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"Mueller, Michael"
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Phenotype of POLE-mutated endometrial cancer
Individualized therapy in endometrial cancer, the most common gynaecologic cancer in the developed world, focuses on identifying specific molecular subtypes. Mutations in the exonuclease domain of the DNA polymerase epsilon (POLE) gene define one such subtype, which causes an ultra-mutated tumour phenotype. These tumours may have an improved progression-free survival and may be receptive to specific therapies. However, the clinical phenotype of these tumours is unknown. The objective of this study was to evaluate the clinical and genetic features of POLE-mutated tumours from a large cohort of women whose cases are characterized by: (1) the availability of detailed clinical and lifestyle data; (2) mutation analysis; and (3) long-term follow-up.
A total of 604 patients with endometrial cancer were included in the study. Data from a detailed questionnaire, including lifestyle and family history information, provided extensive pertinent information on the patients. Sequencing of exons 9-14 of the POLE gene was performed. Follow-up data were gathered and analysed.
Hotspot pathogenic POLE mutations were identified in N = 38/599 patients (6.3%). Patients with a POLE-mutated tumour were significantly younger, were more often nulliparous, and had a history of smoking. POLE-mutated tumours were more frequently aneuploid. Prognosis for patients with hotspot POLE-mutated tumours was significantly better in comparison with patients with non-mutated tumours; however careful selection of pathogenic mutations is essential to the definition of this prognostically favourable group.
This study demonstrates that POLE-mutated endometrial cancer is significantly associated with previously unknown clinicopathologic characteristics. Outcome in POLE-mutated tumours was excellent in cases with hotspot mutations. Our results suggest that prediction of excellent outcome in cases of POLE-mutated EMCA should be restricted to cases of EMCA with hotspot mutations until further data are available on the rising number of mutations with unknown significance.
Journal Article
Parallel targeted and non-targeted quantitative analysis of steroids in human serum and peritoneal fluid by liquid chromatography high-resolution mass spectrometry
We developed and validated a liquid chromatography high-resolution mass spectrometry method for the absolute quantification of 51 steroids for clinical analysis of human serum and, for the first time, peritoneal fluid. Data acquisition was performed in both targeted and untargeted mode simultaneously, thus allowing the accurate and precise quantification of the main components of the classical steroid pathways (17 steroids) as well as the analysis of 34 additional non-classical steroids. For targeted analysis, validation was performed according to FDA guidelines, resulting, among other parameters, in accuracy < 13% RSD and precision < 10% relative error, for both inter- and intra-day validation runs. By establishing steroid-specific response factors, the calibration curves of the targeted analytes can be extended to untargeted analytes. This approach opens novel possibilities for the post hoc analysis of clinical samples as the data can be examined for virtually any steroid even after data acquisition, enabling facile absolute quantification once a standard becomes available. We demonstrate the applicability of the approach to evaluate the differences in steroid content between peripheral serum and peritoneal fluid across the menstrual cycle phases, as well as the effect of the synthetic gestagen dienogest on the steroid metabolome.
Journal Article
Laparoscopic sacrocolpopexy mesh excision step-by-step
Introduction and hypothesis
The objective was to demonstrate the surgical procedure of laparoscopic mesh removal after sacrocolpopexy to aid clinicians facing mesh complications.
Methods
Video footage shows the laparoscopic management of mesh failure and mesh erosion after sacrocolpopexy with narrated video sequences of two patients.
Results
Laparoscopic sacrocolpopexy represents the gold standard in advanced prolapse repair. Mesh complications occur infrequently but infections, failure of prolapse repair and mesh erosions necessitate mesh removal and repeat sacrocolpopexy if applicable.
The video deals with two women referred to our tertiary referral urogynecology unit in the University Women’s Hospital of Bern, Switzerland, after laparoscopic sacrocolpopexies that were carried out in remote hospitals. Both patients were asymptomatic more than 1 year after surgery.
Conclusions
Complete mesh removal after sacrocolpopexy and repeat prolapse surgery can be challenging but is feasible and is aimed at improving patients’ complaints and symptoms.
Journal Article
A Sea Surface–Based Drag Model for Large-Eddy Simulation of Wind–Wave Interaction
Monin–Obukhov similarity theory (MOST) is a well-tested approach for specifying the fluxes when the roughness surfaces are homogeneous. For flow over waves (inhomogeneous surfaces), phase-averaged roughness length scales are often prescribed through models based on the wave characteristics and the wind speed. However, such approaches lack generalizability over different wave ages and steepnesses due to the reliance on model coefficients tuned to specific datasets. In this paper, a sea surface–based hydrodynamic drag model applicable to moving surfaces is developed to model the pressure-based surface drag felt by the wind due to the waves. The model is based on the surface gradient approach of Anderson and Meneveau applicable to stationary obstacles and extended here to the wind–wave problem. The wave drag model proposed specifies the hydrodynamic force based on the incoming momentum flux, wave phase speed, and the surface frontal area. The drag coefficient associated with the wind–wave momentum exchange is determined based on the wave steepness. The wave drag model is used to simulate turbulent airflow above a monochromatic wave train with different wave ages and wave steepnesses. The mean velocity profiles and model form stresses are validated with available laboratory-scale experimental data and show good agreement across a wide range of wave steepnesses and wave ages. The drag force is correlated with the wave surface gradient and out-of-phase with the wave height distribution by a factor of π /2 for the sinusoidal wave train considered. These results demonstrate that the current approach is sufficiently general over a wide parameter space compared to wave phase-averaged models with a minimal increase in computational cost.
Journal Article
Sentinel Node Mapping in Cervical and Endometrial Cancer: Indocyanine Green Versus Other Conventional Dyes—A Meta-Analysis
Background
Historically, blue dyes,
99
Tc or a combination of the two tracers have been used for sentinel lymph node (SLN) mapping in cervical and endometrial cancer patients. Indocyanine green (ICG), as a tracer, has been recently introduced in this setting. Our goal was to assess the differences in overall and bilateral detection rates as well as in false-negative rates among the different tracers.
Methods
The electronic databases PubMed, MEDLINE, and Scopus were searched in January 2016 by searching the terms “sentinel lymph node” and “dye” and “indocyanine green,” and “cervical cancer” or “endometrial cancer.” Series comparing different tracers injected intracervically and reporting the detection rate and/or SLN false-negative rate were selected.
Results
Forty-five studies were retrieved. Six studies including 538 patients met selection criteria. Compared with blue dyes, ICG SLN mapping had higher overall (odds ratio [OR] 0.27; 95 % confidence interval [CI] 0.15–0.50;
p
< 0.0001) and bilateral detection rates (OR 0.27; 95 % CI 0.19–0.40;
p
< 0.00001). No differences were found between ICG and
99
TC, although these results are based on data of a single series. No differences in overall and bilateral detection rates were found between ICG and the combination of blue dyes and
99
TC. The pooled analysis of false-negative rates data showed no difference in false-negative rates between tracers.
Conclusions
In cervical and endometrial cancer, ICG SLN mapping seems to be equivalent to the combination of blue dyes and
99
TC in terms of overall and bilateral detection rates. Its safety profile and ease of use may favor its employment respect to conventional tracers.
Journal Article
Impact of CYGNSS-Derived Winds on Tropical Cyclone Forecasts in a Global and Regional Model
An observing system experiment was conducted to assess the impact of wind products derived from the Cyclone Global Navigation Satellite System (CYGNSS) on tropical cyclone track, maximum 10-m wind speed V max , and minimum sea level pressure forecasts. The experiment used a global data assimilation and forecast system, and the impact of both CYGNSS-derived scalar and vector wind retrievals was investigated. The CYGNSS-derived vector wind products were generated by optimally combining the scalar winds and a gridded a priori vector field. Additional tests investigated the impact of CYGNSS data on a regional model through the impact of lateral boundary and initial conditions from the global model during the developmental phase of Hurricane Michael (2018). In the global model, statistically significant track forecast improvements of 20–40 km were found in the first 60 h. The V max forecasts showed some significant degradations of ~2 kt at a few lead times, especially in the first 24 h. At most lead times, impacts were not statistically significant. Degradations in V max for Hurricane Michael in the global model were largely attributable to a failure of the CYGNSS-derived scalar wind test to produce rapid intensification in the forecast initialized at 0000 UTC 7 October. The storm in this test was notably less organized and symmetrical than in the control and CYGNSS-derived vector wind test. The regional model used initial and lateral boundary conditions from the global control and CYGNSS scalar wind tests. The regional forecasts showed large improvements in track, V max , and minimum sea level pressure.
Journal Article