University Medical Center Freiburg

Purpose Prostate-specific membrane-antigen positron emission tomography (PSMA PET) is a promising candidate for non-invasive characterization of prostate cancer (PCa). This study evaluated whether PET with tracers [⁶⁸Ga]Ga-PSMA-11 or [¹⁸F]PSMA-1007 is capable to depict intratumour heterogeneity of histological PSMA expression. Methods Thirty-five patients with biopsy-proven primary PCa without evidence of metastatic disease nor prior interventions were prospectively enrolled. All patients underwent PSMA PET combined with computer tomography (CT) with either [⁶⁸Ga]Ga-PSMA-11 (cohort I, 20 patients) or [¹⁸F]PSMA-1007 (cohort II, 15 patients) followed by radical prostatectomy. Specimens were scanned by ex-vivo CT and histologically prepared. On digitized whole-mount prostate sections, PCa areas with different morphologies were manually defined and H-Score of immunohistochemical PSMA expression was calculated with assistance by artificial intelligence (AI). PCa areas with similar H-Score were unified in segmentation on ex-vivo CT. After co-registration on PSMA PET-CT, Spearman’s coefficients of PSMA expression to mean and maximum standardized uptake value (SUVmean and SUVmax) were calculated. Furthermore, the agreement of the co-registered tumour areas to gross tumour volume (GTV) in PSMA PET was analysed. Results Thirty-two patients were included in the final analysis. For histological PCa areas, immunohistochemical PSMA expression correlated significantly to SUVmean and SUVmax (p < 0.001, p = 0.001). An approximate linear correlation between H-Score and SUVmean / SUVmax was found for tumour areas larger than 400 μm² in histology (p < 0.001). Tumour areas with strong PSMA expression showed a significantly larger overlap to GTV in PSMA PET after co-registration than tumour areas with very low PSMA expression (p < 0.01). No significant differences were found between the two tracer cohorts (p = 0.72). Conclusion PSMA PET with both [⁶⁸Ga]Ga-PSMA-11 or [¹⁸F]PSMA-1007 is able to detect changes in histological PSMA expression within PCa lesions allowing biologically targeted radiotherapy.

OBJECTIVES Aim of this study was to assess safety and efficiency of multiarterial coronary bypass grafting using bilateral internal thoracic arteries in T-graft technique performed by trainees. METHODS Patients from January 2005 to February 2023 who had undergone multiarterial coronary bypass grafting using bilateral internal thoracic arteries in T-graft technique were analysed. Patients were divided into two groups based on the primary surgeon: Consultant and Trainees. The primary composite outcome measure was all-cause mortality and coronary reintervention after 5 years. Safety and efficiency were assessed using CUSUM analysis. RESULTS A total of 1,764 patients were identified, 1,114 patients (63.2%) were operated on by consultants, 650 patients (37.8%) by trainees. Mortality rates did not differ (0.8% vs 1.0%, p = 0.4). Consultants performed more distal anastomoses (3.38 (0.96) vs 3.06 (0.76); p < 0.001) and achieved more complete revascularization (n = 895 (92%)) than trainees (n = 460 (80%));(p < 0.001). In the CUSUM-analysis, safety of teaching procedures remains within the acceptable range. There was no increase in the expectation/frequency of the composite outcome measure; instead, the expected frequency decreases up to 150 operations. Duration of the operation averages decrease until the 125th operation. Performed distal anastomoses increased with the rising number of operations. CONCLUSIONS Our study demonstrates that training operations multiarterial coronary bypass grafting using bilateral internal thoracic arteries in T-graft technique are equally safe regardless of whether they are performed by consultants or trainees. Each trainee experiences an individual learning curve that falls within acceptable error rates and, therefore, the procedure can be safely learned directly

Constipation and urinary incontinence are common medical conditions that can considerably reduce the quality of life; older women are affected more often. Medicinal treatment options, chances of success and side effects. Presentation of the commonly used medicinal treatment for urinary incontinence and constipation based on the current guidelines. For the medicinal treatment of urinary incontinence, local estrogen application, duloxetine for stress urinary incontinence and anticholinergics as well as beta 3‑adrenoceptor agonists for overactive bladder symptoms are available. The available medications can improve urinary incontinence; however, the compliance is often limited due to frequent side effects. The medicinal treatment of chronic constipation is carried out according to a step by step scheme. First-line medications include macrogol, sodium picosulfate and bisacodyl. Diarrhea or abdominal pain occasionally occur as a side effect. Long-term use is harmless and contrary to popular belief, there is no potential for dependency. If this is not sufficient, medications can be combined or synthetic disaccharides or anthraquinones can be used as second-line medications and, if treatment is still not successful prucalopride or linaclotide can be used. There are good medicinal treatment options for both chronic constipation and urinary incontinence; however, treatment adherence in urinary incontinence is often low due to the side effects of the available medications. There are often unfounded concerns about the use of laxatives due to the potential for dependency but in principle there are also effective forms of drug treatment.

This study aimed to evaluate the impact of the myelodysplasia‐related gene (MRG) as well as additional gene mutations on outcomes in intensively treated patients with NPM1‐mutated (NPM1mut) AML. Targeted DNA sequencing of 263 genes was performed in 568 NPM1mut AML patients (median age: 59 years) entered into the prospective AMLSG 09‐09 treatment trial. Most commonly co‐mutated genes were DNMT3A (49.8%), FLT3‐TKD (25.9%), PTPN11 (24.8%), NRAS (22.7%), TET2 (21.7%), IDH2 (21.3%), IDH1 (18%), and FLT3‐ITD (17.3%). MRG mutations were identified in 18.1% of cases (18–60 years: 9.8%; >60 years: 28.7%). When focusing on the 470 patients with 2022 ELN favorable‐risk NPM1mut AML, multivariable analysis for event‐free survival (EFS) identified age (p < 0.001), DNMT3AR882 (p < 0.001), IDH1 (p = 0.007), and MRG mutations (p = 0.03) as unfavorable factors, cohesin gene co‐mutations (p = 0.001) and treatment with gemtuzumab ozogamicin (p = 0.007) as favorable factors. Restricting the analysis to a subset of CR/CRi patients with available data on NPM1mut measurable residual disease (MRD) status in blood post cycle 2 in the model, MRG mutations lost their significant effect, whereas DNMT3AR882, MYC, and cohesin gene mutations retained the adverse and favorable effects. For OS, age (p < 0.001), DNMT3AR882 (p = 0.042), IDH1 (p = 0.045), and KRAS (0.003) mutations were unfavorable factors, sole favorable factor was IDH2 co‐mutation (p = 0.037). In 2022 ELN favorable‐risk NPM1mut AML, MRG mutations are associated with inferior EFS; however, this effect is no longer present when considering NPM1mut MRD status post cycle 2; DNMT3AR882 and MYC mutations remained adverse, and cohesin gene mutations favorable prognostic factors independent of the NPM1mut MRD status.

The treatment of odontoid fractures in geriatric patients, particularly type II fractures, remains controversial. In biologically young patients, studies suggest advantages of surgical treatment in terms of mortality; however, this advantage is not observed in geriatric patients. While the mortality appears to be higher after conservative treatment in patients aged 65–80 years, there are studies that have shown no differences in mortality for patients aged 80 years or older and even showed advantages of conservative treatment in this age group. The complication rates of both surgical and conservative approaches are comparable. Although conservative treatment is associated with a higher rate of pseudarthrosis, healing in a “rigid” pseudarthrosis is associated with a good clinical outcome and can therefore be considered a treatment success. The central problem with the currently available literature, including the present prospective but nonrandomized data, is selection bias, which significantly limits the comparability of the patient cohorts. So far, no clear superiority of either treatment method has been demonstrated. Therefore, conservative treatment retains its importance in the geriatric patient population and the majority of these patients achieve a very good functional outcome with conservative treatment.

Background Amyloid PET imaging is an established diagnostic tool for Alzheimer’s disease, but its successful integration into clinical practice requires a comprehensive understanding of its impact on patients and the healthcare system. In 2022, the coverage with evidence development (CED) ENABLE study has been approved by the German Federal Joint Committee (trial registration: DRKS00030839). The study is scheduled to start in early 2024. Primary outcome of ENABLE is the change in patients' functional abilities at 18 months after diagnosis with amyloid PET versus without amyloid‐PET. Here we describe the design of an ENABLE sub‐study aimed at performing a process evaluation. Method We will conduct an outcome and process evaluation using a pre‐post descriptive design nested in ENABLE (Figure), based on the Medical Research Council’s Process Evaluation (PE) framework. The PE will focus on acceptability and reach of the target groups of patients and care providers, as well as fidelity of delivery (% of adherence to protocol, study duration), contextual changes and mechanisms (e.g., ability to mirror routine care). We will collect patients’ data independently, but in parallel with ENABLE, using interviews, surveys and checklists to assess acceptance of the intervention, fidelity of adherence to the follow‐up procedures, perceived benefits and challenges. Healthcare providers and administrators will be interviewed to identify implementation hurdles and facilitators, contextual factors influencing uptake and underlying mechanisms. For data analysis we will employ a mixed‐methods approach. Result Expected outcomes will include acceptability and adherence, barriers and facilitators to implementation, contextual factors influencing implementation, perceived utility of the intervention by patients and providers, and mechanisms by which the intervention can be delivered as part of normal care. Conclusion This process evaluation can inform researchers on how to design future CED studies to be implemented into clinical care. The lessons learned during the development and approval process of the ENABLE project in Germany, as well as its process evaluation, can benefit other European CED studies and policy‐makers stakeholders in making informed decisions. Likewise, these findings can be generalized beyond the context of amyloid PET to other diagnostic biomarkers, ultimately improving the diagnosis and management of Alzheimer’s disease.

Background Normal aging is associated with alterations of functional connectivity (FC) in brain neuronal networks. Altered network connectivity may be associated with accelerated cognitive decline. Physical activity is considered a beneficial lifestyle factor for maintaining cognitive health. Higher intensities of physical activity may induce structural and functional changes in the brain, particularly in regions involved in cognitive functions, such as memory, attention and executive functions. However, the underlying neural mechanisms are not widely investigated. Our aim was to examine the association between resting‐state FC of brain networks and baseline physical activity in healthy older adults. Method We analyzed baseline resting‐state fMRI and baseline physical activity data of 149 healthy older adults (mean age: 68 years) from the AgeGain study. Physical activity was measured by using actigraphs worn for 7 days. Different intensities were measured, such as light, mean and moderate‐to‐vigorous activity (min/d). We used Independent Component Analysis (ICA) and seed‐based approaches to examine brain network activity in the Default Mode Network (DMN), Salience Network (SAL), Central Executive Network (CEN), Visual Network (VN) for cognitive effects and Sensorimotor Network (SMN) for physical effects. Result We observed statistically significant associations between functional activation within SMN and light physical activity and spatially restricted effects for DMN and moderate‐to‐vigorous physical activity (p <.01 uncorrected). In addition, we observed an overlap on frontal activation across DMN, SMN and SAL. Results of the seed‐based analysis will be presented at the conference. Conclusion Light to higher intensities of physical activity showed an association with higher functional activation of networks previously associated with cognitive decline and physical activity. This agrees with the notion that physical activity may be a protective factor against cognitive decline. Further research is needed to test the replicability of these results.

Background Recent research indicates a role of gut microbiota in development and progression of life-threatening diseases such as cancer. Carcinomas of the biliary ducts, the so-called cholangiocarcinomas, are known for their aggressive tumor biology, implying poor prognosis of affected patients. An impact of the gut microbiota on cholangiocarcinoma development and progression is plausible due to the enterohepatic circulation and is therefore the subject of scientific debate, however evidence is still lacking. This review aimed to discuss the suitability of complex cell culture models to investigate the role of gut microbiota in cholangiocarcinoma progression. Main body Clinical research in this area is challenging due to poor comparability of patients and feasibility reasons, which is why translational models are needed to understand the basis of tumor progression in cholangiocarcinoma. A promising approach to investigate the influence of gut microbiota could be an organoid model. Organoids are 3D cell models cultivated in a modifiable and controlled condition, which can be grown from tumor tissue. 3D cell models are able to imitate physiological and pathological processes in the human body and thus contribute to a better understanding of health and disease. Conclusion The use of complex cell cultures such as organoids and organoid co-cultures might be powerful and valuable tools to study not only the growth behavior and growth of cholangiocarcinoma cells, but also the interaction with the tumor microenvironment and with components of the gut microbiota.

Background Amyloid PET imaging is an established diagnostic tool for Alzheimer's disease, but its successful integration into clinical practice requires a comprehensive understanding of its impact on patients and the healthcare system. In 2022, the coverage with evidence development (CED) ENABLE study has been approved by the German Federal Joint Committee (trial registration: DRKS00030839). The study is scheduled to start in early 2024. Primary outcome of ENABLE is the change in patients' functional abilities at 18 months after diagnosis with amyloid PET versus without amyloid‐PET. Here we describe the design of an ENABLE sub‐study aimed at performing a process evaluation. Method We will conduct an outcome and process evaluation using a pre‐post descriptive design nested in ENABLE (Figure), based on the Medical Research Council's Process Evaluation (PE) framework. The PE will focus on acceptability and reach of the target groups of patients and care providers, as well as fidelity of delivery (% of adherence to protocol, study duration), contextual changes and mechanisms (e.g., ability to mirror routine care). We will collect patients’ data independently, but in parallel with ENABLE, using interviews, surveys and checklists to assess acceptance of the intervention, fidelity of adherence to the follow‐up procedures, perceived benefits and challenges. Healthcare providers and administrators will be interviewed to identify implementation hurdles and facilitators, contextual factors influencing uptake and underlying mechanisms. For data analysis we will employ a mixed‐methods approach. Result Expected outcomes will include acceptability and adherence, barriers and facilitators to implementation, contextual factors influencing implementation, perceived utility of the intervention by patients and providers, and mechanisms by which the intervention can be delivered as part of normal care. Conclusion This process evaluation can inform researchers on how to design future CED studies to be implemented into clinical care. The lessons learned during the development and approval process of the ENABLE project in Germany, as well as its process evaluation, can benefit other European CED studies and policy‐makers stakeholders in making informed decisions. Likewise, these findings can be generalized beyond the context of amyloid PET to other diagnostic biomarkers, ultimately improving the diagnosis and management of Alzheimer's disease.