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Triple-negative breast cancer (TNBC) is typically treated with chemotherapeutic agents, including carboplatin (Cb), an DNA platinating agent. The O6-methylguanine-DNA-methyltransferase gene (MGMT) encodes for the protein O6-alkylguanine-DNA-alkyltransferase (MGMT protein). MGMT protein is involved in DNA repair mechanisms to remove mutagenic and cytotoxic adducts from O6-guanine in DNA. In glioblastoma multiforme, MGMT methylation status is a predictive biomarker for increased response to temozolomide therapy. It has been suggested, that MGMT protein may have relevance for cellular adaptation and could have an influence on resistance to carboplatin therapy. We investigated the influence of MGMT promoter methylation on pathologic complete response and survival of patients with TNBC treated in the neoadjuvant GeparSixto trial. In 174 of 210 available TNBC tumors a valid MGMT promoter methylation status was determined by pyrosequencing of 5 CpG islands. In 21.8%, we detected a mean MGMT promoter methylation >10%. Overall, MGMT promoter methylation was not significantly associated with pathological complete response (pCR) rate. After stratification for the two therapy arms with and without Cb no statistically significant differences in therapy response rates between the two MGMT promoter methylation groups could be observed. Our results show that different MGMT promoter methylation status is not related to different chemotherapy response rates in the TNBC setting in GeparSixto.

Sherko Kümmel,1 Christian Jackisch,2 Volkmar Müller,3 Andreas Schneeweiss,4 Sandra Klawitter,5 Michael P Lux6 1Breast Unit Essen, Kliniken Essen-Mitte, Essen, Germany; 2Department of Obstetrics and Gynecology, Sana Klinikum Offenbach, Offenbach, Germany; 3Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 4Division of Gynecologic Oncology, National Center for Tumor Diseases, University Hospital, Heidelberg, Germany; 5Medical Affairs – Biostatistics and Epidemiology, Roche Pharma AG, Grenzach-Wyhlen, Germany; 6Department of Gynecology and Obstetrics, Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany Purpose: Although several trials have demonstrated improved progression-free survival (PFS) with first-line regimens for HER2-negative metastatic breast cancer (mBC), overall survival (OS) benefit is elusive. We calculated required sample sizes to power for OS using published data from recent mBC trials.Patients and methods: Randomized superiority trials of first-line chemotherapy/targeted therapy for HER2-negative mBC including >150 patients, meeting the primary efficacy objective, and published in 2000–2018 were identified. The sample sizes required to power for PFS and OS were calculated retrospectively for each trial using observed results and study/recruitment follow-up durations (α=0.05, two-sided log-rank test, 80% power), and summarized as a factor (x) relative to actual sample size.Results: Nine of 13 identified trials reported all information required for retrospective sample size calculation. Six had sample sizes larger than required to demonstrate a significant PFS benefit but all would have required larger sample sizes to demonstrate significant OS benefit with the observed results. In ten trials, the required sample size was ≥5-fold larger to power for OS than PFS.Conclusion: Designing trials to test potential new treatments for HER2-negative mBC is challenging, requiring a balance of regulatory acceptability, feasibility, and realistic medical assumptions to calculate sample sizes. Powering for OS is particularly difficult in heterogeneous populations with long postprogression survival, potential crossover, heterogeneous poststudy therapy, and evolving treatment standards. Validated surrogate endpoints are critical. Ongoing trials of cancer immunotherapy (new mode of action) in triple-negative mBC (more homogeneous, shorter OS and postprogression survival, fewer treatment options) may show a new pattern. Keywords: progression-free survival, overall survival, endpoint, metastatic breast cancer, clinical trial, regulatory authorities

Abstract Background Although adequate physical activity has been shown to be beneficial in early breast cancer, evidence in metastatic breast cancer is sparse and contradictory, which could be related to distinct effects of physical activity on the different molecular cancer subtypes. Therefore, we here evaluated the effect of physical activity on progression-free and overall survival (PFS, OS) in metastatic breast cancer, specifically looking at molecular subtypes. Methods International Physical Activity Questionnaire (IPAQ) questionnaires, filled out by patients enrolled in the prospective PRAEGNANT registry (NCT02338167; n = 1,270) were used to calculate metabolic equivalent task (MET) minutes, which were subsequently categorized into low (n = 138), moderate (n = 995) or high IPAQ categories (n = 137). Cox regression analyses were used to evaluate the impact of IPAQ categories and its interaction with molecular subtypes on PFS and OS. Results Patient and tumor characteristics were equally distributed across IPAQ categories. HER2pos, HRpos and TNBC were present in 23.1%, 65.7% and 11.2% of patients, respectively. IPAQ scores did not have an impact on PFS and OS in addition to established prognostic factors, either overall or in particular molecular subtypes (PFS: p = 0.33 and OS: p = 0.08, likelihood ratio test). Exploratory analyses showed higher overall survival rates for high IPAQ categories compared to low/moderate IPAQ categories in luminal B-like breast cancer. Conclusions Self-reported physical activity using the IPAQ questionnaire did not significantly affect PFS or OS in patients suffering from metastatic breast cancer. Nevertheless, some hypothesis-generating differences between molecular subtypes could be observed, which may be interesting to evaluate further.

Questions: The highest mountain peak of Zagros is located in the Dena mountain system (4409 m a.s.l.), which is identified as the second richest center of plant endemism of Zagros. In this study we (1) investigate floristic affinities of Dena Mts to adjacent mountain ranges based on the endemic species of the Iranian Plateau, (2) identify the species reaching the subnival zone, and (3) characterize the plant communities of the subnival zone of Dena Mts. Study area: Dena Mts is a calcareous mountain system in southern Zagros, Iran. Methods: The list of taxa endemic to the Iranian Plateau present also in Dena Mts was taken from our previously published data. Novel vegetation data were collected using the methodology of Braun-Blanquet. Classification was carried out in JUICE using the Modified TWINSPAN method. Results: Of the 242 taxa endemic to the Iranian Plateau present in Dena Mts, 22 taxa are endemic to the latter. Dena Mts have the strongest floristic affinity with the Yazd-Kerman massif, with which they share 84 taxa compared to 51 taxa shared with Alborz, 37 taxa shared with the Azerbaijan Plateau, and 15 taxa shared with Kopet Dagh-Khorassan. In Dena Mts, 38 taxa reach the subnival zone, most of them being endemic to the Iranian Plateau (68%). From scree habitats in the subnival zone, two new plant associations are described, Aethionemetum umbellati and Zerdanetum anchonioidei. These constitute a newly described alliance Galion pseudokurdici, classified within the class Didymophyso aucheri-Dracocephaletea aucheri. Conclusions: Although Dena Mts lie within a protected area, this will not prevent shrinking of alpine and subnival habitats due to global warming. Consequently, strong attention to the conservation of all range-restricted species of this mountain system, especially of alpine and subnival species, is highly recommended. Taxonomic reference: Flora of Iran (Assadi et al. 1989–2021) and, for families not yet covered in the previous source, Flora Iranica (Rechinger 1963–2015).

Abstract Data on cholestasis and biliary injury in patients with COVID-19 are scarce. The primary aim of this study was to evaluate the prevalence of cholestasis and factors associated with its development and outcome in critically ill patients with COVID-19 associated acute respiratory distress syndrome (ARDS). In this retrospective exploratory study, COVID-19 patients with ARDS admitted to an intensive care unit (ICU) at the Medical University of Vienna were evaluated for the development of cholestasis defined as an alkaline phosphatase level of 1.67x upper limit of normal for at least three consecutive days. Simple and multiple logistic regression analysis was used to evaluate parameters associated with development of cholestasis and survival. Of 225 included patients 119 (53%) developed cholestasis during ICU stay. Patients with cholestasis had higher peak levels of alkaline phosphatase, gamma-glutamyl transferase, bilirubin and inflammation parameters. Factors independently associated with cholestasis were extracorporeal membrane oxygenation support, ketamine use, high levels of inflammation parameters and disease severity. Presence of cholestasis and peak ALP levels were independently associated with worse ICU and 6-month survival. Development of cholestasis is a common complication in critically ill COVID-19 patients and represents a negative prognostic marker for survival. It is associated with disease severity and specific treatment modalities of intensive care.

Abstract Background Increased levels of physical activity are associated with a reduction of breast cancer mortality, especially in postmenopausal women with positive hormone receptor status. So far, previous observational case–control and cohort studies have focused on associations between overall leisure time physical activity and survival of women with breast cancer in general. Methods In this multicenter prospective cohort study, conducted in Germany between 30th August 2012 to 29th December 2017, we investigated general physical activity in a homogenous sample of n = 1440 postmenopausal women with advanced (inoperable locally advanced or metastatic), hormone receptor-positive breast cancer receiving the same therapy (everolimus and exemestane). Self-reported physical activity was assessed using the Godin Leisure Time Exercise Questionnaire (GLTEQ) before and every 3 months during treatment. Participants were then classified into “active” and “insufficiently active” to screen their activity behavior the week prior to medical treatment. In addition, changes in physical activity patterns were assessed. Adjusted Cox regression analyses were performed for the activity categories to determine hazard ratios (HR). Besides progression-free survival (PFS), adverse events (AEs), QoL, and fatigue were assessed every 3 months until study termination. Results Compared to “insufficiently active” patients, “active” individuals indicated a significantly longer PFS (HR: 0.84 [0.74; 0.984], p = .0295). No significant differences were observed for changes of physical activity behavior. Patients who reported to be “active” at baseline revealed significantly fewer AEs compared to “insufficiently” active patients. In detail, both severe and non-severe AEs occurred less frequently in the “active” patients group. In line with that, QoL and fatigue were better in physical “active” patients compared to their insufficient active counterparts at the last post-baseline assessment. Participants who remained or become active indicated less AEs, a higher QoL, and reduced fatigue levels. Conclusions Physical activity behavior prior to medical treatment might have prognostic value in patients with advanced breast cancer in terms of extending the PFS. Moreover, physical activity before and during treatment may reduce treatment-related side effects and improve patients’ QoL and fatigue. Trial registration EUPAS9462. Registered 30th October 2012 “retrospectively registered.”

Abstract Background Patients with pathologic complete response (pCR) to neoadjuvant chemotherapy for invasive breast cancer (BC) have better outcomes, potentially warranting less extensive surgical and systemic treatments. Early prediction of treatment response could aid in adapting therapies. Methods On-treatment biopsies from 297 patients with invasive BC in three randomized, prospective neoadjuvant trials were assessed (GeparQuattro, GeparQuinto, GeparSixto). BC quantity, tumor-infiltrating lymphocytes (TILs), and the proliferation marker Ki-67 were compared to pre-treatment samples. The study investigated the correlation between residual cancer, changes in Ki-67 and TILs, and their impact on pathologic complete response (pCR) and disease-free survival (DFS). Results Among the 297 samples, 138 (46%) were hormone receptor-positive (HR+)/human epidermal growth factor 2-negative (HER2−), 87 (29%) were triple-negative (TNBC), and 72 (24%) were HER2+. Invasive tumor cells were found in 70% of on-treatment biopsies, with varying rates across subtypes (HR+/HER2−: 84%, TNBC: 62%, HER2+: 51%; p

Explanation of natural phenomena at one level of biological organisation almost always involves causes that are found at other levels. Although scientists thinking across levels find it easy to explain physiological phenomena, students often perceive this as a challenge. We developed a new graphic organiser called Zoom Map, which is a mode for structuring biological information along the levels of biological organisation and is designed to guide biology students when they need to consider the levels of organisation. The aim of this study is to examine how Zoom Map helps students explain a common phenomenon in plant physiology: leaves that are upright or wilted. Accordingly, we designed a teaching experiment covering 13 students. During the experiments, the students were videotaped. We used qualitative content analysis to examine the explanations. Our findings indicate that Zoom Map improved students' explanations of the phenomenon across multiple levels of organisation: The students used more levels than before, and they referred to lower levels that were lacking previously. Therefore, it can be concluded that students who use Zoom Map are supported in their ability to explain a biological phenomenon across the levels of biological organisation.

Abstract Background Clinical practice guidelines are crucial for enhancing healthcare quality and patient outcomes. Yet, their implementation remains inconsistent across various professions and disciplines. Previous findings on the implementation of the German guideline for schizophrenia (2019) revealed low adherence rates among healthcare professionals. Barriers to guideline adherence are multifaceted, influenced by individual, contextual, and guideline-related factors. This study aims to investigate the effectiveness of a digital guideline version compared to print/PDF formats in enhancing guideline adherence. Methods A multicenter, cluster-randomized controlled trial was conducted in South Bavaria, Germany, involving psychologists and physicians. Participants were divided into two groups: implementation of the guideline using a digital online version via the MAGICapp platform and the other using the traditional print/PDF version. The study included a baseline assessment and a post-intervention assessment following a 6-month intervention phase. The primary outcome was guideline knowledge, which was assessed using a guideline knowledge questionnaire. Results The study included 217 participants at baseline and 120 at post-intervention. Both groups showed significant improvements in guideline knowledge; however, no notable difference was found between both study groups regarding guideline knowledge at either time points. At baseline, 43.6% in the control group (CG) and 52.5% of the interventional group (IG) met the criterion. There was no significant difference in the primary outcome between the two groups at either time point (T0: Chi2 (1) = 1.65, p = 0.199, T1: Chi2 (1) = 0.34, p = 0.561). At post-intervention, both groups improved, with 58.2% in the CG and 63.5% in the IG meeting this criterion. Conclusions While the study did not include a control group without any implementation strategy, the overall improvement in guideline knowledge following an implementation strategy, independent of the format, was confirmed. The digital guideline version, while not superior in enhancing knowledge, showed potential benefits in shared decision-making skills. However, familiarity with traditional formats and various barriers to digital application may have influenced these results. The study highlights the importance of tailored implementation strategies, especially for younger healthcare providers. Trial registration https://drks.de/search/de/trial/DRKS00028895

Abstract GAIN-2 trial evaluated the optimal intense dose-dense (idd) strategy for high-risk early breast cancer. This study reports the secondary endpoints pathological complete response (pCR) and overall survival (OS). Patients (n = 2887) were randomized 1:1 between idd epirubicin, nab-paclitaxel, and cyclophosphamide (iddEnPC) versus leukocyte nadir-based tailored regimen of dose-dense EC and docetaxel (dtEC-dtD) as adjuvant therapy, with neoadjuvant therapy allowed after amendment. At median follow-up of 6.5 years (overall cohort) and 5.7 years (neoadjuvant cohort, N = 593), both regimens showed comparable 5-year OS rates (iddEnPC 90.8%, dtEC-dtD 90.0%, p = 0.320). In the neoadjuvant setting, iddEnPC yielded a higher pCR rate than dtEC-dtD (51.2% vs. 42.6%, p = 0.045). Patients achieving pCR had significantly improved 5-year iDFS (88.7% vs. 70.1%, HR 0.33, p

Abstract Germline mutations in BRCA1 and BRCA2 (gBRCA1/2) are required for a PARP inhibitor therapy in patients with HER2-negative (HER2−) advanced breast cancer (aBC). However, little is known about the prognostic impact of gBRCA1/2 mutations in aBC patients treated with chemotherapy. This study aimed to investigate the frequencies and prognosis of germline and somatic BRCA1/2 mutations in HER2- aBC patients receiving the first chemotherapy in the advanced setting. Patients receiving their first chemotherapy for HER2- aBC were retrospectively selected from the prospective PRAEGNANT registry (NCT02338167). Genotyping of 26 cancer predisposition genes was performed with germline DNA of 471 patients and somatic tumor DNA of 94 patients. Mutation frequencies, progression-free and overall survival (PFS, OS) according to germline mutation status were assessed. gBRCA1/2 mutations were present in 23 patients (4.9%), and 33 patients (7.0%) had mutations in other cancer risk genes. Patients with a gBRCA1/2 mutation had a better OS compared to non-mutation carriers (HR: 0.38; 95%CI: 0.17–0.86). PFS comparison was not statistically significant. Mutations in other risk genes did not affect prognosis. Two somatic BRCA2 mutations were found in 94 patients without gBRCA1/2 mutations. Most frequently somatic mutated genes were TP53 (44.7%), CDH1 (10.6%) and PTEN (6.4%). In conclusion, aBC patients with gBRCA1/2 mutations had a more favorable prognosis under chemotherapy compared to non-mutation carriers. The mutation frequency of ~5% with gBRCA1/2 mutations together with improved outcome indicates that germline genotyping of all metastatic patients for whom a PARP inhibitor therapy is indicated should be considered.

Abstract Circulating tumor DNA (ctDNA) is the cornerstone of liquid biopsy diagnostics, revealing clinically relevant genomic aberrations from blood of cancer patients. Genomic analysis of single circulating tumor cells (CTCs) could provide additional insights into intra-patient heterogeneity, but it requires whole-genome amplification (WGA) of DNA, which might introduce bias. Here, we describe a novel approach based on mass spectrometry for mutation detection from individual CTCs not requiring WGA and complex bioinformatics pipelines. After establishment of our protocol on tumor cell line-derived single cells, it was validated on CTCs of 33 metastatic melanoma patients and the mutations were compared to those obtained from tumor tissue and ctDNA. Although concordance with tumor tissue was superior for ctDNA over CTC analysis, a larger number of mutations were found within CTCs compared to ctDNA (p = 0.039), including mutations in melanoma driver genes, or those associated with resistance to therapy or metastasis. Thus, our results demonstrate proof-of-principle data that CTC analysis can provide clinically relevant genomic information that is not redundant to tumor tissue or ctDNA analysis.

Abstract CytoSorb is a hemoadsorptive column used to remove high concentrations of proinflammatory cytokines in septic shock. Data on CytoSorb application in acute-on-chronic liver failure (ACLF) is lacking. This retrospective observational study analyzed 21 ACLF patients admitted to ICUs at the Vienna General Hospital who received CytoSorb adsorber therapy between 2017 and 2023. Median ICU length of stay was 8 days (IQR: 3–13), the ICU survival rate was 23.8% (n = 5). Significant decreases in bilirubin (median peak: 20.7 mg/dL to median post-treatment: 10.8 mg/dL; − 47.8%; p

Employing scientific reasoning when giving biological explanations comes easily to the experienced scientist. However, students often encounter difficulty when they attempt to explain biological phenomena. One significant obstacle appears to be the failure or inability to bear in mind the levels of organization. To address this issue, learning strategies, such as the yo-yo learning and teaching strategy, recommend moving across the levels of organization and making those levels explicit in the explanation. To support yo-yo learning, we developed a new graphic organizer, the zoom map. The zoom map combines the levels of organization with concept maps. It is specifically tailored to guide students in biology on ways to distinguish, interrelate and reflect the levels of organization. In this paper, we introduce the zoom map as a tool for instruction and diagnosis. We also provide evidence from teaching experiments that demonstrate how the zoom map benefited learning.

Objective To explore how design emulation and population differences relate to variation in results between randomised controlled trials (RCT) and non-randomised real world evidence (RWE) studies, based on the RCT-DUPLICATE initiative (Randomised, Controlled Trials Duplicated Using Prospective Longitudinal Insurance Claims: Applying Techniques of Epidemiology).Design Meta-analysis of RCT-DUPLICATE data.Data sources Trials included in RCT-DUPLICATE, a demonstration project that emulated 32 randomised controlled trials using three real world data sources: Optum Clinformatics Data Mart, 2004-19; IBM MarketScan, 2003-17; and subsets of Medicare parts A, B, and D, 2009-17.Eligibility criteria for selecting studies Trials where the primary analysis resulted in a hazard ratio; 29 RCT-RWE study pairs from RCT-DUPLICATE.Results Differences and variation in effect sizes between the results from randomised controlled trials and real world evidence studies were investigated. Most of the heterogeneity in effect estimates between the RCT-RWE study pairs in this sample could be explained by three emulation differences in the meta-regression model: treatment started in hospital (which does not appear in health insurance claims data), discontinuation of some baseline treatments at randomisation (which would have been an unusual care decision in clinical practice), and delayed onset of drug effects (which would be under-reported in real world clinical practice because of the relatively short persistence of the treatment). Adding the three emulation differences to the meta-regression reduced heterogeneity from 1.9 to almost 1 (absence of heterogeneity).Conclusions This analysis suggests that a substantial proportion of the observed variation between results from randomised controlled trials and real world evidence studies can be attributed to differences in design emulation.

Background: The capsule formulation of CDK4/6 inhibitor palbociclib has reduced solubility at gastric pH > 4.5 and may have decreased activity when used with proton-pump inhibitors (PPI). Herein, we report the effect of PPI on palbociclib capsule activity and safety in the PARSIFAL study. Methods: First-line endocrine-sensitive, hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) patients received palbociclib capsules plus fulvestrant or letrozole. The primary endpoint was progression-free survival (PFS). This post-hoc analysis compared PPI use. Patients were PPI-naïve (N-PPI) if not on PPI during the study, and either early (E-PPI) or long-term PPI (LT-PPI) if on PPI at study entry or for at least ≥⅔ of treatment, respectively. PPI groups were not mutually exclusive. Results: Among 486 patients, 66.9 % were N-PPI, 13.2 % E-PPI, 18.7 % LT-PPI, and 11.5 % of the PPI users were defined as neither. Median PFS (mPFS) was 29.6 months in the study population, 28.7 months in N-PPI, 23.0 months in E-PPI (Hazard Ratio [HR] 1.5; 95%Confidence Interval [CI] 1.1–2.2; p = 0.024), and 23.0 months in LT-PPI (HR 1.4; 95%CI 1.0–1.9; p = 0.035). By landmark analysis, PPI use was associated with poorer mPFS at 3 and 12 months. Grade ≥3 hematological adverse events occurred in 71.7 % of N-PPI, 57.8 % of E-PPI (p = 0.021), and 54.9 % of LT-PPI (p = 0.003). Dose reductions and dosing delays due to hematological toxicity occurred in 70.8 % of N-PPI, 56.3 % of E-PPI (p = 0.018), and 52.7 % of LT-PPI (p = 0.002). Conclusions: PPI use may reduce palbociclib capsule toxicity, dose modifications, and clinical activity in HR+/HER2- ABC.