Cell-in-cell (CIC) structures in breast cancer have so far been studied in a small inhomogeneous patient population, suggesting the prognostic importance of CIC. In the present study, we focused on ...CIC in early hormone-sensitive breast cancer. With in vitro co-culture experiments, we compared the homotypic phagocytic capacity of two breast cancer cell lines to that of primary human fibroblasts. Afterward, we studied 601 tissue specimens from 147 patients participating in an institutional accelerated partial breast irradiation (APBI) phase II trial. Both breast cancer cell lines performed non-professional phagocytosis at a higher rate than primary human fibroblasts. In this study cohort, 93.2% of the patients had T1 tumours, and 6.8% had T2 tumours. CIC was found in 61.2% of the patients, with a CIC rate ranging from <1/mm
to 556.5/mm
with a mean of 30.9/mm
± 68.4/mm
. CIC structures were prognostically favourable for local recurrence-free survival and disease-free survival. Regarding metastasis-free survival, CIC-positive patients had an unfavourable prognosis. Subgroup analysis indicated a correlation between a high proliferation index and high CIC rates. CIC had the highest prognostic value in young breast cancer patients (
= 0.004). With this study, we provide further evidence of CIC as a prognostic marker in breast cancer.
Background: In head and neck cancer patients, parameters of metabolic and morphologic response of the tumor to single-cycle induction chemotherapy (IC) with docetaxel, cis- or carboplatin are used to ...decide the further course of treatment. This study investigated the effect of adding a double immune checkpoint blockade (DICB) of tremelimumab and durvalumab to IC on imaging parameters and their significance with regard to tumor cell remission. Methods: Response variables of 53 patients treated with IC+DICB (ICIT) were compared with those of 104 who received IC alone. Three weeks after one cycle, pathologic and, in some cases, clinical and endoscopic primary tumor responses were evaluated and correlated with a change in 18F-FDG PET and CT/MRI-based maximum-standardized uptake values (SUVmax) before (SUVmaxpre), after treatment (SUVmaxpost) and residually (resSUVmax in % of SUVmaxpre), and in maximum tumor diameter (Dmax) before (Dmaxpre) and after treatment (Dmaxpost) and residually (resD). Results: Reduction of SUVmax and Dmax occurred in both groups; values were SUVmaxpre: 14.4, SUVmaxpost: 6.6, Dmaxpre: 30 mm and Dmaxpost: 23 mm for ICIT versus SUVmaxpre: 16.5, SUVmaxpost: 6.4, Dmaxpre: 21 mm, and Dmaxpost: 16 mm for IC alone (all p < 0.05). ResSUVmax was the best predictor of complete response (IC: AUC: 0.77; ICIT: AUC: 0.76). Metabolic responders with resSUVmax ≤ 40% tended to have a higher rate of CR to ICIT (88%; n = 15/17) than to IC (65%; n = 30/46; p = 0.11). Of the metabolic nonresponders (resSUVmax > 80%), 33% (n = 5/15) achieved a clinical CR to ICIT versus 6% (n = 1/15) to IC (p = 0.01). Conclusions: ICIT and IC quickly induce a response and 18F-FDG PET is the more accurate modality for identifying complete remission. The rate of discrepant response, i.e., pCR with metabolic nonresponse after ICIT was >30%.
Low-field magnetic resonance imaging (MRI) may offer specific advantages over high-field MRI, e.g. lower susceptibility-dependent distortions and simpler installation. The study aim was to evaluate ...if a novel 0.55 T MRI scanner provides sufficient image accuracy and quality for radiotherapy (RT) treatment planning.
The geometric accuracy of images acquired at a low-field MRI scanner was evaluated in phantom measurements regarding gradient non-linearity-related distortions. Patient-induced B0-susceptibility changes were investigated via B0-field-mapping in ten volunteers. Patients were positioned in RT-setup using a 3D-printed insert for the head/neck-coil that was tested for sufficient signal-to-noise-ratio (SNR). The suitability of the MRI-system for detection of metastases was evaluated in eleven patients. In comparison to diagnostic images, acquired at ≥1.5 T, three physicians evaluated the detectability of metastases by counting them in low- and high-field-images, respectively.
The phantom measurements showed a high imaging fidelity after 3D-distortion-correction with (1.2 ± 0.9) mm geometric distortion in 10 cm radius from isocentre. At the edges remaining distortions were greater than at 1.5 T. The mean susceptibility-induced distortions in the head were (0.05 ± 0.05) mm and maximum 0.69 mm. SNR analysis showed that optimised positioning of RT-patients without signal loss in the head/neck-coil was possible with the RT-insert. No significant differences (p = 0.48) in detectability of metastases were found.
The 0.55 T MRI system provided sufficiently geometrically accurate and high-resolution images that can be used for RT-planning for brain metastases. Hence, modern low-field MRI may contribute to simply access MRI for RT-planning after further investigations.
Non-professional phagocytosis is usually triggered by stimuli such as necrotic cell death. In tumor therapy, the tumors often disappear slowly and only long time after the end of therapy. Here, tumor ...therapy inactivates the cells by inducing senescence. Therefore, study focused whether senescence is a stimulus for non-professional phagocytosis or whether senescent cells themselves phagocytize non-professionally. Senescence was induced in cell lines by camptothecin and a phagocytosis assay was performed. In tissue of a cohort of 192 rectal cancer patients senescence and non-professional phagocytosis was studied by anti-histone H3K9me3 and anti-E-cadherin staining. Senescent fibroblasts and pancreas carcinoma cells phagocytize necrotic cells but are not phagocytized. In the tissue of rectal carcinoma, senescent cells can phagocytize and can be phagocytized. A high number of senescent cells and, at the same time, high numbers of non-professional phagocytizing cells in the rectal carcinoma tissue lead to an extremely unfavorable prognosis regarding overall survival. Senescent cells can be non-professionally phagocytized and at the same time they can non-professionally phagocytize in vivo. In vitro experiments indicate that it is unlikely that senescence is a strong trigger for non-professional phagocytosis. Combined high rates of non-professional phagocytosis and high rates of senescence are an extremely poor prognostic factor for overall survival.
This study aimed to differentiate primary central nervous system lymphoma (PCNSL) and glioblastoma (GBM) via multimodal MRI featuring radiomic analysis. MRI data sets of patients with histological ...proven PCNSL and GBM were analyzed retrospectively. Diffusion-weighted imaging (DWI) and dynamic susceptibility contrast (DSC) perfusion imaging were evaluated to differentiate contrast enhancing intracerebral lesions. Selective (contrast enhanced tumor area with the highest mean cerebral blood volume (CBV) value) and unselective (contouring whole contrast enhanced lesion) Apparent diffusion coefficient (ADC) measurement was performed. By multivariate logistic regression, a multiparametric model was compiled and tested for its diagnostic strength. A total of 74 patients were included in our study. Selective and unselective mean and maximum ADC values, mean and maximum CBV and ratioCBV as quotient of tumor CBV and CBV in contralateral healthy white matter were significantly larger in patients with GBM than PCNSL; minimum CBV was significantly lower in GBM than in PCNSL. The highest AUC for discrimination of PCNSL and GBM was obtained for selective mean and maximum ADC, mean and maximum CBV and ratioCBV. By integrating these five in a multiparametric model 100% of the patients were classified correctly. The combination of perfusion imaging (CBV) and tumor hot-spot selective ADC measurement yields reliable radiological discrimination of PCNSL from GBM with highest accuracy and is readily available in clinical routine.
To evaluate single- and multiparametric MRI models to differentiate recurrent glioblastoma (GBM) and treatment-related changes (TRC) in clinical routine imaging. Selective and unselective apparent ...diffusion coefficient (ADC) and minimum, mean, and maximum cerebral blood volume (CBV) measurements in the lesion were performed. Minimum, mean, and maximum ratios
(CBV
to CBV
) were computed. All data were tested for lesion discrimination. A multiparametric model was compiled via multiple logistic regression using data demonstrating significant difference between GBM and TRC and tested for its diagnostic strength in an independent patient cohort. A total of 34 patients (17 patients with recurrent GBM and 17 patients with TRC) were included. ADC measurements showed no significant difference between both entities. All CBV and ratios
measurements were significantly higher in patients with recurrent GBM than TRC. A minimum CBV of 8.5, mean CBV of 116.5, maximum CBV of 327 and ratio
of 0.17, ratio
of 2.26 and ratio
of 3.82 were computed as optimal cut-off values. By integrating these parameters in a multiparametric model and testing it in an independent patient cohort, 9 of 10 patients, i.e., 90%, were classified correctly. The multiparametric model further improves radiological discrimination of GBM from TRC in comparison to single-parameter approaches and enables reliable identification of recurrent tumors.
Hippocampal-sparing radiotherapy (HSR) is a promising approach to alleviate cognitive side effects following cranial radiotherapy. Microstructural brain changes after irradiation have been ...demonstrated using Diffusion Tensor Imaging (DTI). However, evidence is conflicting for certain parameters and anatomic structures. This study examines the effects of radiation on white matter and hippocampal microstructure using DTI and evaluates whether these may be mitigated using HSR. A total of 35 tumor patients undergoing a prospective randomized controlled trial receiving either conventional or HSR underwent DTI before as well as 6, 12, 18, 24, and 30 (±3) months after radiotherapy. Fractional Anisotropy (FA), Mean Diffusivity (MD), Axial Diffusivity (AD), and Radial Diffusivity (RD) were measured in the hippocampus (CA), temporal, and frontal lobe white matter (TL, FL), and corpus callosum (CC). Longitudinal analysis was performed using linear mixed models. Analysis of the entire patient collective demonstrated an overall FACC decrease and RDCC increase compared to baseline in all follow-ups; ADCC decreased after 6 months, and MDCC increased after 12 months (p ≤ 0.001, 0.001, 0.007, 0.018). ADTL decreased after 24 and 30 months (p ≤ 0.004, 0.009). Hippocampal FA increased after 6 and 12 months, driven by a distinct increase in ADCA and MDCA, with RDCA not increasing until 30 months after radiotherapy (p ≤ 0.011, 0.039, 0.005, 0.040, 0.019). Mean radiation dose correlated positively with hippocampal FA (p < 0.001). These findings may indicate complex pathophysiological changes in cerebral microstructures after radiation, insufficiently explained by conventional DTI models. Hippocampal microstructure differed between patients undergoing HSR and conventional cranial radiotherapy after 6 months with a higher ADCA in the HSR subgroup (p ≤ 0.034).
•45 data sets (18 on a 1.5 T MR and 27 on a 3 T MR) were evaluated for susceptibility induced distortions.•Maximum distortions of up to 1.7 mm were found for organs at risk in standard diagnostic ...settings.•Median distortions ranged between 0.1 and 0.2 mm for all organs at risk.•Active shimming was estimated to reduce distortions by a factor of 2.3 to 2.9.•A safety margin of 1 mm would have encompassed 99.8% of the distortions.
Magnetic resonance imaging (MRI) is a crucial factor in optimal treatment planning for stereotactic radiosurgery. To further the awareness of possible errors in MRI, this work aimed to investigate the magnitude of susceptibility induced MRI distortions for intracranial organs at risk (OARs) and test the effectiveness of actively shimming these distortions.
Distortion maps for 45 exams of 42 patients (18 on a 1.5 T MRI scanner, 27 on a 3 T MRI scanner) were calculated based on a high-bandwidth double-echo gradient echo sequence. The investigated OARs were brainstem, chiasm, eyes, and optic nerves. The influence of active shimming was investigated by comparing unshimmed 1.5 T data with shimmed 3 T data and comparing the results to a model based prediction.
The median distortion for the different OARs was found to be between 0.13 and 0.18 mm for 1.5 T and between 0.11 and 0.13 mm for 3 T. The maximum distortion was found to be between 1.3 and 1.7 mm for 1.5 T and between 1.1 and 1.4 mm for 3 T. The variation of values was much higher for 1.5 T than for 3 T across all investigated OARs. Active shimming was found to reduce distortions by a factor of 2.3 to 2.9 compared to the expected values.
Using a safety margin for OARs of 1 mm would have encompassed 99.8% of the distortions. Since distortions are inversely proportional to the readout bandwidth, they can be further reduced by increasing the bandwidth. Additional error sources like gradient nonlinearities need to be addressed separately.
Idelalisib is approved for the treatment of relapsed chronic lymphocytic leukemia together with Rituximab and for monotherapy of follicular B-cell non-Hodgkin's lymphoma and small lymphocytic ...lymphoma. It is a potent and selective phosphatidylinositol 3-kinase-δ (PI3K-δ) inhibitor. PI3K-δ primarily is expressed in B-cells and prevents effectively proliferation in malignant B-cells.
We provide a detailed report on treatment history and photo documentation of acute adverse effects of radiation therapy with simultaneous Idelalisib medication in one case of B-CLL. Radiosensitivity tests were performed for the index patient under Idelalisib and after the addition of Idelalisib to healthy individuals' blood. Radiosensitivity in human lymphocytes was analyzed with a three color in situ hybridization assay. Primary skin fibroblasts were studied after a treatment with Idelalisib for apoptosis, necrosis and cell cycle using flow cytometry. DNA double-strand break repair was analyzed by γH2AX immunostaining.
The index patient presented a strong grade 2 radiodermatitis and grade 3 mucositis after irradiation with 20 Gy and a simultaneous intake of Idelalisib. Irradiations without Idelalisib medication were well tolerated and resulted in not more than grade 1 radiodermatitis. The index patient under Idelalisib had a radiosensitivity of 0.62 B/M which is in the range of clearly radiosensitive patients. A combined treatment of lymphocytes with 2 Gy and 10 nmol/l Idelalisib showed a tendency to an increased radiosensitivity. We found a clear increase of apoptosis as a result of the combined treatment in the Idelalisib dose range of 1 to 100 nmol/l compared to solely irradiated cells or solely Idelalisib treated cells (p = 0.05).
A combined Idelalisib radiotherapy treatment has an increased risk of side effects. However, combined therapy seems to be feasible when patients are monitored closely.
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