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Purpose: Randomized studies demonstrated the oncological equivalence of (ultra-)hypofractionation compared to a 5-week schedule in postoperative radiotherapy of breast cancer. Due to the low incidence and long latency of secondary malignancies, there are currently no reliable clinical data regarding the influence of fractionation regimens on the development of secondary malignancies. Material and methods: For 20 patients with right or left-sided breast cancer, postoperative treatment plans were created using 3D-CRT (n = 10) or VMAT (n = 10) for three different fractionation schedules: 5-week schedule with 50.4Gy in 1.8Gy (28fx), hypofractionation with 40.05Gy in 2.67Gy (15fx) and ultra-hypofractionation with 26Gy in 5.2Gy (5fx). The EARs (absolute additional cases of disease per 10,000 patient-years) for secondary malignancies in the lung, contralateral breast, esophagus, liver, thyroid, spinal cord, bones and soft tissue were calculated using a fraction-dependent dose-response model. Results: Based on risk modulation, (ultra-)hypofractionation resulted in significantly lower EARs for lung cancer (LC), contralateral breast cancer (CBC) and soft tissue sarcoma (STS) (p

BackgroundChat Generative Pre-Trained Transformer (ChatGPT) is an artificial learning and large language model tool developed by OpenAI in 2022. It utilizes deep learning algorithms to process natural language and generate responses, which renders it suitable for conversational interfaces. ChatGPT’s potential to transform medical education and clinical practice is currently being explored, but its capabilities and limitations in this domain remain incompletely investigated. The present study aimed to assess ChatGPT’s performance in medical knowledge competency for problem assessment in obstetrics and gynecology (OB/GYN).MethodsTwo datasets were established for analysis: questions (1) from OB/GYN course exams at a German university hospital and (2) from the German medical state licensing exams. In order to assess ChatGPT’s performance, questions were entered into the chat interface, and responses were documented. A quantitative analysis compared ChatGPT’s accuracy with that of medical students for different levels of difficulty and types of questions. Additionally, a qualitative analysis assessed the quality of ChatGPT’s responses regarding ease of understanding, conciseness, accuracy, completeness, and relevance. Non-obvious insights generated by ChatGPT were evaluated, and a density index of insights was established in order to quantify the tool’s ability to provide students with relevant and concise medical knowledge.ResultsChatGPT demonstrated consistent and comparable performance across both datasets. It provided correct responses at a rate comparable with that of medical students, thereby indicating its ability to handle a diverse spectrum of questions ranging from general knowledge to complex clinical case presentations. The tool’s accuracy was partly affected by question difficulty in the medical state exam dataset. Our qualitative assessment revealed that ChatGPT provided mostly accurate, complete, and relevant answers. ChatGPT additionally provided many non-obvious insights, especially in correctly answered questions, which indicates its potential for enhancing autonomous medical learning.ConclusionChatGPT has promise as a supplementary tool in medical education and clinical practice. Its ability to provide accurate and insightful responses showcases its adaptability to complex clinical scenarios. As AI technologies continue to evolve, ChatGPT and similar tools may contribute to more efficient and personalized learning experiences and assistance for health care providers.

Abstract Background Thrombocytopenia is a feared complication of preeclampsia (PE) that can additionally complicate the disease course and that carries a poor prognosis. The disease mechanisms of PE on a platelet level are poorly understood and only few platelet-based markers have been investigated. In sepsis, platelet mitochondrial membrane depolarization, a sensitive and early indicator of mitochondrial dysfunction and platelet cell death, correlates with disease severity and outcome as shown in previous studies. The aim of this study was to investigate platelet mitochondrial membrane potential (Mmp-Index) by flow-cytometry in patients with preeclampsia compared to controls and to assess its value in correlation with disease severity of PE and during follow-up after delivery. Methods In this prospective translational case–control study, platelet Mmp-Index was measured in PE (n = 16) by flow cytometry in living platelets in simultaneous comparison to healthy pregnant (n = 32) and non-pregnant controls (n = 16) and was individually reassessed after delivery to investigate recovery of platelet mitochondrial function. Subgroup analysis of patients with severe and non-severe PE was performed. Six patients with isolated gestational hypertension were also included for comparative analysis. Results Platelet Mmp-Index in patients with symptomatic preeclampsia (Mmp-Index non-severe PE 0.72 ([0.591; 0.861]; p = 0.002) was significantly reduced compared to healthy pregnant controls (Mmp-Index 0.97 [0.795; 1.117]) and even more pronounced in patients with severe PE (n = 6) (Mmp-Index severe PE 0.542 [0.361; 0.623]; p = 0.03). In the severe PE group, complementary measurements of platelet Annexin V- and CD62 (P-Selectin) surface expression showed apoptosis of platelet populations in the majority of patients. Platelet Mmp normalized after delivery within few days. Patients with isolated gestational hypertension showed normal Mmp-Index values. Conclusions This study shows for the first time that platelet Mmp-Index is a quantifiable, easy-to-measure intracellular marker of platelet mitochondrial function in vital cells that reflects disease severity of preeclampsia. For future investigations, platelet Mmp may serve as a prognostic marker that may aid clinical risk stratification and adds novel information on potential mechanisms for thrombocytopenia in preeclampsia.

Different immunohistochemical programmed death-ligand 1 (PD-L1) assays and scorings have been reported to yield variable results in triple-negative breast cancer (TNBC). We compared the analytical concordance and reproducibility of four clinically relevant PD-L1 assays assessing immune cell (IC) score, tumor proportion score (TPS), and combined positive score (CPS) in TNBC. Primary TNBC resection specimens (n = 104) were stained for PD-L1 using VENTANA SP142, VENTANA SP263, DAKO 22C3, and DAKO 28–8. PD-L1 expression was scored according to guidelines on virtual whole slide images by four trained readers.The mean PD-L1 positivity at IC-score ≥1% and CPS ≥1 ranged between 53% and 75% with the highest positivity for SP263 and comparable levels for 22C3, 28–8, and SP142. Inter-assay agreement was good between 28–8 and 22C3 across all scores and cut-offs (kappa 0.68–0.74) and for both assays with SP142 at IC-score ≥1% and CPS ≥1 (kappa 0.61–0.67). The agreement between SP263 and all other assays was substantially lower for all scores. Inter-reader agreement for each assay was good to excellent for IC-score ≥1% (kappa 0.73–0.78) and CPS ≥1 (kappa 0.68–0.74), fair to good for CPS ≥10 (kappa 0.52–0.67) and TPS ≥1% (kappa 0.53–0.72). The percentage of overlapping cases in the positive/negative category was >90% between IC-score ≥1% and CPS ≥1 but below when comparing IC-score ≥1% with CPS ≥10. We demonstrate an overall good inter-reader agreement for all PD-L1 assays in TNBC along with assay specific differences in positivity and concordances, which may aid to select the right test strategy in routine diagnostics.

Heat shock protein 70 (Hsp70) is frequently overexpressed in many different tumor types. However, Hsp70 has also been shown to be selectively presented on the plasma membrane of tumor cells, but not normal cells, and this membrane form of Hsp70 (mHsp70) could be considered a universal tumor biomarker. Since viable, mHsp70-positive tumor cells actively release Hsp70 in lipid micro-vesicles, we investigated the utility of Hsp70 in circulation as a universal tumor biomarker and its potential as an early predictive marker of therapeutic failure. We have also evaluated mHsp70 as a target for the isolation and enumeration of circulating tumor cells (CTCs) in patients with different tumor entities. Circulating vesicular Hsp70 levels were measured in the peripheral blood of tumor patients with the compHsp70 ELISA. CTCs were isolated using cmHsp70.1 and EpCAM monoclonal antibody (mAb)-based bead approaches and characterized by immunohistochemistry using cytokeratin and CD45-specific antibodies. In two out of 35 patients exhibiting therapeutic failure two years after initial diagnosis of non-metastatic breast cancer, progressively increasing levels of circulating Hsp70 had already been observed during therapy, whereas levels in patients without subsequent recurrence remained unaltered. With regards to CTC isolation from patients with different tumors, an Hsp70 mAb-based selection system appears superior to an EpCAM mAb-based approach. Extracellular and mHsp70 can therefore serve as a predictive biomarker for therapeutic failure in early-stage tumors and as a target for the isolation of CTCs in various tumor diseases.

Abstract Background The influence of lifestyle factors on the quality of life, incidence and tumor recurrence has been evaluated in several studies and is gaining increasing importance in cancer research. However, the extent of the influence of such lifestyle factors on the quality of life of cancer patients remains largely unclear, as does the number of patients actually pursuing these lifestyle changes. The purpose of this study was to examine the prevalence and predictors of lifestyle changes in patients with gynecological cancer. Methods The survey consisted of a pseudonymous questionnaire that was conducted from January to May 2014 via a telephone interview with 141 patients with a gynaecological malignancy who had undergone surgery at our Department of Gynaecology and Obstetrics. Lifestyle factors (diet, physical activity, stress level, alcohol and nicotine consumption) prior to and after the diagnosis of cancer were evaluated. Results 89% (n = 125) of the patients reported lifestyle changes after being diagnosed with cancer. There was a significant association between the implementation of lifestyle changes and age as well as the use of complementary medicine. Nutrition: 66% of the patients (n = 93) consumed more fruit and vegetables and 65% ate less meat (n = 92). Physical activity: 37% (n = 52) reported no change in their exercise routine, 36% (n = 51) described a decrease, 27% (n = 38) an increase in their physical activity. Subjective feeling of stress: 77% of the patients (n = 108) described a reduction in their perceived level of stress. Nicotine consumption: 63% (n = 12) of the 19 patients who were smokers at the time of the diagnosis quit or reduced smoking thereafter. Alcohol consumption: 47% (n = 61/129) of the patients reduced their alcohol consumption. Conclusions Most of the patients from our study group implemented lifestyle changes after being diagnosed with cancer. Prospective randomized trials are needed in order to determine the benefit of lifestyle changes (physical activity, dietary habits and stress reduction) for cancer survivors. The potential impact of lifestyle on the quality of life and the trajectory of the disease should be discussed with all oncological patients.

Abstract Background High-grade serous ovarian cancer (HGSOC) is the most common and lethal subtype of ovarian cancer. A growing body of evidence suggests tumor-supporting roles of several members of the kallikrein-related peptidase (KLK) family, including KLK5 and KLK7, in this cancer subtype. In normal physiology, KLK5 and KLK7 are the major proteases involved in skin desquamation. Moreover, in several cancer types KLK5 and KLK7 co-expression has been observed. Recently, we have shown that elevated KLK5 mRNA levels are associated with an unfavorable prognosis in HGSOC. Therefore, the aim of this study was to investigate the clinical significance of KLK7 mRNA expression and to explore its relation to KLK5 levels in HGSOC. Methods mRNA expression levels of KLK7 were quantified by qPCR in a well-characterized patient cohort afflicted with advanced high-grade serous ovarian cancer (FIGO III/IV, n = 139). Previously determined KLK5 mRNA as well as KLK5 and KLK7 antigen concentrations were used to evaluate the relationship between the expression patterns of both factors on the mRNA as well as protein level in tumor tissue of HGSOC patients. Results There were strong, significant positive correlations between KLK5 and KLK7 both at the mRNA and the protein level, suggesting coordinate expression of these proteases in HGSOC. In univariate analyses, elevated KLK7 levels as well as the combination of KLK5 + KLK7 (high and/or high versus low/low) were significantly associated with worse progression-free survival (PFS). High mRNA expression levels of KLK7 and the combination of KLK5 and KLK7 showed a trend towards significance for overall survival (OS). In multivariate analyses, KLK7 mRNA expression represented an unfavorable, statistically significant independent predictor for PFS and OS. Conclusions The findings imply that both increased KLK5 and KLK7 mRNA expression levels represent unfavorable prognostic biomarkers in advanced high-grade serous ovarian cancer, whereby multivariate analyses indicate that KLK7 mRNA exhibits a stronger predictive value as compared to KLK5 mRNA and the combination of KLK5 and KLK7.

Abstract Background The serine protease KLK12 belongs to the human fifteen-member family of kallikrein-related peptidases. Differential expression accompanied by either increased or decreased enzymatic activity has been linked to several diseases including cancer. Triple-negative breast cancer (TNBC) represents a very aggressive subgroup of breast cancer with high tumor recurrence rates and poor patient prognosis. Here, we quantified the KLK12 mRNA expression levels in tumor tissue of TNBC patients and analyzed their prognostic value. Methods In the present study, KLK12 mRNA expression in tumor tissue of TNBC patients (n = 116) was determined by quantitative real-time PCR assay. The association of KLK12 mRNA levels with clinical parameters, and patients’ outcome was analyzed using Chi-square tests, Cox regression models and Kaplan-Meier survival analysis. Results Positive, but low KLK12 mRNA levels were detected in about half of the cases (54 out of 116; 47%), the other samples were negative for KLK12 mRNA expression. No significant association was observed between KLK12 mRNA levels and clinicopathological variables (age, lymph node status, tumor size, and histological grade). In univariate Cox analyses, positive KLK12 mRNA expression was significantly associated with shortened disease-free survival (DFS; hazard ratio [HR] = 2.12, 95% CI = 1.19–3.78, p = 0.010) as well as overall survival (OS; HR = 1.91, 95% CI = 1.04–3.50, p = 0.037). In multivariable Cox analysis, including all clinical parameters plus KLK12 mRNA, the latter - together with age - remained an independent unfavorable predictive marker for DFS (HR = 2.33, 95% CI = 1.28–4.24, p = 0.006) and showed a trend towards significance in case of OS (HR = 1.80, 95% CI = 0.96–3.38, p = 0.066). Conclusions Positive KLK12 expression is remarkably associated with shortened DFS and OS, suggesting that KLK12 plays a tumor-supporting role in TNBC.

Objectives: Adjuvant chemotherapy decision in patients with hormone receptor positive, HER2 negative breast cancer (BC) is challenging. Ki-67 is widely used for adjuvant therapy decision in BC. The multigene assay EndoPredict (EP) has shown to provide valid and additional information about the risk of recurrence compared to traditional pathological factors. In this study, we compared Ki-67 with EP assay generated risk groups. Methods: We analyzed the results from prospective EP testing (n = 373) and tumor proliferation assessed by Ki-67 staining in luminal breast cancer. We statistically investigated the association of both parameters and probed for equivalence in risk stratification. Results: Evaluation of Ki-67 was feasible in 307 (82%) BC specimens with known EP test results. The EPscore (now called 12-gene molecular score) delineated 140 low and 167 high scores. After combining the EPscore with pathological tumor stage and nodal status, we received 203 EPclin low-risk and 104 EPclin high-risk classifications. EPscore and EPclin were significantly associated with Ki-67 indices and tumor grade (p

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with poor patient prognosis and limited therapeutic options. A lack of prognostic biomarkers and therapeutic targets fuels the need for new approaches to tackle this severe disease. Extracellular matrix degradation, release, and modulation of the activity of growth factors/cytokines/chemokines, and the initiation of signaling pathways by extracellular proteolytic networks, have been identified as major processes in the carcinogenesis of breast cancer. Members of the kallikrein-related peptidase (KLK) family contribute to these tumor-relevant processes, and are associated with breast cancer progression and metastasis. In this study, the clinical relevance of mRNA expression of two members of this family, KLK10 and KLK11, has been evaluated in TNBC. For this, their expression levels were quantified in tumor tissue of a large, well-characterized patient cohort (n = 123) via qPCR. Although, in general, the overall expression of both factors are lower in tumor tissue of breast cancer patients (encompassing all subtypes) compared to normal tissue of healthy donors, in the TNBC subtype, expression is even increased. In our cohort, a significant, positive correlation between the expression levels of both KLKs was detected, indicating a coordinate expression mode of these proteases. Elevated KLK10 and KLK11 mRNA levels were associated with poor patient prognosis. Moreover, both factors were found to be independent of other established clinical factors such as age, lymph node status, or residual tumor mass, as determined by multivariable Cox regression analysis. Thus, both proteases, KLK10 and KLK11, may represent unfavorable prognostic factors for TNBC patients and, furthermore, appear as promising potential targets for therapy in TNBC.

Abstract Background In ovarian cancer, dysregulation of mRNA expression of several components of the family of the kallikrein-related peptidases (KLKs) is observed. In this study, we have analyzed the KLK5 mRNA expression pattern in tumor tissue of patients suffering from high-grade serous ovarian cancer stage FIGO III/IV. Moreover, we have correlated the KLK5 mRNA levels with clinical outcome. Methods We assessed the mRNA expression levels of KLK5 in tumor tissue of 138 patients using quantitative PCR (qPCR). The mRNA levels were correlated with KLK5 antigen tumor tissue levels measured by ELISA (available for 41 of the 138 patients), established clinical features as well as patients’ outcome, using Chi-square-tests, Mann-Whitney U-tests and Spearman rank calculations as well as Cox regression models, Kaplan-Meier survival analysis and the log-rank test. Results A highly significant correlation between the mRNA expression levels and protein levels of KLK5 in tumor tissues was observed (rs = 0.683, p 0 mm), but not ascites fluid volume (≤500 ml vs. > 500 ml), remained an independent indicator for both OS and PFS (p

Purpose. Breast and gynecological cancer patients undergoing systemic therapy frequently request integrative therapy concepts. The potential of integrative therapy (IM) lies in minimizing side effects of conventional cancer treatments and therefore decreasing treatment delays. IM can help to improve patients’ physical and emotional well-being, optimizing health and quality of life as IM involves patients in their own treatment. A counseling service for integrative medicine concepts as an outpatient program was implemented in our cancer center in 2013. Methods. In 2016 and 2017 144 breast and gynecological cancer patients were included into our specific IM program. The program comprises biological based complementary and alternative medicines (BB-CAM), a structured exercise therapy, manipulative and body-based practices, nutritional counseling, psycho-oncological and relaxing therapies. Therapists with additional specialization for IM, guide the treatment units. The program was evaluated via self-administered questionnaire. Results. 78% of the participating patients noticed an improvement by using BB-CAMs. 86% stated to feel better through participation in the structured exercise program. 74% profited from nutritional counseling and 91% from manual therapy. 93% of the patients treated with body compresses considered the application as soothing. The Bio-Frequency Sound Color Bed led to a relaxation in 96%. Psychological therapy improved coping with the disease in 70% of the patients. Conclusion. Integrative oncology combines the best practices of conventional and complementary therapy, uniting them in a holistic concept. Data show that our integrative therapy concept is well accepted by the patients and that therapy- and disease-related side effects can be reduced.

Introduction: Prospective clinical trials are essential to translate new therapy concepts or rather any scientific development into the medical routine. Besides a sophisticated trial protocol, the success of clinical trials depends on patient recruitment and participation. Patient recruitment remains a challenge and depends on several factors. To get a current picture of the patients’ attitude, we conducted the present survey. Methods: We designed a survey with seven questions, which was given to all oncological patients treated within a timeframe of three months between Mai and July 2017. Participation was voluntary and anonymous. The questionnaire mainly inquires patients’ participation in clinical trials in a university-based setting, their attitude towards clinical trials regarding risks and benefits, and their source of information in this context. Results: 771 patients (1:1 male/female) participated with a median age of 61 years (range 18–91 years) with a response rate of 71.5%. Of all, 17.8% (137/771) were participating in a clinical trial. The most mentioned reason was to serve medical progress and cancer research. Out of the patients not currently participating in a trial, 79 (12.7%, 79/623) refusers named the following main reasons: extensive travel time to the clinic, no therapeutic advantage, and too time-consuming. Out of the patients not offered to take part in a trial, 265 (51.0%, 265/520) would participate if offered. Of all patients, 8.3% (64/771) used the clinics' homepage as a source of information, of those 79.7% (51/64) were satisfied with its content. To enhance patient recruitment strategies, we asked how patients wish to be informed about possible trials: More than half (52.0%) of the questioned patients preferred an individual medical consultation with their physician.We further analyzed the trial participation depending on age, gender, unit, and tumor entity. We could show a significant influence of age (p

Abstract Background Biologically-based complementary medicines (BB-CAM) including herbs and nutritional supplements are frequently taken by breast- and gynecological cancer patients undergoing systemic therapy. The aim of this study was to analyze the use of these natural CAM methods under systemic therapy. Methods From September 2014 to December 2014 and February 2017 to May 2017 all patients (n= 717) undergoing systemic therapy at the day care unit, Department of Gynecology and Obstetrics, Technical University Munich, Germany, with breast- and/or gynecological cancer were included in this survey. The self-administered 8-item questionnaire was developed to obtain information on complementary medication intake during systemic therapy. Results Among 448 respondents 74.1% reported to use complementary medication simultaneous to their systemic therapy. The most frequently applied methods during therapy were vitamins and minerals supplements (72.3%), medicinal teas (46.7%), phytotherapy (30.1%), and mistletoe (25.3%). The analysis showed that various patients-, disease- and therapy characteristics like receiving chemotherapy (p= 0.002), and younger age (younger than 60 years; p=0.017) are significantly associated with BB-CAM use. Conclusions Our data suggest that female cancer patients undergoing systemic therapy frequently use BB-CAM medicine. Therefore, it is indispensable to implement counseling and evidence-based complementary treatments into clinical routine of cancer centers. A counseling service for integrative medicine concepts and an outpatient program (ZIGG) was therefore implemented in our cancer center in 2013. Further research on the CAM intake of cancer patients is needed in order to verify drug interactions and implement specific guidelines for integrative medication concepts.

Abstract Background Although integrative medicine is gaining increasing attention and is claiming more and more its place in modern health care, it still plays a marginal role in conventional maternity care. The present study aims to examine the patterns of Complementary and Alternative Medicine (CAM) use and the demand for integrative therapies, including CAM, relaxation therapies, nutritional counseling, and psychological assistance, among women in pregnancy and childbed. Methods The survey was conducted from April 2017 to July 2017 by means of a pseudo-anonymous 38-item questionnaire at the Department of Gynecology and Obstetrics, Klinikum rechts der Isar, Technical University of Munich. Eligible participants were women hospitalized due to pregnancy related complications and women in childbed. Descriptive statistics were generated to determine patterns of CAM use and demand for integrative therapeutic approaches. Univariate analysis was used to detect associations between patients’ characteristics and their interest in the different integrative therapies. Furthermore, binary logistic regression was used to estimate the odds ratio of demand for CAM. Results A total of 394 out of 503 patients participated in the survey (78%). 60% declared using CAM in general, 45% specifically in relation to their pregnancy or childbed. Most commonly used modalities were vitamins (31% of all patients), yoga (24%), and herbal supplements (23%). Most popular sources of recommendation of CAM use were midwives and gynecologists. Integrative therapy options patients would have wanted alongside conventional maternity care were CAM (64%), relaxation therapies (44%), dietary counseling (28%), and psychological counseling (15%). Furthermore, associations between patients’ sociodemographic characteristics and their demand for integrative therapies were identified. Conclusions The results of this study demonstrate that there is a considerable demand for integrative medicine and widespread use of CAM among women during pregnancy and childbed in Germany. Maternity health care providers should be aware of these findings in order to be able to better address patients’ needs and wishes. Our study findings should be interpreted with regard to patients in an hospital setting.

Abstract Background There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group. Methods The study comprised 802 women (median age 40 years, range 19–76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation. Results A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20–29 years compared to 6.9% in the age group 60–69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50–2.32, p 10% for women diagnosed below approximately 50 years. Conclusions Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.

Abstract Background Women with pathogenic BRCA germline mutations have an increased risk for breast and ovarian cancer that seems to be modified by life-style factors. Though, randomized trials investigating the impact of lifestyle interventions on cancer prevention and prognosis in BRCA carriers are still missing. Methods We implemented a multicenter, prospective randomized controlled trial in BRCA1/2 patients, comparing a lifestyle intervention group (IG) with a control group (CG) with the primary aim to prove feasibility. Intervention comprised a structured, individualized endurance training alongside nutrition education based on the Mediterranean diet (MD) for 3 months, plus monthly group training and regular telephone contact during the subsequent 9 months. The CG attended one session on healthy nutrition and the benefits of physical activity. Primary endpoints were feasibility, acceptance and satisfaction over 12 months. Furthermore, effects on physical fitness, diet profile, body mass index (BMI), quality of life and perceived stress were investigated. Results Sixty-eight participants (mean age 41, mean BMI 23.2 kg/m2) were enrolled, of whom 55 (81%, 26 IG, 29 CG) completed 12 months. 73% (n = 26) participated in at least 70% of all intervention sessions. Predictors for drop-outs (19%; n = 13) or non-adherence (27%; n = 7) were not found. 73% rated the program highly and 80% would participate again. Severe adverse events did not occur. Positive effects in the IG compared to the CG were observed for secondary endpoints: BMI, MD eating pattern and stress levels. Conclusions This lifestyle intervention was feasible, safe and well accepted. Positive results on eating habits, physical fitness and stress levels warrant a larger randomized trial. Trial registration The study has been retrospectively registered at ClinicalTrials.gov (reference: NCT02087592 ) on March 12, 2014. The first patient was included on February 24, 2014.

Abstract Background Health benefits of the Mediterranean Diet (MD) have been shown in different at-risk populations. A German translation of the Mediterranean Diet Adherence Screener (MEDAS) from the PREvención con DIeta MEDiterránea (PREDIMED) consortium was used in the LIBRE study, investigating effects of lifestyle-intervention on women with BRCA1/2 mutations. The purpose of the present study is to validate the MEDAS German version. Methods LIBRE is a multicentre (three university hospitals during this pilot phase), unblinded, randomized, controlled clinical trial. Women with a BRCA1/2 mutation of age 18 or over who provided written consent were eligible for the trial. As part of the assessment, all were given a full-length Food Frequency Questionnaire (FFQ) and MEDAS at baseline and after 3 months. Data derived from FFQ was compared to MEDAS in order to evaluate agreement or concordance between the two questionnaires. Additionally, the association of dietary intake biomarkers in the blood (β-carotene, omega-3, omega-6 and omega-9 fatty acids and high-sensitivity C-reactive protein (hsCRP)) with some MEDAS items was analyzed using t-Tests and a multivariate regression. Results The participants of the LIBRE pilot study were 68 in total (33 Intervention, 35 Control). Only participants who completed both questionnaires were included in this analysis (baseline: 66, month three: 54). The concordance between these two questionnaires varied between the items (Intraclass correlation coefficient of 0.91 for pulses at the highest and −0.33 for sugar-sweetened drinks). Mean MEDAS scores (sum of all items) were 9% higher than their FFQ counter-parts at baseline and 15% after 3 months. Higher fish consumption (at least 3 portions) was associated with lower omega-6 fatty acid levels (p = 0.026) and higher omega-3 fatty acid levels (p = 0.037), both results being statistically significant. Conclusions We conclude that the German MEDAS in its current version could be a useful tool in clinical trials and in practice to assess adherence to MD. Trial registration ClinicalTrials.gov , registered on March 12, 2014, identifier: NCT02087592 . World Health Organization Trial Registration, registered on 3 August 2015, identifier: NCT02087592 .

Objective . The aim of this study was to assess the potential risks of interactions between biologically based complementary and alternative medication (BB-CAM) and conventional drugs during systemic therapy in breast and gynecological cancer patients by analyzing the actual CAM-drug combinations from individual patients’ records. Methods . From September 2014 to December 2014 and from February 2017 to May 2017, all patients (n = 717) undergoing systemic therapy at the Gynecologic Oncology Day Care Unit in the Gynecology and Obstetrics Department of the Technical University of Munich, Germany, were asked to participate in a questionnaire about all their medications. To assess the potential risk of CAM-drug interactions (CDIs), we initially utilized the Lexicomp drug interaction database. This assessment was then expanded with a systematic search of other digital databases, such as the National Center for Complementary and Integrative Health, Memorial Sloan Kettering Cancer Center, PubMed, and MEDLINE as well as the Cochrane Library. Results . Among 448 respondents, 74.1% reported using BB-CAM simultaneously with their systemic therapy. The assessment showed 1 patient with a potentially clinically relevant CDI, where the interaction was based on a self-medicated combination of Echinacea and cyclophosphamide. Furthermore, 81 patients (18.1%) were thought to have interactions because of a combination of BB-CAMs and cytochrome P450 3A4–metabolized anticancer drugs. Conclusions . Our data demonstrated high overall use of BB-CAMs by cancer patients undergoing systemic therapy. The analyses showed only 1 clinically relevant CDI.

INTRODUCTION:Successful breast conserving cancer surgeries come along with tumor free resection margins and account for cosmetic outcome. Positive margins increase the likelihood of tumor recurrence. Intra-operative fluorescence molecular imaging (IFMI) aims to focus surgery on malignant tissue thus substantially lowering the presence of positive margins as compared with standard techniques of breast conservation (ST). A goal of this paper is to assess the incremental number of surgeries and costs of IFMI vs. ST. METHODS:We developed a decision analytical model and applied it for an early evaluation approach. Given uncertainty we considered that IFMI might reduce the proportion of positive margins found by ST from all to none and this proportion is assumed to be reduced to 10% for the base case. Inputs included data from the literature and a range of effect estimates. For the costs of IFMI, respective cost components were added to those of ST. RESULTS:The base case reduction lowered number of surgeries (mean [95% confidence interval]) by 0.22 [0.15; 0.30] and changed costs (mean [95% confidence interval]) by €-663 [€-1,584; €50]. A tornado diagram identified the Diagnosis Related Group (DRG) costs, the proportion of positive margins of ST, the staff time saving factor and the duration of frozen section analysis (FSA) as important determinants of this cost. CONCLUSIONS:These early results indicate that IFMI may be more effective than ST and through the reduction of positive margins it is possible to save follow-up surgeries-indicating further health risk-and to save costs through this margin reduction and the avoidance of FSA.

Adjuvant therapy decisions in early breast cancer are based on accurate risk assessment. Urokinase plasminogen activator (uPA) and plaminogen activator inhibitor-1 (PAI-1) have been the first biomarkers in hormone receptor (HR) positive breast cancer to reach highest level of evidence. The EndoPredict test (EPclin) combines gene expression information with nodal status and tumor size. The aim of this prospective study was to compare uPA/PAI-1 and EPclin as prognostic biomarkers with regard to feasibility, risk stratification and impact on adjuvant therapy recommendation.395 patients with HR positive, HER2 negative, intermediate risk breast cancer were enrolled. Relations and concordance of histologic grading as well as EPclin and uPA/PAI-1 values were assessed by Spearman's rank correlation coefficient and Cohen's Kappa. To compare decision impact of EPclin and uPA/PAI-1 three independent case discussions were held: One with known uPA/PAI-1 and EPclin results, one blinded to EPclin alone and another one blinded to both EPclin and uPA/PAI-1.EPclin could be determined in all 395 (100%), uPA/PAI-1 in 190 (48%) of the tumor samples. EPclin allocated 250 patients (63%) to the low-risk group and 145 patients (37%) to the high-risk group, whereas uPA/PAI-1 allocated 88 patients (46%) to the low-risk group and 102 patients (54%) to the high-risk group. In 59% of cases, both tests showed concordant results. EPclin resulted more frequently in a change of therapy recommendation than the uPA/PAI-1 test (46% vs 24%). Recommendation of adjuvant chemotherapy (CTX) was abandoned twice as often by EPclin (45%) compared to uPA/PAI-1 (22%).In this first prospective comparison of EPclin and uPA/PAI-1 we found, that EPclin is superior to uPA/PAI-1 with respect to feasibility and decision impact. This leads to substantial avoidance of adjuvant CTX in endocrine-sensitive, HER2-negative breast cancer. Data collection for patients´ clinical outcome is ongoing.

KLK9, 10, 11, and 15 may represent potential cancer biomarkers for evaluating ovarian cancer prognosis. In the present study, we selected a homogeneous cohort including 139 patients of advanced high-grade serous ovarian cancer (FIGO stage III/IV) and assessed the mRNA levels of KLK9, 10, 11, and 15 in tumor tissue by quantitative PCR. No significant associations of KLK9, 10, 11, and 15 mRNA with established clinical parameters (residual tumor mass, ascitic fluid volume) were found. Pronounced correlations between KLK10/KLK11 (rs = 0.647) and between KLK9/KLK15 (rs = 0.716) mRNA, but not between other combinations, indicate coordinate expression of distinct pairs of peptidases. In univariate Cox regression analysis, elevated KLK11 mRNA levels were significantly linked with prolonged overall survival (OS; p = 0.021) and progression-free survival (PFS; p = 0.008). KLK15 mRNA levels showed a trend towards significance in case of OS (p = 0.06); KLK9 and KLK10 mRNA expression levels were not associated with patients' outcome. In multivariable Cox analysis, KLK11 mRNA expression levels, apart from residual tumor mass, remained an independent predictive marker for OS (p = 0.007) and PFS (p = 0.015). Here, elevated KLK15 mRNA expression levels turned out to be significantly related to prolonged OS (p = 0.025) as well. High KLK11 but not the other KLK mRNA levels can be considered as strong independent favorable prognostic factor in this major ovarian cancer subtype.

HTRA1 is a highly conserved serine protease which has been implicated in suppression of epithelial-to-mesenchymal-transition (EMT) and cell motility in breast cancer. Its prognostic relevance for breast cancer is unclear so far. Therefore, we evaluated the impact of HTRA1 mRNA expression on patient outcome using a cohort of 131 breast cancer patients as well as a validation cohort including 2809 publically available data sets. Additionally, we aimed at investigating for the presence of promoter hypermethylation as a mechanism for silencing the HTRA1 gene in breast tumors. HTRA1 downregulation was detected in more than 50% of the breast cancer specimens and was associated with higher tumor stage (p = 0.025). By applying Cox proportional hazard models, we observed favorable overall (OS) and disease-free survival (DFS) related to high HTRA1 expression (HR = 0.45 [CI 0.23-0.90], p = 0.023; HR = 0.55 [CI 0.32-0.94], p = 0.028, respectively), with even more pronounced impact in node-positive patients (HR = 0.21 [CI 0.07-0.63], p = 0.006; HR = 0.29 [CI 0.13-0.65], p = 0.002, respectively). Moreover, HTRA1 remained a statistically significant factor predicting DFS among established clinical parameters in the multivariable analysis. Its impact on patient outcome was independently confirmed in the validation set (for relapse-free survival (n = 2809): HR = 0.79 [CI 0.7-0.9], log-rank p = 0.0003; for OS (n = 971): HR = 0.63 [CI 0.48-0.83], log-rank p = 0.0009). In promoter analyses, we in fact detected methylation of HTRA1 in a small subset of breast cancer specimens (two out of a series of 12), and in MCF-7 breast cancer cells which exhibited 22-fold lower HTRA1 mRNA expression levels compared to unmethylated MDA-MB-231 cells. In conclusion, we show that downregulation of HTRA1 is associated with shorter patient survival, particularly in node-positive breast cancer. Since HTRA1 loss was demonstrated to induce EMT and cancer cell invasion, these patients might benefit from demethylating agents or histone deacetylase inhibitors previously reported to lead to HTRA1 upregulation, or from novel small-molecule inhibitors targeting EMT-related processes.

BACKGROUND: Cancer patients carrying mutations in the dihydropyrimidine dehydrogenase gene (DPYD) have a high risk to experience severe drug-adverse effects following chemotherapy with fluoropyrimidine drugs such as 5-fluorouracil (5-FU) or capecitabine. The pretreatment detection of this impairment of pyrimidine catabolism could prevent serious, potentially lethal side effects. As known deleterious mutations explain only a limited proportion of the drug-adverse events, we systematically searched for additional DPYD variations associated with enhanced drug toxicity. METHODOLOGY/PRINCIPAL FINDINGS: We performed a whole gene approach covering the entire coding region and compared DPYD genotype frequencies between cancer patients with good (n = 89) and with poor (n = 39) tolerance of a fluoropyrimidine-based chemotherapy regimen. Applying logistic regression analysis and sliding window approaches we identified the strongest association with fluoropyrimidine-related grade III and IV toxicity for the non-synonymous polymorphism c.496A>G (p.Met166Val). We then confirmed our initial results using an independent sample of 53 individuals suffering from drug-adverse-effects. The combined odds ratio calculated for 92 toxicity cases was 4.42 [95% CI 2.12-9.23]; p (trend)G with toxicity was particularly present in patients with gastroesophageal and breast cancer, but did not reach significance in patients with colorectal malignancies. CONCLUSION: Our results show compelling evidence that, at least in distinct tumor types, a common DPYD polymorphism strongly contributes to the occurrence of fluoropyrimidine-related drug adverse effects. Carriers of this variant could benefit from individual dose adjustment of the fluoropyrimidine drug or alternate therapies.