Comparing presentations and outcomes of children with cancer: a study between a lower-middle-income country and a high-income country.

BACKGROUND: Substantial progress has been achieved in managing childhood cancers in many high-income countries (HICs). In contrast, survival rates in lower-middle-income countries (LMICs) are less favorable. Here, we aimed to compare outcomes and associated factors between two large institutions; Egypt (LMIC) and Germany (HIC). METHODS: A retrospective review was conducted on newly diagnosed children with cancer between 2006 and 2010 in the departments of pediatric oncology at the South Egypt Cancer Institute (SECI) (n = 502) and the University Hospital of Cologne-Uniklinik Köln (UKK) (n = 238). Characteristics including age, sex, diagnosis, travel time from home to the cancer center, the time interval from initial symptoms to the start of treatment, treatment-related complications, compliance, and outcome were analyzed. A Cox proportional hazards regression model was applied to investigate the influence of risk factors. RESULTS: The most common diagnoses in SECI were leukemia (48.8%), lymphomas (24.1%), brain tumors (1%), and other solid tumors (24.7%), compared to 22.3%, 19.3%, 28.6%, and 26.5% in UKK, respectively. Patients from SECI were younger (5.2 vs. 9.0 years, P < 0.001), needed longer travel time to reach the treatment center (1.44 ± 0.07 vs. 0.53 ± 0.03 h, P < 0.001), received therapy earlier (7.53 ± 0.59 vs. 12.09 ± 1.01 days, P = 0.034), showed less compliance (85.1% vs. 97.1%, P < 0.001), and relapsed earlier (7 vs. 12 months, P = 0.008). Deaths in SECI were more frequent (47.4% vs. 18.1%) and caused mainly by infection (60% in SECI, 7% in UKK), while in UKK, they were primarily disease-related (79% in UKK, 27.7% in SECI). Differences in overall and event-free survival were observed for leukemias but not for non-Hodgkin lymphoma. CONCLUSIONS: Outcome differences were associated with different causes of death and other less prominent factors.

Differences of hemiarthroplasty and total hip replacement in orthogeriatric treated elderly patients: a retrospective analysis of the Registry for Geriatric Trauma DGU®.

PURPOSE: Medial femoral neck fractures are typically managed with hemiarthroplasty (HA) or total hip arthroplasty (THA) in elderly patients. There is a debate as to which treatment predominates. The literatures have reported better outcomes for those patients with proximal femur fracture who were treated in an orthogeriatric centres compared to standard orthopaedic hospitals. Therefore, we have analysed the differences of outcome between HA and THA on patients, exclusively treated in orthogeriatric co-management and compared the results with the available literature. METHODS: We conducted a retrospective registry analysis of the Registry for Geriatric Trauma DGU®. Between 2016 and 2018, data for 16,236 patients from 78 different hospitals were available: they were analysed univariably, and differences between HA and THA were examined using propensity score matching, according to the American Society of Anesthesiologists (ASA) grade, Identification-of-Seniors-At-Risk (ISAR) Score, anticoagulation level, sex, age, and walking ability prefracture. RESULTS: There were 4,662 patients treated with HA and 892 with THA, meeting inclusion criteria. Patients in the HA group were older (84 years (IQR 80-89) vs. 79 years (IQR 75-83); p < 0.001), with more severe preexisting conditions, with an ASA grade ≥ 3 in 79% vs. 57% in the THA group (p < 0.001). After matching, the mortality rate, in-house revision rate, and quality of life (QoL) 7 days postoperatively were not significantly different by group. After 120 days, the HA group presented a lower rate of surgical complications (4% vs. 10%; p = 0.006), while the THA group had a higher rate of independent walking (18% vs. 28%; p = 0.001) and a higher QoL, measured by the EQ-5D-3L (0.81 (IQR 0.7-1.0) vs. 0.9 (IQR 0.72-1.0); p = 0.01). CONCLUSIONS: Due to better walking ability and QoL, THA might be the better choice in healthier and more mobile patients, while HA would be better for multimorbid patients to avoid additional complication-associated treatments. Not the age of the patient but the preoperative condition might be important for the choice between THA and HA.

Internal fixation versus hip arthroplasty in patients with nondisplaced femoral neck fractures: short-term results from a geriatric trauma registry.

PURPOSE: To determine whether internal fixation (IF) or hip arthroplasty (HA) is associated with superior outcomes in geriatric nondisplaced femoral neck fracture (FNF) patients. METHODS: Data from the Registry for Geriatric Trauma of the German Trauma Society (ATR-DGU) were analyzed (IF Group 449 and HA Group 1278 patients). In-hospital care and a 120-day postoperative follow-up were conducted. Primary outcomes, including mobility, residential status, reoperation rate, and a generic health status measure (EQ-5D score), and the secondary outcome of mortality were compared between groups. Multivariable analyses were performed to assess independent treatment group associations (odds ratios, ORs) with the primary and secondary end points. RESULTS: Patients in the HA group were older (83 vs. 81 years, p < 0.001) and scored higher on the Identification of Seniors at Risk screening (3 vs. 2, p < 0.001). We observed no differences in residential status, reoperation rate, EQ-5D score, or mortality between groups. After adjusting for key covariates, including prefracture ambulatory capacity, the mobility of patients in the HA group was more frequently impaired at the 120-day follow-up (OR 2.28, 95% confidence interval = 1.11-4.74). CONCLUSION: Treatment with HA compared to treatment with IF led to a more than twofold increase in the adjusted odds of impaired ambulation at the short-term follow-up, while no significant associations with residential status, reoperation rate, EQ-5D index score, or mortality were observed. Thus, IF for geriatric nondisplaced FNFs was associated with superior mobility 120 days after surgery. However, before definitive treatment recommendations can be made, prospective, randomized, long-term studies must be performed to confirm our findings.

Four-month outcome after proximal femur fractures and influence of early geriatric rehabilitation: data from the German Centres of Geriatric Trauma DGU.

This study analyzed the outcome of orthogeriatric patients with hip fracture 4 months after surgery. The overall mortality rate was 12.2%. Sixty-five percent presented a degradation in walking ability, and 16% had to move to a nursing home. Early geriatric rehabilitation reduces the mortality rate and increases the rate of anti-osteoporotic treatment. PURPOSE: Hip fractures are increasingly common with severe consequences. Therefore, the German Trauma Society (DGU) implemented an orthogeriatric co-management and developed the concept for certified Centre for Geriatric Trauma DGU. The patients' treatment data and the optional 120 days of follow-up were collected in the Registry for Geriatric Trauma DGU (ATR-DGU). This study analyzed these 4-month treatment results. METHODS: A retrospective analysis of the ATR-DGU was conducted. Outcome parameters were the rate of readmission, rate of re-surgery, anti-osteoporotic therapy, housing, mortality, walking ability, and quality of life (QoL) 120 days post-surgery. The influence of the early geriatric rehabilitation (EGR) was evaluated using a regression analysis. RESULTS: The follow-up data from 9780 patients were included. After 120 days, the mortality rate was 12.2%, the readmission rate 4%, and the re-surgery rate 3%. The anti-osteoporotic treatment increased from 20% at admission to 32%; 65% of the patients had a degradation in walking ability, and 16% of the patients who lived in their domestic environment pre-surgery had to move to a nursing home. QoL was distinctly reduced. The EGR showed a positive influence of anti-osteoporotic treatment (p<0.001) and mortality (p=0.011) but led to a slight reduction in QoL (p=0.026). CONCLUSION: The 4-month treatment results of the ATR-DGU are comparable to international studies. The EGR led to a significant rise in anti-osteoporotic treatment and a reduction in mortality with a slight reduction in QoL.

Implementation of an integrated care programme to avoid fragility fractures of the hip in older adults in 18 Bavarian hospitals - study protocol for the cluster-randomised controlled fracture liaison service FLS-CARE.

BACKGROUND: The economic and public health burden of fragility fractures of the hip in Germany is high. The likelihood of requiring long-term care and the risk of suffering from a secondary fracture increases substantially after sustaining an initial fracture. Neither appropriate confirmatory diagnostics of the suspected underlying osteoporosis nor therapy, which are well-recognised approaches to reduce the burden of fragility fractures, are routinely initiated in the German healthcare system. Therefore, the aim of the study FLS-CARE is to evaluate whether a coordinated care programme can close the prevention gap for patients suffering from a fragility hip fracture through the implementation of systematic diagnostics, a falls prevention programme and guideline-adherent interventions based on the Fracture Liaison Services model. METHODS: The study is set up as a non-blinded, cluster-randomised, controlled trial with unequal cluster sizes. Allocation to intervention group (FLS-CARE) and control group (usual care) follows an allocation ratio of 1:1 using trauma centres as the unit of allocation. Sample size calculations resulted in a total of 1216 patients (608 patients per group distributed over 9 clusters) needed for the analysis. After informed consent, all participants are assessed directly at discharge, after 3 months, 12 months and 24 months. The primary outcome measure of the study is the secondary fracture rate 24 months after initial hip fracture. Secondary outcomes include differences in the number of falls, mortality, quality-adjusted life years, activities of daily living and mobility. DISCUSSION: This study is the first to assess the effectiveness and cost-effectiveness/utility of FLS implementation in Germany. Findings of the process evaluation will also shed light on potential barriers to the implementation of FLS in the context of the German healthcare system. Challenges for the study include the successful integration of the outpatient sector as well as the future course of the coronavirus pandemic in 2020 and its influence on the intervention. TRIAL REGISTRATION: German Clinical Trial Register (DRKS) 00022237 , prospectively registered 2020-07-09.

Effect of time-to-surgery on in-house mortality during orthogeriatric treatment following hip fracture: A retrospective analysis of prospectively collected data from 16,236 patients of the AltersTraumaRegister DGU®.

BACKGROUND: Time-to-surgery in geriatric hip fractures remains of interest. The majority of the literature reports a significantly decreased mortality rate after early surgery. Nevertheless, there are some studies presenting no effect of time-to-surgery on mortality. The body of literature addressing the effect of an orthogeriatric co-management is growing. Here we investigate the effect of time-to-surgery on in-house mortality in a group of patients treated under the best possible conditions in certified orthogeriatric treatment units. METHODS: We conducted a retrospective cohort registry analysis from prospectively collected data of the AltersTraumaRegister DGU®. Data were analyzed univariably, and the association of early surgery with in-house mortality was assessed with multivariable logistic regression while controlling for specified patient characteristics. Additionally, propensity score matching for time-to-surgery was applied to examine its effect on the in-house mortality rate. FINDINGS: A total of 15,099 patients met the inclusion criteria. The median age was 85 years (IQR 80-89), and 72.1% were female. The overall in-house mortality rate was 5.5%. Most (71.2%) of the patients were treated within 24 h, and 91.6% within 48 h. Neither the multivariable logistic regression model nor the propensity score matching indicated that early surgery was associated with a decreased mortality rate. The most important indicators for mortality were ASA ≥ 3 [Odds ratio (OR) 3.4, 95% confidence interval (CI) 2.35-5.11], fracture event during inpatient stay (OR 2.6, 95% CI 1.48-4.3), ISAR ≥ 2 (OR 1.88, 95% CI 1.33-2.76), and male gender (OR 1.71, 95% CI 1.39-2.09). INTERPRETATION: Our results suggest that for those patients, who were treated in an orthogeriatric co-management under the best possible conditions, there are no significant differences regarding in-house mortality rate between the time-to-surgery intervals of 24 and 48 h or slightly above. This and the comparatively small number of patients who underwent surgery after 24 h show that an extension of the pre-surgery interval, justified by an orthogeriatric treatment team, will not be detrimental to the affected patients.

Management of children with fever and neutropenia: results of a survey in 51 pediatric cancer centers in Germany, Austria, and Switzerland.

PURPOSE: Investigation of the current practice of diagnostics and treatment in pediatric cancer patients with febrile neutropenia. METHODS: On behalf of the German Society for Pediatric Oncology and Hematology and the German Society for Pediatric Infectious Diseases, an Internet-based survey was conducted in 2016 concerning the management of febrile neutropenia in pediatric oncology centers (POC). This survey accompanied the release of the corresponding German guideline to document current practice before its implementation in clinical practice. RESULTS: In total, 51 POCs participated (response rate 73%; 43 from Germany, and 4 each from Austria and Switzerland). Identified targets for antimicrobial stewardship concerned blood culture diagnostics, documentation of the time to antibiotics, the use of empirical combination therapy, drug monitoring of aminoglycosides, the time to escalation in patients with persisting fever, minimal duration of IV treatment, sequential oral treatment in patients with persisting neutropenia, indication for and choice of empirical antifungal treatment, and the local availability of a pediatric infectious diseases consultation service. CONCLUSION: This survey provides useful information for local antibiotic stewardship teams to improve the current practice referring to the corresponding national and international guidelines.

Evaluation of new quality indicators for the TraumaRegister DGU® using the systematic QUALIFY methodology.

BACKGROUND: The TraumaRegister DGU® (TR-DGU) of the German Trauma Society (Deutsche Gesellschaft für Unfallchirurgie, DGU) enables the participating hospitals to perform quality management. For that purpose, nine so-called audit filters have existed, since its foundation, which, inter alia, is listed in the Annual Report. The objective of this study effort is a revision of these quality indicators with the aim of developing pertinent new and reliable quality indicators for the management of severely injured patients. MATERIALS AND METHODS: Apart from indicators already used at national and international levels, a systematic review of the literature revealed further potential key figures for quality of the management of severely injured patients. The latter were evaluated by an interdisciplinary and interprofessional group of experts using a standardized QUALIFY process to assess their suitability as a quality indicator. RESULTS: By means of the review of the literature, 39 potential indicators could be identified. 9 and 14 indicators, respectively, were identified in existing trauma registries (TR-DGU and TARN), 17 in the ATLS® training concept, and 57 in the S3 guideline on the treatment of polytrauma/severe injuries. The exclusion of duplicates and the limitation to indicators that can be collected using the TR-DGU Version 2015 data set resulted in a total of 43 indicators to be reviewed. For each of the 43 indicators, 13 quality criteria were assessed. A consensus was achieved in 305 out of 559 individual assessments. With 13 quality criteria assessed and 43 indicators correspond this to a relative consensus value of 54.6%. None of the indicators achieved a consensus in all 13 quality criteria assessed. The following 13 indicators achieved a consensus in at least 9 quality criteria: time between hospital admission and WBCT, mortality, administration of tranexamic acid to bleeding patients, use of CCT with GCS <14, time until first emergency surgical intervention (7-item list in the TR-DGU), time until surgical intervention for penetrating trauma, application of pelvic sling belt (prehospital), capnometry (etCO2) in intubated patients, time until CCT with GCS < 15, time until surgery for hemorrhagic shock, time until craniotomy for severe TBI, prehospital airway management in unconscious patients (GCS < 9), and complete basic diagnostics available. Two indicators achieved a consensus in 11 criteria and thus represent the maximum consensus achieved within the group of experts. Four indicators only achieved a consensus in three quality criteria. 17 indicators had a mean value for the 3 relevance criteria of ≥ 3.5 and were, therefore, assessed by the group of experts as being highly relevant. CONCLUSION: Not all the key figures published for the management of severely injured patients are suitable for use as quality indicators. It remains to be seen whether the quality indicators identified by experts using the QUALIFY process will meet the requirements in practice. Prior to the implementation of the assessed quality indicators in standardized quality assurance programs, a scientific evaluation based on national data will be required.

Correction to: Evaluation of new quality indicators for the TraumaRegister DGU® using the systematic QUALIFY methodology.

The original version of this article unfortunately contained some mistakes.

[120-day follow-up after proximal femoral fractures-first results from the Geriatric Trauma Registry DGU®]. / 120-Tage-Follow-up nach hüftgelenknahen Frakturen ­ erste Daten aus dem AltersTraumaRegister DGU®.

BACKGROUND: Geriatric trauma centers which are certified to the status of a Geriatic Trauma Center DGU® based on the criteria catalogue as outlined by the German Trauma Society (DGU), are required to participate in the Geriatric Trauma Register (ATR-DGU) for quality management and outcome analyses. The evaluation is pseudoanonymous and includes data on all treated hip fracture patients over 70 years old. This has been in regular use since 2016. This study analyzed the postoperative evaluation of gait, mortality, quality of life, hospital readmission and treatment of osteoporosis after 120 days. METHODS: A voluntary retrospective data evaluation of the ATR-DGU 120-day follow-up from 2017 was carried out. Written consent for the analysis and publication of the data was obtained from six clinics that already participated in the follow-up. The primary target parameters were mortality rate, readmission and revision rates, gait quality, osteoporosis treatment and quality of life according to EQ-5D-3L. The patient data were completely pseudonymized and a descriptive analysis was carried out. RESULTS: In this study 957 patients from the 6 hospitals were included. The average age was 84.5 years (±6.8 years). The mortality rate during the acute treatment phase was 5%. The 120-day follow-up could be evaluated in 412 patients, 10% of these required hospital readmission due to complications oft he same fracture and of these 6% required revision surgery. The mortality rate at 120 days was 12%. In 54% of the patients the fracture led to deterioration of mobility and 49% of patients received osteoporosis treatment after 120 days. The results of the EQ-5D-3L at 120 days revealed improvement as compared to the values on postoperative day 7; however, the preoperative status with respect to mobility and quality of life could not be regained. CONCLUSION: Despite the clear advantages of interdisciplinary treatment, the results are still limited concerning mobilization and quality of life. Further analysis of causative and influencing factors is necessary.

A new risk score for patients after first recurrence of stage 4 neuroblastoma aged ≥18 months at first diagnosis.

BACKGROUND: The prognosis of patients with recurrences from stage 4 neuroblastoma is not uniformly dismal. The evaluation of new therapies therefore needs to consider the individual risks of the treated patients. This study aims to define clinically useful risk criteria. PATIENTS AND METHODS: Inclusion criteria were: first recurrence of neuroblastoma stage 4 aged ≥18 months and enrollment in first line trials between 1997 and 2016. Patients were randomized into a training set (N = 310) and an independent validation set (N = 159). The primary endpoint was secondary event-free survival. The individual treatment elements the patients received during initial and recurrent disease were analyzed as binary and time-dependent variables. A five-step multiple time-dependent Cox regression analysis was performed on the training set to identify prognostic variables adjusted for the individual frontline treatment. The selected variables resulted in a prognostic index (PI) and were used to build a risk score system. The score was validated with the validation set. RESULTS: Of the 469 patients, 372 were treated with curative intent and 97 with palliative intent. The PI included the variables number of recurrence organs (hazard ratio [HR] = 2.27), time to recurrence (HR = 2.03), liver metastasis at diagnosis (HR = 1.77), first recurrence at site of the primary tumor (HR = 1.55), and age (HR = 1.29). Three risk groups were built and confirmed in the validation set. The scoring system was likewise useful for the curatively or palliatively treated subgroups. CONCLUSION: A new risk score system for patients with first recurrence of stage 4 neuroblastoma aged ≥18 months at diagnosis is proposed.

A mechanistic classification of clinical phenotypes in neuroblastoma.

Neuroblastoma is a pediatric tumor of the sympathetic nervous system. Its clinical course ranges from spontaneous tumor regression to fatal progression. To investigate the molecular features of the divergent tumor subtypes, we performed genome sequencing on 416 pretreatment neuroblastomas and assessed telomere maintenance mechanisms in 208 of these tumors. We found that patients whose tumors lacked telomere maintenance mechanisms had an excellent prognosis, whereas the prognosis of patients whose tumors harbored telomere maintenance mechanisms was substantially worse. Survival rates were lowest for neuroblastoma patients whose tumors harbored telomere maintenance mechanisms in combination with RAS and/or p53 pathway mutations. Spontaneous tumor regression occurred both in the presence and absence of these mutations in patients with telomere maintenance-negative tumors. On the basis of these data, we propose a mechanistic classification of neuroblastoma that may benefit the clinical management of patients.

Reproductive Performance after Unilateral or Bilateral Oviduct Transfer of 2-Cell Embryos in Mice.

Embryo transfer (ET) is a frequent procedure in contemporary animal and transgenic facilities. We compared the reproductive performance of mice after unilateral and bilateral ET of 15 to 18 two-cell embryos per recipient. The genetic backgrounds of the donors were C57BL/6J (B6J), C57BL/6N (B6N), or fewer than 5 generations of backcrossing to B6 (unknown substrain, <5G B6). The pregnancy rate was significantly higher for bilateral than for unilateral ET for B6J lines (85.4% compared with 79%) but similar between modes for B6N (73.7% compared with 77.9%) and <5G B6 (77% compared with 74.5%) lines. The birth rates after unilateral and bilateral ET were 30.8% and 33.0% for B6J lines, 24.5% and 26.9% for B6N lines, and 31.0% compared with 28.2% for <5G B6 lines, with no significant difference between the modes of ET. Birth rate was significantly higher for B6J lines than B6N lines after both unilateral and bilateral ET. For B6J and B6N lines, the number of pups born per litter was significantly higher for bilateral than unilateral ET. Unilateral ET yielded 0.24 to 0.31 pup per embryo transferred compared with 0.27 to 0.33 pups after bilateral ET. Over all genetic backgrounds, 3.03 to 4.09 embryos were required to produce a single pup. The present study provides data to aid in decision-making as to whether unilateral or bilateral ET should be performed. Bilateral ET results in a larger litter but increases pain and discomfort in recipients. However, unilateral ET saves time and contributes to refinement because surgical trauma is reduced.

Sense-Antisense lncRNA Pair Encoded by Locus 6p22.3 Determines Neuroblastoma Susceptibility via the USP36-CHD7-SOX9 Regulatory Axis.

Trait-associated loci often map to genomic regions encoding long noncoding RNAs (lncRNAs), but the role of these lncRNAs in disease etiology is largely unexplored. We show that a pair of sense/antisense lncRNA (6p22lncRNAs) encoded by CASC15 and NBAT1 located at the neuroblastoma (NB) risk-associated 6p22.3 locus are tumor suppressors and show reduced expression in high-risk NBs. Loss of functional synergy between 6p22lncRNAs results in an undifferentiated state that is maintained by a gene-regulatory network, including SOX9 located on 17q, a region frequently gained in NB. 6p22lncRNAs regulate SOX9 expression by controlling CHD7 stability via modulating the cellular localization of USP36, encoded by another 17q gene. This regulatory nexus between 6p22.3 and 17q regions may lead to potential NB treatment strategies.

Retrospective analysis of relapsed abdominal high-risk neuroblastoma.

BACKGROUND/PURPOSE: The impact of abdominal topography and surgical technique on resectability and local relapse pattern of relapsed abdominal high-risk neuroblastoma (R-HR-NB) is not clearly defined. METHODS: A sample of thirty-nine patients with R-HR-NB enrolled in the German neuroblastoma trials between 2001 and 2010 was analyzed retrospectively using surgical and imaging reports. We evaluated resectability and local relapse pattern within 6 standardized abdominal regions, impact of extent of the first resective surgery on overall survival (OS), and of number of operations and a higher cumulative surgical assessment score (C-SAS) on OS after the first event. RESULTS: In the left upper abdomen, rates for tumor persistence and relapse were 45.9% and 13.5% and in the left lower abdomen 27.7% and 8.3%, respectively. OS in months did not differ between complete and incomplete first resections (median (interquartile range): 35 (45.6) vs. 40 (65.4), P=.649). Better OS after the first event was associated with repeated as compared to single surgery (47.7 (64.7) vs. 4.3 (12.5), P=.000), and with higher as compared to lower C-SAS (47.7 (64.3) vs. 7.6 (14.7), P=.002). CONCLUSIONS: OS after relapse/progression was not dependent on the extent of first resection. The number of operations was associated with better outcome after event. TYPE OF STUDY: Treatment study. LEVEL OF EVIDENCE: LEVEL III Retrospective comparative study.

Prenatal parental decision-making and postnatal outcome in renal oligohydramnios.

BACKGROUND: Previous studies on renal oligohydramnios (ROH) report highly variable outcome and identify early onset of ROH and presence of extrarenal manifestations as predictors of adverse outcome in most cases. Data on termination of pregnancy (TOP) and associated parental decision-making processes are mostly missing, but context-sensitive for the interpretation of these findings. We provide here a comprehensive analysis on the diagnosis, prenatal decision-making and postnatal clinical course in all pregnancies with ROH at our medical centre over an 8-year period. METHODS: We report retrospective chart review data on 103 consecutive pregnancies from 2008 to 2015 with a median follow-up of 554 days. RESULTS: After ROH diagnosis, 38 families opted for TOP. This decision was associated with onset of ROH (p < 0.001), underlying renal disease (p = 0.001) and presence of extrarenal manifestations (p = 0.02). Eight infants died in utero and 8 cases were lost to follow-up. Of the 49 liveborn children, 11 received palliative and 38 underwent active care. Overall survival of the latter group was 84.2% (n = 32) corresponding to 31% of all pregnancies (32 out of 103) analysed. One third of the surviving infants needed renal replacement therapy during the first 6 weeks of life. CONCLUSIONS: Over one third of pregnancies with ROH were terminated and the parental decision was based on risk factors associated with adverse outcome. Neonatal death was rare in the actively treated infants and the overall outcome promising. Our study illustrates that only careful analysis of the whole process, from prenatal diagnosis via parental decision-making to postnatal outcome, allows sensible interpretation of outcome data.

Influence of repetitive diving in freshwater on pressure equalization and Eustachian tube function in recreational scuba divers.

INTRODUCTION: We investigated the effect of repetitive pressure exposure during freshwater dives on Eustachian tube function and the middle ear, assessed by the Eustachian tube function test (ETFT). METHODS: This prospective observational cohort study included 23 divers over three consecutive days of diving in freshwater lakes in Nordhausen, Germany. Participants underwent otoscopy and ETFT before the first dive, between each dive and after the last dive. ETFT included regular tympanometry (R-tymp), tympanometry after Valsalva (V-tymp) and after swallowing (S-tymp). The peak pressure difference between the R-tymp and the V-tymp (R-VdP) defined effectiveness of pressure equalization after Valsalva manoeuvres. We evaluated the change in compliance and peak pressure and correlated the results to the otoscopic findings and diving experience. RESULTS: Twenty-three divers performed 144 dives. Middle ear barotrauma was assessed using the Edmonds modification of the TEED scoring system. In the ETFT, the R-tymp peak pressure displayed a negative shift from day one to three (P = 0.001) and differed significantly between the experience groups (P = 0.01). R-VdP did not change significantly on any of the three days of diving (all P > 0.05). Participants without MEBt showed significantly lower R-tymp values than did those with barotrauma (P = 0.019). CONCLUSION: Repetitive pressure exposure during three consecutive days of freshwater diving led to a negative shift of the peak pressure in the middle ear. Less experienced divers showed significantly higher middle ear peak pressure and higher pressure differences after equalization manoeuvres. Higher middle ear peak pressure was also associated with a higher prevalence of barotrauma.

Molecular Classification Substitutes for the Prognostic Variables Stage, Age, and MYCN Status in Neuroblastoma Risk Assessment.

BACKGROUND: Current risk stratification systems for neuroblastoma patients consider clinical, histopathological, and genetic variables, and additional prognostic markers have been proposed in recent years. We here sought to select highly informative covariates in a multistep strategy based on consecutive Cox regression models, resulting in a risk score that integrates hazard ratios of prognostic variables. METHODS: A cohort of 695 neuroblastoma patients was divided into a discovery set (n=75) for multigene predictor generation, a training set (n=411) for risk score development, and a validation set (n=209). Relevant prognostic variables were identified by stepwise multivariable L1-penalized least absolute shrinkage and selection operator (LASSO) Cox regression, followed by backward selection in multivariable Cox regression, and then integrated into a novel risk score. RESULTS: The variables stage, age, MYCN status, and two multigene predictors, NB-th24 and NB-th44, were selected as independent prognostic markers by LASSO Cox regression analysis. Following backward selection, only the multigene predictors were retained in the final model. Integration of these classifiers in a risk scoring system distinguished three patient subgroups that differed substantially in their outcome. The scoring system discriminated patients with diverging outcome in the validation cohort (5-year event-free survival, 84.9±3.4 vs 63.6±14.5 vs 31.0±5.4; P<.001), and its prognostic value was validated by multivariable analysis. CONCLUSION: We here propose a translational strategy for developing risk assessment systems based on hazard ratios of relevant prognostic variables. Our final neuroblastoma risk score comprised two multigene predictors only, supporting the notion that molecular properties of the tumor cells strongly impact clinical courses of neuroblastoma patients.

Repetitive freshwater diving: risk factors and prevalence of barotrauma.

OBJECTIVE: The aim was to investigate the influence of repetitive scuba diving in fresh water on the middle ear mucosa. The prevalence of middle ear barotrauma (MEB) and risk factors for MEB were evaluated. STUDY DESIGN: Prospective cohort study, Level of evidence 1b. METHODS: During three days, 23 divers made 144 repetitive dives in a freshwater lake. Participants underwent otoscopic examinations and were questioned about ENT-related complaints in the morning before the first dive, in between the dives and after the last dive. Otoscopic findings were documented and classified according to the TEED scale (0 = normal eardrum to 4 = perforation), for the right and the left ear separately. RESULTS: In total, 416 examinations were performed. ENT-related complaints during diving, mostly failed pressure equalization (74%), were reported after 10% of all dives. Most common pathology was MEB (TEED 1-3, 26%). Valsalva maneuver was possible during all exams. Significant increase of MEB (TEED⟩0) occurred with an increasing cumulative number of dives per day (P ⟨ .0001). Diving depth significantly influenced the MEB distribution (P = .035). MEB with higher TEED levels (2 and 3) was present only in the less experienced and intermediate divers. With increasing TEED level, more participants reported ENT-related problems (P ⟨ .0001). However, 74.4% of divers with MEB were still asymptomatic. CONCLUSION: During three days of diving, the MEB prevalence increased with a cumulative number of dives per day. The major risk factors were diving depth and diving experience. Higher TEED level correlated with an increasing number of subjective ENT-related disorders during diving.

Complete surgical resection improves outcome in INRG high-risk patients with localized neuroblastoma older than 18 months.

BACKGROUND: Although several studies have been conducted on the role of surgery in localized neuroblastoma, the impact of surgical timing and extent of primary tumor resection on outcome in high-risk patients remains controversial. METHODS: Patients from the German neuroblastoma trial NB97 with localized neuroblastoma INSS stage 1-3 age > 18 months were included for retrospective analysis. Imaging reports were reviewed by two independent physicians for Image Defined Risk Factors (IDRF). Operation notes and corresponding imaging reports were analyzed for surgical radicality. The extent of tumor resection was classified as complete resection (95-100%), gross total resection (90-95%), incomplete resection (50-90%), and biopsy (<50%) and correlated with local control rate and outcome. Patients were stratified according to the International Neuroblastoma Risk Group (INRG) staging system. Survival curves were estimated according to the method of Kaplan and Meier and compared by the log-rank test. RESULTS: A total of 179 patients were included in this study. 77 patients underwent more than one primary tumor operation. After best surgery, 68.7% of patients achieved complete resection of the primary tumor, 16.8% gross total resection, 14.0% incomplete surgery, and 0.5% biopsy only. The cumulative complication rate was 20.3% and the surgery associated mortality rate was 1.1%. Image defined risk factors (IDRF) predicted the extent of resection. Patients with complete resection had a better local-progression-free survival (LPFS), event-free survival (EFS) and OS (overall survival) than the other groups. Subgroup analyses showed better EFS, LPFS and OS for patients with complete resection in INRG high-risk patients. Multivariable analyses revealed resection (complete vs. other), and MYCN (non-amplified vs. amplified) as independent prognostic factors for EFS, LPFS and OS. CONCLUSIONS: In patients with localized neuroblastoma age 18 months or older, especially in INRG high-risk patients harboring MYCN amplification, extended surgery of the primary tumor site improved local control rate and survival with an acceptable risk of complications.