Abstract
(1) PURPOSE
The aim of the prospective trial was to determine if cell survival in a breast cancer spheroid model following cytostatic treatment in vitro predicts treatment response in breast ...cancer patients receiving equivalent neoadjuvant therapy.
(2) PATIENTS AND METHODS
Three-dimensional spheroids were directly generated from fresh tumor biopsy samples of 78 patients eligible for neoadjuvant therapy. Cell survival in vitro, as well baseline clinical and pathological characteristics were correlated with the outcome following treatment of each patient to determine the factor(s) most highly associated with pathological complete response (pCR i.e.ypT0/ypN0) at surgery.
(3) RESULTS
Cell survival after treatment in the breast cancer spheroid model proved to be a sensitive and specific predictor for pCR in individual breast cancer patients. A mean cell survival of 21.8% was found in the breast cancer spheroid model for 22 patients with pCR versus 63.8% in 56 patients without pCR (P = .001). A receiver operator characteristic analysis determined an area under the ROC curve of 0.86 (95% CI: 0.77 to 0.96) for cell survival compared to classic factors i.e. negative hormone receptor and positive Her2/neu status, and age ≤ 50 years at primary diagnosis (AUC = 0.80, 95% CI: 0.70 to 0.90). A cutoff of 35% cell survival was proposed, which grouped patients according to likelihood for pCR. Out of the 32 patients with values below this threshold, 21 patients (65.6%) and one patient (2.2%) with a cell survival greater than 35% achieved pCR respectively; (sensitivity 95.5% (95% CI: 0.86 to 1.00); specificity 80.4% (95% CI: 0.70 to 0.91)).The specificity was improved to 81% (95% CI: 58 to 95%) if the patient was treated per-protocol.
A positive correlation was also found between cell survival in vitro and residual tumor size (P = .021), indicating the possibility of the model to predict degree of response.
(4) CONCLUSION
The breast cancer spheroid model is a valuable predictor for treatment outcome in patients undergoing neoadjuvant chemotherapy for primary breast cancer. Preclinical selection of the most efficient drugs is a prerequisite to improve pCR.
Citation Format: Kathrin ML Halfter, Nina Ditsch, Hans-Christian Kolberg, Holger Fischer, Tanja Hauzenberger, Franz Edler von Koch, Ingo Bauerfeind, Gunter von Minckwitz, Ilona Funke, Alexander Crispin, Barbara Mayer. Prospective cohort study using the breast cancer spheroid model as a predictor for response to neoadjuvant therapy – The SpheroNEO study abstract. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-13.
Genetic alterations in the DNA Damage Response (DDR) pathway are a frequent mechanism of resistance to CIT in B-cell malignancies. We have previously shown that the synergy of CIT relies on secretory ...crosstalk elicited by chemotherapy between the tumour cells and macrophages. Here, we show that loss of multiple different members of the DDR pathway inhibits macrophage phagocytic capacity in vitro and in vivo. Particularly loss of TP53 led to decreased phagocytic capacity ex vivo across multiple B-cell malignancies. We demonstrate via in vivo cyclophosphamide treatment using the Eµ-TCL1 mouse model that loss of macrophage phagocytic capacity in Tp53-deleted leukemia is driven by a significant downregulation of a phagocytic transcriptomic signature using scRNA-Seq. By analysing the tumour B-cell proteome, we identified a TP53 specific upregulation of proteins associated with extracellular vesicles (EV). We abrogated EV biogenesis in tumour B-cells via CRISPR-knockout (KO) of RAB27A and confirmed that the EVs from TP53-deleted lymphoma cells were responsible for the reduced phagocytic capacity and the in vivo CIT resistance. Furthermore, we observed that TP53 loss led to an upregulation of both PD-L1 cell surface expression and secretion of EVs by lymphoma cells. Disruption of EV bound PD-L1 by anti-PD-L1 antibodies or PD-L1 CRISPR-KO improved macrophage phagocytic capacity and in vivo therapy response. Thus, we demonstrate enhanced EV-release and increased PD-L1 expression in TP53-deficient B-cell lymphomas as novel mechanisms of macrophage function alteration in CIT resistance. This study indicates the use of checkpoint inhibition in the combination treatment of B-cell malignancies with TP53 loss.
Randomized trials of carotid endarterectomy for high-grade stenosis have shown a benefit for surgery under the condition of low perioperative complication rates. Concerns have been expressed that the ...complication rates of carotid surgery are higher in everyday practice and may vary considerably between centers. We prospectively established the complication rate for carotid surgery in a single institution.
Prospective 2-year study. All patients received pre- and postoperative neurological evaluation. Laboratory tests included pre- and postoperative brain imaging, intracranial and neck vessel sonography, conventional angiography, magnetic resonance angiography, and intraoperative monitoring.
108 consecutive patients: 54 symptomatic patients fulfilling the inclusion criteria of the European Carotid Surgery Trial (ECST) and 54 asymptomatic patients fulfilling the inclusion criteria of the North American Trial on Asymptomatic Stenoses (ACAS).
Single academic center with a high volume of carotid endarterectomies (>50 per year). Participating center in ECST.
Stroke or death as defined in the randomized trials.
The overall complication rate was 8.3% (95% CI 4.1-15.6%). Complications were more frequent in patients with symptomatic stenosis (11.1%, CI 4.6-23.3%) than in asymptomatic cases (5.6%, CI 1.5-16.4%). Three patients died (2 strokes, 1 myocardial infarction). Disabling strokes were found in 2 patients (Rankin scale scores 3 and 4). Nondisabling strokes (Rankin scale score 1 and 2) occurred in 4 patients. The complication rates for symptomatic and asymptomatic patients were higher than the ones reported in the randomized trials, but 95% confidence intervals showed that the differences were not statistically significant. The point estimates of complication rates still supported a benefit of surgery for patients with symptomatic stenosis, but denied a positive effect of endarterectomy for patients with asymptomatic stenosis.
In this center, a beneficial effect of carotid surgery for asymptomatic stenoses cannot be safely assumed.
We report on extensive studies on the intrinsic sensitivity of a combined
3
He/Cs magnetometer. The magnetometer relies on the detection of the free spin precession of nuclear spin polarized
3
He by ...optically pumped cesium magnetometers. We characterize the relevant processes involved in the detection and quantify their impact on the total sensitivity of the magnetometer. An expression is derived that predicts the sensitivity of this magnetometer scheme and the results are compared to experiments. Excellent agreement is found between theory and experiments, and implications for an application of a
3
He/Cs magnetometer in an experiment searching for a permanent neutron electric dipole moment are discussed.
Graphical abstract
Design and performance of an absolute 3He/Cs magnetometer Koch, Hans-Christian; Bison, Georg; Grujić, Zoran D. ...
The European physical journal. D, Atomic, molecular, and optical physics,
8/2015, Letnik:
69, Številka:
8
Journal Article
Recenzirano
Odprti dostop
We report on the design and performance of a highly sensitive combined
3
He/Cs magnetometer for the absolute measurement of magnetic fields. The magnetometer relies on the magnetometric detection of ...the free spin precession of nuclear spin polarized
3
He gas by optically pumped cesium magnetometers. We plan to deploy this type of combined magnetometer in an experiment searching for a permanent electric dipole moment of ultracold neutrons at the Paul-Scherrer Institute (Switzerland). A prototype magnetometer was built at the University of Fribourg (Switzerland) and tested at Physikalisch-Technische Bundesanstalt (Berlin, Germany). We demonstrate that the combined magnetometer allows Cramér-Rao-limited field determinations with recording times in the range of, measurements above being limited by the stability of the applied magnetic field. With a recording time we were able to perform an absolute measurement of a magnetic field of ≈ with a standard uncertainty of, corresponding to Δ
B
/
B
< 6 ×10
−8
.
Graphical abstract
The case of a 12‐year‐old boy with anaplastic astrocytoma of the left thalamus is reported. Postoperative irradiation and chemotherapy could not repress tumor progression; therefore, treatment was ...undertaken with an oncolytic virus, MTH‐68/H, an attenuated strain of Newcastle disease virus (NDV), and valproic acid (VPA), an antiepileptic drug, which also has antineoplastic properties. This treatment resulted in a far‐reaching regression of the thalamic glioma, but 4 months later a new tumor manifestation, an extension of the thalamic tumor, appeared in the wall of the IVth ventricle, which required a second neurosurgical intervention. Under continuous MTH‐68/H – VPA administration the thalamic tumor remained under control, but the rhombencephalic one progressed relentlessly and led to the fatal outcome. In the final stage, a third tumor manifestation appeared in the left temporal lobe. The possible reasons for the antagonistic behavior of the three manifestations of the same type of glioma to the initially most successful therapy are discussed. The comparative histological study of the thalamic and rhombencephalic tumor manifestations revealed that MTH‐68/H treatment induces, similar to
in vitro
observations, a massive apoptotic tumor cell decline. In the rhombencephalic tumor, in and around the declining tumor cells, NDV antigen could be demonstrated immunohistochemically, and virus particles have been found in the cytoplasm of tumor cells at electron microscopic investigation. These findings document that the oncolytic effect of MTH‐68/H treatment is the direct consequence of virus presence and replication in the neoplastic cells. This is the first demonstration of NDV constituents in an MTH‐68/H ‐treated glioma.
Layered Fe super(II)-Fe super(III) hydroxides (green rusts, GR) intercalated with monovalent aliphatic carboxylate anions, called GR-carboxylates, possess hydrophobic interlayer regions which can ...adsorb non-polar organic compounds. GRs are well known reductants and hence GR-carboxylates may have the potential to detoxify adsorbed compounds, such as chlorinated solvents. GR-carboxylates, GR sub(CX), for the first time, were precipitated directly by aerial oxidation of an ethanolic solution containing FeSO sub(4) and linear alkyl carboxylate ions synthesis condition using monovalent carboxylic acids with X, the total number of carbon atoms in the acid, varying from 5 (pentanoic acid) to 14 (tetradecanoic acid), synthesis conditions were tested. GR sub(CX) formed for X >= 9. The syntheses were carried out at constant pH of 8 using 1 M NaOH as neutralizing agent, and with a maximum duration of 3.5 h. The basal spacings of GR sub(CX) increased with X and they were 2.68 nm (GR sub(C9)), 2.94 nm (GR sub(C10)), 3.59 nm (GR sub(C12)) and 4.16 nm (GR sub(C14)). The Moessbauer spectra measured at 80 K of different GR sub(C12) synthesized under identical chemical conditions resulted in hyperfine parameters close to those of other GRs. The Fe super(II)/Fe super(III) ratios of the final products (R) ranged between 1.4 and 2.8 demonstrating that Fe super(II) in GR sub(CX) can be partly oxidized without degradation of the structure. R at various stages of the synthesis decreased from 5.2 at the start of the reaction to 2.8 at the end of synthesis. In the specific case of GR sub(C12), the optimum initial solution concentrations were C12 sub(0) = 25 mM, Fe super(II) sub(0) = 30 mM and 40% (v/v) EtOH/H sub(2)O.
Objective This study estimates the erythema nodosum (EN) incidence in a tuberculosis (TB) endemic setting and evaluates the likelihood of a subsequent TB diagnosis among individuals with ...Mycobacterium tuberculosis infection (MTI) with or without EN. Design We estimated EN incidence rates (IRs) in East Greenland in 2010-2011 and conducted a cohort study following all individuals who tested positive for MTI from 1 January 2010 until 31 December 2012. A personal identifier allowed individual follow-up in the mandatory TB register. MTI was defined by a positive interferon-gamma release assay. TB incidence rate ratios (IRRs) among participants with or without EN were estimated with the Cox proportional hazard model. Results We identified 38 EN cases corresponding to an IR of 500/100,000 inhabitants/year. All cases were among individuals with MTI. The EN IR was 11.79 (95% CI 5.73-24.27) times higher for BCG-unvaccinated compared with BCG-vaccinated individuals. The TB IRR was 25 (95% CI 11-60) within 1 month of EN compared to individuals without EN. Conclusion This study documents a high EN incidence in a TB endemic region. EN occurred only in individuals with MTI, and predominantly among BCG-unvaccinated individuals. EN was significantly associated with a TB diagnosis within 1 month of diagnosis.
We have developed a highly sensitive
3
He magnetometer for the accurate measurement of the magnetic field in an experiment searching for an electric dipole moment of the neutron. By measuring the ...Larmor frequency of nuclear spin polarized
3
He atoms a sensitivity on the femto-Tesla scale can be achieved. A
3
He/Cs-test facility was established at the Institute of Physics of the Johannes Gutenberg University in Mainz to investigate the readout of
3
He free induction decay with a lamp-pumped Cs magnetometer. For this we designed and built an ultra-compact and transportable polarizer unit which polarizes
3
He gas up to 55% by metastability exchange optical pumping. The polarized
3
He was successfully transfered from the polarizer into a glass cell mounted in a magnetic shield and the
3
He free induction decay was detected by a lamp-pumped Cs magnetometer.
PACS numbers
07.55.Ge Magnetometers for magnetic field measurements; 13.40 Electric and magnetic moments; 14.20 Protons and neutrons
Abstract We have developed a highly sensitive ^sup 3^He magnetometer for the accurate measurement of the magnetic field in an experiment searching for an electric dipole moment of the neutron. By ...measuring the Larmor frequency of nuclear spin polarized ^sup 3^He atoms a sensitivity on the femto-Tesla scale can be achieved. A ^sup 3^He/Cs-test facility was established at the Institute of Physics of the Johannes Gutenberg University in Mainz to investigate the readout of ^sup 3^He free induction decay with a lamp-pumped Cs magnetometer. For this we designed and built an ultra-compact and transportable polarizer unit which polarizes ^sup 3^He gas up to 55% by metastability exchange optical pumping. The polarized ^sup 3^He was successfully transfered from the polarizer into a glass cell mounted in a magnetic shield and the ^sup 3^He free induction decay was detected by a lamp-pumped Cs magnetometer. PACS numbers 07.55.Ge Magnetometers for magnetic field measurements; 13.40 Electric and magnetic moments; 14.20 Protons and neutrons
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