year-old girls in Saarland remained well below 50% in 2019. Pediatricians vaccinated the most girls overall, with a particularly high proportion at the recommended vaccination age of 9-14 years, while gynecologists provided more HPV catch-up vaccinations among 15-17-year-old girls, and general practitioners compensated for HPV vaccination in Saarland communities with fewer pediatricians or gynecologists. We also provide evidence for a significant association between attendance at the children´s medical check-ups "U11" or "J1" and HPV vaccination. In particular, participation in HPV vaccination is high on the day of U11. However, obstacles are that U11 is currently not financed by all statutory health insurers and there is a lack of invitation procedures for both U11 and J1, resulting in significantly lower participation rates than for the earlier U8 or U9 screenings, which are conducted exclusively with invitations and reminders. Based on our data, we propose to restructure U11 and J1 screening in Germany, with mandatory funding for U11 and organized invitations for HPV vaccination at U11 or J1 for both boys and girls.

Vena Cava Thrombus in Patients with Wilms Tumor.

(1) Background: Vena cava thrombus (VCT) is rare in Wilms tumor (WT) (4−10%). The aim of this study is to identify factors for an outcome to improve treatment for better survival. (2) Methods: 148/3015 patients with WT (aged < 18 years) and VCT, prospectively enrolled over a period of 32 years (1989−2020) by the German Society for Pediatric Oncology and Hematology (SIOP-9/GPOH, SIOP-93-01/GPOH and SIOP-2001/GPOH), are retrospectively analyzed to describe clinical features, response to preoperative chemotherapy (PC) (142 patients) and surgical interventions and to evaluate risk factors for overall survival (OS). (3) Results: 14 VCT regressed completely with PC and another 12 in parts. The thrombus was completely removed in 111 (85.4%), incompletely in 16 (12.3%), and not removed in 3 (2.3%). The type of removal is unknown in four patients. Patients without VCT have a significantly (p < 0.001) better OS (97.8%) than those with VCT (90.1%). OS after complete resection is (89.9%), after incomplete (93.8%) and with no resection (100%). Patients with anaplasia or stage IV without complete remission (CR) after PC had a significantly worse OS compared to the remaining patients with VCT (77.1% vs. 94.4%; p = 0.002). (4) Conclusions: As a result of our study, two risk factors for poor outcomes in WT patients with VCT emerge: diffuse anaplasia and metastatic disease, especially those with non-CR after PC.

Comparative immunogenicity and reactogenicity of heterologous ChAdOx1-nCoV-19-priming and BNT162b2 or mRNA-1273-boosting with homologous COVID-19 vaccine regimens.

Comparative analyses of the immunogenicity and reactogenicity of homologous and heterologous SARS-CoV-2 vaccine-regimens will inform optimized vaccine strategies. Here we analyze the humoral and cellular immune response following heterologous and homologous vaccination strategies in a convenience cohort of 331 healthy individuals. All regimens induce immunity to the vaccine antigen. Immunity after vaccination with ChAdOx1-nCoV-19 followed by either BNT162b2 (n = 66) or mRNA-1273 (n = 101) is equivalent to or more pronounced than homologous mRNA-regimens (n = 43 BNT162b2, n = 59 mRNA-1273) or homologous ChAdOx1-nCoV-19 vaccination (n = 62). We note highest levels of spike-specific CD8 T-cells following both heterologous regimens. Among mRNA-containing combinations, spike-specific CD4 T-cell levels in regimens including mRNA-1273 are higher than respective combinations with BNT162b2. Polyfunctional T-cell levels are highest in regimens based on ChAdOx1-nCoV-19-priming. All five regimens are well tolerated with most pronounced reactogenicity upon ChAdOx1-nCoV-19-priming, and ChAdOx1-nCoV-19/mRNA-1273-boosting. In conclusion, we present comparative analyses of immunogenicity and reactogenicity for heterologous vector/mRNA-boosting and homologous mRNA-regimens.

Low Vitamin D Status Predicts Poor Clinical Outcome in Advanced Melanoma Treated With Immune Checkpoint or BRAF/MEK Inhibitors: A Prospective Non-Interventional Side-by-Side Analysis.

In melanoma and other malignancies, low vitamin D status is associated with increased risk and poor prognosis. However, there are limited data of the impact of 25(OH)D serum concentration (s.c.) on clinical outcome in advanced melanoma. We tested the hypothesis that vitamin D status is predictive of efficacy and safety in patients treated for metastasized melanoma with B-rapidly accelerated fibrosarcoma (BRAF), mitogen-activated protein kinase kinase (MEK), cytotoxic T lymphocyte-associated protein-4 (CTLA-4), and/or programmed cell death protein-1 (PD-1) inhibitors. Severe vitamin D deficiency [defined as 25(OH)D s.c. <10 ng/ml] was associated with markedly reduced overall (OS) and progress-free (PFS) survival, with increased tumor load [TL; measured as s.c. of S100 protein or lactate dehydrogenase (LDH)], and with a trend for higher frequency of adverse events (AEs). An increase in average 25(OH)D s.c. of 1 ng/ml was associated with a 3.9% reduced risk for progressive disease [hazard ratio (HR) = 0.961, p = 0.044], with a reduction of LDH s.c. of 3.86 U/l (p = 0.034, indicating a reduction of TL), and with a trend for reduced frequency of AEs (AE ratio -0.005; p = 0.295). Patients with average 25(OH)D s.c. ≥10 ng/ml and BRAF-mutant melanoma showed a trend for a higher frequency of AEs as compared to individuals with BRAF wild-type melanomas. Our data indicate that vitamin D deficiency is associated with poor clinical outcome in patients treated for metastasized melanoma with BRAF/MEK inhibitors or immunotherapy. Although it needs to be proven in future interventional trials whether optimizing serum 25(OH)D improves clinical outcome in these patients, we recommend that 25(OH)D s.c. should be analyzed and vitamin D deficiency treated in all patients with advanced melanoma.

German federal-state-wide seroprevalence study of 1st SARS-CoV-2 pandemic wave shows importance of long-term antibody test performance.

Background: Reliable data on the adult SARS-CoV-2 infection fatality rate in Germany are still scarce. We performed a federal state-wide cross-sectional seroprevalence study named SaarCoPS, that is representative for the adult population including elderly individuals and nursing home residents in the Saarland. Methods: Serum was collected from 2940 adults via stationary or mobile teams during the 1st pandemic wave steady state period. We selected an antibody test system with maximal specificity, also excluding seroreversion effects due to a high longitudinal test performance. For the calculations of infection and fatality rates, we accounted for the delays of seroconversion and death after infection. Results: Using a highly specific total antibody test detecting anti-SARS-CoV-2 responses over more than 180 days, we estimate an adult infection rate of 1.02% (95% CI: [0.64; 1.44]), an underreporting rate of 2.68-fold (95% CI: [1.68; 3.79]) and infection fatality rates of 2.09% (95% CI: (1.48; 3.32]) or 0.36% (95% CI: [0.25; 0.59]) in all adults including elderly individuals, or adults younger than 70 years, respectively. Conclusion: The study highlights the importance of study design and test performance for seroprevalence studies, particularly when seroprevalences are low. Our results provide a valuable baseline for evaluation of future pandemic dynamics and impact of public health measures on virus spread and human health in comparison to neighbouring countries such as Luxembourg or France.