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Abstract Background The risk of breast cancer patients for long-term side effects of therapy such as neurotoxicity and cardiotoxicity as well as late effects regarding comorbidities varies from individual to individual. Personalised follow-up care concepts that are tailored to individual needs and the risk of recurrences, side effects and late effects are lacking in routine care in Germany. Methods We describe the methodology of BETTER-CARE, a parallel-arm cluster-randomised controlled trial conducted at 15 intervention and 15 control centres, aiming to recruit 1140 patients, and the results of the pilot phase. The needs- and risk-adapted complex intervention, based on existing development frameworks, includes a multidisciplinary network and digital platforms for symptom and need documentation and just-in-time adaptive interventions. The control group comprises usual care according to clinical guidelines. The primary outcome is health-related quality of life (EORTC QLQ-C30 global health), and secondary outcomes include treatment adherence. Results The 2-month pilot phase comprising 16 patients in one intervention and one control pilot centre demonstrated the feasibility of the BETTER-CARE approach. Discussion BETTER-CARE is a feasible intervention and study concept, investigating individualised needs- and risk-adapted breast cancer follow-up care in Germany. If successful, the approach could be implemented in German routine care. Trial registration German Clinical Trial Register DRKS00028840. Registered on April 2022.

Abstract Background Cervical cancer often originates from cervical cell dysplasia. Previous studies mainly focused on surgical margins and high-risk human papillomavirus persistence as factors predicting recurrence. New research highlights the significance of positive findings from endocervical curettage (ECC) during excision treatment. However, the combined influence of surgical margin and ECC status on dysplasia recurrence risk has not been investigated. Methods In this retrospective study, data from 404 women with high-grade squamous intraepithelial lesions (HSIL) who underwent large loop excision of the transformation zone (LLETZ) were analyzed. Records were obtained retrospectively from the hospital’s patient database including information about histopathological finding from ECC, endocervical margin status with orientation of residual disease after LLETZ, recurrent/persistent dysplasia after surgical treatment and need for repeated surgery (LLETZ or hysterectomy). Results Patients with cranial (= endocervical) R1-resection together with cells of HSIL in the ECC experienced re-surgery 17 times. With statistical normal distribution, this would have been expected to happen 5 times (p

Abstract Background 3D printing holds great potential of improving examination, diagnosis and treatment planning as well as interprofessional communication in the field of gynecological oncology. In the current manuscript we evaluated five individualized, patient-specific models of cervical cancer FIGO Stage I-III, created with 3D printing, concerning their value for translational oncology. Methods Magnetic resonance imaging (MRI) of the pelvis was performed on a 3.0 Tesla MRI, including a T2-weighted isotropic 3D sequence. The MRI images were segmented and transferred to virtual 3D models via a custom-built 3D-model generation pipeline and printed by material extrusion. The 3D models were evaluated by all medical specialties involved in patient care of cervical cancer, namely surgeons, radiologists, pathologists and radiation oncologists. Information was obtained from evaluated profession-specific questionnaires which were filled out after inspecting all five models. The questionnaires included multiple-select questions, questions based on Likert scales (1 = „strongly disagree “ or „not at all useful “ up to 5 = „strongly agree “ or „extremely useful “) and dichotomous questions (“Yes” or “No”). Results Surgeons rated the models as useful during surgery (4.0 out of 5) and for patient communication (4.7 out of 5). Furthermore, they believed that the models had the potential to revise the patients’ treatment plan (3.7 out of 5). Pathologists evaluated with mean ratings of 3.0 out of 5 for the usefulness of the models in diagnostic reporting and macroscopic evaluation. Radiologist acknowledged the possibility of providing additional information compared to imaging alone (3.7 out of 5). Radiation oncologists strongly supported the concept by rating the models highly for understanding patient-specific pathological characteristics (4.3 out of 5), assisting interprofessional communication (mean 4.3 out of 5) and communication with patients (4.7 out of 5). They also found the models useful for improving radiotherapy treatment planning (4.3 out of 5). Conclusion The study revealed that the 3D printed models were generally well-received by all medical disciplines, with radiation oncologists showing particularly strong support. Addressing the concerns and tailoring the use of 3D models to the specific needs of each medical speciality will be essential for realizing their full potential in clinical practice.

IntroductionRespiratory viral infections (RVIs) are a major global contributor to morbidity and mortality. The susceptibility and outcome of RVIs are strongly age-dependent and show considerable inter-population differences, pointing to genetically and/or environmentally driven developmental variability. The factors determining the age-dependency and shaping the age-related changes of human anti-RVI immunity after birth are still elusive. MethodsWe are conducting a prospective birth cohort study aiming at identifying endogenous and environmental factors associated with the susceptibility to RVIs and their impact on cellular and humoral immune responses against the influenza A virus (IAV), respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The MIAI birth cohort enrolls healthy, full-term neonates born at the University Hospital Würzburg, Germany, with follow-up at four defined time-points during the first year of life. At each study visit, clinical metadata including diet, lifestyle, sociodemographic information, and physical examinations, are collected along with extensive biomaterial sampling. Biomaterials are used to generate comprehensive, integrated multi-omics datasets including transcriptomic, epigenomic, proteomic, metabolomic and microbiomic methods. DiscussionThe results are expected to capture a holistic picture of the variability of immune trajectories with a focus on cellular and humoral key players involved in the defense of RVIs and the impact of host and environmental factors thereon. Thereby, MIAI aims at providing insights that allow unraveling molecular mechanisms that can be targeted to promote the development of competent anti-RVI immunity in early life and prevent severe RVIs.Clinical trial registrationhttps://drks.de/search/de/trial/, identifier DRKS00034278.

Therapy of cerebral diseases such as brain metastatic breast cancer is still challenging. Due to the blood-brain barrier (BBB), a tight barrier that protects the brain and prevents the passage of many drugs, therapeutically sufficient drug concentrations in the brain are often not achieved. Therefore, methods and drugs to manipulate the BBB permeability are required. Here we used high-throughput screening (HTS) to identify chemicals that may increase BBB permeability. Human BBB in vitro model derived from hematopoietic CD34+ stem cells (differentiated to brain-like endothelial cells, BLECs) was used. BLECs were seeded on 96-well plates coated with biotinylated gelatin, treated with respective chemicals for 24 h followed by addition of FITC-avidin for permeability estimation. Selected substances were further tested in vitro on BLECs. Cell viability, gene and protein expression were measured using CellTiter-Glo®, qPCR and Western blot, respectively. From 1,278 compounds, we identified 175 substances that cause at least a 50 percent increase in BBB permeability. Two substances from the substance classes used in breast cancer therapy, GW2974 (tyrosine kinase inhibitor) and 4-amino-1,8-naphthalimide (ANI) (PARP inhibitor), were analyzed in more detail. ANI was nontoxic to BLECs, while GW2974 decreased or increased viability depending on the concentration used. Both compounds significantly increased BBB permeability and altered protein and mRNA expression in BLECs. Influencing the BBB permeability in patients with brain metastases could increase the response rate to systemic therapy. Using HTS, we were able to accurately and quickly identify compounds that increase BBB permeability and show that using this type of screening method can be applied to endothelial paracellular permeability testing.

Abstract Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.

Background: Previous studies with the majority of breast cancer (BC) patients treated up to 2000 provided evidence that radiation dose to the heart from radiotherapy (RT) was linearly associated with increasing risk for long-term cardiac disease. RT techniques changed substantially over time. This study aimed to investigate the dose-dependent cardiac risk in German BC patients treated with more contemporary RT. Methods: In a cohort of 11,982 BC patients diagnosed in 1998–2008, we identified 494 women treated with 3D-conformal RT who subsequently developed a cardiac event. Within a nested case-control approach, these cases were matched to 988 controls. Controls were patients without a cardiac event after RT until the index date of the corresponding case. Separate multivariable conditional logistic regression models were used to assess the association of radiation to the complete heart and to the left anterior heart wall (LAHW) with cardiac events. Results: Mean dose to the heart for cases with left-sided BC was 4.27 Gy and 1.64 Gy for cases with right-sided BC. For controls, corresponding values were 4.31 Gy and 1.66 Gy, respectively. The odds ratio (OR) per 1 Gy increase in dose to the complete heart was 0.99 (95% confidence interval (CI): 0.94–1.05, P = .72). The OR per 1 Gy increase in LAHW dose was 1.00 (95% CI: 0.98–1.01, P = .68). Conclusions: Contrary to previous studies, our study provided no evidence that radiation dose to the heart from 3D-conformal RT for BC patients treated between 1998 and 2008 was associated with risk of cardiac events.

Plain Language Summary The global pandemic of COVID-19 (coronavirus induced disease 2019) is challenging our society in many ways. Especially pregnant women are facing extraordinary conditions and worries, like uncertain risks for mother and fetus in case of infection, restricted prenatal classes or restricted visitor regulations in hospitals. Particularly it is known that pregnancy and the postnatal period are presenting a more psychologically vulnerable time in a woman’s life. Developing the GeZeCO study, we aimed to focus on the pandemic’s effects on mental health of pregnant women during this time. Women giving birth in the department of obstetrics of the University Hospital Würzburg were asked to participate in the study. In total, 94 women completed several questionnaires concerning their mental health postpartum and again after 3 to 6 months. Further, we took blood samples of the women during the delivery stay and registered sociodemographic and obstetric data. Our results showed, that the women’s concern relating to COVID-19, as well as the level of depression and anxiety raised during the pandemic. In addition, the self-efficacy of the mothers was affected by the restriction measures. Despite this, the women had at large a good mother–child-bonding and their competence of active coping increased during time. In summary, we did find that the mental health of obstetric patients is impaired by the COVID-19 pandemic. This points out the importance of not only attending to physical health but also taking care of psychological stress and mental health problems of obstetric patients during this exceptional time.

Abstract Background Simulation in the field of gynecological pelvic examination with educational purposes holds great potential. In the current manuscript we evaluate a 3D printed model of the female pelvis, which improves practical teaching of the gynecological pelvic examination for medical staff. Methods We evaluated the benefit of a 3D printed model of the female pelvis (Pelvisio®) as part of a seminar (“skills training”) for teaching gynecological examination to medical students. Each student was randomly assigned to Group A or B by picking a ticket from a box. Group A underwent the skills training without the 3D printed model. Group B experienced the same seminar with integration of the model. Both groups evaluated the seminar by answering five questions on Likert scales (1–10, 1 = “very little” or “very poor”, 10 equals “very much” or “very good”). Additionally, both groups answered three multiple-choice questions concerning pelvic anatomy (Question 6 to 8). Finally, Group B evaluated the 3D printed model with ten questions (Question 9 to 18, Likert scales, 1–10). Results Two of five questions concerning the students’ satisfaction with the seminar and their gained knowledge showed statistically significant better ratings in Group B (6.7 vs. 8.2 points and 8.1 vs. 8.9 points (p

BackgroundExecutive functions (EF) consolidate during adolescence and are impaired in various emerging psychiatric disorders, such as pediatric Major Depressive Disorder (pMDD) and Borderline Personality Disorder. Previous studies point to a marked heterogeneity of deficits in EF in pMDD. We examined the hypothesis that deficits in EF in adolescents with pMDD might be related to comorbid Borderline Personality features (BPF).MethodsWe examined a sample of 144 adolescents (15.86 ± 1.32) diagnosed with pMDD. Parents rated their child’s EF in everyday life with the Behavior Rating Inventory of Executive Function (BRIEF) and BPF with the Impulsivity and Emotion Dysregulation Scale (IED-27). The adolescents completed equivalent self-rating measures. Self- and parent-ratings of the BRIEF scores were compared with paired t-Tests. Correlation and parallel mediation analyses, ICC, and multiple regression analyses were used to assess symptom overlap, parent-child agreement, and the influence of depression severity.ResultsOver the whole sample, none of the self- or parent-rated BRIEF scales reached a mean score above T > 65, which would indicate clinically impaired functioning. Adolescents tended to report higher impairment in EF than their parents. Depression severity was the strongest predictor for BPF scores, with Emotional Control predicting parent-rated BPF and Inhibit predicting self-rated BPF. Furthermore, the Behavioral Regulation Index, which includes EF closely related to behavioral control, significantly mediated the relationship between depression severity and IED-27 factors emotional dysregulation and relationship difficulties but not non-suicidal self-injuries.ConclusionOn average, adolescents with depression show only subtle deficits in executive functioning. However, increased EF deficits are associated with the occurrence of comorbid borderline personality features, contributing to a more severe overall psychopathology. Therefore, training of executive functioning might have a positive effect on psychosocial functioning in severely depressed adolescents, as it might also improve comorbid BPF.Clinical trial registrationwww.ClinicalTrials.gov, identifier NCT03167307.