We study quantum metrology for unitary dynamics. Analytic solutions are given for both the optimal unitary state preparation starting from an arbitrary mixed state and the corresponding optimal ...measurement precision. This represents a rigorous generalization of known results for optimal initial states and upper bounds on measurement precision which can only be saturated if pure states are available. In particular, we provide a generalization to mixed states of an upper bound on measurement precision for time-dependent Hamiltonians that can be saturated with optimal Hamiltonian control. These results make precise and reveal the full potential of mixed states for quantum metrology.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM
The tumor microenvironment appears essential in cancer progression and chemokines are mediators of the communication between cancer cells and stromal cells. We have previously shown that the ligands ...of the chemokine receptor CXCR2 were expressed at higher levels in triple-negative breast cancers (TNBC). Our hypothesis was that CXCR2 expression could also be altered in breast cancer. Here, we have analyzed the potential role of CXCR2 in breast cancer in a retrospective cohort of 105 breast cancer patients. Expression of CXCR2, CD11b (a marker of granulocytes) and CD66b (a marker of neutrophils) was analyzed by immunohistochemistry on tumor samples. We demonstrated that CXCR2 stained mainly stromal cells and in particular neutrophils. CXCR2, CD11b and CD66b expression were correlated with high grade breast cancers. Moreover, TNBC displayed a higher expression of CXCR2, CD11b and CD66b than hormone receptor positive or Her2 positive tumors. High levels of CXCR2 and CD11b, but not CD66b, were associated with a higher infiltration of T lymphocytes and B lymphocytes. We also observed a correlation between CXCR2 and AP-1 activity. In univariate analyses, CXCR2, but not CD11b or CD66b, was associated with a lower risk of relapse; CXCR2 remained significant in multivariate analysis. Our data suggest that CXCR2 is a stromal marker of TNBC. However, higher levels of CXCR2 predicted a lower risk of relapse.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Various population pharmacokinetic models have been developed to describe the pharmacokinetics of tacrolimus in adult liver transplantation. However, their extrapolated predictive performance remains ...unclear in clinical practice. The purpose of this study was to predict concentrations using a selected literature model and to improve these predictions by tweaking the model with a subset of the target population.
A literature review was conducted to select an adequate population pharmacokinetic model (L). Pharmacokinetic data from therapeutic drug monitoring of tacrolimus in liver-transplanted adults were retrospectively collected. A subset of these data (70%) was exploited to tweak the L-model using the $PRIOR subroutine of the NONMEM software, with 2 strategies to weight the prior information: full informative (F) and optimized (O). An external evaluation was performed on the remaining data; bias and imprecision were evaluated for predictions a priori and Bayesian forecasting.
Seventy-nine patients (851 concentrations) were enrolled in the study. The predictive performance of L-model was insufficient for a priori predictions, whereas it was acceptable with Bayesian forecasting, from the third prediction (ie, with ≥2 previously observed concentrations), corresponding to 1 week after transplantation. Overall, the tweaked models showed a better predictive ability than the L-model. The bias of a priori predictions was -41% with the literature model versus -28.5% and -8.73% with tweaked F and O models, respectively. The imprecision was 45.4% with the literature model versus 38.0% and 39.2% with tweaked F and O models, respectively. For Bayesian predictions, whatever the forecasting state, the tweaked models tend to obtain better results.
A pharmacokinetic model can be used, and to improve the predictive performance, tweaking the literature model with the $PRIOR approach allows to obtain better predictions.
The chemotherapy triplet FOLFOXIRI combined to the anti-VEGF antibody bevacizumab is an option in selected patients with metastatic colorectal cancer. In this setting, RAS-mutated metastatic ...colorectal cancer do not benefit the same from treatment than RAS-wildtype metastatic colorectal cancer do. Together with its antiangiogenic properties, the tyrosine-kinase inhibitor regorafenib has also anti-proliferative activities whatever the RAS status is. The present trial aims at studying the safety and the efficacy of regorafenib in combination with FOLFIRINOX - a chemotherapy triplet using a different dosing schedule than FOLFOXIRI - in patients with RAS-mutated metastatic colorectal cancer.
FOLFIRINOX-R is a prospective, multicentric, non-randomised, dose-finding phase 1-2 trial. The primary endpoints are the determination of the maximum tolerated dose, the recommended phase 2 dose, and the proportion of patients achieving disease control at 48-weeks. Phase 1 follows a 3 + 3 design (12 to 24 patients to be included). Sixty nine patients will be necessary in phase 2, including 5% non-evaluable ones, with the following assumptions, one-stage Fleming design, α = 5%, β = 20%, p0 = 35% and p1 = 50%. Key eligibility criteria include Eastern Cooperative Oncology Group Performance Status of ≤1 and RAS-mutated metastatic colorectal cancer not amenable to surgery with curative intent and not previously treated for metastatic disease. FOLFIRINOX (oxaliplatin 85 mg/m
, folinic acid 400 mg/m
, irinotecan 150-180 mg/m
, 5-fluorouracil: 400 mg/m
then 2400 mg/m
over 46 h) is administered every 14 days. Regorafenib (80 to 160 mg, as per dose-level) is administered orally, once daily on days 4 to 10 of each cycle.
FOLFIRINOX-R is the first phase I/II study to evaluate the safety and efficacy of regorafenib in combination with FOLFIRINOX as frontline therapy for patients with RAS-mutated metastatic colorectal cancer.
EudraCT: 2018-003541-42 ; ClinicalTrials.gov: NCT03828799 .
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background:
Bone-only (BO) metastatic breast cancer (MBC) is considered a more favorable entity than other MBC presentations. However, only few retrospective series and data from selected randomized ...controlled trials have been reported so far.
Methods:
Using the French national multicenter ESME (Epidemiological Strategy and Medico Economics) Data Platform, the primary objective of our study was to compare the overall survival (OS) of patients with BO versus non-BO MBC at diagnosis, with adjustment on main prognostic factors using a propensity score. Secondary objectives were to compare first-line progression-free survival (PFS1), describe treatment patterns, and estimate factors associated with OS.
Results:
Out of 20,095 eligible women, 5041 (22.4%) patients had BO disease hormone-receptor positive (HR+)/human epidermal growth-factor-receptor-2 negative (HER2−), n = 4 102/13,229 (31%); HER2+, n = 644/3909 (16.5%); HR−/HER2−, n = 295/2 957 (10%). BO MBC patients had a better adjusted OS compared with non-BO MBC 52.1 months (95% confidence interval (CI) 50.3–54.1) versus 34.7 months (95% CI 34.0–35.6) respectively. The 5-year OS rate of BO MBC patients was 43.4% (95% CI 41.7–45.2). They also had a better PFS1 13.1 months (95% CI 12.6–13.8) versus 8.5 months (95% CI 8.3–8.7), respectively. This observation could be repeated in all subtypes. BO disease was an independent prognostic factor of OS hazard ratio 0.68 (95% CI 0.65–0.72), p < 0.0001. Results were concordant in all analyses.
Conclusion:
BO MBC patients have better outcomes compared with non-BO MBC, consistently, through all MBC subtypes.
Background and Aims:
Because of its low prevalence, metastatic breast cancer (MBC) in males is managed based on clinical experience with women. Using a real-life database, we aim to provide a ...comprehensive analysis of male MBC characteristics, management and outcome.
Methods:
The Epidemiological Strategy and Medical Economics Data Platform collected data for all men and women ⩾18 years with MBC in 18 participating French Comprehensive Cancer Centers from January 2008 to November 2016. Demographic, clinical, and pathological characteristics were retrieved, as was treatment modality. Men were matched 1:1 to women with similar characteristics.
Results:
Of 16,701 evaluable patients, 149 (0.89%) men were identified. These men were older (median age 69 years) and predominantly had hormone receptor HR+/HER2– disease (78.3%). Median overall survival (OS) was 41.8 months 95% confidence interval (CI: 26.9–49.7) and similar to women. Median progression-free survival (PFS) with first-line therapy was 9.3 months 95% CI (7.4–11.5). In the HR+/HER2– subpopulation, endocrine therapy (ET) alone was the frontline treatment for 43% of patients, including antiestrogens (n = 19), aromatase inhibitors (n = 15) with luteinizing hormone-releasing hormone (LHRH) analogs (n = 3), and various sequential treatments. Median PFS achieved by frontline ET alone was similar in men 9.8 months, 95% CI (6.9–17.4) and in women 13 months, 95% CI (8.4–30.9) (p = 0.80). PFS was similar for HR+/HER2– men receiving upfront ET or chemotherapy: 9.8 months 95% CI (6.9–17.4) versus 9.5 months 95% CI (7.4–11.7) (p = 0.22), respectively.
Conclusion:
MBC management in men and women leads to similar outcomes, especially in HR+/HER2– patients for whom ET should also be a cornerstone. Unsolved questions remain and successfully recruiting trials for men are still lacking.
OBJECTIVEDiffuse low-grade gliomas (DLGG) are defined by continuous growth and an almost unavoidable malignant transformation. Foci of malignant glioma can be found within DLGG samples obtained from ...surgical resections. As the medical management of patients is classically based on the higher tumor grade, an immediate adjuvant treatment is usually proposed. To determine whether postponing the medical treatment in selected patients is feasible, we conducted a single-center retrospective study.
METHODSThis was a single-center retrospective analysis of a consecutive series of DLGG managed with this conservative strategy. Inclusion criteria were at least 1 focus of malignant tumor (grade III–IV, WHO 2016), no previous chemotherapy or radiotherapy, no less than a subtotal resection of the fluid-attenuated inversion recovery tumor volume, no intention of treating with immediate adjuvant therapy, and minimum 2 years of follow-up. The time interval to the following oncologic medical treatment was analyzed, as well as the functional and survival results.
RESULTSForty-four patients met the inclusion criteria (median age 36, median time interval from diagnosis 7 months). Most tumors (88%) were IDH-mutant and 1p19q intact (59%); 9 presented with grade IV foci. With a median follow-up of 6.7 years, 75% of patients received a subsequent medical treatment, after a median time of 3.4 years since surgery. At the time of analysis, 9 patients (20.0%) had died (5- and 7-year survival rates95% and 67.0%). Most surviving patients were still active professionally, without seizures.
CONCLUSIONSPostponing the medical treatment in DLGG with foci of malignant tumor following total or subtotal resection should be considered in selected patients.
Metastatic breast cancer (MBC) behaviour differs depending on hormone receptors (HR) and human epidermal growth factor receptor (HER2) statuses.
The kinetics of central nervous system (CNS) ...metastases (CNS metastasis-free survival, CNSM-FS) and subsequent patient's prognosis (overall survival, OS) according to the molecular subtype were retrospectively assessed in 16703 MBC patients of the ESME nationwide multicentre MBC database (Kaplan-Meier method).
CNS metastases occurred in 4118 patients (24.6%) (7.2% at MBC diagnosis and 17.5% later during follow-up). Tumours were HER2-/HR+ (45.3%), HER2+/HR+ (14.5%), HER2+/HR- (14.9%) and triple negative (25.4%). Median age at CNS metastasis diagnosis was 58.1 years (range: 22.8-92.0). The median CNSM-FS was 10.8 months (95% CI: 16.5-17.9) among patients who developed CNS metastases. Molecular subtype was independently associated with CNSM-FS (HR = 3.45, 95% CI: 3.18-3.75, triple-negative and HER2-/HR+ tumours). After a 30-month follow-up, median OS after CNS metastasis diagnosis was 7.9 months (95% CI: 7.2-8.4). OS was independently associated with subtypes: median OS was 18.9 months (HR = 0.57, 95% CI: 0.50-0.64) for HER2+/HR+ , 13.1 months (HR = 0.72, 95% CI: 0.65-0.81) for HER2+/HR-, 4.4 months (HR = 1.55, 95% CI: 1.42-1.69) for triple-negative and 7.1 months for HER2-/HR+ patients (p <0.0001).
Tumour molecular subtypes strongly impact incidence, kinetics and prognosis of CNS metastases in MBC patients.
NCT03275311.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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