LOGGIC/FIREFLY-2: a phase 3, randomized trial of tovorafenib vs. chemotherapy in pediatric and young adult patients with newly diagnosed low-grade glioma harboring an activating RAF alteration.

BACKGROUND: Pediatric low-grade glioma (pLGG) is essentially a single pathway disease, with most tumors driven by genomic alterations affecting the mitogen-activated protein kinase/ERK (MAPK) pathway, predominantly KIAA1549::BRAF fusions and BRAF V600E mutations. This makes pLGG an ideal candidate for MAPK pathway-targeted treatments. The type I BRAF inhibitor, dabrafenib, in combination with the MEK inhibitor, trametinib, has been approved by the United States Food and Drug Administration for the systemic treatment of BRAF V600E-mutated pLGG. However, this combination is not approved for the treatment of patients with tumors harboring BRAF fusions as type I RAF inhibitors are ineffective in this setting and may paradoxically enhance tumor growth. The type II RAF inhibitor, tovorafenib (formerly DAY101, TAK-580, MLN2480), has shown promising activity and good tolerability in patients with BRAF-altered pLGG in the phase 2 FIREFLY-1 study, with an objective response rate (ORR) per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria of 67%. Tumor response was independent of histologic subtype, BRAF alteration type (fusion vs. mutation), number of prior lines of therapy, and prior MAPK-pathway inhibitor use. METHODS: LOGGIC/FIREFLY-2 is a two-arm, randomized, open-label, multicenter, global, phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy vs. current standard of care (SoC) chemotherapy in patients < 25 years of age with pLGG harboring an activating RAF alteration who require first-line systemic therapy. Patients are randomized 1:1 to either tovorafenib, administered once weekly at 420 mg/m2 (not to exceed 600 mg), or investigator's choice of prespecified SoC chemotherapy regimens. The primary objective is to compare ORR between the two treatment arms, as assessed by independent review per RANO-LGG criteria. Secondary objectives include comparisons of progression-free survival, duration of response, safety, neurologic function, and clinical benefit rate. DISCUSSION: The promising tovorafenib activity data, CNS-penetration properties, strong scientific rationale combined with the manageable tolerability and safety profile seen in patients with pLGG led to the SIOPe-BTG-LGG working group to nominate tovorafenib for comparison with SoC chemotherapy in this first-line phase 3 trial. The efficacy, safety, and functional response data generated from the trial may define a new SoC treatment for newly diagnosed pLGG. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05566795. Registered on October 4, 2022.

Confirmatory Adaptive Designs for Clinical Trials With Multiple Time-to-Event Outcomes in Multi-state Markov Models.

The analysis of multiple time-to-event outcomes in a randomized controlled clinical trial can be accomplished with existing methods. However, depending on the characteristics of the disease under investigation and the circumstances in which the study is planned, it may be of interest to conduct interim analyses and adapt the study design if necessary. Due to the expected dependency of the endpoints, the full available information on the involved endpoints may not be used for this purpose. We suggest a solution to this problem by embedding the endpoints in a multistate model. If this model is Markovian, it is possible to take the disease history of the patients into account and allow for data-dependent design adaptations. To this end, we introduce a flexible test procedure for a variety of applications, but are particularly concerned with the simultaneous consideration of progression-free survival (PFS) and overall survival (OS). This setting is of key interest in oncological trials. We conduct simulation studies to determine the properties for small sample sizes and demonstrate an application based on data from the NB2004-HR study.

Second trimester fetal thymus size in association to preterm birth.

OBJECTIVES: The aim of this study was to compare the second trimester thymus-thorax-ratio (TTR) between fetuses born preterm (study group) and those born after 37 weeks of gestation were completed (control group). METHODS: This study was conducted as a retrospective evaluation of the ultrasound images of 492 fetuses in the three vessel view. The TTR was defined as the quotient of a.p. thymus diameter and a.p. thoracic diameter. RESULTS: Fetuses that were preterm showed larger TTR (p<0.001) the second trimester than those born after 37 weeks of gestation were completed. The sensitivity of a binary classifier based on TTR for predicting preterm birth (PTB) was 0.792 and the specificity 0.552. CONCLUSIONS: In our study, fetuses affected by PTB showed enlarged thymus size. These findings led us to hypothesize, that inflammation and immunomodulatory processes are altered early in pregnancies affected by PTB. However, TTR alone is not able to predict PTB.

Confirmatory adaptive group sequential designs for single-arm phase II studies with multiple time-to-event endpoints.

Existing methods concerning the assessment of long-term survival outcomes in one-armed trials are commonly restricted to one primary endpoint. Corresponding adaptive designs suffer from limitations regarding the use of information from other endpoints in interim design changes. Here we provide adaptive group sequential one-sample tests for testing hypotheses on the multivariate survival distribution derived from multi-state models, while making provision for data-dependent design modifications based on all involved time-to-event endpoints. We explicitly elaborate application of the methodology to one-sample tests for the joint distribution of (i) progression-free survival (PFS) and overall survival (OS) in the context of an illness-death model, and (ii) time to toxicity and time to progression while accounting for death as a competing event. Large sample distributions are derived using a counting process approach. Small sample properties are studied by simulation. An already established multi-state model for non-small cell lung cancer is used to illustrate the adaptive procedure.

Telomerase activation by genomic rearrangements in high-risk neuroblastoma.

Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type. In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumours, TERT expression was also elevated in MYCN-amplified tumours, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodelling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodelling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the centre of transformation in a large fraction of these tumours.

Doubling Recruitment of Pediatric Low-grade Glioma within Two Decades does not change Outcome - Report from the German LGG Studies.

BACKGROUND: Successive multicenter studies for pediatric low-grade glioma (LGG) in Germany were accompanied by a doubling of annual recruitment over 2 decades. We investigated whether this increase conveyed a change of epidemiologic characteristics or survival. METHODS AND RESULTS: Participating centers reported 4634 patients with the radiologic/histologic diagnosis of LGG (1996-2018), rising from 109 to 278/year. Relating these numbers to all pediatric CNS tumors registered at the German Childhood Cancer Registry, the LGG fraction and annual crude incidence rates increased (32% to 51%; 0.94 to 2.12/100,000 children/adolescents<15 years). The consecutive LGG studies recruited 899 (HIT-LGG 1996), 1592 (SIOP-LGG 2004), and 1836 (LGG-registry) patients with similar distribution of tumor-sites, histology, and dissemination. 5-year overall survival was 96%-98% at median observation time of 8.1 years. Acknowledging unequal follow-up periods, 589/899 (66%), 1089/1582 (69%), and 1387/1836 (76%) patients remained under observation, while 1252/4317 received adjuvant treatment with decreasing frequency of front-line radiotherapy from 16% to 5%. CONCLUSION: Pediatric LGG incidence rates in Germany are now comparable to other European countries. The rise in patient numbers followed implementation of standard-of-care treatment protocols, but did not result in relevant changes of epidemiologic or clinical parameters or survival. Shifts in patient distribution between treatment arms reflect growing acceptance of the LGG therapy algorithm. HINTERGRUND: In den vergangenen 20 Jahren hat sich die jährliche Patientenrekrutierung in den aufeinanderfolgenden multizentrischen Studien für pädiatrische niedrig-gradige Gliome (LGG) in Deutschland verdoppelt. Wir haben untersucht, ob sich mit dieser Zunahme auch epidemiologische Merkmale oder das Überleben verändert haben. METHODIK UND ERGEBNISSE: Zwischen 1996 und 2018 meldeten die teilnehmenden Zentren insgesamt 4634 Patienten mit der radiologischen/histologischen Diagnose eines LGG. Die Zahl stieg von anfangs 109 bis 278 Patienten pro Jahr. Gleichzeitig stieg der Anteil der LGGs an allen am Deutschen Kinderkrebsregister gemeldeten pädiatrischen Hirntumoren von 32 auf 51%, die jährliche Inzidenz erhöhte sich von 0,94 auf 2,12/100 000 Kinder/Jugendliche<15 Jahre. Die aufeinanderfolgenden LGG-Studien rekrutierten 899 (HIT-LGG 1996), 1592 (SIOP-LGG 2004) und 1836 (LGG-Register) Patienten mit vergleichbarer Verteilung von Tumorsitz, Histologie und Disseminierung. Das 5-Jahres-Überleben lag bei einer medianen Nachbeobachtungszeit von 8,1 Jahren zwischen 96 und 98%. Unter Berücksichtigung der ungleich langen Follow-up-Zeit wurden 589/899 (65,5%), 1089/1582 (68,8%) und 1387/1836 (75,5%) Patienten bislang beobachtet, während 1252/4317 eine adjuvante Therapie erhielten. Dabei sank der Anteil der primären Radiotherapie von 16 auf 5%. SCHLUSSFOLGERUNG: Die Rekrutierung pädiatrischer LGG ist dank Implementierung verbindlicher Therapiestandards in Deutschland gestiegen, ohne zu relevanten Veränderungen epidemiologischer oder klinischer Merkmale oder des Überlebens zu führen. Die Inzidenz ist mit anderen europäischen Ländern vergleichbar. Verschiebungen der Patientenzuteilung zwischen den Therapiearmen spiegeln die zunehmende Akzeptanz des LGG-Therapie-Algorithmus wider.

OF-Pelvis classification of osteoporotic sacral and pelvic ring fractures.

OBJECTIVES: Osteoporotic fractures of the pelvis (OFP) are an increasing issue in orthopedics. Current classification systems (CS) are mostly CT-based and complex and offer only moderate to substantial inter-rater reliability (interRR) and intra-rater reliability (intraRR). MRI is thus gaining importance as a complement. This study aimed to develop a simple and reliable CT- and MRI-based CS for OFP. METHODS: A structured iterative procedure was conducted to reach a consensus among German-speaking spinal and pelvic trauma experts over 5 years. As a result, the proposed OF-Pelvis CS was developed. To assess its reliability, 28 experienced trauma and orthopedic surgeons categorized 25 anonymized cases using X-ray, CT, and MRI scans twice via online surveys. A period of 4 weeks separated the completion of the first from the second survey, and the cases were presented in an altered order. While 13 of the raters were also involved in developing the CS (developing raters (DR)), 15 user raters (UR) were not deeply involved in the development process. To assess the interRR of the OF-Pelvis categories, Fleiss' kappa (κF) was calculated for each survey. The intraRR for both surveys was calculated for each rater using Kendall's tau (τK). The presence of a modifier was calculated with κF for interRR and Cohen's kappa (κC) for intraRR. RESULTS: The OF-Pelvis consists of five subgroups and three modifiers. Instability increases from subgroups 1 (OF1) to 5 (OF5) and by a given modifier. The three modifiers can be assigned alone or in combination. In both surveys, the interRR for subgroups was substantial: κF = 0.764 (Survey 1) and κF = 0.790 (Survey 2). The interRR of the DR and UR was nearly on par (κF Survey 1/Survey 2: DR 0.776/0.813; UR 0.748/0.766). The agreement for each of the five subgroups was also strong (κF min.-max. Survey 1/Survey 2: 0.708-0.827/0.747-0.852). The existence of at least one modifier was rated with substantial agreement (κF Survey 1/Survey 2: 0.646/0.629). The intraRR for subgroups showed almost perfect agreement (τK = 0.894, DR: τK = 0.901, UR: τK = 0.889). The modifier had an intraRR of κC = 0.684 (DR: κC = 0.723, UR: κC = 0.651), which is also considered substantial. CONCLUSION: The OF-Pelvis is a reliable tool to categorize OFP with substantial interRR and almost perfect intraRR. The similar reliabilities between experienced DRs and URs demonstrate that the training status of the user is not important. However, it may be a reliable basis for an indication of the treatment score.

Loss of efficacy of subsequent nonsurgical therapy after primary treatment failure in pediatric low-grade glioma patients-Report from the German SIOP-LGG 2004 cohort.

First-line treatment of pediatric low-grade glioma using surgery, radio- or chemotherapy fails in a relevant proportion of patients. We analyzed efficacy of subsequent surgical and nonsurgical therapies of the German cohort of the SIOP-LGG 2004 study (2004-2012, 1558 registered patients; median age at diagnosis 7.6 years, median observation time 9.2 years, overall survival 98%/96% at 5/10 years, 15% neurofibromatosis type 1 [NF1]). During follow-up, 1078/1558 patients remained observed without (n = 217), with 1 (n = 707), 2 (n = 124) or 3 to 6 (n = 30) tumor volume reductions; 480/1558 had 1 (n = 332), 2 (n = 80), 3 or more (n = 68) nonsurgical treatment-lines, accompanied by up to 4 tumor-reductive surgeries in 215/480; 265/480 patients never underwent any neurosurgical tumor volume reduction (163/265 optic pathway glioma). Patients with progressing tumors after first-line adjuvant treatment were at increased risk of suffering further progressions. Risk factors were young age (<1 year) at start of treatment, tumor dissemination or progression within 18 months after start of chemotherapy. Progression-free survival rates declined with subsequent treatment-lines, yet remaining higher for patients with NF1. In non-NF1-associated tumors, vinblastine monotherapy vs platinum-based chemotherapy was noticeably less effective when used as second-line treatment. Yet, for the entire cohort, results did not favor a certain sequence of specific treatment options. Rather, all can be aligned as a portfolio of choices which need careful balancing of risks and benefits. Future molecular data may predict long-term tumor biology.

Favorable prognosis in pediatric brainstem low-grade glioma: Report from the German SIOP-LGG 2004 cohort.

Reports on pediatric low-grade glioma (LGG) of the caudal brainstem are retrospective with heterogeneous cohorts, variable treatments and inconsistent outcome data. We analyzed their natural history and asked whether brainstem location proved unfavorable for survival within the framework of the comprehensive SIOP-LGG 2004 management strategy. Within the prospectively registered, population-based German SIOP-LGG 2004 cohort 116 patients (age 0.2-16.5 years, 10% Neurofibromatosis NF1) were diagnosed with LGG of the pons (27%) and medulla oblongata (73%). After biopsy (23%), variable resection (63%) or radiologic diagnosis only (14%), 59 patients received no adjuvant treatment. Radiologic progression or severe neurologic symptoms prompted chemo- (n = 39) or radiotherapy (n = 18). After further progression (28/57), salvage treatments included multiple treatment lines for 12/28 patients. Five-years event-free survival dropped to 0.40, while 5-years overall survival was 0.95 (median observation time 6.8 years). Higher extent of resection yielded lower progression rate (p = 0.001), but at a cost of 21/100 patients suffering from new postsurgical complications including respiratory insufficiency. Central review confirmed pilocytic astrocytoma (56%), diffuse astrocytoma (8%) or glioneuronal histology (16%) (others 4%, no histology 17%). Malignant evolution was documented in five patients associated with Histone3 mutation in 2/5. Our treatment algorithm conveyed high overall survival for pediatric brainstem LGG. Extensive neurosurgical resection did increase additional postoperative neurologic deficits but not overall survival in this often-chronic disease. More than half of all patients can be safely followed by observation, while multimodal adjuvant treatment can control progressive tumors. Molecular assessment should confirm low-grade diagnosis and may detect patterns prognostic for malignant evolution.

Prognostic impact of distinct genetic entities in pediatric diffuse glioma WHO-grade II-Report from the German/Swiss SIOP-LGG 2004 cohort.

Reports on pediatric low-grade diffuse glioma WHO-grade II (DG2) suggest an impaired survival rate, but lack conclusive results for genetically defined DG2-entities. We analyzed the natural history, treatment and prognosis of DG2 and investigated which genetically defined sub-entities proved unfavorable for survival. Within the prospectively registered, population-based German/Swiss SIOP-LGG 2004 cohort 100 patients (age 0.8-17.8 years, 4% neurofibromatosis [NF1]) were diagnosed with a DG2. Following biopsy (41%) or variable extent of resection (59%), 65 patients received no adjuvant treatment. Radiologic progression or severe neurologic symptoms prompted chemotherapy (n = 18) or radiotherapy (n = 17). Multiple lines of salvage treatment were necessary for 19/35 patients. Five years event-free survival dropped to 0.44, while 5 years overall survival was 0.90 (median observation time 8.3 years). Extensive genetic profiling of 65/100 DG2 identified Histone3-K27M-mutation in 4, IDH1-mutation in 11, BRAF-V600-mutation in 12, KIAA1549-BRAF-fusions in 6 patients, while the remaining 32 tumor tissues did not show alterations of these genes. Progression to malignant glioma occurred in 12 cases of all genetically defined subgroups within a range of 0.5 to 10.8 years, except for tumors carrying KIAA1549-BRAF-fusions. Histone3-K27M-mutant tumors proved uniformly fatal within 0.6 to 2.4 years. The current LGG treatment strategy seems appropriate for all DG2-entities, with the exemption of Histone3-K27M-mutant tumors that require a HGG-related treatment strategy. Our data confirm the importance to genetically define pediatric low-grade diffuse gliomas for proper treatment decisions and risk assessment.

Monitoring the Structural Health of Glass Fibre-Reinforced Hybrid Laminates Using Novel Piezoceramic Film.

This work investigates a new generation structural health monitoring (SHM) system for fibre metal laminates (FML) based on an embedded thermoplastic film with compounded piezoceramics, termed piezo-active fibre metal laminate (PFML). The PFML is manufactured using near-series processes and its potential as a passive SHM system is being investigated. A commercial Polyvinylidene fluoride (PVDF) sensor film is used for comparative evaluation of the sensor signals. Furthermore, thermoset and thermoplastic-based FML are equipped with the sensor films and evaluated. For this purpose, static and dynamic three-point bending tests are carried out and the data are recorded. The data obtained from the sensors and the testing machine are compared with the type and time of damage by means of intelligent signal processing. By using a smart sensor system, further investigations are planned which the differentiation between various failure modes, e.g., delamination or fibre breakage.

[Treatment of a necrotizing soft tissue infection]. / Therapie einer nekrotisierenden Weichgewebeinfektion.

The surgical procedure for the life-threatening course of a necrotizing soft tissue infection of the leg after minor trauma is described. The necessary consistent resection of extensive fascial and muscular necroses required the reconstruction of soft tissue defects of the knee, the ankle joint and peroneal tendons exposed over a long distance. The functional outcome is presented 1 year after use of MatriDerm® and a split-thickness skin graft for defect coverage.

Increased soluble fms-like tyrosine kinase 1 after ischemia reperfusion contributes to adverse clinical outcomes following kidney transplantation.

Renal ischemia reperfusion injury (IRI) adversely affects clinical outcomes following kidney transplantation. Understanding the cellular mechanisms and the changes in gene/protein expression following IRI may help to improve these outcomes. Serum soluble fms-like tyrosine kinase 1 (sFlt-1), a circulating antiangiogenic protein, is increased in the first week following kidney transplantation. We evaluated the casual relationship of elevated sFlt-1 levels with renal microvascular dysfunction following IRI in a longitudinal study of 93 kidney transplant recipients and in several animal models. Transplant recipients with higher sFlt-1 levels had higher odds of delayed graft function, graft rejection, impaired graft function, and death. In a subgroup of 25 participants who underwent kidney biopsy within 4 months of kidney transplantation, peritubular capillary area was lower in those with elevated serum sFtl-1 levels. The administration of recombinant sFlt-1 into rodents resulted in significant structural and functional changes of the renal microvasculature, including reduced peritubular capillary density and intracapillary blood volume, and lead to increased expression of inflammatory genes and increased fibrosis. In a murine model of IRI, the kidney was a site of sFlt-1 production, and systemic neutralization of sFlt-1 preserved peritubular capillary density and alleviated renal fibrosis. Our data indicate that high sFlt-1 levels after IRI play an important role in the pathogenesis of microvascular dysfunction, thereby contributing to adverse clinical outcomes following kidney transplantation.

Procedure related risk of premature delivery and fetal growth reduction following amniocentesis, transcervical and transabdominal chorionic villus sampling: a retrospective study.

Background The aim of this study was to compare transabdominal and transcervical chorionic villus sampling (CVS) as well as amniocentesis (AC) with respect to their rates of premature delivery and fetal growth restriction. Methods We retrospectively evaluated the mentioned procedures of invasive prenatal testing performed in a single center between 2001 and 2016. Seven hundred and ninety-nine cases of AC and 719 cases of CVS were included, of which 400 were performed transvaginally. Only singleton pregnancies with a normal karyotype and delivery after 24 + 0 weeks of gestation were included. Fetal growth restriction was defined as birth weight below the 10th percentile. Premature delivery was defined as delivery before 37 + 0 weeks of gestation. Data were compared to a control group without an invasive procedure. Results The frequency of premature delivery was 8.5% after transabdominal CVS, 6.3% after transcervical CVS and 10.5% after AC as compared to 10.8% in the control group. The frequency of fetal growth restriction was 8.2% after transabdominal CVS 6.8% after transcervical CVS and 8.4% after AC as compared to 9.7% in the control group. Conclusion Our study supports that the three different methods of invasive prenatal testing do not lead to a higher risk of either premature delivery or fetal growth restriction when compared to controls. We found no difference in risk profile among the three techniques.

[If People Can't Stand Their Own Smell - A Review and Case History about Olfactory Reference Disorder]. / Wenn man sich selbst einfach nicht "riechen" kann.

Olfactory Reference Disorder is a little explored and widely unknown phenomenon, even research has shown more interest in it during the last years. This review summarizes the existing literature and illustrates its findings with a case history. The databases PubMed, PsychNet, PsychPub, Hogrefe EContent and the Cochrane Library (CENTRAL) were searched for keywords. The identified literature shows that there is a big lack of well-designed studies concerning ORS, in all areas of its nosology. The suffering of persons with ORS, however, is really incriminating.

Adaptive designs for the one-sample log-rank test.

Traditional designs in phase IIa cancer trials are single-arm designs with a binary outcome, for example, tumor response. In some settings, however, a time-to-event endpoint might appear more appropriate, particularly in the presence of loss to follow-up. Then the one-sample log-rank test might be the method of choice. It allows to compare the survival curve of the patients under treatment to a prespecified reference survival curve. The reference curve usually represents the expected survival under standard of the care. In this work, convergence of the one-sample log-rank statistic to Brownian motion is proven using Rebolledo's martingale central limit theorem while accounting for staggered entry times of the patients. On this basis, a confirmatory adaptive one-sample log-rank test is proposed where provision is made for data dependent sample size reassessment. The focus is to apply the inverse normal method. This is done in two different directions. The first strategy exploits the independent increments property of the one-sample log-rank statistic. The second strategy is based on the patient-wise separation principle. It is shown by simulation that the proposed adaptive test might help to rescue an underpowered trial and at the same time lowers the average sample number (ASN) under the null hypothesis as compared to a single-stage fixed sample design.

Management of Primary Tectal Plate Low-Grade Glioma in Pediatric Patients: Results of the Multicenter Treatment Study SIOP-LGG 2004.

BACKGROUND: Tectal plate low-grade gliomas (LGGs) most often present with increased intracranial pressure and sometimes as incidental findings from brain imaging. Prognostic factors predicting outcome are largely unknown. METHODS: From 2004 until 2012, 71 patients with tectal plate LGG from Germany and Switzerland were followed within the SIOP-LGG 2004 study. Median age at diagnosis was 9.7 (range: 0.1-17.5) years, and median follow-up time of surviving patients was 6.3 (interquartile range: 4.9-8.3) years. RESULTS: A total of 41 out of 71 patients received no tumor treatment (12 with and 29 without biopsy). The 10-year event-free survival (EFS) rate (± standard error ) for patients with an initial tumor volume of ≤3 cm3 was 56% (±7%), as opposed to 12% (±8%) for those with tumors >3 cm3 (p < 0.001). The 10-year EFS for patients without contrast enhancement on initial magnetic resonance imaging (MRI) was 52% (±9%), and for those with enhancement, it was 23% (±9%) (p = 0.003). The 10-year overall survival rate was 96% (±3%) (death due to disease, 1; ventriculoperitoneal shunt infection, 1). Sixty-three (89%) patients had at least one cerebrospinal fluid diversion procedure. CONCLUSIONS: More than half of patients were managed without tumor treatment. Favorable prognostic factors for EFS were small initial tumor volume (≤3cm3) and the absence of initial contrast enhancement on MRI. Overall survival was excellent.

Assessment of strain and dyssynchrony in normal fetuses using speckle tracking echocardiography - comparison of three different ultrasound probes.

OBJECTIVE: To evaluate segmental left (LV-S) and right (RV-S) ventricular strain as well as longitudinal mechanical myocardial dyssynchrony as a time difference between peaks in strain of both ventricles in fetuses (two-chamber-dyssynchrony, 2C-DYS) using speckle tracking echocardiography (STE). The aim of our study was to evaluate the influence of data acquisition on the results of STE measurement using different ultrasound probes. METHODS: We prospectively recorded cardiac cycles of four-chamber views of 56 normal fetuses with three different ultrasound probes and analyzed them offline with speckle tracking imaging software. Furthermore, we looked at a possible influence of heartbeat variability (beat-to-beat variability). RESULTS: The evaluation of the parameters was feasible with all three probes in 53 cases. There was no influence of heartbeat variability and no noticeable differences in 2C-DYS, LV-S and RV-S in all cases and for all three probes determined. CONCLUSION: Assessment of strain and dyssynchrony using STE with three different probes is comparable. Further research is needed to validate dyssynchrony as a predictor for fetal outcome.

Assessing changes in tissue oxygenation by near-infrared spectroscopy following brachial plexus block for arteriovenous fistula surgery: A prospective observational pilot study.

BACKGROUND: Near-infrared spectroscopy (NIRS) can be used to measure tissue oxygen saturation (StO2) in different sites and in a wide range of clinical scenarios. Peripheral regional anaesthesia induces vascular changes causing increased arterial blood flow and venodilatation, but its effect on StO2 is still under debate. This is especially so for patients undergoing arteriovenous fistula surgery, wherein latest data suggest an improved outcome under brachial plexus block (BPB) compared with local anaesthesia, but no data are available. OBJECTIVE: The aim of this study was to investigate changes in StO2 following BPB prior to arteriovenous fistula surgery using NIRS. DESIGN: A prospective observational study. SETTING: A secondary teaching hospital from August 2016 to March 2017. PATIENTS: Fifteen patients undergoing arteriovenous fistula surgery. INTERVENTION: Ultrasound-guided BPB in 15 patients undergoing arteriovenous fistula surgery. OUTCOME MEASURES: StO2 at baseline and compared with baseline and the contralateral arm following BPB measured using NIRS of the thenar eminence (NIRSth). RESULTS: Baseline values of StO2 assessed by NIRSth were 42.6 ±â€Š7.7% in the arteriovenous fistula arm and 42.7 ±â€Š9.7% in the contralateral arm. There was no significant difference between the two. Five minutes after BPB, there was a significant increase in StO2 of the blocked arm, compared with the control arm expressed as difference of absolute values (7.1 ±â€Š9.7%). At 60 min, an absolute difference of 21.0 ±â€Š13.5% was reached. The absolute increase in StO2 of the blocked arm compared with baseline reached significance after 5 min (8.8 ±â€Š4.6%) and increased up to 23.2 ±â€Š8.2% after 60 min. CONCLUSION: NIRSth indicates that BPB significantly increases StO2 of the arteriovenous fistula arm in patients undergoing haemodialysis. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03044496.

Finding an upper limit of what might be achievable by patients: oral cleanliness in dental professionals after self-performed manual oral hygiene.

AIMS: Though patients have been shown to have difficulties in achieving oral cleanliness after self-performed oral hygiene, scientifically and empirically justified standards for the degree of oral cleanliness they should achieve are lacking. Oral cleanliness of dental staff was therefore assessed as an indicator of what might be an upper limit of what can be expected by patients. MATERIALS AND METHODS: In a multicentre study, N = 64 university dentists, N = 33 dental students and N = 30 dental assistants were asked to perform manual oral hygiene to the best of their abilities. The presence or absence of dental plaque adjacent to gingival margins was assessed by the marginal plaque index (MPI). As full-crown index, the Turesky modification of the Quigley and Hein Index (QHIm) was applied. RESULTS: Only three participants showed papillary bleeding and only one a clinical pocket depth of more than 3.5 mm. After self-performed oral hygiene, no differences between groups were observed with respect to plaque nor did results differ between those who habitually used a powered toothbrush only and those who did not. Most participants (96%) achieved oral cleanliness at more than 70% of their gingival margins and QHIm levels below .63. Half of the participants showed QHIm levels below .17 and oral cleanliness at 96% of gingival margins. CONCLUSIONS AND CLINICAL RELEVANCE: Considering that half of the dental professionals achieved oral cleanliness at 96% of gingival margins and QHIm levels below .17 after thorough oral hygiene, this might reflect an upper limit of what can be expected by patients.