Universitätsklinikum Tübingen

Background Fracture detection by artificial intelligence and especially Deep Convolutional Neural Networks (DCNN) is a topic of growing interest in current orthopaedic and radiological research. As learning a DCNN usually needs a large amount of training data, mostly frequent fractures as well as conventional X-ray are used. Therefore, less common fractures like acetabular fractures (AF) are underrepresented in the literature. The aim of this pilot study was to establish a DCNN for detection of AF using computer tomography (CT) scans. Methods Patients with an acetabular fracture were identified from the monocentric consecutive pelvic injury registry at the BG Trauma Center XXX from 01/2003–12/2019. All patients with unilateral AF and CT scans available in DICOM-format were included for further processing. All datasets were automatically anonymised and digitally post-processed. Extraction of the relevant region of interests was performed and the technique of data augmentation (DA) was implemented to artificially increase the number of training samples. A DCNN based on Med3D was used for autonomous fracture detection, using global average pooling (GAP) to reduce overfitting. Results From a total of 2,340 patients with a pelvic fracture, 654 patients suffered from an AF. After screening and post-processing of the datasets, a total of 159 datasets were enrolled for training of the algorithm. A random assignment into training datasets (80%) and test datasets (20%) was performed. The technique of bone area extraction, DA and GAP increased the accuracy of fracture detection from 58.8% (native DCNN) up to an accuracy of 82.8% despite the low number of datasets. Conclusion The accuracy of fracture detection of our trained DCNN is comparable to published values despite the low number of training datasets. The techniques of bone extraction, DA and GAP are useful for increasing the detection rates of rare fractures by a DCNN. Based on the used DCNN in combination with the described techniques from this pilot study, the possibility of an automatic fracture classification of AF is under investigation in a multicentre study.

Objective To assess the tolerability of multimodal therapy in soft tissue sarcoma patients, particularly with regard to their quality of life and level of distress. Materials and methods A retrospective cohort study enrolled individuals receiving sarcoma therapy at the sarcoma center of the University of Tuebingen between 2017 and 2022. Participants completed an online survey that included the EORTC’s questionnaire (QLQ-C30), coupled with the distress thermometer and demographic inquiries. The primary emphasis was on comparing three distinct modalities: Radiation, Chemotherapy and Surgery. The data were analysed performing one-way ANOVA. Results A total of 237 patients were included in the study. There was a significant difference (p < 0.001) in quality of life according to the EORTC scores (high score = high quality of life) between the different treatments: chemotherapy (mean: 26.8 [standard deviation: 19.5]), radiotherapy (51.0 [21.5]), and surgery (46.9 [28.3]). Similarly, a statistically significant discrepancy (p < 0.001) was found in average distress levels (high score = high level of distress) corresponding to each treatment type: radiation (5.0 [2.7]), surgery (6.0 [2.9]), and chemotherapy (7.4 [2.4]). The rates of patients willing to undergo the same treatment varied across groups, with the highest percentage observed in the surgery group (94.2%), followed by radiation (87.4%), and chemotherapy (73.5%). Conclusion Patients receiving multimodal therapy for soft tissue often find chemotherapy particularly demanding. Impairment of both quality of life and physical well-being is more likely and tends to be more severe compared with radiation or surgery. These observations should be taken into consideration when consenting patients and offering treatment plans.

A 65-year-old woman with a history of ductal mammary carcinoma and recent autonomic dysfunction underwent a Rb-82 chloride (RbCl) cardiac PET/CT scan that showed no ischemia or scarring, but significantly reduced myocardial flow reserve (MFR) (global: 1.5) and a CAC-Score of 0. The patient’s chemotherapy history (paclitaxel, carboplatin, epirubicin, pembrolizumab 2 years before) with elevated Troponin T and NT-pro-BNP levels at that time, and now reduced MFR with 0 CAC suggests cancer-therapy-related cardiotoxicity. An important differential diagnosis to the more common CAD-associated microvascular disease. Furthermore, tumor recurrence with a PET-avid lymph node metastasis was found additionally.

Objectives To evaluate (1) the association between nailfold capillaroscopy pattern and 5-year risk for incident interstitial lung disease and (2) the association between transition in nailfold capillaroscopy pattern and risk of incident interstitial lung disease. Methods Data of adult patients from the EUSTAR database fulfilling the ACR-EULAR criteria with a disease duration ⩽5 years, having a scleroderma pattern at nailfold capillaroscopy with high-resolution computed tomography confirmed absence of interstitial lung disease (i.e. baseline) was used. Interstitial lung disease-free survival was assessed for up to 5 years of follow-up with a Cox proportional hazards model stratified on nailfold capillaroscopy pattern at baseline. The association of annual transition in nailfold capillaroscopy pattern on the risk to develop interstitial lung disease was assessed with a mixed logistic regression analysis. Results Out of 771 eligible patients, 283 (37%) had an early pattern, 377 (49%) had an active pattern, and 111 (14%) had a late pattern. The Cox proportional hazard model including the identified confounders did not show an association between severity of nailfold capillaroscopy pattern at baseline and increased risk for interstitial lung disease during 5-year follow-up (hazard ratio (95 confidence interval; p value): 1.09 (0.86–1.39; 0.47)). The mixed logistic regression analysis revealed an increased annual risk for incident interstitial lung disease with increasing severity of capillaroscopic pattern (odds ratio (95% confidence interval); p value 3.76 (1.99–7.11; <0.01)). Conclusion Our study shows that worsening of nailfold capillaroscopy has a strong association with an increased annual risk to develop interstitial lung disease. Of note, a worse scleroderma pattern at nailfold capillaroscopy is not associated with the long-term risk to develop interstitial lung disease.

Telomerase is reactivated by genomic TERT rearrangements in ~30% of diagnosed high-risk neuroblastomas. Dismal patient prognosis results if the RAS/MAPK/ALK signaling transduction network also harbors mutations. We present a liquid biopsy-based monitoring strategy for this particularly vulnerable pediatric patient subgroup, for whom real-time molecular diagnostic tools are limited to date. Droplet digital PCR assays quantifying patient-individualized TERT rearrangement breakpoint copies, ALK copy numbers and allelic ALK p.R1275Q mutation frequencies were applied to longitudinally collected liquid biopsies (peripheral blood and bone marrow plasma, n=44 biosamples), the mononuclear cell fraction from bone marrow and matched tumor samples. Marker detection was compared with current gold standard diagnostics. Reanalysis of whole-genome and targeted panel sequencing data from 169 patients identified 64 TERT-rearranged neuroblastoma samples collected at initial and/or relapse diagnosis from 55 patients (254 total TERT rearrangement events). Detection and quantification of unique TERT rearrangement breakpoints in as little as 1ng of total cell-free DNA in peripheral blood plasma improved therapy response assessment and early relapse detection in individual patients. Proof-of-concept is provided for minimal residual disease detection in the bone marrow niche, from which relapses frequently arise, by analyzing unique TERT rearrangement breakpoints in bone marrow plasma-derived cell-free DNA. TERT rearrangement breakpoints, as a single marker or combined with mutations in the RAS/MAPK/ALK signaling transduction network, can serve as robust and highly sensitive biomarkers for disease activity and spatially and temporally resolve disease better than current gold standard diagnostics in individual patients with TERT-driven neuroblastoma.

Including sensor information in medical interventions aims to support surgeons to decide on subsequent action steps by characterizing tissue intraoperatively. With bladder cancer, an important issue is tumor recurrence because of failure to remove the entire tumor. Impedance measurements can help to classify bladder tissue and give the surgeons an indication on how much tissue to remove. Over the years of research, it became obvious that electrical impedance spectroscopy is a very promising tool for tissue differentiation, but also a very sensitive one. While differentiation in preliminary studies shows great potential, challenges arise when transferring this concept to real, intraoperative conditions, mainly due to the influence of preoperative radiotherapy, possibly different tumor types, and mechanical tissue deformations due to peristalsis or unsteady contact force of the sensor. This work proposes a patient-based classification approach that evaluates the distance of an unknown measurement to a healthy reference of the same patient, essentially a relative classification of the difference in impedance that is robust against inter-individual differences and systematic errors. A diversified dataset covering multiple disturbance scenarios is recorded. Two alternatives to define features from the impedance data are investigated, namely using measurement points and model-based parameters. Based on the distance of the feature vector of a unknown measurement to a healthy reference, a Gaussian process classifier is trained. The approach achieves a high classification accuracy of up to 100% on noise-free impedance data recorded under controlled conditions. Even when the differentiation is more ambiguous due to external disturbances, the presented approach still achieves a classification accuracy of 80%. These results are a starting point to tackle intraoperative bladder tissue characterization and decrease the recurrence rate.

Purpose The management of soft tissue sarcoma (STS) at reference centers with specialized multidisciplinary tumor boards (MTB) improves patient survival. The German Cancer Society (DKG) certifies sarcoma centers in German-speaking countries, promoting high standards of care. This study investigated the variability in treatment recommendations for localized STS across different German-speaking tertiary sarcoma centers. Methods In this cross-sectional case-based survey study, 5 anonymized patient cases with imaging data of localized STS were presented to MTBs of 21 German-speaking tertiary referral hospitals. Centers provided recommendations on treatment sequence and modalities, along with the consensus level within their MTB. Agreement percentages were calculated, and consensus levels were rated on a scale of 1 to 10. Results Five patient cases were discussed resulting in 105 recommendations. Agreement percentages for case 1 to 5 were 14.3%, 61.9%, 33.3%, 52.4% and 9.3%, with a median agreement percentage of 33.3%. Grouping pre- and postoperative therapies as "perioperative" and including recommendations with and without regional hyperthermia raised the median agreement to 47.6%. The mean consensus level within each center across all 5 cases was 9.5. Conclusion This first case-based analysis of inter-center agreement for STS management in German-speaking countries reveals low inter-center agreement but high intra-center consensus. Our study includes nearly all tertiary sarcoma centers in German-speaking countries, affirming its strong external validity. These findings suggest potential and clinically very relevant differences in treatment standards among sarcoma centers. Enhanced case-based exchanges and collaborative efforts are needed to reduce discrepancies and standardize the management of STS patients.

The transitioning of named patient products (NPPs) of therapy allergens is regulated under the German therapy allergen ordinance (TAO) since 2008. The establishment of a sound dose–response relationship constitutes a pivotal aspect in clinical development programs of drugs in general. Up to now, there are only few comprehensive studies dedicated to the determination of a dose–response relationship in allergen immunotherapy (AIT) because of various challenges. Among these aggravating factors are high placebo effects, variability of trial endpoints and especially for native allergens a narrow therapeutic window and safety profile. The phase II trials of the modified allergen tyrosine associated—monophosphoryl lipid A (MATA MPL) platform for birch and grasses established convincing and significant dose–response relationships decisive for AIT product optimization. The significant dose–response relationship for birch and grass allergoids reached an efficacy plateau and allowed the definition of critical milestones in drug development such as the median effective dose (ED50) for the MATA MPL platform combining modified allergens (allergoids) with microcrystalline tyrosine (MCT) and MPL in an adjuvant system. This marked a pivotal milestone in AIT drug development allowing the definition of the “optimal dose” (optimal risk–benefit ratio) to be taken forward to phase III trial. The MATA MPL platform is characterized by a scientifically sound dose–response relationship across allergens which underlines the pivotal role of a well-defined optimal dose as a success factor for phase III.

Background Up to now, the optimal duration of immune checkpoint inhibitors (ICI) has not been evaluated in prospective studies. However, current clinical practice requires decisions to be made regarding the duration of ICI in complete responders. Material and Methods A survey was sent to 80 DeCOG skin cancer centers to assess how decisions are made on treatment duration of ICI in melanoma after having reached complete response, and staging intervals after ICI discontinuation. All responses received by March 10, 2024 (51 centers) were included. Results The duration of ICI after having achieved complete remission varies between centers from three to 36 months. In total, 66% of the DeCOG centers continue treatment for up to 6 months, after having achieved complete remission (CR) with ICI. In the first year after discontinuation of ICI, most centers perform staging intervals (CT/MRI) every 3 months. More than 60% of centers continue staging at least once per year even in the 4th and 5th year after discontinuation. Conclusions There are significant differences between the centers regarding staging intervals and duration of ICI upon CR. Prospective studies are necessary to determine the optimal time point of ICI discontinuation and follow‐up.