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Objectives: To investigate the signal-enhancement properties of the tetrameric gadolinium-based contrast agent (GBCA) gadoquatrane in relation to the administered dose and compare its properties to those of a standard dose of gadobutrol, as a representative of the currently established macrocyclic GBCAs for magnetic resonance imaging., Materials and Methods: In this randomized, single-blind, 4 × 4 crossover study, 43 healthy adults (19-50 years of age) received 3 single IV injections of gadoquatrane (0.01, 0.03, and 0.06 mmol gadolinium/kg body weight) and 1 injection of gadobutrol (0.1 mmol gadolinium/kg body weight) in randomized sequence with 1-week washout periods between administrations. The relative signal enhancement (RSE) was determined in predefined areas of interest in magnetic resonance image sets of the head-neck region. RSE-vs-dose curves (dose-response curves) were established by linear regression, and comparator-equivalent doses were determined by Bayesian inverse regression analysis. Further, 3 blood samples were taken after each injection for pharmacokinetic analyses, and safety data were assessed., Results: The RSE increased with gadoquatrane dose. A linear function adequately fitted this relationship. In line with the more than 2-fold higher r1 relaxivity of gadoquatrane per gadolinium ion, gadobutrol-equivalent RSE was achieved with gadoquatrane at less than half the gadolinium dose and less than one eighth of the molecule dose.Administration of gadoquatrane and gadobutrol resulted in very similar dose-normalized gadolinium concentrations in plasma, indicating that the pharmacokinetic profiles are essentially the same. Both contrast agents were well tolerated. Adverse events were rare and not dependent on the dose administered., Conclusions: Gadoquatrane has the potential to be an effective GBCA that can be used at substantially lower doses in clinical routine than the currently established macrocyclic GBCAs., Competing Interests: Conflicts of interest and sources of funding: The study was sponsored by Bayer AG. All authors are or were working at Bayer AG or on behalf of Bayer AG., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

The aim of this study was to evaluate how the COVID-19 pandemic may have impacted the number and patterns of sexual assault victims within a German metropolitan city. A retrospective single center analysis of the gynecology examination reports of all women presenting to the emergency department of a university hospital after a sexual offense between 03/2013 and 02/2021 (n = 1167). Comparison of the first year of the pandemic 03/2000-03/2021) to previous years (03/2017-02/2020) and comparison of periods of government-imposed social distancing (03/12/2020-05/23/2020 and 10/23/2020-02/28/2021) with corresponding periods of pre-pandemic years. The overall number of sexual assault cases did not change during the first year of the COVID-19 pandemic. However, during the stay-at-home orders, the number of women presenting to the emergency department decreased by 38% (n=45 vs. 72). Fewer victims filed a police report during the pandemic (49.5% vs. 73.9%, p<0.001) and the lockdown period (50% vs. 76.5%, p<0.001). Less genital injuries after sexual assault were detected during the pandemic (14.3% vs. 25.2%, p<0.02), but there was an increase of illegal substance abuse (19.5% vs. 9.3%, p<0.003). During the stay-at-home orders fewer victims reported alcohol consumption (42.4% vs. 62.5 %, p<0.023). Despite the decrease in sexual offense related police reports, the number of sexual assault cases remained consistent, and the usage of illegal drugs increased during the COVID-19 pandemic. These findings represent the importance of providing support to sexual assault victims, as well as the implementation of preventative measures, especially in times of crisis., (© 2023. The Author(s).)

Introduction: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is still a rare extralymphatic lymphoma. As of March 1, 2023, approximately 1,355 cases of BIA-ALCL have been reported worldwide. However, no such case has yet been described with pectoral implants in male patients. Most patients with BIA-ALCL present with nonspecific implant-associated symptoms such as late-onset seroma, swollen breasts, and deformation of implants., Case Presentation: Here, we describe BIA-ALCL in a 76-year-old male patient who presented with a late-onset seroma in order to raise awareness for BIA-ALCL also in men after esthetic chest surgery with silicone pectoral implants. The patient had undergone augmentation of the pectoralis muscle with implants for esthetic reasons 9 years before. First cytological specimens showed no malignancy. A repeated cytological assessment after 6 weeks from recurring seroma showed characteristic CD30+ T-cell clones. Surgery with complete bilateral capsulectomy and implant removal was performed. Due to the early-stage ALCL being limited only to the capsule and no evidence of systemic disease, adjuvant systemic treatment was not considered necessary., Conclusion: Any persisting late-onset seroma also in male patients with pectoral implants should raise suspicion of ALCL as differential diagnosis and should be assessed with cytological examination., Competing Interests: Prof. Dr. Eike Burandt: advisory boards for Novartis and Daiichi Sankyo, and speaker’s honoria for AstraZeneca, Eisai, and NOGGO. All remaining authors have no conflicts of interest to declare., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Objectives: Gadolinium (Gd)-based contrast agents are well established in clinical routine and have been proven safe and effective. However, there is a need for "next-generation" Gd-based contrast agents that would allow lowering the Gd dose used for routine contrast-enhanced magnetic resonance imaging procedures. The objective of this first-in-human study was to investigate the pharmacokinetic profile, safety, and tolerability of gadoquatrane, a novel high-relaxivity Gd-based contrast agent., Materials and Methods: This study was conducted in 2018/2019 as a prospective, randomized, single-blind, single-dose, placebo-controlled, escalating-dose study. Healthy volunteers were randomly assigned (6:2) to intravenous administration of gadoquatrane (0.025 to 0.2 mmol Gd/kg body weight) or placebo. Study procedures included collection of blood samples and excreta for pharmacokinetic analyses and safety assessments., Results: Forty-nine healthy study participants (mean age ± SD, 35 ± 6.3 years; 24 female) were evaluated. The effective half-life of gadoquatrane in plasma was short and similar in all dose groups (1.4-1.7 hours). Plasma concentrations around the lower quantitation limit (0.0318 μmol Gd/L) were reached 15-72 hours after administration. The volume of distribution at steady state was ~0.2 L/kg in all dose groups. The clearance (total and renal) was ~0.1 L/h per kilogram in all groups. Across dose groups, the exposure of gadoquatrane increased dose-proportionally. Metabolite profiling revealed no hint of degradation in vivo or release of free Gd. Seven of 36 participants (19.4%) receiving gadoquatrane and 4 of 13 participants (30.8%) receiving placebo experienced mild or moderate treatment-emergent adverse events. No serious adverse events occurred. The analysis of the Gd concentration-QTc interval relationship indicated no risk of QT/QTc prolongation (>10 milliseconds) with gadoquatrane at clinical dose levels., Conclusions: Gadoquatrane with its high-relaxivity, pharmacokinetic similarity to established Gd-based contrast agents and high tolerability is a promising "next-generation" contrast agent for magnetic resonance imaging., Competing Interests: Conflicts of interest and sources of funding: The study was sponsored by Bayer AG. All authors are or were working at Bayer AG or on behalf of Bayer AG., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Around 5 percent of all patients with metastatic breast cancer go on to develop distant metastases in the meninges, also known as meningeal carcinomatosis. The median survival of these patients is between 3.5 and 4.5 months. Current treatment approaches are based on radiotherapy, systemic and intrathecal therapy. Methotrexate, liposomal cytarabine and trastuzumab are the most common substances used for intrathecal therapy. The aim of this review was to provide an overview of these intrathecal therapy options for meningeal carcinomatosis. A systematic search of the literature was carried out in PubMed using the following search terms: "meningeal metastases", "meningeal carcinomatosis", "leptomeningeal metastasis", "leptomeningeal carcinomatosis", "leptomeningeal disease", "breast cancer", "MTX", "methotrexate", "DepoCyte", "liposomal cytarabine", "trastuzumab" and "anti-HER2". This search resulted in 75 potentially relevant studies, 11 of which were included in this review after meeting the previously determined inclusion and exclusion criteria. The studies differ considerably with regards to study design, cohort size, and dosages of administered drugs. In principle, intrathecal therapy has a tolerable side-effects profile and offers promising results in terms of the median overall survival following treatment with trastuzumab for HER2-positive primary tumors. The focus when treating meningeal carcinomatosis must be on providing a multimodal individual therapeutic approach. However, comprehensive studies which compare the efficacy and side effects of individual pharmaceuticals are lacking. Because of the poor prognosis associated with meningeal carcinomatosis, an approach which treats only the symptoms (best supportive care) should always be considered and discussed with affected patients., Competing Interests: Conflict of Interest MM: no conflict of interest relating to the topic of this review. EL: no conflict of interest relating to the topic of this review. KR: no conflict of interest relating to the topic of this review. IW: no conflict of interest relating to the topic of this review. VM: speaker’s fees: AstraZeneca, Daiichi-Sankyo, Eisai, GSK, Pfizer, MSD, Medac, Novartis, Roche, Seagen, Onkowissen, high5 Oncology, Medscape, Gilead, Pierre Fabre, Medscape. Consultancy services: Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi-Sankyo, Eisai, Lilly, Sanofi, Seagen, Gilead, Stemline, ClinSol. Research support to employer: Novartis, Roche, Seagen, Genentech, AstraZeneca. Travel expenses: Roche, Pfizer, Daiichi-Sankyo., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Up to 30% of metastatic breast cancer (BC) patients develop brain metastases (BM). Prognosis of patients with BM is poor and long-term survival is rare. Identification of factors associated with long-term survival is important for improving treatment modalities., Patients and Methods: A total of 2889 patients of the national registry for BM in BC (BMBC) were available for this analysis. Long-term survival was defined as overall survival (OS) in the upper third of the failure curve resulting in a cut-off of 15 months. A total of 887 patients were categorized as long-term survivors., Results: Long-term survivors compared to other patients were younger at BC and BM diagnosis (median 48 versus 54 years and 53 versus 59 years), more often had HER2-positive tumors (59.1% versus 36.3%), less frequently luminal-like (29.1% versus 35.7%) or triple-negative breast cancer (TNBC) (11.9% versus 28.1%), showed better Eastern Cooperative Oncology Group (ECOG) performance status (PS) at the time of BM diagnosis (ECOG 0-1, 76.9% versus 51.0%), higher pathological complete remission rates after neoadjuvant chemotherapy (21.6% versus 13.7%) and lower number of BM (n = 1, BM 40.9% versus 25.4%; n = 2-3, BM 26.5% versus 26.7%; n ≥4, BM 32.6% versus 47.9%) (P < 0.001). Long-term survivors had leptomeningeal metastases (10.4% versus 17.5%) and extracranial metastases (ECM, 73.6% versus 82.5%) less frequently, and asymptomatic BM more often at the time of BM diagnosis (26.5% versus 20.1%), (P < 0.001). Median OS in long-term survivors was about two times higher than the cut-off of 15 months: 30.9 months [interquartile range (IQR) 30.3] overall, 33.9 months (IQR 37.1) in HER2-positive, 26.9 months (IQR 22.0) in luminal-like and 26.5 months (IQR 18.2) in TNBC patients., Conclusions: In our analysis, long-term survival of BC patients with BM was associated with better ECOG PS, younger age, HER2-positive subtype, lower number of BM and less extended visceral metastases. Patients with these clinical features might be more eligible for extended local brain and systemic treatment., Competing Interests: Disclosure IW received speaker’s honoraria from Astra Zeneca, Merck, Pfizer, Roche, Daiichi-Sankyo, Seagen, Gilead and Novartis. KL received speaker’s honoraria from Roche, Novartis, Pfizer, Exact Sciences, MSD, Eisai, Lilly, Seagen, AstraZeneca and Daiichy Sankyo. MS has received personal fees from AstraZeneca, BioNTech, Daiichi-Sankyo, Eisai, Lilly, MSD, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche and Seagen. His institution has received research funding from AstraZeneca, BioNTech, Eisai, Genentech, German Breast Group, Novartis, Palleos, Pantarhei Bioscience, Pierre Fabre and Seagen. In addition, he has a patent for EP 2390370 B1 and a patent for EP 2951317 B1 issued. SL reports grants, non-financial support and other from Daiichi-Sankyo, during the conduct of the study; grants and other from Abbvie, other from Amgen, grants and other from AstraZeneca, other from BMS, grants and other from Celgene, other from Eirgenix, other from Eisai Europe Ltd, other from GSK, grants, non-financial support and other from Immunomedics/Gilead, other from Lilly, other from Merck, grants from Molecular Health, grants, non-financial support and other from Novartis, grants, non-financial support and other from Pfizer, other from Pierre Fabre, other from Relay Therapeutics, grants, non-financial support and other from Roche, other from Sanofi, non-financial support and other from Seagen, other from Olema Pharmaceutics, outside the submitted work; In addition, SL has a patent EP14153692.0 pending, a patent EP21152186.9 pending, a patent EP15702464.7 issued, a patent EP19808852.8 pending and a patent Digital Ki67 Evaluator with royalties paid. CD reports advisory role for MSD Oncology, Daiichi-Sankyo, Molecular Health, AstraZeneca, Roche and Lilly; CD received research funding from Myriad Genetics, Roche and German Breast Group; CD owns following patents: VMScope digital pathology software, Patent WO2020109570A1, Patent WO2015114146A1, Patent WO2010076322A1. MT received personal fees from Agendia, Amgen, Art tempi, AstraZeneca, Aurikamed, Celgene, Daiichi-Sankyo, Eisai, Exact Sciences, Gilead Science, Grünenthal, GSK, Hexal, Lilly, MSD, Novartis, Onkowissen, Organon, Pfizer, Pierre Fabre, Roche, Seagen, Servier, Streamd Up!, Viatris, Vifor, trial funding from Exact Science and institutional trial honoraria from AstraZeneca, Celgene, Novartis, Roche. VM received speaker honoraria from Amgen, Astra Zeneca, Daiichi-Sankyo, Eisai, GSK, Pfizer, MSD, Medac, Novartis, Roche, Teva, Seagen, Onkowissen, high5 Oncology, Medscape, Gilead and Pierre Fabre; consultancy honoraria from Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi-Sankyo, Eisai, Lilly, Sanofi, Seagen and Gilead; Institutional research support from Novartis, Roche, Seagen, Genentech; travel grants: Roche, Pfizer, Daiichi-Sankyo, Gilead. RW received support for advisory, consultancy, speaker and travel grants from Agendia, Amgen, Aristo, AstraZeneca, Boeringer Ingelheim, Carl Zeiss, Celgene, Clinsol, Clovis Oncology, Daiichi-Sankyo, Eisai, Exact Sciences, Genomic Health, Gilead, Glaxo Smith Kline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Mylan, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PINK, PumaBiotechnolgogy, Riemser, Roche, Sandoz/Hexal, Sanofi Genzyme, Seattle Genetics /Seagen, Stemline, Tesaro Bio, Teva, Veracyte and Viatris. TD received Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Novartis, IOMEDICO and participated on a Data Safety Monitoring Board or Advisory Board for Novartis, IOMEDICO. All other authors have declared no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Up to 40% of patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer develop brain metastases (BMs). Understanding of clinical features of these patients with HER2-positive breast cancer and BMs is vital., Patients and Methods: A total of 2948 patients from the Brain Metastases in Breast Cancer registry were available for this analysis, of whom 1311 had primary tumors with the HER2-positive subtype., Results: Patients with HER2-positive breast cancer and BMs were-when compared with HER2-negative patients-slightly younger at the time of breast cancer and BM diagnosis, had a higher pathologic complete response rate after neoadjuvant chemotherapy and a higher tumor grade. Furthermore, extracranial metastases at the time of BM diagnosis were less common in HER2-positive patients, when compared with HER2-negative patients. HER2-positive patients had more often BMs in the posterior fossa, but less commonly leptomeningeal metastases. The median overall survival (OS) in all HER2-positive patients was 13.2 months (95% confidence interval 11.4-14.4). The following factors were associated with shorter OS (multivariate analysis): older age at BM diagnosis [≥60 versus <60 years: hazard ratio (HR) 1.63, P < 0.001], lower Eastern Cooperative Oncology Group status (2-4 versus 0-1: HR 1.59, P < 0.001), higher number of BMs (2-3 versus 1: HR 1.30, P = 0.082; ≥4 versus 1: HR 1.51, P = 0.004; global P = 0.015), BMs in the fossa anterior (HR 1.71, P < 0.001), leptomeningeal metastases (HR 1.63, P = 0.012), symptomatic BMs at diagnosis (HR 1.35, P = 0.033) and extracranial metastases at diagnosis of BMs (HR 1.43, P = 0.020). The application of targeted therapy after the BM diagnosis (HR 0.62, P < 0.001) was associated with longer OS. HER2-positive/hormone receptor-positive patients showed longer OS than HER2-positive/hormone receptor-negative patients (median 14.3 versus 10.9 months; HR 0.86, P = 0.03), but no differences in progression-free survival were seen between both groups., Conclusions: We identified factors associated with the prognosis of HER2-positive patients with BMs. Further research is needed to understand the factors determining the longer survival of HER2-positive/hormone receptor-positive patients., Competing Interests: Disclosure MT serves on the advisory board for Amgen, AstraZeneca, AURIKAMED, Becton/Dickinson, Biom‘Up, Celgene, ClearCut, Clovis, Daiichi Sankyo, Eisai, Exact Sciences, Gilead Science, Lilly, MSD, Norgine, NeoDynamics, Novartis, Onkowissen, Pfizer, pfm Medical, Pierre-Fabre, Roche, RTI Surgical, Seagen and Sysmex; reports manuscript support from Amgen, Celgene, ClearCut, pfm medical, Roche and Servier; support for travel expenses from Amgen, Art Tempi, AstraZeneca, Celgene, Cleracut, Clovis, Connect Medica, Daiichi Sankyo, Eisai, Exact Sciences, Hexal, I-Med-Institute, Lilly, MCI, Medtronic, MSD, Norgine, Novartis, OmniaMed, Pfizer, pfm medical, Roche and RTI Surgical; support for congress expenses from Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Hexal, NeoDynamics, Novartis, Pfizer and Roche; support for speech expenses: Amgen, Art Tempi, AstraZeneca, Celgene, Clovis, Connect Medica, Eisai, Exact Sciences, Gilead Science, Hexal, I-Med-Institute, Jörg Eickeler, Lilly, MCI, Medtronic, MSD, Novartis, OmniaMed, Pfizer, pfm Medical, Roche, RTI Surgical, Seagen, Sysmex, Vifor and Viatris; trial funding support from Endomag and Exact Sciences. All remaining authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Several scores have been developed in order to estimate the prognosis of patients with brain metastases (BM) by objective criteria. The aim of this analysis was to validate all three published graded-prognostic-assessment (GPA)-scores in a subcohort of 882 breast cancer (BC) patients with BM in the Brain Metastases in the German Breast Cancer (BMBC) registry. The median age at diagnosis of BM was 57 years. All in all, 22.3% of patients ( n = 197) had triple-negative, 33.4% ( n = 295) luminal A like, 25.1% ( n = 221) luminal B/HER2-enriched like and 19.2% ( n = 169) HER2 positive like BC. Age ≥60 years, evidence of extracranial metastases (ECM), higher number of BM, triple-negative subtype and low Karnofsky-Performance-Status (KPS) were all associated with worse overall survival (OS) in univariate analysis ( p < 0.001 each). All three GPA-scores were associated with OS. The breast-GPA showed the highest probability of classifying patients with survival above 12 months in the best prognostic group (specificity 68.7% compared with 48.1% for the updated breast-GPA and 21.8% for the original GPA). Sensitivities for predicting 3 months survival were very low for all scores. In this analysis, all GPA-scores showed only moderate diagnostic accuracy in predicting the OS of BC patients with BM.

Currently, the dichotomous definition of human epidermal growth factor receptor 2 (HER2)-positive versus HER2-negative disease undergoing a change through inclusion of the identification of the "HER2-low" category, for which new therapeutic compounds in the form of potent antibody drug conjugates (ADC) may be effective. In addition, resistance to HER2-directed targets has become a clinical challenge and, therefore, strategies to bypass the HER2 receptor are of high interest. These are new HER2 ADCs and tyrosine kinase inhibitors, such as tucatinib or neratinib. The underlying mechanisms of resistance to anti-HER2 therapies and compensatory pathways are complex and a wide range of mechanisms of resistance may coexist in the same cell. Therefore, the combined treatment with agents that interact with HER2-associated downstream signaling pathways like the phosphoinositide-3-kinase (PI3K) and the serine/threonine kinases AKT and mTOR might overcome HER2 resistance. In addition, targeting other members of the HER family is a promising approach to improve outcomes in breast cancer patients. This review gives an overview of treatment strategies in targeting HER2 and other members of the HER family, not only in HER2-positive breast cancer, but also in HER2-low expressing tumors, and of approaches to overcome HER2 resistance., Competing Interests: K.R. has no conflict of interest to declare. I.W. received speakers' honoraria from Amgen, Pfizer, Novartis, Roche, MSD, Daichi Sankyo, and Pierre Fabre Pharma, and institutional (non-personal) funding from MSD., (Copyright © 2020 by S. Karger AG, Basel.)

It is known that co-administration of CYP3A inducers may decrease the effectiveness of oral contraceptives containing progestins as mono-preparations or combined with ethinylestradiol. In a randomized clinical drug-drug interaction study, we investigated the effects of CYP3A induction on the pharmacokinetics of commonly used progestins and ethinylestradiol. Rifampicin was used to induce CYP3A. The progestins chosen as victim drugs were levonorgestrel, norethindrone, desogestrel, and dienogest as mono-products, and drospirenone combined with ethinylestradiol. Postmenopausal women (n = 12-14 per treatment group) received, in fixed sequence, a single dose of the victim drug plus midazolam without rifampicin, with rifampicin 10 mg/day (weak induction), and with rifampicin 600 mg/day (strong induction). The effects on progestin exposure were compared with the effects on midazolam exposure (as a benchmark). Unbound concentrations were evaluated for drugs binding to sex hormone binding globulin. Weak CYP3A induction, as confirmed by a mean decrease in midazolam exposure by 46%, resulted in minor changes in progestin exposure (mean decreases: 15-37%). Strong CYP3A induction, in contrast, resulted in mean decreases by 57-90% (mean decrease in midazolam exposure: 86%). Namely, the magnitude of the observed induction effects varied from weak to strong. Our data might provide an impetus to revisit the currently applied clinical recommendations for oral contraceptives, especially for levonorgestrel and norethindrone-containing products, and they might give an indication as to which progestin could be used, if requested, by women taking weak CYP3A inducers-although it is acknowledged that the exact exposure-response relationship for contraceptive efficacy is currently unclear for most progestins., (© 2020 Bayer AG. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background : Brain metastases (BM) have become a major challenge in patients with metastatic breast cancer. Methods : The aim of this analysis was to characterize patients with asymptomatic BM ( n = 580) in the overall cohort of 2589 patients with BM from our Brain Metastases in Breast Cancer Network Germany (BMBC) registry. Results : Compared to symptomatic patients, asymptomatic patients were slightly younger at diagnosis (median age: 55.5 vs. 57.0 years, p = 0.01), had a better performance status at diagnosis (Karnofsky index 80-100%: 68.4% vs. 57%, p < 0.001), a lower number of BM (>1 BM: 56% vs. 70%, p = 0.027), and a slightly smaller diameter of BM (median: 1.5 vs. 2.2 cm, p < 0.001). Asymptomatic patients were more likely to have extracranial metastases (86.7% vs. 81.5%, p = 0.003) but were less likely to have leptomeningeal metastasis (6.3% vs. 10.9%, p < 0.001). Asymptomatic patients underwent less intensive BM therapy but had a longer median overall survival (statistically significant for a cohort of HER2-positive patients) compared to symptomatic patients (10.4 vs. 6.9 months, p < 0.001). Conclusions : These analyses show a trend that asymptomatic patients have less severe metastatic brain disease and despite less intensive local BM therapy still have a better outcome (statistically significant for a cohort of HER2-positive patients) than patients who present with symptomatic BM, although a lead time bias of the earlier diagnosis cannot be ruled out. Our analysis is of clinical relevance in the context of potential trials examining the benefit of early detection and treatment of BM.

This open label, parallel-group study investigated the pharmacokinetics and safety of a single oral 2-mg dose of the novel selective progesterone receptor modulator vilaprisan in participants with impaired renal function compared with age, weight, sex, and race matched controls with normal renal function. Systemic exposure (area under the plasma concentration-time curve [AUC]) and maximum observed concentrations (C max ) were compared among 9 participants with moderate renal impairment and matched controls by ANOVA. An additional 4 participants, each with severe renal impairment or normal renal function, contributed to a linear regression analysis exploring any monotone relationship between individual variables and the estimated glomerular filtration rate. The geometric mean AUC was increased by a factor of 1.35 in renally impaired participants compared to normal controls (not statistically significant: least squares mean, 1.346; 90% confidence interval, 0.918-1.973). C max was similar in participants with moderate renal impairment and normal renal function (least squares mean, 1.026; 90% confidence interval, 0.779-1.351). Considering the overall variability, there was no correlation between renal function (estimated glomerular filtration rate) and C max or AUC of vilaprisan. Single oral administration of vilaprisan 2 mg was well tolerated by all participants, both men and women and irrespective of renal function. The incidence of treatment-emergent adverse events was similar across all groups. Results from this study do not indicate that a dose adjustment will be necessary for vilaprisan when treating patients up to moderate renal impairment., (© 2020 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Olaptesed pegol (NOX-A12) is a pegylated structured L-oligoribonucleotide that binds and neutralizes CXCL12, a chemokine tightly regulating the life cycle of chronic lymphocytic leukemia cells. The resulting inhibition of CXCR4 and CXCR7 signaling reduces the protective activity of the bone marrow and lymph node microenvironment. CXCL12 inhibition mobilizes chronic lymphocytic leukemia cells into the circulation and prevents their homing into the protective niches. In this phase I/II study, 28 patients with relapsed/refractory chronic lymphocytic leukemia were treated with olaptesed pegol in combination with bendamustine and rituximab. Combination treatment was preceded by single escalating pilot doses of olaptesed pegol in the first ten patients for evaluation of safety and pharmacokinetics. Peak concentrations and systemic exposure of olaptesed pegol were dose-linear; plasma elimination was monophasic with a 53.2 h half-life. A rapid increase in circulating chronic lymphocytic leukemia cells was observed already 1 h after administration of olaptesed pegol and lasted for at least 72 h. Single-agent treatment was well tolerated and no dose-limiting toxicity was observed. The combination regimen yielded an overall response rate of 86%, with 11% of patients achieving a complete response and 75% a partial response. Notably, all ten high-risk patients, including four with a 17p deletion, responded to treatment. The median progression-free survival was 15.4 (95% confidence interval: 12.2, 26.2) months while the median overall survival was not reached with >80% of patients alive after a median follow-up of 28 months. Olaptesed pegol was well tolerated and did not result in additional toxicity when combined with bendamustine and rituximab ( ClinicalTrials.gov identifier: NCT01486797 ). Further clinical development of this novel CXCL12 inhibitor is thus warranted., (Copyright© 2019 Ferrata Storti Foundation.)

Aims: The study objective was to evaluate the pharmacokinetics of the selective progesterone receptor modulator vilaprisan in participants with hepatic impairment. Additionally, the safety and tolerability of vilaprisan were investigated., Methods: In this phase 1, open-label, nonrandomised, parallel-group, pharmacokinetic study, men and women with mild or moderate hepatic impairment (Child-Pugh grade A or B) and control participants with normal hepatic function matched by age, weight and sex received a single oral 2 mg dose of vilaprisan. Key pharmacokinetic parameters, relationships between parameters and safety outcomes were measured., Results: Thirty-six participants completed the study: 9 with mild hepatic impairment, 9 with moderate hepatic impairment and 18 matched control participants with normal hepatic function. Vilaprisan reached maximum plasma concentrations after 1-2 hours. Unbound vilaprisan exposure was 1.44-fold higher for participants with mild hepatic impairment vs controls (90% confidence interval: 0.91-2.26), and 1.74-fold higher for participants with moderate impairment vs controls (90% confidence interval: 1.09-2.78). The maximum observed unbound peak concentrations were similar for participants with hepatic impairment and matched controls. Vilaprisan 2 mg was well tolerated and the incidence of treatment-emergent adverse events was similar across cohorts., Conclusion: Only mild increases of <1.75-fold in exposure were observed in participants with mild or moderate hepatic impairment compared with control participants. No safety concern was identified. These data, alongside the excellent safety profile observed in phase 1 and 2 studies, do not indicate that a dose adjustment would be required in patients with mild or moderate hepatic impairment., (© 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background and Purpose: Anaemia of chronic disease is characterized by impaired erythropoiesis due to functional iron deficiency, often caused by excessive hepcidin. Lexaptepid pegol, a pegylated structured l-oligoribonucleotide, binds and inactivates hepcidin., Experimental Approach: We conducted a placebo-controlled study on the safety, pharmacokinetics and pharmacodynamics of lexaptepid after single and repeated i.v. and s.c. administration to 64 healthy subjects at doses from 0.3 to 4.8 mg·kg(-1) ., Key Results: After treatment with lexaptepid, serum iron concentration and transferrin increased dose-dependently. Iron increased from approximately 20 μmol·L(-1) at baseline by 67% at 8 h after i.v. infusion of 1.2 mg·kg(-1) lexaptepid. The pharmacokinetics showed dose-proportional increases in peak plasma concentrations and moderately over-proportional increases in systemic exposure. Lexaptepid had no effect on hepcidin production or anti-drug antibodies. Treatment with lexaptepid was generally safe and well tolerated, with mild and transient transaminase increases at doses ≥2.4 mg·kg(-1) and with local injection site reactions after s.c. but not after i.v. administration., Conclusions and Implications: Lexaptepid pegol inhibited hepcidin and dose-dependently raised serum iron and transferrin saturation. The compound is being further developed to treat anaemia of chronic disease., (© 2016 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Purpose: Several prognostic indices (PI) have been developed to stratify patients with brain metastases in groups with good or bad prognosis. The aim of our study was to compare nine prognostic scores for patients with brain metastases (BM) of breast cancer receiving radiotherapy., Methods: The clinical data of 139 breast cancer patients with BM were collected retrospectively. All patients were treated with cerebral radiotherapy or surgery followed by radiotherapy between January 2007 and December 2012. The prognostic value and accuracy of recursive partitioning analysis (RPA), RPA II, graded prognostic assessment (GPA), basic score for BM, Breast-RPA, Breast-GPA, Rades Score 2011, Germany Score and Breast Rades Score were assessed., Results: The median survival after BM diagnosis in our cohort was 14 months. The overall 6-month, 1-, 2- and 3-year survival rates were 49.6, 37.4, 20.9 and 13.7 %, respectively. Most of the PI were associated with OS, but univariate analysis favored GPA regarding OS. GPA was the most accurate score to identify patients with long (longer than 12 months) and Breast-GPA patients with short (<3 months) life expectancy., Conclusions: GPA and Breast-GPA seem to be the most useful scores and perform better than other PI for breast cancer patients with BM receiving radiotherapy.

Increased hepcidin production is key to the development of anemia of inflammation. We investigated whether lexaptepid, an antihepcidin l-oligoribonucleotide, prevents the decrease in serum iron during experimental human endotoxemia. This randomized, double-blind, placebo-controlled trial was carried out in 24 healthy males. At T = 0 hours, 2 ng/kg Escherichia coli lipopolysaccharide was intravenously administered, followed by an intravenous injection of 1.2 mg/kg lexaptepid or placebo at T = 0.5 hours. The lipopolysaccharide-induced inflammatory response was similar in subjects treated with lexaptepid or placebo regarding clinical and biochemical parameters. At T = 9 hours, serum iron had increased by 15.9 ± 9.8 µmol/L from baseline in lexaptepid-treated subjects compared with a decrease of 8.3 ± 9.0 µmol/L in controls (P < .0001). This study delivers proof of concept that lexaptepid achieves clinically relevant hepcidin inhibition enabling investigations in the treatment of anemia of inflammation. This trial was registered at www.clinicaltrial.gov as #NCT01522794., (© 2014 by The American Society of Hematology.)

2,3,7,8-Tetrachloro-dibenzo-p-dioxin (TCDD) is an ubiquitously distributed xenobiotic. It has been postulated that the effects of TCDD on T-lymphocytes are mediated by modulation of the thymic microenvironment. There is growing evidence of a modified interplay between thymocytes and thymic epithelium related to changes in extracellular matrix (ECM) proteins. Eighteen male marmosets (Callithrix jacchus) were treated with single subcutaneous TCDD doses (1, 10, 100 ng/kg body weight) or vehicle and sacrificed 2 or 4 weeks thereafter. Thymus samples were stained with fluorescein isothiocyanate-conjugated antibodies for ECM proteins and examined immunohistochemically by semi-quantitative image analysis. Thymus samples of animals treated with 1 and 10 ng/kg were additionally analysed by Western blotting for ECM proteins, transforming growth factor-beta(1) (TGF-beta(1)) and integrin chain content (CD49a, CD49e, CD49f and CD29). Monkeys showed no overt signs of toxicity after TCDD treatment. Immunohistochemistry revealed an increase of ECM proteins at 100 ng/kg after 2 and 4 weeks. Western blotting confirmed immunohistochemistry showing a dose-dependent increase of several ECM proteins in animals treated with the lower TCDD doses of 1 and 10 ng/kg. Additionally, dose-dependent increases were observed in integrin chain and TGF-beta(1) contents. We demonstrated changes of thymic ECM in marmosets following low single TCDD doses. Combined with altered integrin expression and enhanced TGF-beta(1) stimulation our findings suggest a modified interplay between thymic epithelium and thymocytes. The extracellular matrix may play a more central role in mediating adverse effects of TCDD in organs than yet acknowledged.

We studied the sensitising and allergenic potentials of the textile dyes disperse yellow 3, disperse orange 30, disperse red 82, disperse yellow 211 and two metabolites of disperse yellow 3, 4-aminoacetanilide and 2-amino-p-cresol, using modified protocols of the murine "local lymph node assay" (LLNA). Test substances were applied either to the dorsum of the mice ears (sensitisation protocol) or they were first applied to the skin of their backs and 2 weeks later to their ears (sensitisation-challenge protocol). In addition to the endpoints weight and cell number of the draining ear lymph nodes we analysed lymphocyte subpopulations by flow cytometry. In the sensitisation protocol, disperse yellow 3 and its metabolite 4-aminoacetanilide did not induce significant effects, whereas in the sensitisation-challenge protocol cell number and lymph node weight increased significantly indicating a sensitising potential in NMRI mice. Hence, two-phase treatment (skin of the back, ear) increased the sensitivity of this assay. The second metabolite of disperse yellow 3, 2-amino-p-cresol, showed distinct effects in both treatment protocols; this applied mainly to the parameters cell number and lymph node weight. The dye disperse red 82 caused ambiguous increases in lymph node weight and cell number in the sensitisation protocol which were not reproduced in the sensitisation-challenge protocol, ruling out a relevant sensitising potential for this dye in NMRI mice. Disperse yellow 211 and disperse orange 30 did not induce relevant changes under our experimental conditions. Phenotyping of lymphocytes did not influence the assessment of these dyes.

The original local lymph node assay (LLNA) is based on the use of radioactive labelling to measure cell proliferation. Other endpoints for the assessment of proliferation are also authorized by the OECD Guideline 429 provided there is appropriate scientific support, including full citations and description of the methodology (OECD, 2002. OECD Guideline for the Testing of Chemicals; Skin Sensitization: Local Lymph Node Assay, Guideline 429. Paris, adopted 24th April 2002.). Here, we describe the outcome of the second round of an inter-laboratory validation of alternative endpoints in the LLNA conducted in nine laboratories in Europe. The validation study was managed and supervised by the Swiss Agency for Therapeutic Products (Swissmedic) in Bern. Ear-draining lymph node (LN) weight and cell counts were used to assess LN cell proliferation instead of [3H]TdR incorporation. In addition, the acute inflammatory skin reaction was measured by ear weight determination of circular biopsies of the ears to identify skin irritation properties of the test items. The statistical analysis was performed in the department of statistics at the university of Bern. Similar to the EC(3) values defined for the radioactive method, threshold values were calculated for the endpoints measured in this modification of the LLNA. It was concluded that all parameters measured have to be taken into consideration for the categorisation of compounds due to their sensitising potencies. Therefore, an assessment scheme has been developed which turned out to be of great importance to consistently assess sensitisation versus irritancy based on the data of the different parameters. In contrast to the radioactive method, irritants have been picked up by all the laboratories applying this assessment scheme.

The new OECD guideline 429 (skin sensitization: local lymph node assay) is based upon a protocol, which utilises the incorporation of radioactivity into DNA as a measure for cell proliferation in vivo. The guideline also enables the use of alternative endpoints in order to assess draining lymph node (LN) cell proliferation. Here we describe the first round of an inter-laboratory validation of alternative endpoints in the LLNA conducted in seven laboratories. The validation study was managed and supervised by the Swiss Agency for Therapeutic Products, Swissmedic. Statistical analyses of all data were performed by an independent centre at the University of Bern, Department of Statistics. Ear-draining, LN weight and cell count were used to assess proliferation instead of radioactive labeling of lymph node cells. In addition, the acute inflammatory skin reaction was measured by ear swelling and weight of circular biopsies of the ears to identify skin irritating properties of the test items. Hexylcinnamaldehyde (HCA) and three blinded test items were applied to female, 8--10 weeks old NMRI and BALB/c mice. Results were sent via the independent study coordinator to the statistician. The results of this first round showed that the alternative endpoints of the LLNA are sensitive and robust parameters. The use of ear weights added an important parameter assessing the skin irritation potential, which supports the differentiation of pure irritative from contact allergenic potential. There were absolute no discrepancies between the categorisation of the three test substances A--C determined by each single participating laboratories. The results highlighted also that many parameters do have an impact on the strength of the responses. Therefore, such parameters have to be taken into consideration for the categorisation of compounds due to their relative sensitizing potencies.

2,3,7,8-Tetrachloro-dibenzo- p-dioxin (TCDD) is a ubiquitously distributed xenobiotic. The adverse effects of TCDD on the mammalian immune system have been studied for decades, but it is still unclear whether TCDD has direct effects on T-lymphocytes or whether it acts via the thymic microenvironment. We have studied the effects of TCDD on primary cultures of human thymic epithelial cells (TEC) focusing on differentiation markers, integrins and adhesion molecules involved in cell-cell and in cell-matrix interactions. TEC were treated with TCDD at concentrations of 0.001, 0.01, 0.1, 1.0 or 10.0 nM or with 100 nM PCB 126 (3,3',4,4',5-pentachlorobiphenyl) for 3 days, and were then analysed by flow cytometry for expression of surface antigens using monoclonal antibodies against Hassall's bodies (TE-8, TE-16) or against surface structures such as CD29, CD49b, CD49e, CD49f, CD51, CD54, CD58, CD61 and CD106. At TCDD concentrations as low as 0.01 nM we found a significant increase in terminally differentiated, TE-16-positive TEC; at a ten-fold greater concentration the number of cells marked with the TE-8 antibody was also increased. With both markers the most pronounced effect (approximately +15%) was observed at 1 nM TCDD. An increase of cells expressing the integrin alpha-chains CD49b, CD49e and CD51 as well as CD54 was observed at concentrations of 0.1 nM TCDD or higher. The proportion of cells expressing CD106 or CD49f decreased significantly upon treatment with TCDD. No effects on the integrin beta-chains CD29 and CD61 could be detected. Overall, PCB 126 induced similar changes to TCDD. In summary, TCDD and a coplanar PCB induced terminal differentiation of human TEC along with changes of integrins and other adhesion molecules. These receptors and their interplay with the extracellular matrix have key functions in the maturation of T-lymphocytes and it is plausible that their alteration would be involved in TCDD-induced immunotoxicity.

Single high oral doses of fluoroquinolones (e.g., 1,200 mg of ofloxacin/kg of body weight) are chondrotoxic in juvenile rats. Characteristic cartilage lesions are detectable as early as 12 h after treatment. Since this dosing regimen does not reflect the therapeutic situation, we studied the effects of a 5- or 7-day treatment with ofloxacin at lower oral doses (10, 30, and 100 mg/kg twice a day [b.i.d.]) on joint cartilage in 4-week-old rats. We additionally investigated whether the effects of ofloxacin under these conditions are enhanced in animals kept on a magnesium-deficient diet during treatment. Knee joints were examined histologically. The concentrations of ofloxacin and magnesium were determined in plasma and cartilage. The lowest ofloxacin dose at which cartilage lesions occurred in animals on a standard diet was 100 mg/kg b.i.d. for 5 days. Peak plasma ofloxacin levels were approximately 10 mg/liter in these rats and thus were in the same range as the levels in the plasma of humans during therapy with high doses of ofloxacin. Treatment with 30 mg of ofloxacin/kg b.i.d. for 7 days caused no cartilage lesions in rats on a standard diet, but lesions did occur in 10 of 12 rats that were simultaneously fed a magnesium-deficient diet. Magnesium concentrations in bone, plasma, and cartilage from animals on an Mg(2+)-deficient diet were significantly lower than those in the controls. The concentration in plasma from animals on an Mg(2+)-deficient diet was 0.27 +/- 0.03 mmol/liter, whereas it was 0.88 +/- 0.08 mmol/liter in plasma from rats on a standard diet (means +/- standard deviations). Ofloxacin treatment did not change the total magnesium concentrations in tissues, as determined with ashed samples. The incidence of ofloxacin-induced lesions was higher in the magnesium-deficient animals, suggesting a synergistic effect. These results must be taken into account for a benefit-risk evaluation if ofloxacin is considered for use in the pediatric population.

Epidemiological studies have suggested an association between exposure to dioxins and cardiovascular morbidity and mortality. However, cardiotoxic effects of low doses of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) in animals have not been reported so far. We studied the hearts of male marmosets ( Callithrix jacchus)after treatment with single subcutaneous doses of 1, 10 or 100 ng TCDD/kg body weight or vehicle (toluene/DMSO 1+2 v/v, 100 microl/kg body weight). The animals were killed 2 or 4 weeks after treatment. Tissue samples of left ventricular myocardium were stained with picrosirius red and examined histologically along with quantitative image analysis. Extracellular matrix proteins were additionally analysed by western blotting. Monkeys showed no overt signs of toxicity nor did their relative heart weights differ significantly depending on treatment. Histology revealed an increase of picrosirius red-positive area above control values in 2 of 4 (1 ng TCDD/kg body weight), 6 of 12 (10 ng/kg) and 6 of 10 (100 ng/kg) marmosets. Western blotting confirmed these histological findings showing an increase of collagen, fibronectin and laminin in the hearts of TCDD-treated animals. Western blotting additionally showed an increased concentration of transforming growth factor beta1 (TGF-beta1) as well as TGF-beta receptor type I which could be a functional link to the effects on extracellular matrix. Our findings might explain the association of TCDD exposure with increased cardiovascular mortality observed in epidemiological studies and should stimulate further research on the role of changes in the extracellular matrix in the toxic effects of dioxins and related substances on other organs.

Background: Indinavir is an antiviral agent used for the treatment of HIV infection. We studied its developmental toxicity in rats., Methods: Pregnant animals were treated orally with 500 mg indinavir/kg body weight (bw) from day 6 to 15 of gestation (once daily) or from day 9 to 11 (twice daily). Fetuses were evaluated for external and skeletal anomalies on day 21 of gestation. In addition, 19 rats were treated from day 9 of gestation to day 24 postnatally with 500 mg indinavir/kg bw once daily; a control group of 17 rats was treated with the vehicle accordingly. Developmental landmarks were recorded. Sixteen offspring each were studied on postnatal days 7, 14, 21, and 35 for hepatic enzyme activity. Liver tissue was examined by electron microscopy., Results: Fetal examination on day 21 of pregnancy showed no treatment-related effects on number, weight, and viability of the fetuses; however, an increased incidence was noted in the supernumerary ribs and variations of the vertebral ossification centers in both indinavir-treated groups. Postnatal evaluation showed delayed fur development, eye opening, and descensus testis. The most striking finding was unilateral anophthalmia, observed in 7 pups (3%) from 2 out of 19 litters exposed to indinavir, but not in controls. Only minor changes in hepatic monooxygenase activities occurred in dams. Electron microscopy of liver samples showed hepatocellular inclusions of lipids and myelin figure-like structures in maternal livers and infiltration with granulocytes in offspring livers., Conclusions: Further studies on reproductive toxicity, including combinations of three or more antiretroviral agents as used therapeutically, are needed to determine the hazards of such a treatment., (Copyright 2000 Wiley-Liss, Inc.)

Callithrix jacchus, the common marmoset, is particularly suitable for immunological studies in vivo and in vitro since many antibodies directed against epitopes of human cells do also react with their analogues from this non-human primate. We studied the reactivity of antibodies against human epitopes on primary cultures of thymic epithelial cells from marmosets and humans by flow-cytometry after different culture periods. The antibodies against integrins, including CD61, reacted with thymic epithelial cells from both humans and marmosets, as did anti-CD44 and anti-CD106. Antibodies specific for thymic epithelial cells (TE-3, TE-4, TE-8, TE-15, TE-16, TE-19) also bound to cells from marmosets but expression of all epitopes was not observed in all cultures studied. The expression of CD51, CD54, CD58 and CD106 on human cells declined after 4 weeks of culture. Our findings indicate that marmosets are a valuable model for immunological studies of effects of xenobiotics on the thymic epithelium.

Experience with drugs and other xenobiotics indicates that both animal testing and epidemiological studies are necessary to provide adequate data for an estimation of risks that might be associated with exposure to a chemical substance. In this review, the pros and cons of test systems for reproductive toxicity are discussed. Usually, several studies are performed to cover the different phases of the reproductive cycle. In the preclinical development of drugs, the three so-called 'segment testing protocols' have been used for several decades now. More recently, new testing concepts have been accepted internationally which include more flexibility in implementation. Several examples of compounds with the potential for reproductive toxicity are presented in more detail in a discussion of some pitfalls of the tests for fertility (phthalates and fluoroquinolones), teratogenicity (acyclovir and protease inhibitors) and postnatal developmental toxicity (fluoroquinolones). In addition, important aspects of kinetics and metabolism as a prerequisite for a rational interpretation of results from toxicological studies are briefly discussed. In vitro assays are useful for supplementing the routinely used in vivo approaches or for studying an expected or defined effect, but they are not suitable for revealing an unknown effect of a chemical on the complex reproductive process.