Search

Abstract In 70 patients with KIT D816V positive systemic mastocytosis (SM) including 36 patients with advanced SM (AdvSM), we correlated the extent of reported mucosal mast cell ([m]MC) infiltration of the upper and/or lower gastrointestinal tract (UGIT, n = 63; LGIT, n = 64; both, n = 57) with symptoms and markers of MC burden/subtype. GI symptoms were reported by all patients (mean 2.1 number of symptoms). A strong mMC infiltration was identified in 24 patients (UGIT, 17/63, 27%; LGIT, 19/64, 30%). Concurrent involvement of UGIT and LGIT (n = 12) correlated with female gender (75%) and a higher symptom burden (mean 2.7) but not with MC burden or subtype. Significant differences between non-AdvSM and AdvSM were reported regarding food intolerance (54% vs. 17%), cramping (54% vs. 22%) and weight loss (0% vs. 64%). KIT D816V was identified in 54/56 (96%) available biopsies. In 46 patients, digital PCR revealed a correlation with low albumin levels (r = − 0.270, P = 0.069) and the KIT D816V VAF in peripheral blood (r = 0.317, P = 0.036) but not with the extent of mMC infiltration or markers of MC burden/subtype. Although MC mediator triggered GI symptoms have a substantial impact on the quality of life, correlation to objective disease parameters is lacking thus making its systematic assessment challenging.

Abstract Biomarkers to identify metastatic breast cancer (mBC) patients resistant to CDK4/6 inhibition (CDK4/6i) are currently missing. We evaluated the usefulness of the monocyte-to-lymphocyte ratio (MLR), the neutrophil–to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) as predictive markers for de novo resistance to CDK4/6i. Various blood cell counts and MLR, NLR, PLR were recorded before treatment initiation (baseline) and four weeks later from 97 mBC patients receiving endocrine therapy (ET) alone or in combination with CDK4/6i. Binary blood cell count/ratios (mean = cut-off) were related to outcome using Cox regression. High MLR (p = 0.001) and high NLR (p = 0.01) at baseline significantly correlated with a shorter progression-free survival (PFS) in the CDK4/6i cohort, independent of any other clinical parameter as determined by multivariate Cox regression. Both, high MLR (p = 0.008) and high NLR (p = 0.043) as well as a decrease in PLR after four weeks of CDK4/6i first line treatment (p = 0.01) indicated a shorter overall survival. Moreover, decreasing PLR (p = 0.043) and increasing mean corpuscular volume (MCV; p = 0.011) within the first cycle of CDK4/6i correlated with a shorter PFS and decreasing MLR (p = 0.039) within the first cycle of first-line CDK4/6i was also correlated with shorter PFS. In summary, easily assessable blood cell parameter were shown to have predictive, monitoring and prognostic value and thus, could, in future, be used for individualized CDK4/6i therapy management. Most importantly, the imbalance of NLR and MLR at baseline might serve as predictive marker for de novo resistance to CDK4/6i in mBC patients.

Abstract Background Efficacy and quality of life (QoL) are key criteria for therapy selection in metastatic breast cancer (MBC). In hormone receptor positive (HR +) human epidermal growth factor receptor 2 negative (HER2 −) MBC, addition of targeted oral agents such as everolimus or a cycline-dependent kinase 4/6 (CDK 4/6) inhibitor (e.g., palbociclib, ribociclib, abemaciclib) to endocrine therapy substantially prolongs progression-free survival and in the case of a CDK 4/6i also overall survival. However, the prerequisite is adherence to therapy over the entire course of treatment. However, particularly with new oral drugs, adherence presents a challenge to disease management. In this context, factors influencing adherence include maintaining patients’ satisfaction and early detection/management of side effects. New strategies for continuous support of oncological patients are needed. An eHealth-based platform can help to support therapy management and physician–patient interaction. Methods PreCycle is a multicenter, randomized, phase IV trial in HR + HER2 − MBC. All patients (n = 960) receive the CDK 4/6 inhibitor palbociclib either in first (62.5%) or later line (37.5%) together with endocrine therapy (AI, fulvestrant) according to national guidelines. PreCycle evaluates and compares the time to deterioration (TTD) of QoL in patients supported by eHealth systems with substantially different functionality: CANKADO active vs. inform. CANKADO active is the fully functional CANKADO-based eHealth treatment support system. CANKADO inform is a CANKADO-based eHealth service with a personal login, documentation of daily drug intake, but no further functions. To evaluate QoL, the FACT-B questionnaire is completed at every visit. As little is known about relationships between behavior (e.g., adherence), genetic background, and drug efficacy, the trial includes both patient-reported outcome and biomarker screening for discovery of forecast models for adherence, symptoms, QoL, progression free survival (PFS), and overall survival (OS). Discussion The primary objective of PreCycle is to test the hypothesis of superiority for time to deterioration (TTD) in terms of DQoL = “Deterioration of quality of life” (FACT-G scale) in patients supported by an eHealth therapy management system (CANKADO active) versus in patients merely receiving eHealth-based information (CANKADO inform). EudraCT Number: 2016–004191-22

IntroductionTriple negative breast cancer (TNBC) shows an aggressive growing and spreading behavior and has limited treatment options, often leading to inferior disease outcome. Therefore, surrogate markers are urgently needed to identify patients at high risk of recurrence and more importantly, to identify additional therapeutic targets enabling further treatment options. Based on the key role of the non-classical human leukocyte antigen G (HLA-G) and its related receptor immunoglobulin-like transcript receptor-2 (ILT-2) in immune evasion mechanisms of tumors, members of this ligand-receptor axis appear to be promising tool for both, defining risk groups and potential therapeutic targets.Materials and methodsTo follow this, sHLA-G levels before and after chemotherapy (CT), HLA-G 3’ UTR haplotypes, and allele variations rs10416697 at the distal gene promoter region of ILT-2 were defined in healthy female controls and early TNBC patients. The results obtained were associated with clinical status, presence of circulating tumor cell (CTC) subtypes, and disease outcome of patients in terms of progression-free or overall survival.ResultssHLA-G plasma levels were increased in TNBC patients post-CT compared to levels of patients pre-CT or controls. High post-CT sHLA-G levels were associated with the development of distant metastases, the presence of ERCC1 or PIK3CA-CTC subtypes post-CT, and poorer disease outcome in uni- or multivariate analysis. HLA-G 3’ UTR genotypes did not influence disease outcome but ILT-2 rs10416697C allele was associated with AURKA-positive CTC and with adverse disease outcome by uni- and multivariate analysis. The prognostic value of the combined risk factors (high sHLA-G levels post-CT and ILT-2 rs10416697C allele carrier status) was an even better independent indicator for disease outcome in TNBC than the lymph nodal status pre-CT. This combination allowed the identification of patients with high risk of early progression/death with positive nodal status pre-CT or with non-pathological complete therapy responseConclusionThe results of this study highlight for the first time that the combination of high levels of sHLA-G post-CT with ILT-2 rs10416697C allele receptor status is a promising tool for the risk assessment of TNBC patients and support the concept to use HLA-G/ILT-2 ligand-receptor axis as therapeutic targets.

Abstract Background The free-breathing T1-weighted 3D Stack of Stars GRE (StarVIBE) MR sequence potentially reduces artifacts in chest MRI. The purpose of this study was to evaluate StarVIBE for the detection of pulmonary nodules in 18F-FDG PET/MRI. Material and methods In this retrospective analysis, conducted on a prospective clinical trial cohort, 88 consecutive women with newly diagnosed breast cancer underwent both contrast-enhanced whole-body 18F-FDG PET/MRI and computed tomography (CT). Patients’ chests were examined on CT as well as on StarVIBE and conventional T1-weighted VIBE and T2-weighted HASTE MR sequences, with CT serving as the reference standard. Presence, size, and location of all detectable lung nodules were assessed. Wilcoxon test was applied to compare nodule features and Pearson’s, and Spearman’s correlation coefficients were calculated. Results Out of 65 lung nodules detected in 36 patients with CT (3.7 ± 1.4 mm), StarVIBE was able to detect 31 (47.7%), VIBE 26 (40%) and HASTE 11 (16.8%), respectively. Overall, CT showed a significantly higher detectability than all MRI sequences combined (65 vs. 36, difference 44.6%, p

Aim: The multicentre non-interventional AVANTI study assessed safety, effectiveness and patient-reported outcomes with approved first-line bevacizumab-containing regimens for HER2-negative locally recurrent/metastatic breast cancer (LR/MBC) in German routine oncology practice. Methods: Eligible patients had HER2-negative LR/MBC, no bevacizumab contraindications and no prior chemotherapy for LR/MBC. Chemotherapy schedule, diagnostics and follow-up were at physicians’ discretion. Data were collected for 1 year after starting bevacizumab, then every 6 months for 1.5 years (maximum follow-up: 2.5 years). Patients and physicians rated treatment satisfaction. Subgroup analyses were prespecified in clinically relevant populations, including triple-negative breast cancer (TNBC). Results: Between November 1, 2009 and April 30, 2016, 2065 eligible patients at 346 centres received bevacizumab with paclitaxel or capecitabine. Patients receiving bevacizumab–capecitabine were less likely to have de novo disease and more likely to have TNBC, age ≥60 years and prior anthracycline/taxane and/or endocrine therapy. Median PFS was 12.6 (95% CI 11.9–13.2) months (12.8 with bevacizumab–paclitaxel, 10.5 with bevacizumab–capecitabine); median OS was 23.9 (95% CI 22.2–25.1) months. Outcomes were worse in patients with TNBC, prior anthracycline/taxane or prior endocrine therapy. Grade ≥3 adverse events occurred in 27% of patients. Treatment was discontinued for adverse events in 15%. Treatment satisfaction was rated as good or better by 304/394 responding patients (77%) at week 54 and in 1393/2065 patients (67%) by physicians overall. Conclusions: In routine clinical practice, effectiveness and safety of first-line bevacizumab-containing therapy for LR/MBC were consistent with experience from phase III trials. Patient and physician treatment satisfaction showed high concordance.

Abstract Background Single liquid biopsy analytes (LBAs) have been utilized for therapy selection in metastatic breast cancer (MBC). We performed integrative statistical analyses to examine the clinical relevance of using multiple LBAs: matched circulating tumor cell (CTC) mRNA, CTC genomic DNA (gDNA), extracellular vesicle (EV) mRNA, and cell-free DNA (cfDNA). Methods Blood was drawn from 26 hormone receptor-positive, HER2-negative MBC patients. CTC mRNA and EV mRNA were analyzed using a multi-marker qPCR. Plasma from CTC-depleted blood was utilized for cfDNA isolation. gDNA from CTCs was isolated from mRNA-depleted CTC lysates. CTC gDNA and cfDNA were analyzed by targeted sequencing. Hierarchical clustering was performed within each analyte, and its results were combined into a score termed Evaluation of multiple Liquid biopsy analytes In Metastatic breast cancer patients All from one blood sample (ELIMA.score), which calculates the contribution of each analyte to the overall survival prediction. Singular value decomposition (SVD), mutual information calculation, k-means clustering, and graph-theoretic analysis were conducted to elucidate the dependence between individual analytes. Results A combination of two/three/four LBAs increased the prevalence of patients with actionable signals. Aggregating the results of hierarchical clustering of individual LBAs into the ELIMA.score resulted in a highly significant correlation with overall survival, thereby bolstering evidence for the additive value of using multiple LBAs. Computation of mutual information indicated that none of the LBAs is independent of the others, but the ability of a single LBA to describe the others is rather limited—only CTC gDNA could partially describe the other three LBAs. SVD revealed that the strongest singular vectors originate from all four LBAs, but a majority originated from CTC gDNA. After k-means clustering of patients based on parameters of all four LBAs, the graph-theoretic analysis revealed CTC ERBB2 variants only in patients belonging to one particular cluster. Conclusions The additional benefits of using all four LBAs were objectively demonstrated in this pilot study, which also indicated a relative dominance of CTC gDNA over the other LBAs. Consequently, a multi-parametric liquid biopsy approach deconvolutes the genomic and transcriptomic complexity and should be considered in clinical practice.

IntroductionChemotherapy-induced polyneuropathy (CIPN) and post-chemotherapy cognitive impairment (PCCI) are frequent side effects of paclitaxel treatment. CIPN/PCCI are potentially irreversible, reduce quality of life and often lead to treatment limitations, which affect patients’ outcome. We previously demonstrated that paclitaxel enhances an interaction of the Neuronal calcium sensor-1 protein (NCS-1) with the Inositol-1,4,5-trisphosphate receptor (InsP3R), which disrupts calcium homeostasis and triggers neuronal cell death via the calcium-dependent protease calpain in dorsal root ganglia neurons and neuronal precursor cells. Prophylactic treatment of rodents with lithium inhibits the NCS1-InsP3R interaction and ameliorates paclitaxel-induced polyneuropathy and cognitive impairment, which is in part supported by limited retrospective clinical data in patients treated with lithium carbonate at the time of chemotherapy. Currently no data are available from a prospective clinical trial to demonstrate its efficacy.Methods and analysisThe PREPARE study will be conducted as a multicenter, randomized, double-blind, placebo-controlled phase-2 trial with parallel group design. N = 84 patients with breast cancer will be randomized 1:1 to either lithium carbonate treatment (targeted serum concentration 0.5–0.8 mmol/l) or placebo with sham dose adjustments as add-on to (nab-) paclitaxel. The primary endpoint is the validated Total Neuropathy Score reduced (TNSr) at 2 weeks after the last (nab-) paclitaxel infusion. The aim is to show that the lithium carbonate group is superior to the placebo group, meaning that the mean TNSr after (nab-) paclitaxel is lower in the lithium carbonate group than in the placebo group. Secondary endpoints include: (1) severity of CIPN, (2) amount and dose of pain medication, (3) cumulative dose of (nab-) paclitaxel, (4) patient-reported symptoms of CIPN, quality of life and symptoms of anxiety and depression, (5) severity of cognitive impairment, (6) hippocampal volume and changes in structural/functional connectivity and (7) serum Neurofilament light chain protein concentrations.Ethics and disseminationThe study protocol was approved by the Berlin ethics committee (reference: 21/232 – IV E 10) and the respective federal agency (Bundesinstitut für Arzneimittel und Medizinprodukte, reference: 61-3910-4044771). The results of the study will be published in peer-reviewed medical journals as well as presented at relevant (inter)national conferences.Clinical trial registration[https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00027165], identifier [DRKS00027165].

Despite major improvements in diagnostics and therapy in early as well as in locally advanced breast cancer (LABC), metastatic relapse occurs in about 20% of patients, often explained by early micro-metastatic spread into bone marrow by disseminated tumor cells (DTC). Although neoadjuvant chemotherapy (NACT) has been a successful tool to improve overall survival (OS), there is growing evidence that various environmental factors like the non-classical human leukocyte antigen-G (HLA-G) promotes cancer invasiveness and metastatic progression. HLA-G expression is associated with regulatory elements targeting certain single-nucleotide polymorphisms (SNP) in the HLA-G 3’ untranslated region (UTR), which arrange as haplotypes. Here, we systematically evaluated the impact of HLA-G 3’UTR polymorphisms on disease status, on the presence of DTC, on soluble HLA-G levels, and on therapy and disease outcome in non-metastatic LABC patients. Although haplotype frequencies were similar in patients (n = 142) and controls (n = 204), univariate analysis revealed that the UTR-7 haplotype was related to patients with low tumor burden, whereas UTR-4 was associated with tumor sizes >T1. Furthermore, UTR-4 was associated with the presence of DTC, but UTR-3 and UTR-7 were related to absence of DTC. Additionally, increased levels of soluble HLA-G molecules were found in patients carrying UTR-7. Regarding therapy and disease outcome, univariate and multivariate analysis highlighted UTR-1 or UTR-2 as a prognostic parameter indicative for a beneficial course of disease in terms of complete response towards NACT or progression-free survival (PFS). At variance, UTR-4 was an independent risk factor for a reduced OS besides already known parameters. Taken into account the most common HLA-G 3’UTR haplotypes (UTR-1–UTR-7, UTR-18), deduction of the UTR-1/2/4 haplotypes to specific SNPs revealed that the +3003C variant, unique for UTR-4, seemed to favor a detrimental disease outcome, while the +3187G and +3196G variants, unique for UTR-1 or UTR-2, were prognostic parameters for a beneficial course of disease. In conclusion, these data suggest that the HLA-G 3’UTR variants +3003C, +3187G, and +3196G are promising candidates for the prediction of therapy and disease outcome in LABC patients.

ObjectivesTo compare the diagnostic accuracy of contrast-enhanced thoraco-abdominal computed tomography and whole-body 18F-FDG PET/MRI in N and M staging in newly diagnosed, histopathological proven breast cancer.Material and methodsA total of 80 consecutive women with newly diagnosed and histopathologically confirmed breast cancer were enrolled in this prospective study. Following inclusion criteria had to be fulfilled: (1) newly diagnosed, treatment-naive T2-tumor or higher T-stage or (2) newly diagnosed, treatment-naive triple-negative tumor of every size or (3) newly diagnosed, treatment-naive tumor with molecular high risk (T1c, Ki67 >14%, HER2neu over-expression, G3). All patients underwent a thoraco-abdominal ceCT and a whole-body 18F-FDG PET/MRI. All datasets were evaluated by two experienced radiologists in hybrid imaging regarding suspect lesion count, localization, categorization and diagnostic confidence. Images were interpreted in random order with a reading gap of at least 4 weeks to avoid recognition bias. Histopathological results as well as follow-up imaging served as reference standard. Differences in staging accuracy were assessed using Mc Nemars chi2 test.ResultsCT rated the N stage correctly in 64 of 80 (80%, 95% CI:70.0-87.3) patients with a sensitivity of 61.5% (CI:45.9-75.1), a specificity of 97.6% (CI:87.4-99.6), a PPV of 96% (CI:80.5-99.3), and a NPV of 72.7% (CI:59.8-82.7). Compared to this, 18F-FDG PET/MRI determined the N stage correctly in 71 of 80 (88.75%, CI:80.0-94.0) patients with a sensitivity of 82.1% (CI:67.3-91.0), a specificity of 95.1% (CI:83.9-98.7), a PPV of 94.1% (CI:80.9-98.4) and a NPV of 84.8% (CI:71.8-92.4). Differences in sensitivities were statistically significant (difference 20.6%, CI:-0.02-40.9; p = 0.008). Distant metastases were present in 7/80 patients (8.75%). 18 F-FDG PET/MRI detected all of the histopathological proven metastases without any false-positive findings, while 3 patients with bone metastases were missed in CT (sensitivity 57.1%, specificity 95.9%). Additionally, CT presented false-positive findings in 3 patients.Conclusion18F-FDG PET/MRI has a high diagnostic potential and outperforms CT in assessing the N and M stage in patients with primary breast cancer.

Background: We analyzed mRNA profiles of prostate cancer related genes in circulating tumor cells (CTCs) of primary, non-metastatic triple-negative breast cancer (TNBC) patients (pts) before and after neoadjuvant chemotherapy to elucidate the potential of prostate cancer targets in this BC subgroup.Method: Blood from 41 TNBC pts (n = 41 before / 26 after therapy) was analyzed for CTCs applying the AdnaTest EMT-2/Stem Cell Select. Multimarker RT-qPCR allowed the detection of the prostate specific antigen PSA, the prostate specific membrane antigen PSMA, full-length androgen receptor (AR-FL), and AR splice-variant seven (AR-V7).Results: Before therapy, at least one prostate cancer related gene was detected in 15/41 pts (37%). Notably, in 73% of AR-FL positive cases, AR-V7 was co-expressed. After therapy, CTCs of only one patient harbored prostate cancer related genes. AR-V7+ and PSMA+ CTCs significantly correlated with early relapse (p = 0.041; p = 0.00039) whereas PSMA+ CTCs also associated with a reduced OS (p = 0.0059). This correlation was confirmed for PSMA+ CTCs in univariate (PFS p = 0.002; OS p = 0.015), but not multivariate analysis.Conclusion: Although CTCs that expressed prostate cancer related genes were eliminated by the given therapy, PSMA+ CTCs significantly identified pts at high risk for relapse. Furthermore, AR inhibition, often discussed for this BC subgroup, might not be successful in the primary setting of the disease since we identified AR-FL+ CTCs together with AR-V7+ CTCs, associated with therapeutic failure.

Abstract Background Tumor-infiltrating lymphocytes (TILs) are described as an important immune modulator in the tumor microenvironment and are associated with breast cancer (BC) outcome. The spatial analysis of TILs and TIL subtype distribution at the invasive tumor front (ITF) and the tumor center (TC) might provide further insights into tumor progression. Methods We analyzed core biopsies from 87 pre-therapeutic BC patients for total TILs and the following subtypes: CD3+, CD4+, CD8+, CD20+ and CD68+ cells in correlation to clinicopathological parameters and disseminated tumor cells (DTCs) in the bone marrow. Results TILs and TIL subtypes showed significantly different spatial distribution among both tumor areas. TILs, especially CD3+ T cells were associated with the tumor status and tumor grading. BC patients responding to neoadjuvant chemotherapy had significantly more TILs and CD3+ T cells at the TC. The presence of DTCs after NACT was related to CD4+ infiltration at the TC. Conclusion The dissimilar spatial association of TILs and TIL subtypes with clinicopathological parameters, NACT response and minimal residual disease underlines the necessity of detailed TIL analysis for a better understanding of immune modulatory processes.

Background: The chemokine receptor CXCR4 and the transcription factor JUNB, expressed on a variety of tumor cells, seem to play an important role in the metastatic process. Since disseminated tumor cells (DTCs) in the bone marrow (BM) have been associated with worse outcomes, we evaluated the expression of CXCR4 and JUNB in DTCs of primary, nonmetastatic breast cancer (BC) patients before the onset of any systemic treatment. Methods: Bilateral BM (10 ml) aspirations of 39 hormone receptor (HR)-positive, HER2-negative BC patients were assessed for the presence of DTCs using the following combination of antibodies: pan-cytokeratin (A45-B/B3)/CXCR4/JUNB. An expression pattern of the examined proteins was created using confocal laser scanning microscopy, Image J software and BC cell lines. Results: CXCR4 was overexpressed in cancer cells and DTCs, with the following hierarchy of expression: SKBR3 > MCF7 > DTCs > MDA-MB231. Accordingly, the expression pattern of JUNB was: DTCs > MDA-MB231 > SKBR3 > MCF7. The mean intensity of CXCR4 (6411 ± 334) and JUNB (27725.64 ± 470) in DTCs was statistically higher compared with BM hematopoietic cells (2009 ± 456, p = 0.001; and 11112.89 ± 545, p = 0.001, respectively). The (CXCR4+JUNB+CK+) phenotype was the most frequently detected [90% (35/39)], followed by the (CXCR4–JUNB+CK+) phenotype [36% (14/39)]. However, (CXCR4+JUNB–CK+) tumor cells were found in only 5% (3/39) of patients. Those patients harboring DTCs with the (CXCR4+JUNB+CK+) phenotype revealed lower overall survival (Cox regression: p = 0.023). Conclusions: (CXCR4+JUNB+CK+)-expressing DTCs, detected frequently in the BM of BC patients, seem to identify a subgroup of patients at higher risk for relapse that may be considered for close follow up.

According to a position paper of the European Commission Initiative on Breast Cancer (ECIBC), DBT is close to being introduced in European breast cancer screening programmes. Our study aimed to examine radiation dose delivered by digital breast tomosynthesis (DBT) and digital mammography (FFDM) in comparison to sole FFDM in a clinical follow-up setting and in an identical patient cohort. Retrospectively, 768 breast examinations of 96 patients were included. Patients received both DBT and FFDM between May 2015 and July 2019: (I) FFDM in cranio-caudal (CC) and DBT in mediolateral oblique (MLO) view, as well as a (II) follow-up examination with FFDM in CC and MLO view. The mean glandular dose (MGD) was determined by the mammography system according to Dance’s model. The MGD (standard deviation (SD), interquartile range (IQR)) was distributed as follows: (I) (CCFFDM+MLODBT) (a) left FFDMCC 1.40 mGy (0.36 mGy, 1.13–1.59 mGy), left DBTMLO 1.62 mGy (0.51 mGy, 1.27–1.82 mGy); (b) right FFDMCC 1.36 mGy (0.34 mGy, 1.14–1.51 mGy), right DBTMLO 1.59 mGy (0.52 mGy, 1.27–1.62 mGy). (II) (CCFFDM+MLOFFDM) (a) left FFDMCC 1.35 mGy (0.35 mGy, 1.10–1.60 mGy), left FFDMMLO 1.40 mGy (0.39 mGy, 1.12–1.59 mGy), (b) right FFDMCC 1.35 mGy (0.33 mGy, 1.12–1.48 mGy), right FFDMMLO 1.40 mGy (0.36 mGy, 1.14–1.58 mGy). MGD was significantly higher for DBT mlo views compared to FFDM (p < 0.001). Radiation dose was significantly higher for DBT in MLO views compared to FFDM. However, the MGD of DBT MLO lies below the national diagnostic reference level of 2 mGy for an FFDM view. Hence, our results support the use of either DBT or FFDM as suggested in the ECIBC’s Guidelines.

BackgroundRecently, radiomics has emerged as a non-invasive, imaging-based tissue characterization method in multiple cancer types. One limitation for robust and reproducible analysis lies in the inter-reader variability of the tumor annotations, which can potentially cause differences in the extracted feature sets and results. In this study, the diagnostic potential of a rapid and clinically feasible VOI (Volume of Interest)-based approach to radiomics is investigated to assess MR-derived parameters for predicting molecular subtype, hormonal receptor status, Ki67- and HER2-Expression, metastasis of lymph nodes and lymph vessel involvement as well as grading in patients with breast cancer.MethodsA total of 98 treatment-naïve patients (mean 59.7 years, range 28.0-89.4) with BI-RADS 5 and 6 lesions who underwent a dedicated breast MRI prior to therapy were retrospectively included in this study. The imaging protocol comprised dynamic contrast-enhanced T1-weighted imaging and T2-weighted imaging. Tumor annotations were obtained by drawing VOIs around the primary tumor lesions followed by thresholding. From each segmentation, 13.118 quantitative imaging features were extracted and analyzed with machine learning methods. Validation was performed by 5-fold cross-validation with 25 repeats.ResultsPredictions for molecular subtypes obtained AUCs of 0.75 (HER2-enriched), 0.73 (triple-negative), 0.65 (luminal A) and 0.69 (luminal B). Differentiating subtypes from one another was highest for HER2-enriched vs triple-negative (AUC 0.97), followed by luminal B vs triple-negative (0.86). Receptor status predictions for Estrogen Receptor (ER), Progesterone Receptor (PR) and Hormone receptor positivity yielded AUCs of 0.67, 0.69 and 0.69, while Ki67 and HER2 Expressions achieved 0.81 and 0.62. Involvement of the lymph vessels could be predicted with an AUC of 0.8, while lymph node metastasis yielded an AUC of 0.71. Models for grading performed similar with an AUC of 0.71 for Elston-Ellis grading and 0.74 for the histological grading.ConclusionOur preliminary results of a rapid approach to VOI-based tumor-annotations for radiomics provides comparable results to current publications with the perks of clinical suitability, enabling a comprehensive non-invasive platform for breast tumor decoding and phenotyping.

Dynamics of mRNA from circulating tumor cells (CTCs), mRNA from extracellular vesicles (EVs), and cell-free DNA (cfDNA) were assessed to examine the relevance of a longitudinal multi-parametric liquid biopsy strategy. Eighteen milliliters of blood was drawn from 27 hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) patients at disease progression and at two subsequent radiologic staging time points. CTC mRNA and EV mRNA were analyzed using multi-marker qPCR, and cfDNA was analyzed using targeted next-generation sequencing (NGS). The presence of ERBB2 or ERBB3 overexpression signals in CTCs significantly correlated with disease progression (87% specificity, 36% sensitivity, p-value = 0.023), and the presence of either ERBB3 signals in CTCs or EVs or cfDNA variants in ERBB3 also showed a significant association with progressive MBC. Fluctuations during treatment were detected in the EV fraction with the appearance of hitherto undetected ERCC1 signals correlating with progressive disease (97% specificity, 18% sensitivity, p-value = 0.030). Allele frequency development of ESR1 and PIK3CA variants detected at subsequent staging time points could be used as a predictor for therapy success and, importantly, might help guide therapy decisions. The three analytes, each with their own unique features for disease monitoring, were shown to be complementary, underlining the usefulness of the longitudinal multi-parametric liquid biopsy approach.

Background: The aim of this study was to determine the treatment outcome of the use of a porcine monolayer collagen matrix (mCM) to increase soft-tissue volume as a part of implant site development. Materials and Methods: Implants were placed in single sites in 27 patients. In the test group, mCM was used for soft-tissue augmentation. No graft was placed in the control group. Soft-tissue thickness (STTh) was measured at the time of surgery (T0) and 6 months postoperatively (T1) at two sites (STTh 1, 1 mm below the gingival margin; STTh 2, 3 mm below the mucogingival margin). Results: Significant increases (P < 0.001) in STTh (STTh 1 = 1.06 mm, 117%; STTh 2 = 0.89 mm, 81%) were observed in the test group. Biopsy results showed angiogenesis and mature connective tissue covered by keratinized epithelium. Conclusions: Within the limitations of this study, it could be concluded that mCM leads to a significant increase of peri-implant soft-tissue thickness, with good histological integration and replacement by soft tissue and may serve as an alternative to connective tissue grafting.

Extracellular vesicles (EVs) have been discussed as a diagnostic tool for minimal residual disease (MRD) evaluation in breast cancer (BC) in addition to the analysis of circulating tumor cells (CTCs). Therefore, we investigated circulating EV levels as surrogate markers for disease monitoring and prediction of prognosis in primary, non-metastatic, locally advanced BC patients. EVs were enriched from blood samples of BC patients before and after neoadjuvant chemotherapy (NACT) and from healthy females. EV marker expression analysis was performed and EV sizes and concentrations were determined by nanoparticle tracking analysis. The results were associated with disease status, outcome and CTC presence, evaluated by gene expression analysis after enrichment. We demonstrated that i) the EV concentration was 40-fold higher in BC patients compared to healthy females, ii) the EV concentration increased during therapy, iii) an increased EV concentration pre-NACT was associated with therapy failure and iv) an elevated EV concentration post-NACT was associated with a reduced three-year progression-free and overall survival. Of note, residual stem cell-like and/or resistant CTCs after therapy were associated with a lower EV concentration post-NACT. Our study highlights that the concentration of EVs within BC blood samples may serve as a complementary parameter reflecting the status of MRD as well as therapy and disease outcome in parallel with CTC investigation.