The JMU-SalVac-System: A Novel, Versatile Approach to Oral Live Vaccine Development.

Salmonella enterica Serovar Typhi Ty21a (Ty21a) is the only licensed oral vaccine against typhoid fever. Due to its excellent safety profile, it has been used as a promising vector strain for the expression of heterologous antigens for mucosal immunization. As the efficacy of any bacterial live vector vaccine correlates with its ability to express and present sufficient antigen, the genes for antigen expression are traditionally located on plasmids with antibiotic resistance genes for stabilization. However, for use in humans, antibiotic selection of plasmids is not applicable, leading to segregational loss of the antigen-producing plasmid. Therefore, we developed an oral Ty21a-based vaccine platform technology, the JMU-SalVac-system (Julius-Maximilians-Universität Würzburg) in which the antigen delivery plasmids (pSalVac-plasmid-series) are stabilized by a ΔtyrS/tyrS+-based balanced-lethal system (BLS). The system is made up of the chromosomal knockout of the essential tyrosyl-tRNA-synthetase gene (tyrS) and the in trans complementation of tyrS on the pSalVac-plasmid. Further novel functional features of the pSalVac-plasmids are the presence of two different expression cassettes for the expression of protein antigens. In this study, we present the construction of vaccine strains with BLS plasmids for antigen expression. The expression of cytosolic and secreted mRFP and cholera toxin subunit B (CTB) proteins as model antigens is used to demonstrate the versatility of the approach. As proof of concept, we show the induction of previously described in vivo inducible promoters cloned into pSalVac-plasmids during infection of primary macrophages and demonstrate the expression of model vaccine antigens in these relevant human target cells. Therefore, antigen delivery strains developed with the JMU-SalVac technology are promising, safe and stable vaccine strains to be used against mucosal infections in humans.

PEGylation of Human Vascular Endothelial Growth Factor.

Vascular endothelial growth factor A-165 (VEGF-A165) positively modulates neointimal hyperplasia, lumen stenosis, and neovascularization. One challenge for the use of VEGF-A165 for potential therapy is its short serum half-life. Therefore, we are designing VEGF-A165 bioconjugates carrying polyethylene glycol (PEG). The purity of the recombinantly expressed human VEGF-A165 exceeded 90%. The growth factor had a half-maximal effective concentration of 0.9 ng/mL (EC50) and induced tube formation of human umbilical vein endothelial cells. PEGylation was conducted by Schiff base reaction followed by reductive amination. After purification, two species were obtained, with one or two PEG attached per VEGF-A165 dimer. Both resulting bioconjugates had a purity exceeding 90%, wild-type bioactivity, and increased hydrodynamic radii as required for prolonging the half-life.

Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment.

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/ß2-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.

Psycho-Oncological Care Provision in Highly Distressed Breast Cancer Patients.

Objective To evaluate the proportion of breast cancer (BC) patients with distress or psychological comorbidity as well as offer and use of psychological support in subgroups of BC patients with different extents of distress. Methods 456 patients with BC were evaluated at baseline (t1) and until 5 years after diagnosis (t4) at the BRENDA certified BC centers. Logistic regression was used to analyze if patients with distress at t1 received offers and actual psychological support more often than patients without distress at t1. Regression analyses were used to examine if acute, emerging or chronic disease was associated with higher rates of offer and use of psychotherapy as well as intake of psychotropic drugs. Results In 45% of BC patients psychological affection was detected at t4. The majority of patients with moderate or severe distress at t1 (77%) received the offer for psychological service, while 71% of those received the offer for support at t4. Patients, who were psychologically affected at t1, have not been offered psychological services more often than those without, but they significantly more often used services if offered. Especially patients with acute comorbidity received significantly more often an offer for psychotherapy compared to unimpaired patients, while those patients with emerging or chronic disease did not. 14% of BC patients took psychopharmaceuticals. This mainly concerns patients with chronic comorbidity. Conclusion Psychological services were offered to and used by a fair amount of BC patients. All subgroups of BC patients should be addressed, in order to improve the comprehensive supply with psychological services.

Predictors of Decreased Quality of Life in Breast Cancer Survivors Five Years After Diagnosis.

PURPOSE: Due to improved therapy, early diagnosis, and growing incidence rates, the number of long-term breast cancer survivors is increasing. Survivors can still be affected by aftercare, resulting in reduced quality of life (QoL). Thus, in this study, we investigated possible predictors of decreased physical and social functioning in breast cancer survivors. METHODS: In a German multicenter prospective study, we enrolled 759 female patients with breast cancer before surgery (t1), and contacted them again 5 years after surgery (t4). Data on QoL were assessed at t4 using the European Organization for Research and Treatment of Cancer QoL Core Questionnaire (EORTC QLQ-C30) and its breast cancer module EORTC QLQ-BR23. Predictors of decreased physical and social functioning were analyzed using logistic regression with odds ratios as effect estimates and 95% confidence intervals. Thresholds for the clinical importance of detrimental effects on QoL were defined according to Giesinger. RESULTS: Questionnaires from 759 patients were retrieved at t1. Of these, 456 participated in the study at t4. Poor QoL 5 years after diagnosis was reported by 20%-50% of the participants. Age, mastectomy, chemotherapy, education, employment, cohabitation, psychiatric comorbidities at t1, anxiety, depression, and intensity of physical activity emerged as predictors of decreased physical and social functioning 5 years after diagnosis. CONCLUSION: Relief of symptoms and improvement in the QoL should be priorities in aftercare. Detecting patients with a decreased QoL is a rising challenge. Healthcare providers should take special care of patients aged 50-59 years, patients with psychiatric comorbidities and depression, and patients who have undergone mastectomy.

Next-generation humanized NSG-SGM3 mice are highly susceptible to Staphylococcus aureus infection.

Humanized hemato-lymphoid system mice, or humanized mice, emerged in recent years as a promising model to study the course of infection of human-adapted or human-specific pathogens. Though Staphylococcus aureus infects and colonizes a variety of species, it has nonetheless become one of the most successful human pathogens of our time with a wide armory of human-adapted virulence factors. Humanized mice showed increased vulnerability to S. aureus compared to wild type mice in a variety of clinically relevant disease models. Most of these studies employed humanized NSG (NOD-scid IL2Rgnull) mice which are widely used in the scientific community, but show poor human myeloid cell reconstitution. Since this immune cell compartment plays a decisive role in the defense of the human immune system against S. aureus, we asked whether next-generation humanized mice, like NSG-SGM3 (NOD-scid IL2Rgnull-3/GM/SF) with improved myeloid reconstitution, would prove to be more resistant to infection. To our surprise, we found the contrary when we infected humanized NSG-SGM3 (huSGM3) mice with S. aureus: although they had stronger human immune cell engraftment than humanized NSG mice, particularly in the myeloid compartment, they displayed even more pronounced vulnerability to S. aureus infection. HuSGM3 mice had overall higher numbers of human T cells, B cells, neutrophils and monocytes in the blood and the spleen. This was accompanied by elevated levels of pro-inflammatory human cytokines in the blood of huSGM3 mice. We further identified that the impaired survival of huSGM3 mice was not linked to higher bacterial burden nor to differences in the murine immune cell repertoire. Conversely, we could demonstrate a correlation of the rate of humanization and the severity of infection. Collectively, this study suggests a detrimental effect of the human immune system in humanized mice upon encounter with S. aureus which might help to guide future therapy approaches and analysis of virulence mechanisms.

Evaluation of different imaging modalities for axillary lymph node staging in breast cancer patients to provide a personalized and optimized therapy algorithm.

PURPOSE: The reliable detection of tumor-infiltrated axillary lymph nodes for breast cancer [BC] patients plays a decisive role in further therapy. We aimed to find out whether cross-sectional imaging techniques could improve sensitivity for pretherapeutic axillary staging in nodal-positive BC patients compared to conventional imaging such as mammography and sonography. METHODS: Data for breast cancer patients with tumor-infiltrated axillary lymph nodes having received surgery between 2014 and 2020 were included in this study. All examinations (sonography, mammography, computed tomography [CT] and magnetic resonance imaging [MRI]) were interpreted by board-certified specialists in radiology. The sensitivity of different imaging modalities was calculated, and binary logistic regression analyses were performed to detect variables influencing the detection of positive lymph nodes. RESULTS: All included 382 breast cancer patients had received conventional imaging, while 52.61% of the patients had received cross-sectional imaging. The sensitivity of the combination of all imaging modalities was 68.89%. The combination of MRI and CT showed 63.83% and the combination of sonography and mammography showed 36.11% sensitivity. CONCLUSION: We could demonstrate that cross-sectional imaging can improve the sensitivity of the detection of tumor-infiltrated axillary lymph nodes in breast cancer patients. Only the safe detection of these lymph nodes at the time of diagnosis enables the evaluation of the response to neoadjuvant therapy, thereby allowing access to prognosis and improving new post-neoadjuvant therapies.

Prognostic effect of HER2 evolution from primary breast cancer to breast cancer metastases.

PURPOSE: Therapeutic options for breast cancer (BC) treatment are constantly evolving. The Human Epidermal Growth Factor 2 (HER2)-low BC entity is a new subgroup, representing about 55% of all BC patients. New antibody-drug conjugates demonstrated promising results for this BC subgroup. Currently, there is limited information about the conversion of HER2 subtypes between primary tumor and recurrent disease. METHODS: This retrospective study included women with BC at the University Medical Centre Wuerzburg from 1998 to 2021. Data were retrieved from patients' records. HER2 evolution from primary diagnosis to the first relapse and the development of secondary metastases was investigated. RESULTS: In the HR-positive subgroup without HER2 overexpression, HER2-low expression in primary BC was 56.7 vs. 14.6% in the triple-negative subgroup (p < 0.000). In the cohort of the first relapse, HER2-low represented 64.1% of HR-positive vs. 48.2% of the triple-negative cohort (p = 0.03). In patients with secondary metastases, HER2-low was 75.6% vs. 50% in the triple negative subgroup (p = 0.10). The subgroup of HER2-positive breast cancer patients numerically increased in the course of disease; the HER2-negative overall cohort decreased. A loss of HER2 expression from primary BC to the first relapse correlated with a better OS (p = 0.018). No clinicopathological or therapeutic features could be identified as potential risk factors for HER2 conversion. CONCLUSION: HER2 expression is rising during the progression of BC disease. In view of upcoming therapeutical options, the re-analysis of newly developed metastasis will become increasingly important.

Optimized process quality in certified breast centers through adherence to stringent diagnostic and therapeutic algorithms effects of structural as well as socio-demographic factors on start of therapy.

PURPOSE: An increasing incidence of breast cancer can be observed worldwide. Since a delay of therapy can have a negative impact on prognosis, timely cancer care is an important quality indicator. By receiving treatment at a certified breast cancer center, the patient has the best chance of treatment in accordance with guidelines and the best prognosis. The identification of risk factors for a delay of therapy is of central importance and should be the basis for a continuous optimization of treatment at breast cancer centers. METHODS: This retrospective study included women with breast cancer (primary diagnosis, relapse, or secondary malignancy) at the University Hospital Würzburg in 2019 and 2020. Data were retrieved from patients' records. Correlations and regression analyses were performed to detect potential risk factors for treatment delay. RESULTS: Patients who received the histological confirmation of breast cancer at an external institution experienced a later therapy start than those patients who received the histological confirmation at the University Hospital Würzburg itself. (35.7 vs. 32.2 days). The interval between histological confirmation and the first consultation at the University Hospital Würzburg correlated statistically significant with age, distress and distance to the hospital. CONCLUSION: Patients with an in-house diagnosis of breast cancer are treated more quickly than those whose diagnosis was confirmed in an external institution. We identified factors such as increased age, greater distance to the hospital as well as increased distress to prolong the time until start of oncological treatment. Intensified patient care should be offered to these subgroups.

The impact of the COVID-19 pandemic on stress and other psychological factors in pregnant women giving birth during the first wave of the pandemic.

BACKGROUND: The onset of mental illness such as depression and anxiety disorders in pregnancy and postpartum period is common. The coronavirus induced disease 2019 (COVID-19) pandemic and the resulting public policy responses represent an exceptional situation worldwide and there are hints for adverse psychosocial impact, hence, the study of psychological effects of the pandemic in women during hospitalization for delivery and in the postpartum period is highly relevant. METHODS: Patients who gave birth during the first wave of the COVID-19 pandemic in Germany (March to June 2020) at the Department of Obstetrics and Gynecology, University of Würzburg, Germany, were recruited at hospital admission for delivery. Biosamples were collected for analysis of SARS-CoV-2 infection and various stress hormones and interleukin-6 (IL-6). In addition to sociodemographic and medical obstetric data, survey questionnaires in relation to concerns about and fear of COVID-19, depression, stress, anxiety, loneliness, maternal self-efficacy and the mother-child bonding were administered at T1 (delivery stay) and T2 (3-6 months postpartum). RESULTS: In total, all 94 recruited patients had a moderate concern of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at T1 with a significant rise at T2. This concern correlated with low to low-medium general psychosocial stress levels and stress symptoms, and the women showed a significant increase of active coping from T1 to T2. Anxiety levels were low and the Edinburgh Postnatal Depression Scale showed a medium score of 5 with a significant (T1), but only week correlation with the concerns about SARS-CoV-2. In contrast to the overall good maternal bonding without correlation to SARS-CoV-2 concern, the maternal self-efficiency correlated negatively with the obstetric impairment caused by the COVID-19 pandemic. CONCLUSION: Obstetric patients` concerns regarding SARS-CoV-2 and the accompanying pandemic increased during the course of the pandemic correlating positively with stress and depression. Of note is the increase in active coping over time and the overall good mother-child-bonding. Maternal self-efficacy was affected in part by the restrictions of the pandemic. Clinical trial registration DRKS00022506.

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 mother­child-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.

Evaluating the value of a 3D printed model for hands-on training of gynecological pelvic examination.

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 < 0.001 and p < 0.009). The other three questions showed no statistically significant differences between the traditional teaching setting vs. the 3D printed model (p < 0.411, p < 0.344 and p < 0.215, respectively). The overall mean score of Question 1 to 5 showed 8.4 points for Group B and 7.8 points for Group A (p < 0.001). All three multiple-choice questions, asking about female pelvic anatomy, were answered more often correctly by Group B (p < 0.001, p < 0.008 and p < 0.001, respectively). The mean score from the answers to Questions 9 to 18, only answered by Group B, showed a mean of 8.6 points, indicating, that the students approved of the model. CONCLUSION: The presented 3D printed model Pelvisio® improves the education of female pelvic anatomy and examination for medical students. Hence, training this pivotal examination can be supported by a custom designed anatomical model tailored for interactive and explorative learning.

MRSA Infection in the Thigh Muscle Leads to Systemic Disease, Strong Inflammation, and Loss of Human Monocytes in Humanized Mice.

MRSA (Methicillin-resistant Staphylococcus aureus) is the second-leading cause of deaths by antibiotic-resistant bacteria globally, with more than 100,000 attributable deaths annually. Despite the high urgency to develop a vaccine to control this pathogen, all clinical trials with pre-clinically effective candidates failed so far. The recent development of "humanized" mice might help to edge the pre-clinical evaluation closer to the clinical situation and thus close this gap. We infected humanized NSG mice (huNSG: (NOD)-scid IL2Rγnull mice engrafted with human CD34+ hematopoietic stem cells) locally with S. aureus USA300 LAC* lux into the thigh muscle in order to investigate the human immune response to acute and chronic infection. These mice proved not only to be more susceptible to MRSA infection than wild-type or "murinized" mice, but displayed furthermore inferior survival and signs of systemic infection in an otherwise localized infection model. The rate of humanization correlated directly with the severity of disease and survival of the mice. Human and murine cytokine levels in blood and at the primary site of infection were strongly elevated in huNSG mice compared to all control groups. And importantly, differences in human and murine immune cell lineages surfaced during the infection, with human monocyte and B cell numbers in blood and bone marrow being significantly reduced at the later time point of infection. Murine monocytes in contrast behaved conversely by increasing cell numbers. This study demonstrates significant differences in the in vivo behavior of human and murine cells towards S. aureus infection, which might help to sharpen the translational potential of pre-clinical models for future therapeutic approaches.

Evaluating a novel 3D printed model for simulating Large Loop Excision of the Transformation Zone (LLETZ).

BACKGROUND: Electrosurgical excisions are common procedures for treating cervical dysplasia and are often seen as minor surgeries. Yet, thorough training of this intervention is required, as there are considerable consequences of inadequate resections, e.g. preterm birth, the risk of recurrence, injuries and many more. Unfortunately, there is a lack of sufficiently validated possibilities of simulating electrosurgeries, which focus on high fidelity and patient safety. METHODS: A novel 3D printed simulator for examination and electrosurgical treatment of dysplastic areas of the cervix was compared with a conventional simulator. Sixty medical students experienced a seminar about cervical dysplasia. Group A underwent the seminar with the conventional and Group B with the novel simulator. After a theoretical introduction, the students were randomly assigned by picking a ticket from a box and went on to perform the hands-on training with their respective simulator. Each student first obtained colposcopic examination training. Then he or she performed five electrosurgical excisions (each). This was assessed with a validated score, to visualize their learning curve. Furthermore, adequate and inadequate resections and contacts between electrosurgical loop and vagina or speculum were counted. Both groups also assessed the seminar and their simulator with 18 questions (Likert-scales, 1-10, 1 = strongly agree / very good, 10 = strongly disagree / very bad). Group B additionally assessed the novel simulator with four questions (similar Likert-scales, 1-10). RESULTS: Nine of 18 questions showed statistically significant differences favoring Group B (p < 0.05). Group B also achieved more adequate R0-resections and less contacts between electrosurgical loop and vagina or speculum. The learning curves of the performed resections favored the novel simulator of Group B without statistically significant differences. The four questions focusing on certain aspects of the novel simulator indicate high appreciation of the students with a mean score of 1.6 points. CONCLUSION: The presented novel simulator shows several advantages compared to the existing model. Thus, novice gynecologists can be supported with a higher quality of simulation to improve their training and thereby patient safety.

[Patient blood management in the preparation for birth, obstetrics and postpartum period]. / Patient Blood Management in der Geburtsvorbereitung, Geburtshilfe und postpartalen Phase.

The implementation of patient blood management (PBM) is increasingly becoming standard in operative medicine. Recently, interest has also been shown for the vulnerable collective of pregnant women and neonates. As the information regarding anesthesiological procedures for pregnant women and the peripartum period including an informed consent process should be carried out long before childbirth, this provides a good possibility in this connection to incorporate PBM. An anesthesiological risk estimation as well as the diagnostic workup and treatment of potential anemia should be carried out during the pregnancy. Furthermore, loss of blood in anticipation of bleeding complications should be reduced by interdisciplinary preventive measures and an individually coordinated postpartum care should be organized. This results in an early diagnosis of anemia or iron deficiency with subsequent treatment also postpartum, analogous to the prepartum period.

Introducing a novel model for simulating large loop excision of the transformation zone (LLETZ) using 3D printing technique.

PURPOSE: Electrosurgery is the gold-standard procedure for the treatment of cervical dysplasia. The quality of the outcome depends on the accuracy of performance, which underlines the role of adequate training of surgeons, especially, as this procedure is often performed by novice surgeons. According to our knowledge, medical simulation has up until now lacked a model, which focuses on realistically simulating the treatment of cervical dysplasia with the concerning anatomy. METHODS AND RESULT: In our work, we present a model created using 3D printing for holistically simulating diagnostic, as well as surgical interventions of the cervix, as realistically as possible. CONCLUSION: This novel simulator is compared to an existing model and both are evaluated. By doing so, we aim to provide novice gynecologists with standardized and high-quality simulation models for practicing to improve their proficiency.

BRENDA-Score, a Highly Significant, Internally and Externally Validated Prognostic Marker for Metastatic Recurrence: Analysis of 10,449 Primary Breast Cancer Patients.

Background Current research in breast cancer focuses on individualization of local and systemic therapies with adequate escalation or de-escalation strategies. As a result, about two-thirds of breast cancer patients can be cured, but up to one-third eventually develop metastatic disease, which is considered incurable with currently available treatment options. This underscores the importance to develop a metastatic recurrence score to escalate or de-escalate treatment strategies. Patients and methods Data from 10,499 patients were available from 17 clinical cancer registries (BRENDA-project [1]. In total, 8566 were used to develop the BRENDA-Index. This index was calculated from the regression coefficients of a Cox regression model for metastasis-free survival (MFS). Based on this index, patients were categorized into very high, high, intermediate, low, and very low risk groups forming the BRENDA-Score. Bootstrapping was used for internal validation and an independent dataset of 1883 patients for external validation. The predictive accuracy was checked by Harrell's c-index. In addition, the BRENDA-Score was analyzed as a marker for overall survival (OS) and compared to the Nottingham prognostic score (NPS). Results: Intrinsic subtypes, tumour size, grading, and nodal status were identified as statistically significant prognostic factors in the multivariate analysis. The five prognostic groups of the BRENDA-Score showed highly significant (p < 0.001) differences regarding MFS:low risk: hazard ratio (HR) = 2.4, 95%CI (1.7-3.3); intermediate risk: HR = 5.0, 95%CI.(3.6-6.9); high risk: HR = 10.3, 95%CI (7.4-14.3) and very high risk: HR = 18.1, 95%CI (13.2-24.9). The external validation showed congruent results. A multivariate Cox regression model for OS with BRENDA-Score and NPS as covariates showed that of these two scores only the BRENDA-Score is significant (BRENDA-Score p < 0.001; NPS p = 0.447). Therefore, the BRENDA-Score is also a good prognostic marker for OS. Conclusion: The BRENDA-Score is an internally and externally validated robust predictive tool for metastatic recurrence in breast cancer patients. It is based on routine parameters easily accessible in daily clinical care. In addition, the BRENDA-Score is a good prognostic marker for overall survival. Highlights: The BRENDA-Score is a highly significant predictive tool for metastatic recurrence of breast cancer patients. The BRENDA-Score is stable for at least the first five years after primary diagnosis, i.e., the sensitivities and specificities of this predicting system is rather similar to the NPI with AUCs between 0.76 and 0.81 the BRENDA-Score is a good prognostic marker for overall survival.

The effects of the COVID-19 pandemic on psychological stress in breast cancer patients.

BACKGROUND: The majority of breast cancer patients are severely psychologically affected by breast cancer diagnosis and subsequent therapeutic procedures. The COVID-19 pandemic and associated restrictions on public life have additionally caused significant psychological distress for much of the population. It is therefore plausible that breast cancer patients might be particularly susceptible to the additional psychological stress caused by the pandemic, increasing suffering. In this study we therefore aimed to assess the level of psychological distress currently experienced by a defined group of breast cancer patients in our breast cancer centre, compared to distress levels pre-COVID-19 pandemic. METHODS: Female breast cancer patients of all ages receiving either adjuvant, neoadjuvant, or palliative therapies were recruited for the study. All patients were screened for current or previous COVID-19 infection. The participants completed a self-designed COVID-19 pandemic questionnaire, the Stress and Coping Inventory (SCI), the National Comprehensive Cancer Network® (NCCN®) Distress Thermometer (DT), the European Organization for Research and Treatment of Cancer (EORTC) QLQ C30, and the BR23. RESULTS: Eighty-two breast cancer patients were included. Therapy status and social demographic factors did not have a significant effect on the distress caused by the COVID-19 pandemic. The results of the DT pre and during COVID-19 pandemic did not differ significantly. Using the self-designed COVID-19 pandemic questionnaire, we detected three distinct subgroups demonstrating different levels of concerns in relation to SARS-CoV-2. The subgroup with the highest levels of concern reported significantly decreased life quality, related parameters and symptoms. CONCLUSIONS: This monocentric study demonstrated that the COVID-19 pandemic significantly affected psychological health in a subpopulation of breast cancer patients. The application of a self-created "COVID-19 pandemic questionnaire" could potentially be used to help identify breast cancer patients who are susceptible to increased psychological distress due to the COVID-19 pandemic, and therefore may need additional intensive psychological support. TRIAL REGISTRATION: DRKS-ID: DRKS00022507 .

Laparoscopic Management of a Heterotopic Pregnancy in the Tubal Stump.

STUDY OBJECTIVE: To demonstrate how a heterotopic tubal stump pregnancy can be safely managed with laparoscopy, preserving the intrauterine pregnancy. DESIGN: Stepwise demonstration of the technique by means of a video tutorial. SETTING: The management of pregnancies in the tubal stump after salpingectomy involves either a surgical intervention or systemic therapy. In case of a simultaneous intrauterine pregnancy, although the prognosis for the fetus remains good with live births in approximately 70% of the cases, the surgical management of the tubal stump pregnancy is challenging owing to the risk of bleeding from the uterine horn [1-5]. We present an effective and reproducible laparoscopic technique on the basis of a 31-year-old patient with 2 prior right fallopian tube pregnancies, which were later treated with salpingectomy. The patient is now presenting in the sixth week of gestation after transfer from 2 oocytes with a pregnancy in the tubal stump and a concomitant vital intrauterine pregnancy. INTERVENTIONS: The key steps of laparoscopic surgery include (1) continuous absorbable monofilament suture on the uterine horn around the tubal stump to achieve hemostasis and exposure of the proximal part of the tube, (2) removal of ectopic pregnancy, and (3) closure of the excision site with continuous absorbable polyfilament suture. The instillation of vasoconstrictive substances and the use of electrical coagulation should be avoided. CONCLUSION: The demonstrated laparoscopic technique is a feasible method of removal of a tubal stump pregnancy without interfering with the vital intrauterine pregnancy. The blood loss can be minimized, and laparotomy can be avoided.

Trastuzumab Biosimilars in the Therapy of Breast Cancer - "Real World" Experiences from four Bavarian University Breast Centres.

Introduction With the introduction of the first trastuzumab biosimilar in the summer of 2018, biosimilar antibodies for breast cancer have found their way into the area of gynaecological oncology. The switch of anti-human epidermal growth factor receptor 2 (HER2) therapy from the reference drug Herceptin ® to a biosimilar has presented challenges to the clinics. In addition to structural and organisational measures, training of employees as well as patient briefing and acceptance were major challenges. The study presented here records - within the context of quality assurance - how the switch to a trastuzumab biosimilar was implemented at four Bavarian university clinics in the Purchasing Association of Bavarian University Pharmacies. Materials/Methods Questionnaires on treatment figures and the switching process were sent to breast centres and pharmacies of four Bavarian university clinics between July and December 2019. The neoadjuvant, adjuvant and metastasised anti-HER2 therapy with trastuzumab with or without pertuzumab was recorded, evaluated and summarised. Results In the anti-HER2-therapy, trastuzumab was used intravenously (i. v.) and subcutaneously. Between July and December 2018, all four clinics in the Purchasing Association switched the i. v. trastuzumab therapy from the reference drug (Herceptin) to a biosimilar (for 2018: Kanjinti ® ). Over 200 patients were treated with trastuzumab i. v. in each of the two half-years of 2018 (before and after the switch). The spectrum of side effects and pCR rates under therapy with the biosimilar were comparable to the experiences made with the reference drug. Three out of four clinics provided training to employees and informed patients by means of a defined information leaflet. Patient acceptance was high. Summary The anti-HER2 therapy could be switched successfully and safely to trastuzumab biosimilars at the Bavarian university hospitals. This may serve as guideline for the further implementation of biosimilars. The structures necessary for this initial switching process have been prepared with trastuzumab as an example.

Effect of adjuvant radiotherapy in elderly patients with breast cancer.

BACKGROUND: Radiotherapy (RT) is of critical importance in the locoregional management of early breast cancer. Although RT is routinely used following breast conserving surgery (BCS), patients may occasionally be effectively treated with BCS alone. Currently, the selection of patients undergoing BCS who do not need breast irradiation is under investigation. With the advancement of personalized medicine, there is an increasing interest in reduction of aggressive treatments especially in older women. The primary objective of this study was to identify elderly patients who may forego breast irradiation after BCS without measurable consequences on local tumor growth and survival. METHODS: We analyzed 2384 early breast cancer patients aged 70 and older who were treated in 17 German certified breast cancer centers between 2001 and 2009. We compared RT versus no RT after guideline adherent (GA) BCS. The outcomes studied were breast cancer recurrence (RFS) and breast cancer-specific survival (BCSS). Low-risk patients were defined by luminal A, tumor size T1 or T2 and node-negative whereas higher-risk patients were defined by patients with G3 or T3/T4 or node-positive or other than Luminal A tumors. To test if there is a difference between two or more survival curves, we used the Gp family of tests of Harrington and Fleming. RESULTS: The median age was 77 yrs (mean 77.6±5.6 y) and the median observation time 46 mths (mean 48.9±24.8 mths). 950 (39.8%) patients were low-risk and 1434 (60.2%) were higher-risk. 1298 (54.4%) patients received GA BCS of which 85.0% (1103) received GA-RT and only 15% (195) did not. For low-risk patients with GA-BCS there were no significant differences in RFS (log rank p = 0.651) and in BCSS (p = 0.573) stratified by GA-RT. 5 years RFS in both groups were > 97%. For higher-risk patients with GA-BCS we found a significant difference (p<0.001) in RFS and tumor-associated OS stratified by GA-RT. The results remain the same after adjusting by adjuvant systemic treatment (AST) and comorbidity (ASA and NYHA). CONCLUSIONS: Patients aged 70 years and older suffering from low-risk early breast cancer with GA-BCS can avoid breast irradiation with <3% chance of relapse. In the case of higher-risk, breast irradiation should be used routinely following GA-BCS. As a side effect of these results, removing the entire breast of elderly low risk patients to spare them from breast irradiation seems to be not necessary.