Low-Risk Women with Suspicious Microcalcifications in Mammography—Can an Additional Breast MRI Reduce the Biopsy Rate?

Background: In the German Mammography Screening Program, 62% of ductal carcinoma in situ (DCIS) and 38% of invasive breast cancers are associated with microcalcifications (MCs). Vacuum-assisted stereotactic breast biopsies are necessary to distinguish precancerous lesions from benign calcifications because mammographic discrimination is not possible. The aim of this study was to investigate if breast magnetic resonance imaging (MRM) could assist the evaluation of MCs and thus help reduce biopsy rates. Methods: In this IRB-approved study, 58 women (mean age 58 +/− 24 years) with 59 suspicious MC clusters in the MG were eligible for this prospective single-center trial. Additional breast magnetic resonance imaging (MRI) was conducted before biopsy. Results: The breast MRI showed a sensitivity of 86%, a specificity of 84%, a positive predictive value (PPV) of 75% and a negative predictive value (NPV) of 91% for the differentiation between benign and malignant in these 59 MCs found with MG. Breast MRI in addition to MG could increase the PPV from 36% to 75% compared to MG alone. The MRI examination led to nine additional suspicious classified lesions in the study cohort. A total of 55% (5/9) of them turned out to be malignant. A total of 32 of 59 (54 %) women with suspicious MCs and benign histology were classified as non-suspicious by MRI. Conclusion: An additionally performed breast MRI could have increased the diagnostic reliability in the assessment of MCs. Further, in our small cohort, a considerable number of malignant lesions without mammographically visible MCs were revealed

Development of actionable targets of multi-kinase inhibitors (AToMI) screening platform to dissect kinase targets of staurosporines in glioblastoma cells

Therapeutic resistance to kinase inhibitors constitutes a major unresolved clinical challenge in cancer and especially in glioblastoma. Multi-kinase inhibitors may be used for simultaneous targeting of multiple target kinases and thereby potentially overcome kinase inhibitor resistance. However, in most cases the identification of the target kinases mediating therapeutic effects of multi-kinase inhibitors has been challenging. To tackle this important problem, we developed an actionable targets of multi-kinase inhibitors (AToMI) strategy and used it for characterization of glioblastoma target kinases of staurosporine derivatives displaying synergy with protein phosphatase 2A (PP2A) reactivation. AToMI consists of interchangeable modules combining drug-kinase interaction assay, siRNA high-throughput screening, bioinformatics analysis, and validation screening with more selective target kinase inhibitors. As a result, AToMI analysis revealed AKT and mitochondrial pyruvate dehydrogenase kinase PDK1 and PDK4 as kinase targets of staurosporine derivatives UCN-01, CEP-701, and K252a that synergized with PP2A activation across heterogeneous glioblastoma cells. Based on these proof-of-principle results, we propose that the application and further development of AToMI for clinically applicable multi-kinase inhibitors could provide significant benefits in overcoming the challenge of lack of knowledge of the target specificity of multi-kinase inhibitors.Peer reviewe

Feasibility of In Vivo Metal Artifact Reduction in Contrast-Enhanced Dedicated Spiral Breast Computed Tomography

Background: Radiopaque breast markers cause artifacts in dedicated spiral breast-computed tomography (SBCT). This study investigates the extent of artifacts in different marker types and the feasibility of reducing artifacts through a metal artifact reduction (MAR) algorithm. Methods: The pilot study included 18 women who underwent contrast-enhanced SBCT. In total, 20 markers of 4 different types were analyzed for artifacts. The extent of artifacts with and without MAR was measured via the consensus of two readers. Image noise was quantitatively evaluated, and the effect of MAR on the detectability of breast lesions was evaluated on a 3-point Likert scale. Results: Breast markers caused significant artifacts that impaired image quality and the detectability of lesions. MAR decreased artifact size in all analyzed cases, even in cases with multiple markers in a single slice. The median length of in-plain artifacts significantly decreased from 31 mm (range 11–51 mm) in uncorrected to 2 mm (range 1–5 mm) in corrected images (p ≤ 0.05). Artifact size was dependent on marker size. Image noise in slices affected by artifacts was significantly lower in corrected (13.6 ± 2.2 HU) than in uncorrected images (19.2 ± 6.8 HU, p ≤ 0.05). MAR improved the detectability of lesions affected by artifacts in 5 out of 11 cases. Conclusion: MAR is feasible in SBCT and improves the image quality and detectability of lesions.</p

Monotherapy efficacy of blood-brain barrier permeable small molecule reactivators of protein phosphatase 2A in glioblastoma

Glioblastoma is a fatal disease in which most targeted therapies have clinically failed. However, pharmacological reactivation of tumour suppressors has not been thoroughly studied as yet as a glioblastoma therapeutic strategy. Tumour suppressor protein phosphatase 2A is inhibited by non-genetic mechanisms in glioblastoma, and thus, it would be potentially amendable for therapeutic reactivation. Here, we demonstrate that small molecule activators of protein phosphatase 2A, NZ-8-061 and DBK-1154, effectively cross the in vitro model of blood-brain barrier, and in vivo partition to mouse brain tissue after oral dosing. In vitro, small molecule activators of protein phosphatase 2A exhibit robust cell-killing activity against five established glioblastoma cell lines, and nine patient-derived primary glioma cell lines. Collectively, these cell lines have heterogeneous genetic background, kinase inhibitor resistance profile and stemness properties; and they represent different clinical glioblastoma subtypes. Moreover, small molecule activators of protein phosphatase 2A were found to be superior to a range of kinase inhibitors in their capacity to kill patient-derived primary glioma cells. Oral dosing of either of the small molecule activators of protein phosphatase 2A significantly reduced growth of infiltrative intracranial glioblastoma tumours. DBK-1154, with both higher degree of brain/blood distribution, and more potent in vitro activity against all tested glioblastoma cell lines, also significantly increased survival of mice bearing orthotopic glioblastoma xenografts. In summary, this report presents a proof-of-principle data for blood-brain barrier-permeable tumour suppressor reactivation therapy for glioblastoma cells of heterogenous molecular background. These results also provide the first indications that protein phosphatase 2A reactivation might be able to challenge the current paradigm in glioblastoma therapies which has been strongly focused on targeting specific genetically altered cancer drivers with highly specific inhibitors. Based on demonstrated role for protein phosphatase 2A inhibition in glioblastoma cell drug resistance, small molecule activators of protein phosphatase 2A may prove to be beneficial in future glioblastoma combination therapies.Peer reviewe

Detection of Microcalcifications in Spiral Breast Computed Tomography with Photon-Counting Detector Is Feasible: A Specimen Study

The primary objective of the study was to compare a spiral breast computed tomography system (SBCT) to digital breast tomosynthesis (DBT) for the detection of microcalcifications (MCs) in breast specimens. The secondary objective was to compare various reconstruction modes in SBCT. In total, 54 breast biopsy specimens were examined with mammography as a standard reference, with DBT, and with a dedicated SBCT containing a photon-counting detector. Three different reconstruction modes were applied for SBCT datasets (Recon1 = voxel size (0.15 mm)3, smooth kernel; Recon2 = voxel size (0.05 mm)3, smooth kernel; Recon3 = voxel size (0.05 mm)3, sharp kernel). Sensitivity and specificity of DBT and SBCT for the detection of suspicious MCs were analyzed, and the McNemar test was used for comparisons. Diagnostic confidence of the two readers (Likert Scale 1 = not confident; 5 = completely confident) was analyzed with ANOVA. Regarding detection of MCs, reader 1 had a higher sensitivity for DBT (94.3%) and Recon2 (94.9%) compared to Recon1 (88.5%; p 0.05). The diagnostic confidence of reader 1 was better with SBCT than with DBT (DBT 4.48 ± 0.88, Recon1 4.77 ± 0.66, Recon2 4.89 ± 0.44, and Recon3 4.75 ± 0.72; DBT vs. Recon1/2/3: p < 0.05), while reader 2 found no differences. Sensitivity and specificity for the detection of MCs in breast specimens is equal for DBT and SBCT when a small voxel size of (0.05 mm)3 is used with an equal or better diagnostic confidence for SBCT compared to DBT

Development of actionable targets of multi-kinase inhibitors (AToMI) screening platform to dissect kinase targets of staurosporines in glioblastoma cells

Therapeutic resistance to kinase inhibitors constitutes a major unresolved clinical challenge in cancer and especially in glioblastoma. Multi-kinase inhibitors may be used for simultaneous targeting of multiple target kinases and thereby potentially overcome kinase inhibitor resistance. However, in most cases the identification of the target kinases mediating therapeutic effects of multi-kinase inhibitors has been challenging. To tackle this important problem, we developed an actionable targets of multi-kinase inhibitors (AToMI) strategy and used it for characterization of glioblastoma target kinases of staurosporine derivatives displaying synergy with protein phosphatase 2A (PP2A) reactivation. AToMI consists of interchangeable modules combining drug-kinase interaction assay, siRNA high-throughput screening, bioinformatics analysis, and validation screening with more selective target kinase inhibitors. As a result, AToMI analysis revealed AKT and mitochondrial pyruvate dehydrogenase kinase PDK1 and PDK4 as kinase targets of staurosporine derivatives UCN-01, CEP-701, and K252a that synergized with PP2A activation across heterogeneous glioblastoma cells. Based on these proof-of-principle results, we propose that the application and further development of AToMI for clinically applicable multi-kinase inhibitors could provide significant benefits in overcoming the challenge of lack of knowledge of the target specificity of multi-kinase inhibitors

Image quality assessment using deep learning in high b-value diffusion-weighted breast MRI

AbstractThe objective of this IRB approved retrospective study was to apply deep learning to identify magnetic resonance imaging (MRI) artifacts on maximum intensity projections (MIP) of the breast, which were derived from diffusion weighted imaging (DWI) protocols. The dataset consisted of 1309 clinically indicated breast MRI examinations of 1158 individuals (median age [IQR]: 50 years [16.75 years]) acquired between March 2017 and June 2020, in which a DWI sequence with a high b-value equal to 1500 s/mm2 was acquired. From these, 2D MIP images were computed and the left and right breast were cropped out as regions of interest (ROI). The presence of MRI image artifacts on the ROIs was rated by three independent observers. Artifact prevalence in the dataset was 37% (961 out of 2618 images). A DenseNet was trained with a fivefold cross-validation to identify artifacts on these images. In an independent holdout test dataset (n = 350 images) artifacts were detected by the neural network with an area under the precision-recall curve of 0.921 and a positive predictive value of 0.981. Our results show that a deep learning algorithm is capable to identify MRI artifacts in breast DWI-derived MIPs, which could help to improve quality assurance approaches for DWI sequences of breast examinations in the future.</jats:p

γ-H2AX Kinetics as a Novel Approach to High Content Screening for Small Molecule Radiosensitizers

Persistence of γ-H2AX after ionizing radiation (IR) or drug therapy is a robust reporter of unrepaired DNA double strand breaks in treated cells.DU-145 prostate cancer cells were treated with a chemical library ±IR and assayed for persistence of γ-H2AX using an automated 96-well immunocytochemistry assay at 4 hours after treatment. Hits that resulted in persistence of γ-H2AX foci were tested for effects on cell survival. The molecular targets of hits were validated by molecular, genetic and biochemical assays and in vivo activity was tested in a validated Drosophila cancer model.We identified 2 compounds, MS0019266 and MS0017509, which markedly increased persistence of γ-H2AX, apoptosis and radiosensitization in DU-145 cells. Chemical evaluation demonstrated that both compounds exhibited structurally similar and biochemical assays confirmed that these compounds inhibit ribonucleotide reductase. DNA microarray analysis and immunoblotting demonstrates that MS0019266 significantly decreased polo-like kinase 1 gene and protein expression. MS0019266 demonstrated in vivo antitumor activity without significant whole organism toxicity.MS0019266 and MS0017509 are promising compounds that may be candidates for further development as radiosensitizing compounds as inhibitors of ribonucleotide reductase